http://www.medconnect.me/default.aspxThe latest Breaking News.Copyright 2005 - 2009 EPMI. All rights reserved.RALEIGH, NORTH CAROLINA (EGMN) – Once-daily application of an emollient from birth through age 6 months has shown considerable promise as a means of preventing atopic dermatitis, according to the Barrier Enhancement for Eczema Prevention study. BEEP was a multicenter, international, randomized controlled pilot study assessing the feasibility, safety, and effectiveness of a novel approach to the prevention of atopic dermatitis. The study hypothesis was that protecting the skin barrier early in life can prevent this common skin disease, explained Dr. Eric L. Simpson of Oregon Health and Science University, Portland. The rationale for this approach lies in previous work demonstrating that skin barrier dysfunction precedes eczema development. And emollients can be effective in treating mild disease and preventing flares, he said at the annual meeting of the Society for Investigative Dermatology.BEEP involved 124 infants in Portland and at four medical centers in the United Kingdom. All were deemed high risk for atopic dermatitis because they had one or more first-degree relatives with a history of asthma, hay fever, or atopic dermatitis. Participating families were randomized to either once-daily application of an emollient to the baby’s entire body except the scalp and diaper area starting before age 3 weeks and continuing for 6 months, or to a control group that agreed to refrain from regular use of emollients. All families received advice on best-practice skin care, namely to minimize the use of harsh cleansers and hot water bathing. The 6-month cumulative incidence of investigator-diagnosed eczema was 21.8% in the daily emollient group, compared with 43.3% in controls, for a 67% reduction in risk. It was a considerably more dramatic effect than what the investigators had anticipated. “This was kind of a surprising finding to us,” Dr. Simpson admitted. Patients will be followed up at 1 and 2 years to learn whether the early-life treatment actually prevented or simply delayed onset of atopic dermatitis. In a subanalysis, skin barrier function studies were carried out in 15 patients divided between a control and intervention arm. Children in the control arm showed favorable albeit nonsignificant trends for less transepidermal water loss and a lower skin pH. Parents in the intervention arm were given a choice of three emollients of various viscosities: sunflower seed oil; Cetaphil cream in the United States or Doublebase gel in the United Kingdom; or Aquaphor in the United States or 50-50 ointment, a white soft paraffin/liquid paraffin product marketed in the United Kingdom. More than two-thirds of families opted for Cetaphil cream or Doublebase gel. Ninety-six percent of families in the intervention arm found their emollient acceptable, and 80% indicated they used it at least 5 days per week. No cases of irritant or contact dermatitis occurred in the emollient group. Three mild skin infections occurred in each study arm. Dr. Simpson’s BEEP coinvestigators included atopic dermatitis experts such as Dr. Hywel C. Williams, professor of dermatology at the University of Nottingham (England) and Dr. Jon M. Hanifin, professor emeritus of dermatology at Oregon Health and Science University. The researchers are now planning a larger, definitive, randomized controlled trial of emollient therapy early in life as a means of preventing the development of atopic dermatitis. This study will be powered to look at the relative efficacy of different emollients. Also, it will include objective measures of adherence, such as volume of emollient used, rather than simply relying upon parental report. Audience members expressed enthusiasm over the BEEP findings. The prevalence of atopic dermatitis has been rising for decades; the disease exacts a steep toll in terms of quality of life; and to date, there has been no established eczema prevention strategy. Moreover, there is the prospect that by preventing eczema via a simple topical therapy it will be possible to halt the “atopic march” to asthma and other comorbidities. Dr. Simpson noted that BEEP was a small-scale feasibility study carried out because investigators were initially unsure if families would be willing to participate in a clinical trial where they could be randomized to avoiding emollients. But 28%-59% of the families approached at the participating centers agreed to enroll. BEEP was funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Oregon Clinical and Translational Research Institute, and the U.K. National Institute for Health Research. Dr. Simpson reported having no financial conflicts of interest.http://www.medconnect.me/tabid/92/ct1/c45613/Daily-Emollient-Prevented-Eczema-in-67-of-Infants/Default.aspx2012-05-18BOSTON (EGMN) – Many infants with a fever of unknown origin can be safely discharged from the hospital sooner than the routinely recommended 48 hours, a study has shown.A review of 11 years’ worth of data found that just 0.5% of these infants’ blood and cerebrospinal fluid cultures took more than 24 hours to come back positive. These patients all had concerning signs on their clinical exam or initial labs, suggesting that infants with a low-risk profile can probably be safely discharged by 24 hours.“Institutions that are hospitalizing all of these infants for 48 hours can think about changing that to 36 or even 24 hours for infants who have normal labs and look clinically well,” Vikram Fielding-Singh said at the annual meeting of the Pediatric Academic Societies. Mr. Fielding-Singh, a medical student at Stanford (California) University, reviewed the university’s inpatient records from 1999 to 2010. All patients in his analysis were 30 days old or younger, and underwent a diagnostic work-up for fever of unknown origin; tests included blood and CSF cultures.The study comprised 1,880 cultures taken from 1,145 infants. Of these patients, 483 were hospitalized for fever without a known source. Of the total group, 31 infants (3%) had positive blood or CSF cultures. Only six (0.5%) of these took more than 24 hours to return a positive result. In the subset of infants hospitalized for a fever work-up, 24 (5%) had positive cultures. Again, just six (1%) returned a positive result after 24 hours.All of these infants had warning signs of a serious illness, either on clinical exam or in other lab work, Mr. Fielding-Singh said. No infant with normal labs at presentation had a positive culture that took more than 24 hours to return a positive result.Five infants had bacteremia – four with a concurrent urinary tract infection – and one had bacterial meningitis. All of these patients had concerning lab findings – a positive urine culture result, elevated white blood cell levels, or an increased absolute band count. Five also had other abnormal findings, including pleocytosis, a chest radiograph showing infiltrate, or an elevated C-reactive protein level.Mr. Fielding-Singh also performed a sequential review of one of every four hospitalizations (121) for the fever of unknown origin work-up. More than half (56%) were considered low risk according to their labs and clinical evaluation, he said.Dr. Alan R. Schroeder, who supervised the project, said it showed that physicians can “safely do less” with many patients.“It’s our moral obligation to look at practices that put children at risk and that aren’t necessarily evidence based,” said Dr. Schroeder, a pediatric critical care specialist at the Santa Clara Valley Medical Center, San Jose, California. “This is a practice that is almost rote for many institutions. These babies get all kinds of tests and are hospitalized for 48 hours almost without much thought.”A routine 48-hour admission for every infant with a presumed fever without source “puts a pretty big burden” on hospital resources, Dr. Schroeder said in an interview, not to mention putting small patients at great risk for nosocomial complications.“If you could lessen the hospital stay [for] more than half of these kids, that should have a positive impact on resource utilization and certainly on the iatrogenic harms that can occur to these little babies,” he said.Click here to view a video interview with Mr. Fielding-Singh and Dr. Schroeder.Neither Mr. Fielding-Singh nor Dr. Schroeder reported having any relevant financial disclosures.http://www.medconnect.me/tabid/92/ct1/c45612/Infants-May-Not-Need-48-Hour-Hospitalization-for-Fever-Work-Up/Default.aspx2012-05-18SAN DIEGO (EGMN)–Oral tranexamic acid tablets at a dose of up to 3.9 g/day reduced blood loss by a mean of at least 60-65 mL per menstrual period in women aged 30 or older with heavy menstrual bleeding, a pooled analysis of two pivotal trials found.Dr. Jeffrey B. Baker and his associates analyzed data for 383 women from the two randomized, double-blind, placebo-controlled studies who were randomized to either a 3.9-g/day group or placebo. One study also included a treatment arm using 1.95 g/day of tranexamic acid (Lysteda), but that dosage did not reduce menstrual bleeding by at least 50 mL, the minimum required by the U.S. Food and Drug Administration to show a significant difference, he said at the annual meeting of the American College of Obstetricians and Gynecologists.In November 2010, the FDA approved the 3.9 g/day dosage of Lysteda to treat heavy menstrual bleeding based on results from the pivotal trials (Obstet. Gynecol. 2010;116:865-75; Am. J. Obstet. Gynecol. 2011;205:319.e1-7).Women who were randomized to the 3.9 g/day groups took the drug for up to 5 days per menstrual cycle for either three or six menstrual cycles, depending on the study. They could decide to take it for no days or for up to 5 days in any one cycle; they averaged 2.5 days of the medication per cycle. In the current analysis of data pooled from both studies, reductions in menstrual blood loss tended to be greater with increasing patient age. Women younger than 30 years had a mean reduction in menstrual blood loss of approximately 40 mL, below the desired 50-mL threshold. A 60- to 65-mL reduction in bleeding was seen in women in age groups of 30-34 years, 35-39 years, and 40-49 years. The reduction in blood loss in women aged 45 years or older averaged more than 80 mL per period, said Dr. Baker, an ob.gyn. and clinical researcher in private practice in Idaho Falls, Idaho.For women on placebo in those age groups, the mean change in menstrual blood loss ranged from an approximately 10-mL reduction to slight increases in blood loss.“What tranexamic acid offers to clinicians and patients is another tool amongst the many tools that are available for heavy menstrual bleeding,” he said.Some of the available hormonal treatments for heavy menstrual bleeding, such as the Mirena IUD, also act as contraceptives. Lysteda is a nonhormonal lysine analog that acts as a competitive plasmin inhibitor; it is not a contraceptive. The studies excluded the use of any hormonal products that might compromise the effectiveness of Lysteda, so women used barrier techniques, tubal ligations, or vasectomies for birth control, he said.Women with fibroids saw a slightly greater reduction in menstrual blood loss, compared with those without fibroids (approximately 75 mL and 60 mL, respectively). Women with a body mass index less than 25 kg/m2 had an approximately 75-mL reduction in blood loss, compared with approximately 65-mL reductions for women in two other BMI categories (25-29, or 30 or greater).Treatment-emergent serious adverse events in the 3.9-g/day groups included tachycardia in one woman, low blood sugar in one woman, severe ovarian torsion in one woman, and complaints of severe dyspepsia, severe gastritis, and severe chest pain in one woman. The investigators considered these to be unrelated to treatment. Four women in the 3.9-g/day groups withdrew from the studies. The reasons given were mild myalgias, elevated FSH level, rash, or palpitations, each of which resolved by the time of the follow-up visit.The most common adverse events in the Lysteda groups were upper respiratory infection (7%), musculoskeletal pain (5%), and myalgia (5%) in one study, and headache (11%), nausea (10%), and menstrual discomfort (8%) in the other study. Most adverse events were mild to moderate in severity. The Lysteda and placebo groups did not differ significantly in treatment-emergent adverse events.In response to a question from the audience, Dr. Baker said that the studies did not screen patients for underlying thrombophilias.The studies included adult women with no abnormal findings on pelvic examination as well as normal cervical cytology results and normal findings on transvaginal ultrasound. Women with fibroids or simple ovarian cysts were allowed to participate. The studies excluded women with severe anemia or other identifiable causes of abnormal menstrual bleeding.Two previous studies found that tranexamic acid reduced menstrual blood loss in women with heavy menstrual bleeding, Dr. Baker noted (Acta Obstet. Gynecol. Scand. 1994;73:274-7; Drugs 2003;63:1417-33). Ferring Pharmaceuticals, which markets Lysteda, funded the study. Dr. Baker has been a speaker and advisor for Ferring. One of his coinvestigators is an employee of Ferring, and the other has been a speaker and advisor for Ferring and a consultant or researcher for multiple other companies. http://www.medconnect.me/tabid/92/ct1/c45611/Drug-for-Heavy-Menses-More-Effective-With-Increasing-Age/Default.aspx2012-05-18BOSTON (EGMN) – Tweaking implantable cardioverter defibrillator settings to lengthen the detection window is safe and significantly reduces inappropriate antitachycardia pacing and shocks, an investigator said at the annual meeting of the Heart Rhythm Society.Patients with ICDs programmed with a number of intervals to detect (NID) of 30/40 beats had a 37% reduction in ventricular therapies (antitachycardia pacing and shocks), compared with patients with ICDs programmed with a NID of 18/24 beats, with no significant differences in syncope or deaths between the groups, reported Dr. Maurizio Gasparini of Istituto Clinico Humanitas IRCCS, Milan.“This strategy is demonstrated to be safe and effective in reducing unnecessary ICD therapy, and increasing consequently the quality of life of these patients,” Dr. Gasparini said on behalf of coinvestigators in the randomized ADVANCE III (Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III) trial.In a previous trial, Dr. Gasparini and colleagues showed that 66% of ventricular fibrillation (VF) episodes, and 91% of fast ventricular tachycardia (FVT) episodes terminated spontaneously within 30 beats (Eur. Heart. J. 2009;30:2758-67), yet two major ICD manufacturers still have nominal (in-the-box) settings of only 2-3 seconds for a VF detection window, potentially leading to unpleasant and unnecessary shocks, he said.The ADVANCE III investigators enrolled 1,902 patients from 94 centers with single-chamber, dual-chamber, or cardiac resynchronization therapy-defibrillator (CRT-D) ICDs. In all, 891 of those assigned to NID 18/24 programming with antitachycardia pacing (ATP) during charging and 876 patients assigned to NID 30/40 with ATP had available clinical data for the primary end point: a 20% or greater reduction in ATP and shocks for spontaneous arrhythmia with a cycle length of 320 ms or less. The patients were predominantly male (84% in each arm) with a mean age of 65. Nearly half of patients in each group had New York Heart Association class III or IV heart failure, and 60% had coronary artery disease. The mean left ventricular ejection fraction in each group was 30%.The devices were implanted for primary prevention in about 75% of patients in each arm. About 40% had CRT-Ds, 31% had dual-chamber devices, and 29% had single-chamber ICDs.At a median follow-up of 12 months in an intention-to-treat analysis, 97 patients assigned to NID 30/40 had experienced 346 therapies (ATP or shock deliveries), compared with 149 patients and 557 therapies in those assigned to NID 18/24 (incidence rate ratio [IRR] 0.63, P less than .001), meeting the primary end point. A Kaplan-Meier analysis also showed that the longer detection window was significantly better at keeping patients therapy free over 12 months. There were no significant differences in syncopal events, which occurred in 1.5% of patients in the 30/40 group, compared with 0.8% in the 18/24 group, or in deaths, which occurred in 5.1% of patients randomized to the 30/40 strategy, and 5.9% of those assigned to 18/24.The results suggest that “in many cases the nominal ICD settings are probably too conservative,” Dr. Gasparini said. Session comoderator Dr. Christine M. Albert, director of the center for arrhythmia prevention at Brigham and Women’s Hospital in Boston, challenged the safety findings, noting that the incidence of syncope in both treatment arms was extremely low.Dr. Gasparini agreed, but noted that in each arm of the study population, about 20% of participants had experienced one or more syncopal episodes prior to device implantation. “This was a population that theoretically may have a high incidence of syncope; nonetheless, we did not observe very high incidence of it,” he said.The study was supported by Medtronic. Dr. Gasparini reported having no conflicts of interest. Two of the study coauthors are Medtronic employees. Dr. Albert has previously received research support from St. Jude Medical and was a consultant to Novartis.http://www.medconnect.me/tabid/92/ct1/c45608/Longer-ICD-Detection-Window-Reduces-Inappropriate-Shocks/Default.aspx2012-05-18NEW ORLEANS (EGMN) – The incidence of hospitalizations for status epilepticus rose nearly fourfold during 1980-2009, according to researchers who analyzed the U.S. National Center for Health Statistics’ National Hospital Database Survey.The population-adjusted incidence increased from 3.7/100,000 to 14.2/100,000, although the median hospital length of stay for status epilepticus (SE) remained relatively stable at a median of 4-5 days. Hospitalizations for SE also tended to follow a bimodal distribution with the greatest incidence in the first decade of life and between the 5th and 6th decades.The data on the epidemiology of SE are “quite limited” and come mainly from small, population-based studies, which often do not have findings that are generalizable to the U.S. population and do not provide temporal trends, said Dr. Bhavpreet Dham of the University of Medicine and Dentistry of New Jersey, Camden.Dr. Dham also noted that it is estimated that $4 billion is spent each year in the United States on status epilepticus hospitalizations, which is even more than is spent on myocardial infarctions or heart failure (Seizure 2005;14:46-51).He and his colleagues analyzed 699,690 patient discharges in the study’s 30-year time span. These hospitalizations accounted for just 0.07% of about 1 billion hospitalizations in the database. The database covers hospitals in all 50 states and the District of Columbia and uses abstracted ICD-9 codes for diagnoses.“We believe that this is one of the largest epidemiological studies of SE,” Dr. Dham said.In most of the years, the incidence of SE was about 10% higher in men than in women, and nonwhite patients also had a higher incidence than did whites.In-hospital mortality (about 8.4% overall) did not differ between the sexes. Although mortality was lowest among patients aged 10 years or younger (2.7%) and highest among those older than 80 years (19%), the incidence of hospitalizations was lowest for patients in the first decade of life and highest in those older than 80 years.These changes may be the result of a temporal shift in population age distribution during the past 30 years because of more adults living to an older age than there were 30 years ago. In recent years more people have been diagnosed with SE, Dr. Dham noted.He said that the study is limited by the investigators’ inability to audit the database to review patient charts and the lack of morbidity and mortality data for patients once they left the hospital. Furthermore, the investigators could not differentiate between convulsive, nonconvulsive, and refractory SE because the ICD-9 coding does not allow it.Dr. Dham said that he had no relevant financial disclosures.http://www.medconnect.me/tabid/92/ct1/c45607/Status-Epilepticus-Hospitalizations-Nearly-Quadrupled-Since-1980/Default.aspx2012-05-18SAN DIEGO (EGMN) – As birth weight increases, progression in labor was slower both in successful trial of labor patients and in patients who ultimately had cesarean deliveries.The findings come from a retrospective review of electronic data from the Consortium on Safe Labor, an observational study of labor and delivery practices led by the Eunice Kennedy Shriver U.S. National Institute of Child Health and Human Development (NICHD) and the U.S. National Institutes of Health (NIH) that was conducted at 12 clinical centers from 2002 to 2008.“Since the 1950s, obstetricians have been using the Friedman labor curve in order to assist in interpreting normal and abnormal labor patterns,” lead study author Heidi K. Leftwich, D.O., said at the annual meeting of the American College of Obstetricians and Gynecologists. “However, we have [a] very different patient population these days. There is more obesity, less active management of the second stage of labor, we use more epidurals, and we have an older population, with women waiting later to begin their families.”With the cesarean section rate escalating, she continued, “current research has been focusing on variables which might alter the labor curve, and challenging the notion that one labor curve can apply to all women.”The objective of the current study was to examine data from the Consortium on Safe Labor to determine whether birth weight alters the labor pattern in nulliparas and multiparas. Inclusion criteria consisted of patients with cephalic presentation, singleton gestation, gestational age of 34 weeks or more, who had undergone two or more cervical exams. Those patients with fetal anomalies, elective repeat cesarean section, and lacking birth weight data were excluded from the study.The researchers created five birth weight categories separated by 500 g increments: less than 2,500 g (category 1), 2,500-2,999 g (category 2), 3,000-3,499 g (category 3), 3,500-3,999 g (category 4), and greater than or equal to 4,000 g (category 5). They used interval-censored regression to estimate the duration of labor, or “traverse times,” and repeated measures analysis to construct mean labor curves by parity as well as by birth weight categories.“The traverse times is more of an approximation of the time it takes for the cervix to dilate a centimeter,” explained Dr. Leftwich, a fellow of maternal-fetal medicine in the department of obstetrics and gynecology at the University of Illinois at Chicago. “This is stratified by cervical dilation at admission, as well as exams performed in labor.”A total of 146,904 maternal records met inclusion criteria. Cesarean sections occurred in 21% of group 1, 14% of group 2, 14% of group 3, 17% of group 3, and 25% of group 5. Dr. Leftwich reported that in nulliparas, traverse times increased as birth weight increased, for both vaginal and cesarean deliveries (P less than .001). In multiparas, traverse times increased as birth weight increased from 5-8 cm dilation, for both vaginal and cesarean deliveries (P less than .001). “From 8 cm-10 cm, traverse times still increased by birth weight, but this was not statistically significant secondary to minimal cervical exams,” Dr. Leftwich said.A limitation of the study, she noted, was that “rapid progression of labor in multiparas makes traverse times less accurate for the active phase.”The study was supported by a contract from the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and an award from the University of Illinois at Chicago Center for Clinical and Translational Science. Dr. Leftwich said that she had no relevant financial disclosures.http://www.medconnect.me/tabid/92/ct1/c45606/Increasing-Birth-Weight-Impacts-Normal-Labor-Curve/Default.aspx2012-05-18BARCELONA (EGMN)– It is a long held and substantiated belief that osteoarthritis is a biomechanical disease, but evidence is accumulating to support an inflammatory cause. As testament to the strength of both possible causes of the disease, the vote after the World Congress on Osteoarthritis debate, titled “Is OA a mechanical disease or an inflammatory disease?��� resulted in a swing from approximately 70/30 in favor of a biomechanical explanation, to 50/50.Dr. David T. Felson, professor of medicine and public health, and principal investigator of the NIH-funded Boston University Multipurpose Arthritis and Musculoskeletal Diseases Center, argued in favor of OA as a disease of mechanics.In opposition, Dr. Francis Berenbaum, head of the department of rheumatology, Saint-Antoine Hospital, Paris, advanced his case for OA as an inflammatory disease.Dr. Felson went first, noting that “OA is caused by increased physical forces across a local area of a joint. This is either from abnormal anatomy leading to increased stress with normal load, or excess overall load such as with obesity, or a combination of the two.”The animal models of OA almost all have relied on joint injury and major injury to knees such as meniscal tears, which would support a biomechanical origin for OA. “But diseases are often [the result of] the interplay between different causes,” he conceded.Meniscal tears account for 40%-50% of knee OA, Dr. Felson said, adding: “Multiple studies show surgery to remove tears increases focal stress on the cartilage and causes a high rate of subsequent OA.” Dr. Felson’s argument for abnormal stress as being the cause of OA was further supported when he pointed out that congenital dysplasia increases focal load and markedly increases risk of hip OA at a young age. He also listed various occupations and related sites of OA: for example, cotton workers’ fingers; farmers’ hips and knees; and miners’ knees and spines.The second major tenet of Dr. Felson’s talk centered on the fact that once OA had developed, pathomechanics overwhelmed all other factors. He described the vicious cycle of joint damage caused by a misaligned knee. “Increased focal stress across one area causes cartilage debris and bone damage.” Dr. Felson noted that the inflammation seen in OA is caused by absorption of debris by the synovium, which precipitated more cartilage damage and worsened misalignment. Dr. Felson supported his point about the role of misalignment worsening OA with data from the Multicenter Osteoarthritis Study (MOST) (Ann. Rheum. Dis. 2012 May 1 [doi: 10.1136/annrheumdis-2011-201070]), which found that 82% of knees with OA had misalignment. Furthermore, he said, “I would contend to you that the genetics of OA is probably predominantly related to abnormally shaped joints. Only 5% of OA is associated with systemic genetics.”Finally, conceding that inflammation was a feature of OA but not a primary cause, Dr. Felson explained its role in the disease. “Inflammation in OA is mostly a consequence of pathomechanics, that is meniscal tears and [anterior cruciate ligament] tears that lead to cytokine release in the synovium and induces joint damage.”If the injury was severe or there were multiple injuries then there was no requirement for inflammatory cytokine release because OA could occur without it, Dr. Felson concluded.During his presentation, Dr. Berenbaum quoted some renowned names in the field of OA research, and linked them to papers on inflammatory causes of OA. He joked that in light of these papers, his job was nearly done; however he then began to build his expert case for OA as an inflammatory disease. Approaching the first pillar of his argument from a clinical standpoint, Dr. Berenbaum described the existence of flares in OA that sometimes resembled other inflammatory arthritis. “There’s pain at night, morning stiffness, and swelling.”Focusing on both the macroscopic and histological levels, Dr. Berenbaum added that OA showed evidence of synovitis, featuring different levels of inflammation. “It is a patchy synovitis rather than pannus as in [rheumatoid arthritis], but the degree of inflammation has been shown to be correlated to prognosis, which is more severe when a high degree of synovitis is present,” he commented.This synovitis has been well characterized using MRI and ultrasound, according to Dr. Berenbaum. He addressed the evidence on a tissue and cellular level, by saying that inflammatory and immunologic cells have been seen in the OA synovium. “T-cells, B-cells, and macrophages, which play a role in cartilage degradation, have been shown in a murine experimental model. If macrophages are removed from the synovium in collagenase-induced OA, the cartilage is protected from degradation,” explained Dr. Berenbaum.Inflammatory mediators play critical roles in the three most characterized phenotypes, that is, in posttrauma OA, metabolic OA and aging, he continued.All joint tissue including subchondral bone cells, synovial cells, and chondrocytes were able to produce inflammatory cytokines, according to Dr. Berenbaum. “Moreover, nonphysiologic mechanical stress applied on cartilage or subchondral bone induces the release of inflammatory mediators by chondrocytes, or osteoblasts and osteocytes via mechanoreceptors present at the surface of these cells.” “So mechanical stress is a cytokine,” he stated.Findings from experimental models of posttrauma OA provide “...evidence that complement pathways and innate immunity are involved in the OA process.” Adipokines or cytokines produced by the adipose tissue may play a role in OA, he suggested. Hand OA is twice as common in obese patients as in those of normal weight, meaning that systemic mediators may act on joints in obesity, Dr. Berenbaum said. To reinforce his point that inflammatory causes rather than mechanical were to blame, Dr. Berenbaum quipped, “I don’t see many obese patients walking on their hands.”Dr. Berenbaum then drew further rationale for his case by describing the features and functions of a particular type of chondrocyte. “The secretory phenotype of a chondrocyte is a well known characteristic of chondrocyte senescence and leads to overexpression of several inflammatory mediators by these cells.”“This means that when exposed to the same level of stress as a younger cell, aging cells produce more cytokines,” he explained.Finally, Dr. Berenbaum described findings supporting the likelihood that there is a systemic effect of low-grade inflammation induced by OA. He discussed a recent paper showing that in a murine model of Alzheimer’s, disease could be accelerated by the presence of OA in multiple joints through the release of the inflammatory mediator interleukin-6 in the blood. He added that support for this hypothesis was found in publications of studies showing an increase in cytokine production in the blood of patients with OA.In conclusion, he agreed that in the case of trauma, inflammation was secondary, “but other phenotypes exist which provide signals that inflammation can actually drive OA,” he said.Audience member Dr. Marc Hochberg, professor of medicine, epidemiology, and preventive medicine, and head of the division of rheumatology and clinical immunology, University of Maryland, Baltimore, asked the presenters if their beliefs about biomechanical and inflammatory drivers explained the sex differences seen in OA. Dr. Felson replied: “I think women’s joints are anatomically smaller and we haven’t seen much study on size of joint relative to size of person and whether stress is greater in relatively smaller joints. But certainly women are weaker than men and weakness is predisposing to disease. They also have greater dynamic laxity in their joints than men which might predispose them to more mechanical injury than men.”An audience member from Copenhagen highlighted the conundrum of treating OA with pain relief when pain relief actually led to increased mechanical loading. “This is one of the reasons why finding treatments in OA has been so difficult,” answered Dr. Felson. “If we treat successfully by diminishing pain we face the increased risk of more loading and then more damage and acceleration of the OA. This might be the explanation for the tanezumab story, in that pain is beautifully ablated only to have some patients go on to have rapid joint destruction.”He added that he thought this was an argument in favor of biomechanical therapies that aimed to address the underlying etiology. “This would enable loading that is healthier to the joint and to promote more levels of activity.”The congress was sponsored by Osteoarthritis Research Society International.http://www.medconnect.me/tabid/92/ct1/c45605/OARSI-Debate-Are-Mechanics-Just-Another-Cytokine-/Default.aspx2012-05-18BOSTON (EGMN) – Preventive antifungal therapy and changes in broad-spectrum antibiotic use were associated with a significant decrease in the incidence of invasive candidiasis in neonatal intensive care units.As these changes took place in a large group of neonatal intensive care units, Candida infections dropped from 4 to 1 per 1,000 patients. In the smallest infants – those weighing less than 750 grams – incidence dropped from 83 to 24 per 1,000, Dr. Sofia Aliaga said at the annual meeting of the Pediatric Academic Societies.Dr. Aliaga, a neonatologist at the University of North Carolina at Chapel Hill, and her colleagues used a large administrative database to determine the incidence of invasive candidiasis over a 14-year period (1997-2010). In addition to disease incidence, they looked at changes in both antifungal prophylaxis and empirical treatment, and the use of broad-spectrum antibiotics in the NICUs.The database contained information on 709,325 infants seen at 322 units, all of which were managed by a single medical group. There were 2,101 episodes of invasive candidiasis in 2,063 infants.The researchers divided the cohort into four groups by weight: less than 750 g, 750-999 g, 1,000-1,499 g, and 1,500 g or heavier.Over the study period, antifungal prophylaxis increased significantly among the smallest babies, from 4 to 119 admissions per 1,000. At the same time, empirical antifungal therapy for these infants also increased, from 4 to 11 admissions per 1,000 overall. The biggest change with empirical therapy occurred in the smallest babies, increasing from 4 to 111 per 1,000.Finally, the units decreased their use of broad-spectrum antibiotics for all admissions. Use fell from 276 to 48 admissions per 1,000. This change was seen across all weight groups.The incidence of invasive candidiasis fell from 4 to 1 per 1,000 admissions. The greatest decrease occurred among babies weighing less than 750 g. In this group, the infection fell from 83 to 24 per 1,000.Overall changes in NICU management also might have influenced the incidence of candidiasis, Dr. Aliaga acknowledged.“During this time, there was a big push to do quality improvement projects with central line catheters to decrease infection rates ... Babies in the NICU also spend a lot less time on ventilators now than they did 10 years ago, so with less time with an endotracheal tube there are fewer ventilator-associated infections. But I do think the decrease in disease we’re seeing is real, and related to the changes we have made.”Dr. Aliaga said she had no relevant financial disclosures.http://www.medconnect.me/tabid/92/ct1/c45604/Neonatal-Candidiasis-Decreases-With-Prophylactic-Antifungals/Default.aspx2012-05-18NEW ORLEANS (EGMN) – How long does it take before the cumulative effect of repeated blows to the head result in significant cognitive changes? Preliminary results from a longitudinal study of boxers and mixed martial arts fighters suggest that it takes maybe a dozen years – but that anatomical changes begin showing up in half that time.The results so far in 109 fighters suggest that “if you wait for people to get symptomatic, the disease has possibly progressed a fair amount,” said Dr. Charles Bernick, lead investigator of the study and associate medical director of the Cleveland Clinic’s Lou Ruvo Center for Brain Health in Las Vegas. Clinicians may need to be assessing fighters sooner for potential damage, he said at the annual meeting of the American Academy of Neurology. Although it is not yet known, perhaps rest periods or even stopping fighting altogether might halt the neurodegenerative process.Dr. Bernick and his colleagues at the center aim to enroll 600 people in the Professional Fighters Brain Health Study by the time funding runs out 4 years from now. Because it is longitudinal, it has a running enrollment. Those already enrolled will be continually followed.“The real payoff will be following these guys over time and looking at the trajectories,” Dr. Bernick said in an interview. The investigators are conducting volumetric brain MRI and computerized cognitive testing. Participants also are tested for mood disorders and impulsivity, and they also undergo speech analysis as well, said Dr. Bernick. The researchers obtain fighting history, including years of fighting and fights per year, from self-reports and published records. The study will also examine biomarkers, genetic profiles, and serum proteins that might be markers of damage, he said.In the preliminary analysis, the investigators divided the fighters into three groups based on median years of fighting: less than 6 years, 6-12 years, and greater than 12 years. The relationship between exposure variables, brain volumetrics, and cognitive results were examined by correlational analysis. The 32 fighters who fought 6 years or more had lower hippocampal and thalamic volumes. But cognitive changes – measured in lower scores on memory tests and processing speed – were found only in the 39 fighters who had fought more than 12 years. The relationships remained even after adjusting for the effect of age.The ongoing study is funded by the Lincy Foundation. Dr. Bernick reported having no financial disclosures.http://www.medconnect.me/tabid/92/ct1/c45603/Fighters-Study-Gives-Clues-to-Chronic-Traumatic-Encephalopathy/Default.aspx2012-05-18SAN FRANCISCO (EGMN) – Data from the Interagency Registry for Mechanically Assisted Circulatory Support has identified significant risk factors for death following implantation of left ventricular assist devices as destination therapy. The findings will allow better targeting of patients who can expect 1- and 2-year survival rates on left ventricular assist devices (LVADs) that approach those seen with heart transplantation, according to Dr. James K. Kirklin. “If we focus on the subset of stable patients without renal or severe right ventricular failure and without previous cardiac surgery, the 2-year survival with a continuous flow device is 80%,” said Dr. Kirklin, professor of medicine and director of the division of cardiothoracic surgery at the University of Alabama at Birmingham.LVAD destination therapy is not appropriate for patients with rapid hemodynamic deterioration, cardiogenic shock, or right ventricular failure, Dr. Kirklin said at the annual meeting of the American Association for Thoracic Surgery. But there is a significant subset of patients who do benefit, including many patients who have advanced heart failure and are not candidates for transplantation. “Of particular importance is the INTERMACS [Interagency Registry for Mechanically Assisted Circulatory Support] level, which describes subsets of NYHA Class IV patients,” Dr. Kirklin said. For example, level 1 describes patients in cardiogenic shock at the time of LVAD implant and was “the most important risk factor for early mortality.” Of 112 patients with level 1 designation, 32 died during the study. Also, right ventricular failure severe enough to require right ventricular assist device support in the same operation was the strongest predictor of mortality in the constant phase (hazard ratio, 3.2).LVADs are increasingly being used as destination therapy, with LVADs accounting for nearly one-third of all mechanical circulatory support activity in the U.S. Dr. Kirklin and his colleagues studied 5,407 patients who received a durable ventricular assist device or total artificial heart between June 2006 and December 2011 in the U.S. National Heart, Lung, and Blood Institute’s INTERMACS. The 1,287 patients who were not transplant-eligible and received a LVAD for destination therapy comprised the study group.Significant risk factors for death included older age, larger body mass index, diabetes, a history of coronary artery bypass graft surgery, cardiogenic shock, low sodium, increased bilirubin, and use of a pulsatile flow LVAD, the results of a multivariate analysis indicated. This is a “timely and important presentation,” said invited study discussant Dr. Soon J. Park. “[The researchers] report that a significant percentage of destination therapy patients are achieving a survival rate that is comparable to those who undergo heart transplantation. Such a finding is especially astonishing in that these patients, by definition, were those deemed inappropriate [for] donor hearts. For a significant fraction of patients who were destined to die because heart transplant was not an option for them ... a vast majority will now be able to enjoy life on VAD support.” Dr. Park is a cardiovascular surgeon at the Mayo Clinic Transplant Center in Rochester, Minnesota. Representative survival after cardiac transplantation from the International Society for Heart and Lung Transplant Registry is approximately 80% at 2 years in a population with generally less comorbidities than the current destination therapy study group, Dr. Kirklin said. Of note, the INTERMACS destination therapy patients were older, a mean of 67 years, compared with 55 years in the transplant reference group. This survival rate of 80% was figured into the multivariate mortality risk factor analysis. “Heart transplant had been the only option to prolong lives in patients with end-stage heart failure. With recent developments in VAD therapy, heart transplant seems to be the only viable option no longer,” Dr. Park said. “VAD therapy can be rendered immediately and abundantly and it is going to change the natural history of end-stage heart failure dramatically, whether [the patient is] transplant eligible or not.” During a discussion that followed presentation of the study results, Dr. John Conte, director of mechanical circulatory support and a professor of surgery at Johns Hopkins Medicine, asked Dr. Kirklin if he is now ready to refer a subset of patients to mechanical support instead of heart transplantation. “Yes,” Dr. Kirklin replied. “I must say the actual identification of patients from the transplant list who could be triaged to mechanical support will depend on their comorbidity. “Remember that the low-risk, 40-year-old patient undergoing cardiac transplantation without other important comorbidities is not the patient one would want to triage to mechanical support. It will only be those patients on the transplant list with multiple, adverse comorbidities that we will initially select for triage.”Dr. Park asked Dr. Kirklin if it would ever make sense to consider VAD as primary therapy and reserve heart transplant as a secondary therapy.“Of course the goal in the future will be to have an array of therapies which maximize long-term survival for patients, so whether that means initial VAD therapy followed by transplant or initial transplant followed by total artificial heart of course depends upon the rigorous analyses we will need to do in the future,” Dr. Kirklin replied.Although permanent treatment is the intention of destination therapy, the clinical situation may evolve over time and some patients may be considered for cardiac transplantation or device explant, Dr. Kirklin said. “These outcomes can be tracked. In the current era, less than 5% of DT [destination therapy] patients underwent transplant or explant within 2 years.”Dr. Kirklin is the principal investigator of the INTERMACS NHLBI contract.http://www.medconnect.me/tabid/92/ct1/c45601/Mechanical-Circulatory-Support-for-Select-Patients-Nears-Transplant-Survival-Rates/Default.aspx2012-05-18Just as Sanofi-Aventis loses its exclusivity for its blockbuster drug Plavix (clopidogrel) this month, several generic formulations of the antiplatelet agent have been approved, the U.S. Food and Drug Administration announced on May 17. Clopidogrel, a P2Y12 platelet inhibitor taken orally once a day, is approved for the treatment of acute coronary syndrome and for patients who have had a recent myocardial infarction, recent stroke, or established peripheral artery disease. The approved indication includes the statement that clopidogrel “has been shown to reduce the combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.” Clopidogrel was initially approved by the Food and Drug Administration in 1997, and has been marketed as Plavix by Sanofi-Aventis. The agent generated $5 billion in sales in 2010 alone.In the FDA statement announcing the approval, Keith Webber, Ph.D., deputy director of the Office of Pharmaceutical Science in the FDA’s Center for Drug Evaluation and Research, referred to the importance of having effective and affordable medications available for people with chronic health conditions. “The generic products approved today will expand those options for patients,” he said. Generic formulations of both the 75-mg daily dose and the 300-mg loading dose have been approved, according to the FDA. The manufacturers of the approved 300-mg generic formulations are Dr. Reddy’s Laboratories, Gate Pharmaceuticals, Mylan Pharmaceuticals, and Teva Pharmaceuticals. The manufacturers of the approved 75-mg doses are Mylan, Teva, Apotex Corporation, Aurobindo Pharma, Roxane Laboratories, Sun Pharma, and Torrent Pharmaceuticals.The clopidogrel prescribing information includes a boxed warning about the smaller effect of clopidogrel on platelet function in people who are poor metabolizers of CYP2C19, and the higher rate of cardiovascular events in this population, when treated with recommended doses after acute coronary syndrome or percutaneous coronary intervention.The FDA statement also points out the interactions with omeprazole and esomeprazole, which reduce the antiplatelet activity of clopidogrel, and says that these drugs should be avoided in people taking clopidogrel.http://www.medconnect.me/tabid/92/ct1/c45592/U-S-Agency-Approves-Generic-Clopidogrel-/Default.aspx2012-05-17NEW ORLEANS (EGMN) – Women with epilepsy appear to have a significantly greater number of unintended pregnancies than does the general population and cite a wide variety of reasons for discontinuing different contraceptive methods, according to preliminary results from the Epilepsy Birth Control Registry.In the survey of 350 women with epilepsy, pregnancy was unintended in 125 (86%) of the 146 women who had pregnancies and in 215 (63%) of the 340 total pregnancies. This was significantly higher than the rate of 49% observed in a general U.S. population survey of 7,643 women.This was surprising to senior study investigator Dr. Andrew G. Herzog, director of the Harvard Neuroendocrine Unit at Beth Israel Deaconess Medical Center, Wellesley, Massachusetts. “The epilepsy population, which is thought to have a lower fertility rate [than the general population], nevertheless had the higher unintended pregnancy rate,” he said in an interview.The frequency of unintended pregnancy differed significantly between various combinations of contraceptive methods and types of antiepileptic drug (AED), and was highest for those who used enzyme-inducing AEDs (EIAEDs) and hormonal birth control such as depot medroxyprogesterone acetate. EIAEDs also proved to be the only significant AED-related reason for stopping contraception, at least for women who were using hormonal birth control.“There are some reciprocal interactions between antiepileptic drugs and contraceptive hormones, which can compromise both contraceptive efficacy and also seizure control,” Dr. Herzog noted. “We now know that enzyme-inducing and glucuronidated AEDs such as lamotrigine interact with hormonal contraceptives.” For instance, high estrogen levels decrease levels of lamotrigine but increase levels of EIAEDs.Studies have shown that many women with epilepsy who take hormonal contraceptives also do not know that they can interact with AEDs or that some AEDs have a high teratogenic potential.“Our goal is to get enough information so that we can develop some meaningful guidelines for safe and effective contraception for women with epilepsy ... and also for their health care providers,” Dr. Herzog said. “Neurologists need to be informed and knowledgeable about the interactions between hormones and the antiepileptic drugs, and need to be comfortable in talking to their patients about contraception and these interactions because gynecologists are comfortable in discussing contraception, but they have a limited number of patients with epilepsy, like 1% perhaps.”The investigators promoted the Epilepsy Birth Control Registry through online advertisements and Facebook as an educational website for epilepsy birth control in which women could get educational material after taking a 30-question survey. It is the first community-based study of contraceptive methods and AED use in women with epilepsy.Demographic characteristics of the survey respondents, aged 18-47 years, indicated that they were “somewhat younger than the general epilepsy population and somewhat better educated,” Dr. Herzog said at the annual meeting of the American Academy of Neurology.Respondents reported contraceptive methods including withdrawal, barrier, hormonal, hormonal-depot, and intrauterine device (IUD). AEDs were grouped into enzyme-inducing, non–enzyme-inducing, glucuronidated (lamotrigine), enzyme-inhibiting (valproate), or none.All of the expected frequencies for contraceptive methods and AED categories assumed equal risk of stoppage and unintended pregnancies because no data are available to set expected values. In statistical comparisons, the contraceptive methods and AED categories were adjusted for differences in frequency of their use in the survey population.Of 408 total stoppages of contraceptives, 214 (53%) were for adverse reasons – not because of a desire to become pregnant, sexual inactivity, or tubal ligation. Participants cited 22 different reasons for stopping their contraceptive method, which the investigators collated into 8 categories: menstrual disorder, increasing seizures, logistical issues related to the method, pregnancy on the method, concerns about the reliability of the method, headache, emotional changes, and concern about AED interaction.Respondents stopped birth control for an adverse reason most often with depot medroxyprogesterone acetate (56%); followed by hormonal (oral pill, patch, or vaginal ring) (47%); withdrawal (38%); IUD (28%); and barrier (condom or diaphragm) (21%). Frequencies of stoppage for each of the categories of adverse reasons differed significantly between the contraceptive methods, Arielle Saporta, a research assistant in Dr. Herzog’s lab, reported at the meeting.The reasons for stoppage varied from method to method. For withdrawal and barrier methods, they included reliability and pregnancy (as well as logistical concerns for barrier). Hormonal contraception was stopped over concerns about seizures and menstrual disorder (irregular cycles, heavy menses, or irregular bleeding). Depot medroxyprogesterone acetate was often stopped because of menstrual disorder and logistical reasons. IUDs were discontinued largely because of menstrual disorder.Among the different types of AEDs, only EIAEDs were significantly associated with a reason for stopping birth control. For example, menstrual disorder as a reason for stopping birth control was significantly associated with use of EIAEDs. Overall, 29% of respondents who used EIAEDs and hormonal birth control cited menstrual disorder as a reason for stopping, which was twice as often as for women not taking AEDs.An earlier report from the registry showed that 18% of women on hormonal contraceptives had worsening of their seizures, compared with 3% of women on nonhormonal contraceptives. These results also led some audience members to wonder who was prescribing AEDs to women on unreliable contraceptive methods such as withdrawal. Indeed, only one-fourth of women who completed the survey consulted a neurologist about what contraceptive methods might be most appropriate for their type of epilepsy and treatment. This was a “surprise,” Dr. Herzog said. “Either they don’t think their neurologist know about the topic, or maybe they are correct that [we] don’t know about the topic. And for gynecologists, epilepsy makes up only about 1% of their practice, so it’s not their major focus either.”The investigators now have 550 completed surveys and hope to get 1,000. They are planning to set up a prospective arm of the study in which patients can check back into the registry every 3 months, which will hopefully provide rates of unintended pregnancy for each kind of contraceptive in terms of woman-years of contraceptive use, which is the standard measurement for contraceptive efficacy.The registry is funded in part by the Epilepsy Foundation. Dr. Herzog and Ms. Saporta had no relevant disclosures.http://www.medconnect.me/tabid/92/ct1/c45591/Pregnancy-Contraception-Data-Highlighted-in-Epilepsy-Registry/Default.aspx2012-05-17The recently approved cancer drug crizotinib draws strong responses in children whose cancers have mutations in the gene targeted by the drug, according to early data from a phase I dose-escalating study.The most dramatic improvements occurred in anaplastic large-cell lymphoma, with complete and durable responses observed in 7 of 8 children with the ALK mutation, which is common in the disease. Crizotinib also appeared to be active in subsets of children with inflammatory myofibroblastic tumor and neuroblastoma, though the early data were less clear in these cancers.“Crizotinib appears to have a high degree of activity in children with anaplastic large-cell lymphoma – the majority of whom are driven by the ALK oncogene,” lead author Dr. Yael P. Mosse said during a press briefing in advance of the annual meeting of the American Society of Clinical Oncology. She noted that these are phase I results and should be taken with caution. “Certainly for the eight patients that we enrolled with anaplastic large cell lymphoma – seven of whom have had a complete response and a durable response – I think that this is dramatic activity and has already met the bar for what you would look for in a phase-II trial ... for neuroblastoma there is still a lot of work to be done,” said Dr. Mosse of Children’s Hospital of Philadelphia and the University of Pennsylvania.The story is really a glimpse at the new paradigm for understanding of cancer and drug development,” said ASCO President Dr. Michael Link, comoderator of the press briefing. “It’s no longer adequate to identify a tumor based on histology organ of origin. It’s now understood that tumors are heterogeneous and it’s key to understand the particular molecular driver, “said Dr. Link of Stanford (California) University. “If you understand the molecular driver of the tumor and pick an appropriate inhibitor – in this case crizotinib for ALK-driven tumors – we have the prospect of seeing dramatic responses.”The ALK (anaplastic lymphoma receptor tyrosine kinase) gene is part of a family of proteins called receptor tyrosine kinases, which transmit signals from the cell surface into the cell via signal transduction. Though the specific function of ALK is unknown, it is thought to act early in development to help regulate the proliferation of nerve cells.ALK is involved in the formation of several human cancers, including anaplastic large cell lymphoma (ALCL), which typically occurs in childhood. Activating mutations in the ALK gene “are the leading cause for most cases of the hereditary form of neuroblastoma and ... these mutations are also somatically acquired in 14% of patients with the aggressive form of this disease,” Dr. Mosse said.Crizotinib, an oral small-molecule inhibitor of ALK, was approved in August 2011 for the treatment of patients with locally-advanced or metastatic non–small cell lung cancer (NSCLC) that is ALK positive based on a diagnostic test approved concurrently by the U.S. Food and Drug Administration.Dr. Mosse and colleagues conducted the phase I study to assess the safety and efficacy of crizotinib in pediatric patients aged 1-21 years with relapsed or refractory cancer. The children received the drug orally, twice daily for 28-day cycles. Based on the results, the recommended phase II dose for children is 280 mg/m2 per day. This is roughly twice the recommended phase II dose for adults, according to Dr. Mosse.Eight patients with anaplastic large-cell lymphoma were enrolled in the current study. All had an ALK translocation and were heavily pretreated. Seven children had a complete response with doses ranging from 165 mg/m2 per day to 280 mg/m2 per day. They remain on the drug, with no progression observed for as long as 18 months.Investigators also enrolled seven patients with inflammatory myofibroblastic tumor – all had an ALK translocation. Of these, one had a minor response and remains on the drug after 2 years. One patient had a partial response and remains on the drug after 10 cycles. It is too early to determine response for five patients. Lastly, the researchers enrolled 35 patients with neuroblastoma; 27 were evaluable. Eight of these patients had known ALK mutations. Two of these patients have germline mutations. One of these patients had a complete response to therapy and remains on treatment (more than 6 months). The second patient with a germline mutation had a minor response and continues treatment (more than 15 months). A third patient with a somatic ALK mutation has had stable disease for more than eight cycles.There were 19 neuroblastoma patients who had unknown ALK status. One patient had a complete response and remains on treatment (more than 24 cycles). Six patients have had prolonged stable disease and remain on treatment (7-29 cycles).Overall, the drug was “exceedingly well tolerated,” Dr. Mosse said. “Most of the toxicities were extremely low-grade and did not affect overall quality of life. At the highest dose level that we tested, we saw irritation of the liver enzymes that were reversible.” The study was sponsored by the Children’s Oncology Group with collaboration from the U.S. National Cancer Institute. Dr. Mosse reported receiving research funding from Pfizer, which makes crizotinib.http://www.medconnect.me/tabid/92/ct1/c45590/Crizotinib-Shows-Strong-Activity-Against-ALK-Driven-Pediatric-Cancers/Default.aspx2012-05-17SAN DIEGO (EGMN) – Women with vulvodynia who received one counseling session with a licensed social worker after their diagnosis reported increased knowledge about their condition and less impact of vulvar symptoms on their lives, compared with women who did not receive the session, results from a pilot study showed.“Several studies have shown a positive effect of individual and group psychosocial therapy programs in women with vulvodynia,” a chronic pain syndrome affecting the vulvar area, Dr. Molly B. Moravek said at the annual meeting of the American College of Obstetricians and Gynecologists. “However, this sort of long-term therapy is not feasible for all women due to time or financial constraints. No studies to date have investigated whether benefit can be derived from a single counseling session performed at the time of diagnosis,” she noted.Reported psychosocial effects from vulvodynia, a condition thought to affect 6%-15% of women seeking gynecologic care, include increased depression, anxiety, emotional distress, irritability, anger, perfectionistic traits, fear of negative evaluation, preoccupation with symptoms, somatization, and catastrophization. “Causation [of vulvodynia] is not known, but theories include neurological, physiological, and psychological etiologies,” said Dr. Moravek of the department of obstetrics and gynecology at the University of Michigan Hospitals and Health System, Ann Arbor, who conducted the study along with colleagues in the university’s department of family medicine.The aims of the current study were to determine the effect of a single session of a psychosexual counseling intervention compared with medical treatment alone on illness perceptions and coping mechanisms among women with vulvodynia, and to assess alterations in sexual function and pain perception after a single session of a psychosocial intervention.Over a 4-month period, the researchers recruited 31 women from a specialty clinic dedicated to the treatment of vulvar diseases. All study participants were newly diagnosed with vulvodynia and were randomly assigned to receive either a 30- to 45-minute counseling session plus written educational materials or written materials alone (control group).All patients were asked to complete a survey prior to randomization and at 6 weeks, including basic demographic information, the Female Sexual Function Index (FSFI), the Brief Illness Perception Questionnaire (BIPQ), and questions about knowledge of sexual and vulvar health.The counseling session intervention was led by a licensed social worker who is certified in sex therapy and was tailored to the particulars of each patient’s psychosocial and medical situation. “The primary aims of the session were to increase knowledge about, and confidence in ability to deal with, vulvodynia; address common psychological effects from vulvodynia; and discuss sexual strategies for women who were having pain with intercourse,” Dr. Moravek explained.The mean age of the 31 women was 39 years; 16 received the intervention and 15 did not. At the 6-week follow-up, women in the intervention group trended toward increased sexual function in each of the six domains of the FSFI (desire, arousal, lubrication, orgasm, satisfaction, and pain), “whereas the controls showed more mixed results, and some even trended toward decreased function at the 6-week follow-up,” she said. However, the mean total FSFI significantly favored the intervention group, with a P value of .02.On the BIPQ, women in both groups reported an increased sense of control over their vulvodynia symptoms that reached statistical significance (P = .007 in controls and P = .006 in the intervention group). However, only women in the intervention group reported statistically significant improvements in their understanding of their illness (P = .011), the impact vulvodynia had on their lives (P = .009), how long they thought their symptoms would continue (P = .04), their concern over their symptoms (P = .003), and the emotional effect of their symptoms (P = .004). Additionally, only women in the intervention group scored significantly better on their self-perceived knowledge of vulvar health (P = .003) and sexual health (P = .025) at the 6-week follow-up.Although the study is limited by its sample size, “we believe that it justifies a larger study examining the role of a single-session psychosocial intervention for patients with vulvodynia,” Dr. Moravek said. “Future studies should also investigate different therapy modalities and durations, and the best way to incorporate a psychosocial intervention into the patient’s medical care.”The study was supported by the Ansbacher Fund for Resident/Fellow Education and Research at the University of Michigan. Dr. Moravek said that she had no relevant financial disclosures. http://www.medconnect.me/tabid/92/ct1/c45589/Single-Counseling-Session-May-Help-Vulvodynia/Default.aspx2012-05-17Combining the BRAF inhibitor dabrafenib with the MEK inhibitor trametinib dramatically delays metastatic melanoma progression without the skin toxicities associated with vemurafenib therapy.Median progression-free survival reached 10.8 months in the subset of 24 patients given the recommended dose of the two oral experimental agents in the dose-escalation portion of a phase I/II trial involving 77 patients without prior therapy targeting the BRAF kinase gene. The median for the entire cohort was 7.4 months, which was said to be comparable to results from past trials of single-agent vemurafenib.Moreover, there were fewer dermatologic side effects than with any BRAF inhibitor alone seen to date, Dr. Jeffrey S. Weber said during a press briefing in advance of the upcoming annual meeting of the American Society of Clinical Oncology.“Obviously, we have to be cautious. It’s only a cohort of 24 patients, but it looks extremely encouraging,” he said.Overall, cutaneous squamous cell carcinoma occurred in 3% of patients, which compares favorably with a 15%-20% incidence with dabrafenib and other BRAF inhibitors, said Dr. Weber, director of the Donald A. Adam Comprehensive Melanoma Research Center at the Moffitt Cancer Center in Tampa.Similarly, actinic keratosis occurred in 5% of patients and skin papilloma in 2%, compared with a 20%-40% incidence seen with BRAF-targeted monotherapy. Skin rashes occurred in 22%, but the acneiform rash often seen with MEK (MAP/ERK kinase) inhibitors was essentially absent in these patients, he said.Notably, grade 3 or worse squamous cell carcinoma was reported in 12% of patients given the oral BRAF inhibitor vemurafenib in the pivotal BRIM-3 (BRAF Inhibitor in Melanoma-3) trial. Vemurafenib was approved last August by the U.S. Food and Drug Administration for the first-line treatment of both metastatic and unresectable melanomas with V600E mutations in the BRAF gene, a mutation that occurs in roughly half of melanomas.The dramatic reduction in dermatologic toxicity observed in the current trial was offset, however, by a corresponding increase in pyrexia. Grade 3 or 4 pyrexia, which is relatively uncommon with a BRAF inhibitor alone, was observed in 8% of patients and led to dose reductions or delays in 23% of those patients, Dr. Weber acknowledged.Other grade 3/4 events included nausea in 34% of patients, fatigue in 37%, and chills in 38% of patients, leading to dose reductions in 10%.The investigators were initially surprised that combining BRAF and MEK inhibition reduced skin toxicity. But as evidence began to accumulate on BRAF inhibition in normal cells, Dr. Weber said they and other researchers realized there is a paradoxical activation of the MAP (mitogen-activated protein) kinase pathway through promotion of c-Raf signaling, which then leads down that pathway. If activation can be blocked with a MEK inhibitor, however, that would lead to a decrease in the off-target effects on normal cells that occur with a BRAF inhibitor, he explained.ASCO president-elect Dr. Sandra M. Swain, who comoderated the press conference, said the findings show that researchers are finding more creative ways to effectively treat one of the most challenging cancers.“We know cancers are smart,” said Dr. Swain, medical director of the Cancer Institute at Washington Hospital Center in Washington, D.C. “They find mechanisms to escape or work around pathways, and in this case we are seeing a very innovative approach that ostensibly blocks off some of these side pathways. This is very exciting research.”The current analysis focused on 77 of 125 patients with V600 BRAF-mutant solid tumors enrolled in the phase I/II trial who were treated with four escalating doses of dabrafenib and trametinib, a MEK 1/2 inhibitor. They all had measurable disease according to RECIST criteria, 91% had V600E-mutant tumors, and 26% had prior brain metastases. Their mean age was 52 years.The subset of 24 patients with the longest progression-free survival received the recommended dose of twice-daily dabrafenib 150 mg and daily trametinib 2 mg, which will be tested in a phase III trial, Dr. Weber said.Among all 77 patients, responses were observed in 44 (57%), including 6 complete and 38 partial responses. Among the 24 patients on the recommended dose, the response rate reached 63%, including 2 complete responses and 13 partial responses, with the remainder all having stable disease.Survival data on the cohort will be reported at a future date, he said. Results are also anticipated from the trial’s expansion cohort that includes patients with prior BRAF inhibition therapy as well as patients with BRAF-mutant colorectal cancer.The abstract can be viewed at www.abstract.asco.org, and will be formally presented at ASCO at 3:30 p.m. June 4.The trial was funded by GlaxoSmithKline. Dr. Weber reports consulting for and receiving honoraria and research funding from GSK. His coauthors report similar relationships, as well as employment/leadership positions and stock ownership with GSK. http://www.medconnect.me/tabid/92/ct1/c45588/In-the-Pipeline-BRAF-Plus-MEK-Inhibition-Slows-Melanoma/Default.aspx2012-05-17The number of reported wild polio virus cases decreased by 52% worldwide, from 1,352 cases in 2010 to 650 cases in 2011, according to the U.S. Centers for Disease Control and Prevention.This progress occurred despite a shortage of funding to eradicate polio globally, a goal that the World Health Organization established in January of this year. The achievement of polio eradication also varied significantly by region. In India in 2011, the number of cases declined 98%, and the last identified case was in January of that year. The country is now considered polio-free.Cases increased, however, in Afghanistan (by 69%), Nigeria (by 66%), and Pakistan (by 27%) in 2011, and circulation there continues, according to the May 18 Morbidity and Mortality Weekly Report (MMWR 2012; 61[19]:353-7).Outbreaks continue to occur as a result of importation from polio-reservoir countries to areas previously polio free for 12 or more months; 11 different outbreaks occurred globally, including 9 new outbreaks in eight countries, including China and seven countries in Africa, according to the report.In the first quarter of 2012, 59% fewer cases have been reported worldwide, compared with the same period in 2011, and all wild polio virus cases were reported from Afghanistan, Chad, Nigeria, and Pakistan. No new outbreaks have been reported, but persistent circulations, particularly in Nigeria and Pakistan, pose an ongoing threat to eradication efforts.Following the WHO’s 2012 declaration regarding the public health emergency posed by ongoing poliovirus transmission, countries with endemic or reestablished transmission developed national emergency plans for interrupting transmission.If global eradication is to be achieved, full implementation of these emergency plans is urgently needed, according to an editorial note included in the report. http://www.medconnect.me/tabid/92/ct1/c45587/Polio-Declines-Globally-but-Troublesome-Pockets-Persist/Default.aspx2012-05-17NEW ORLEANS (EGMN) – Think ‘chronic gastric volvulus’ when a patient with a history of hiatal hernia presents with nonspecific symptoms such as difficulty in swallowing food and uncomfortable fullness after eating. Gastric volvulus – a torsional twisting of the stomach – is an underrecognized complication of hiatal hernia. It occurs most often in patients with a large paraesophageal hiatal hernia or with an intrathoracic stomach that has come loose from its abdominal moorings, Dr. Conor G. Loftus explained at the conference. Acute gastric volvulus is a surgical emergency. It typically presents suddenly with severe pain in the lower chest or upper abdomen, often accompanied by persistent nonproductive retching. It’s often mistaken for an acute MI. Yet acute gastric volvulus is no less serious an event, according to Dr. Loftus, a gastroenterologist at the Mayo Clinic, Rochester, Minnesota. In contrast, chronic gastric volvulus is characterized by considerably milder, nonspecific symptoms. When clinical suspicion focuses on this possible diagnosis, the best confirmatory test is a barium esophagram. Dr. Loftus presented an illustrative case: a 70-year-old man who presents complaining of nonpainful difficulty in swallowing solid food but not liquids for the past several years. He has a history of hiatal hernia as well as long-standing gastroesophageal reflux disease controlled with once-daily proton pump inhibitor therapy. He hasn’t lost weight. A gastroenterologist performed upper endoscopy with grossly normal findings, albeit with a notation that it was somewhat difficult to pass the probe across a tortuous esophagus and stomach. In this vignette, Dr. Loftus observed, the clinical presentation and endoscopic findings raise a red flag for chronic gastric volvulus. In particular, the reported earlier difficulty in passing the endoscope suggests a mechanical problem. Ordering esophageal manometry would be the right choice if a dysmotility disorder were suspected; however, a recent-onset dysmotility disorder would be unusual in an aged individual and, in any case, it would typically present with both liquid and solid food dysphagia. Endoscopic ultrasound of the gastroesophageal junction or CT scan of the chest would be the appropriate imaging study if a malignancy was suspected. But the lack of weight loss in a patient with a 3-year history of symptoms argues strongly against that possibility, he continued. Repeating the earlier upper endoscopy, this time obtaining esophageal biopsies, would be a good move if eosinophilic esophagitis was suspected; however, this disorder is uncommon at an advanced age, Dr. Loftus noted. He reported having no financial conflicts. http://www.medconnect.me/tabid/92/ct1/c45586/Hiatal-Hernia-History-Consider-Gastric-Volvulus/Default.aspx2012-05-17Many primary care physicians – and even some oncologists – are unaware of common long-term side effects of four widely used breast and colorectal cancer drugs, a national survey by the National Cancer Institute reveals.Only 6% of primary care physicians were able to identify the main long-term effects (LEs) of doxorubicin, paclitaxel, oxaliplatin, and cyclophosphamide, compared with 65% of oncologists surveyed.The results are not surprising, but they underscore the need for ongoing education among all physicians who care for the more than 12 million cancer survivors in the United States, lead author Dr. Larissa Nekhlyudov said during a press briefing highlighting research to be presented at the upcoming annual meeting of the American Society of Clinical Oncology (ASCO).“These findings emphasize that in the transition of patients from oncology to primary care settings, primary care providers should be informed about the late effects of cancer treatment so that they may be better prepared to recognize and address these among cancer survivors in their care,” said Dr. Nekhlyudov, a primary care physician (PCP) with Harvard Medical School in Boston and Harvard Vanguard Medical Associates in Kenmore, Massachusetts. “Whether this will be achieved with survivorship care plans needs to be evaluated.”The “Survey of Physician Attitudes Regarding the Care of Cancer Survivors” was launched by the National Cancer Institute in 2009, with one survey mailed to a nationally representative sample of 1,072 PCPs and the other to 1,130 medical oncologists who only cared for patients with colorectal or breast cancer.When asked to report the five LEs they had observed and/or had seen reported in the literature for each of the four standard chemotherapy drugs, 95% of oncologists identified cardiac dysfunction as an LE of doxorubicin, compared with 55% of PCPs (P less than .0001), Dr. Nekhlyudov said.Similarly, peripheral neuropathy was correctly identified as an LE of paclitaxel and of oxaliplatin by 97% of oncologists, but by only 27% and 22%, respectively, of PCPs (both P less than .0001).The survey suggests, however, that some oncologists could also use additional continuing education. Premature menopause and secondary malignancies – two long-term effects associated with the alkylating agent cyclophosphamide – were identified by only 71% and 62% of oncologists, respectively, along with 15% and 17%, respectively, of PCPs.Oncologists and PCPs mostly missed pulmonary fibrosis as a late effect for paclitaxel (5% and 6%, respectively; P = .42) or oxaliplatin (5% and. 9%, respectively; P = .0002). They did a little better in pointing out a possible association with cyclophosphamide (20.6% and 13%; P less than .0001), which has been noted in the literature, she observed.Dr. Nekhlyudov suggested that the lack of awareness among oncologists is likely because much of the focus has been on the treatment of cancer, and only recently have physicians become aware of the importance of survivorship and the potential for late effects.“While it is surprising that oncologists were not more aware of late effects, I think that as more and more attention is placed on cancer survivorship, oncologists will become more equipped with that information,” she said.ASCO president and press briefing comoderator Dr. Michael Link said the problem of survivorship has long been recognized in pediatric oncology, where patients frequently relocate, outgrow their pediatrician, or even deny they ever had cancer. Groups such as ASCO and the U.S.-based Institute of Medicine, most recently through its “Lost in Transition” report, have offered guidance for improving transitions among survivors, including the provision of a cancer care plan.“I think the need for all of this has been highlighted in this abstract and certainly, it’s a shot across the bow with things that need to be done,” he said.In adjusted analyses, oncologists who were not board certified were less likely to identify the main LEs for all four drugs (odds ratio, 0.58).Oncologists were more likely to know their LEs if they spent 51%-90% of their time on patient care (OR, 1.87) or more than 90% of their time with patients (OR, 1.82). Age, sex, race, U.S. training, type of practice, and percentage of uninsured patients were not associated with LE awareness, Dr. Nekhlyudov said.Previous results from the survey reported at last year’s ASCO annual meeting indicated that PCPs had low confidence in their knowledge of breast and colon cancer survivors, and reported low marks for their skills in caring for these patients. In addition, neither PCPs nor oncologists felt that a PCP-led model was ideal for survivorship care (J. Clin. Oncol. 2011;29[suppl.];abstract CRA9006). Dr. Nekhlyudov will formally present her study at ASCO at 5:30 p.m. June 2. The abstract can be viewed at www.abstract.asco.org. The authors reported no disclosures. http://www.medconnect.me/tabid/92/ct1/c45585/Docs-Need-Primer-on-Long-Term-Effects-of-Chemotherapy/Default.aspx2012-05-17BALTIMORE (EGMN) – Robotic procedures compare favorably with vaginal apical prolapse repair in elderly women, for whom pelvic organ prolapse repair is the most common gynecologic procedure. In a retrospective study of 136 patients, estimated blood loss and need for postoperative transfusion were significantly lower in the robotic surgery group. Estimated blood loss was 91 mL in the robotic surgery group, compared with 172 mL in the vaginal surgery group. No patients needed postoperative transfusion in the robotic group, compared with 10 patients in the vaginal group, reported Dr. Barbara L. Robinson at the annual meeting of the Society of Gynecologic Surgeons. Total operative and total anesthesia times were significantly lower in the vaginal surgery group. Total operative time was 139 minutes for the vaginal surgery group, compared with 201 minutes in the robotic surgery group; total anesthesia time was 168 and 237 minutes in the vaginal and robotic groups, respectively.“We demonstrate low rates of perioperative morbidity in elderly women undergoing both robotic and vaginal reconstructive procedures for apical prolapse repair,” said Dr. Robinson of the department of obstetrics and gynecology, University of North Carolina at Chapel Hill.The researchers conducted a chart review of women aged 65 years and older who underwent robotic or vaginal apical support surgery (including colpocleisis) between March 2006 and April 2011. Patients were excluded if they had undergone a primary abdominal or laparoscopic apical support procedure for malignancy.Preoperative risks were assessed using the American Society of Anesthesiologists (ASA) physical classification system and the Charlson Comorbidity Index (CCI). The CCI predicts 10-year mortality risk based on age and comorbidities. The ASA physical classification system is used to assess patient fitness prior to surgery. The researchers sought to determine if these measures of preoperative risk can predict risk in this population, and to characterize complications during apical support procedures using the Dindo classification of surgical complications. The Dindo system is used to grade and define perioperative complications. This system has five grades; a greater grade is associated with more severe complications. Cases were reviewed for surgical complications up to 12 months after surgery, and a Dindo grade was assigned accordingly.Dr. Robinson and her colleagues identified a total of 136 patients – 70 had robotic surgery and 66 had vaginal surgery. The average age was 72 years, although patients in the vaginal surgery group were significantly older (74 vs. 70 years). The two groups did not significantly differ by body mass index, parity, or smoking status. The average apical prolapse stage was significantly lower in women who had vaginal surgery compared with robotic surgery – 1.6 vs. 2.1.In the robotic surgery group, sacrocolpopexy was the most common procedure. In the vaginal group, uterine sacral ligament suspension and colpocleisis were the two most common procedures. Length of hospital stay was significantly longer for the vaginal surgery group than the robotic group – 2.2 vs. 2.0 days, respectively.The most common preoperative comorbidities were hypertension, coronary artery disease, and diabetes. These morbidities were not significantly different between the two groups. However, history of a myocardial infarction was significantly lower in patients who had robotic surgery than in the vaginal surgery group (9% vs. 21%), as was the presence of dementia (0% vs. 9%).“The [overall] study population was generally healthy, with a low mean CCI of 0.97. However, the vaginal surgery group had more severe comorbidities than the robotic surgery group based on the CCI,” said Dr. Robinson. In contrast, based on ASA class, comorbidity was similar for the two groups. The most commonly assigned ASA classes were 2 and 3. No patients were assigned as class 5 or 6.There were no significant differences in overall intraoperative complications, including cystotomy, trocar injury to the bladder, ureteral injury, bowel injury, or intraoperative transfusion. However, there were significantly fewer urinary tract infections – 6% vs. 18% – in the robotic surgery group following the procedure, she said at the meeting, which was jointly sponsored by the American College of Surgeons.Overall, the majority of procedures – both robotic (67%) and vaginal (56%) – were associated with no complications based on Dindo class, she said. No patients were classified as grade IV or V. The Dindo classification was similar between the two groups. “Neither the ASA or CCI correlated significantly with the Dindo grade,” he said. Given the lack of correlation with the Dindo classification, ASA and CCI may have limited utility in elderly women undergoing pelvic floor reconstruction.The authors reported that they had no relevant financial disclosures.http://www.medconnect.me/tabid/92/ct1/c45584/Robotic-Surgery-Safe-for-Vaginal-Apical-Prolapse/Default.aspx2012-05-17PHILADELPHIA (EGMN) – High doses of the anesthetic ketamine hydrochloride injected into the anterior thigh are the first line of defense when treating a patient with excited delirium syndrome, Dr. James R. Roberts reported at the meeting.Excited delirium syndrome (ExDS) is characterized by delirium, agitation, acidosis, and hyper adrenergic autonomic dysfunction, according to the Journal of Emergency Medicine (J. Emerg. Med. 2011 March 24 [doi: 10.1016/j.jemermed.2011.02.017]). It is often comorbid with serious mental illness, drug abuse, or a combination of the two, said Dr. Roberts, who serves as director of emergency medicine at Mercy Philadelphia Hospital and Mercy Fitzgerald Hospital, and has more than 40 years of experience working in emergency departments. Dr. Roberts said ExDS patients often have symptoms that include severe hypothermia, high levels of testosterone, elevated temperature, extreme paranoia, and tolerance to pain, and sweating. These patients also often display super-human strength and are non-compliant with police. Some ExDS patients have an attraction to glass or mirrors. After an episode, patients also tend to have no memory of the event. According to the American College of Emergency Physicians (ACEP), which published a white paper on ExDS and formally recognized the illness as a unique syndrome in 2009, more than 95% of published fatal cases of ExDS involve males with a mean age of 36. After the cohort of people who abuse stimulants, those with psychiatric illness make up the second-largest and “distinctly smaller cohort of ExDS cases and deaths,” according to the white paper. Death from ExDS is often sudden and can result from several conditions, including cardiac arrest, renal failure, or hypothermia. The mortality is nearly 75%, yet ExDS is neither well recognized nor understood within the medical community, Dr. Roberts said. He also noted an absence of coding that can be used to classify the syndrome. Diagnosis and research of ExDS is tricky, the report noted, because of a lack of well-defined and consistent case definitions, as well as shared characteristics with other diseases. For example, ExDS can be confused with heat stroke, alcohol withdrawal, and post-seizures.To help decrease mortality and complications, Dr. Roberts encouraged physicians and law enforcement to raise their awareness of the condition. “In the heat of the battle [between the patient and law enforcement], the patient stops struggling. The [police are] happy, but what really happens is the patient is dying and they’re not aware of it,” Dr. Roberts said. He added that police often mistake ExDS for another psychiatric disease, such as schizophrenia, and they often feel compelled to use physical force to encourage compliance. Tasers, he added, should only be used to remove any weapons the patient might have. Tasers increase the patient’s physiological stress and increase likelihood of death, he said. Medical treatment should be used as soon as possible to improve outcomes. “The cooler heads have to prevail,” Dr. Roberts said. “Doctors have to set the example.”http://www.medconnect.me/tabid/92/ct1/c45583/Excited-Delirium-Syndrome-Lacks-Research-Coding-/Default.aspx2012-05-17Internet-based cognitive-behavioral therapy is a treatment approach that can benefit patients with anxiety and depression, researchers report.The study, conducted by Matthew Sunderland, Ph.D., and colleagues, bolsters the case for the web-based approach as a way of overcoming treatment obstacles such as the lack of rural-based services and wait time (Behavior Res. and Therapy 2012;50:374-80). Dr. Sunderland and his colleagues have been engaged in creating a web-based option for general practitioners and other front-line workers to treat patients, freeing therapy time for those patients in need of more intensive treatment. Hindering this goal has been a lack of information on the “trajectory of change” of patients during the treatment course, reported Dr. Sunderland of the University of New South Wales, Sydney. The investigators studied 663 patients who completed an online cognitive-behavioral therapy (CBT) course for depression (n=302; 58% female) and generalized anxiety disorder (GAD) (n=361; 74% female). The patients’ average age was 43. The primary outcome measure was the Kessler-10 psychological distress scale. The time course of depression and GAD was respectively determined using the Patient Health Questionnaire-9 and GAD-7 instruments. Levels of functional impairment over the previous 30 days were measured using the World Health Organization Disability Assessment Schedule 2.0.Most (75%-80%) patients with either psychological disorder displayed progressive and clinically significant improvements over the period of the six online course lessons, corroborating previous studies. But the rest were “low responders,” whose initial improvement leveled off and even slightly regressed in the later sessions, indicating to the researchers that Internet CBT for anxiety and depression “may be better suited as an initial step within a stepped care model for treatment.” When asked about the results, Erik Andersson, M.Sc., of the department of clinical neuroscience, Karolinska Institutet, Stockholm, said his overall impression is that they are impressive. “The rate of responders is high and much better than, for example, pharmacological treatments. Of course, one could wish they had more predictor variables, such as genetic data,” he said. “That is an important issue for future research.” He also said the results should be compared to traditional live therapy. What factors determine the good and low responses remain to be clarified. “That is indeed the billion dollar question,” Mr. Andersson said. “The authors have found some predictive variables, but it is always hard to tell on an individual level. Some patients really surprise you as a clinician. In my view, the ability to predict treatment success beforehand is still impossible to decide on an individual level. But this article gives some guidance in the clinical decision process.Gerhard Andersson, Ph.D., said in an interview that it is unclear whether the low responders would indeed benefit from another form of therapy. “My impression is that there is a group (albeit small) who is less likely to benefit from therapy regardless what form of psychotherapy, said Dr. Andersson, of the department of behavioural sciences and learning at Linköping University, Sweden. “For depression, it is possible that combined treatment may lead to more responders, such as if Internet CBT and medication are combined.”Dr. Sunderland reported several study limitations, including the absence of a control group and the inability to look into the kinds of barriers that might have prevented people from benefiting from online CBT courses. “Further research with more robust experimental designs is required to address some of the questions regarding the defining features of the sub-classes raised in the current study,” they wrote.Dr. Sunderland reported no relevant financial conflicts of interest.http://www.medconnect.me/tabid/92/ct1/c45582/Online-CBT-for-Depression-GAD-Is-Effective-for-Most/Default.aspx2012-05-17Neoadjuvant abiraterone helped clear tumors in one-third of men with localized, high-risk prostate cancer in an ongoing randomized phase II trial, investigators report.At 6 months, a pathological complete response (pCR) or near pCR was achieved by 34% of men given abiraterone (Zytiga) plus prednisone and leuprolide, compared with 15% of men given leuprolide alone (P = .089). Both groups underwent biopsy and further combination therapy with abiraterone, prednisone, and leuprolide before radical prostatectomy.The 34% response rate is higher than historic controls and unique in the treatment of prostate cancer, where unlike breast and other cancers, neoadjuvant therapies have not shown a benefit to date, Dr. Mary-Ellen Taplin said during a press briefing highlighting research to be presented at the upcoming annual meeting of the American Society of Clinical Oncology (ASCO).Abiraterone, a highly selective oral CYP17A1 (17 alpha-hydroxylase/C17,20 lyase complex) inhibitor, was approved last September, for use in combination with prednisone for the treatment of men with metastatic castration-resistant prostate cancer previously treated with chemotherapy containing docetaxel (Taxotere). Dr. Taplin, a medical oncologist at the Dana-Farber Cancer Institute in Boston, said the long-term significance of obtaining a complete response needs to be validated in large, randomized trials, but characterized the response rates as “very impressive given the high-risk features of these patients.”Notably, 71% of the 58 patients had a Gleason score of 8-10, 19% had a prostate-specific antigen (PSA) of more than 20 ng/mL, and all had T3 or T4 disease on prostate exam.Presscast moderator Dr. Nicholas Vogelzang, cochair of the genitourinary committee for U.S. Oncology and the Southwestern Oncology Group, remarked that “This is one of the first, if not the first study, to show that you can make prostate cancer in the prostate gland itself disappear in a reproducible number of patients.“This is reminiscent of what we see with rectal cancer when we give chemotherapy and radiation prior to surgery and this is what has now become a standard for breast cancer. Theoretically, at least in the breast cancer literature, when you get a complete disappearance in the primary disease, the outcomes are much better than historically.”When asked whether the current data will push clinicians to use abiraterone off-label in earlier-stage disease, Dr. Taplin said it’s unlikely based on results from a safety trial and the cost of the drug at roughly US$7,000/month.The trial enrolled patients with newly diagnosed intermediate and high-risk prostate cancer with at least three positive biopsies and either a Gleason score of 7 or more, stage T3 disease and a PSA of at least 20 ng/mL or a PSA velocity of more than 2 ng/mL per year. Their median age was 58 years.The men were randomized to 12 weeks of abiraterone 1,000 mg/day plus prednisone 5 mg/day and leuprolide 22.5 mg or leuprolide 22.5 mg alone. A prostate biopsy was then performed and the men received 12 additional weeks of the triple-combination therapy followed by radical prostatectomy. A pCR was observed in 10% of the 29 men given all 24 weeks of combination abiraterone and 4% of the 27 men given only 12 weeks of the combination therapy (P = .33), Dr. Taplin said. A near CR, defined by tumor size of 5 mm or less, was reported in 24% and 11% of patients, respectively.When asked whether patients with a pCR could forgo surgery, Dr. Taplin said it’s possible, but that it would take a very carefully designed trial to make that leap at this point. “We’re relatively far from doing this at this point, but these drugs, these new hormonal agents are very powerful and it will definitely be an area of investigation,” she said.The neoadjuvant therapy resulted in low systemic and surgical toxicity. Grade 3 adverse events included elevated AST/ALT in 9% and hypokalemia in 5% of all patients. No grade 4 mineralocorticoid-related adverse events were observed.“We were able to prove in this study that half the amount of prednisone given in more advanced patients – that is just 5 mg/day – prevented any side effects from abiraterone and may reduce the use of higher doses of steroids in all patients being treated with this drug,” Dr. Taplin said.She noted that a similar trial is being planned that would add the novel androgen-receptor antagonist ARN509 to abiraterone and leuprolide, while a second study is ongoing investigating abiraterone and the experimental hormone drug MDV3100 in this group of patients. The abstract can be viewed at ASCO��s website and will be formally presented at ASCO on June 2 (Abstract 4521). In related news, the European National Institute for Health and Clinical Excellence just gave abiraterone the nod for late-stage cancer patients in England and Wales, after initially rejecting the drug for not being cost effective at roughly £3,000 a month.Cougar Biotechnology sponsored the trial. Dr. Taplin reported consulting or advising for and honoraria and research funding from Johnson & Johnson, which markets abiraterone through Janssen Pharmaceuticals. Her coauthors reported financial relationships with several firms including employment and stock ownership with Johnson & Johnson. http://www.medconnect.me/tabid/92/ct1/c45574/Neoadjuvant-Abiraterone-Helps-Clear-Aggressive-Early-Stage-Prostate-Tumors/Default.aspx2012-05-16The shifting balance of data for and against broader use of statin treatment tilted again toward more liberal use, with results from a meta-analysis of more than 170,000 participants showing a clear, positive, overall effect from statin treatment in all types of adults, even those with a relatively low baseline risk for major vascular events.Among people with a 5-year risk of major vascular events lower than 10%, each 1-mmol/L (39-mg/dL) reduction in low-density lipoprotein cholesterol from statin treatment produced an absolute reduction in 11 major vascular events per 1,000 people during 5 years of treatment, reported the Cholesterol Treatment Trialists Collaborators, a team based in Oxford, England, in an article published online May 16 in the Lancet (doi: 10.1016./S0140-6736(12)60367-5).The analysis showed that “statin therapy significantly reduced the risk of major vascular events in individuals with 5-year risk lower than 10% (in whom the mean risks were 2%-6% for major coronary events plus 3% for other major vascular events), even in those with no previous history of vascular disease, diabetes, or chronic kidney disease.” The meta-analysis included data on 174,149 people from 27 controlled trials, and included participants with a broad range of baseline cardiovascular-event risk, ranging from a 5-year risk of less than 5% to a risk of greater than 30%The degree of relative risk reduction among trial participants with a 5-year risk of less than 5%, or 5% to less than 10%, was roughly similar to the risk reduction seen in participants with higher baseline risk levels, even in those with a baseline 5-year risk of 30% or more. The overall relative risk reduction for all people at all baseline risk levels in the analysis was 21% for each 1-mmol/L reduction in LDL cholesterol achieved with statin treatment. For those with a baseline, 5-year risk of less than 5%, the relative risk reduction was 38% for each 1-mmol/L reduction in LDL cholesterol, and for those with a baseline 5-year risk of 5% to less than 10%, the relative risk reduction from statin use was 31% for this level of LDL reduction.Based on this new analysis, the authors concluded that the benefits of statin treatment, even in people at low risk, “greatly” outweigh the risks: “Any long-term effects of any small excesses in hemorrhagic strokes and in diagnoses of diabetes [triggered by statin use] are not associated with long-term effects on major vascular events that are sufficiently large to outweigh the persistent benefits of statin therapy,” they wrote.“These findings confirm the efficacy of statins for primary prevention, resolving concerns about possible serious adverse effects, and potential sources of bias in randomized trials,” wrote Dr. Shah Ebrahim and Dr. Juan P. Casas in a comment that accompanied the meta-analysis (Lancet 2012 May 16 [doi: 10.1016/S0140-6736(12)60367-5]).The new analysis predicted that 16 and 15 major vascular events would be avoided per 1,000 people treated for 5 years in the two lowest-risk categories, respectively, if they achieved a 1-mmol/L cut in their baseline level of LDL cholesterol, which translates into numbers needed to treat of 167 and 67, said Dr. Ebrahim, an epidemiologist at the London School of Hygiene & Tropical Medicine, and Dr. Casas, an epidemiologist at University College London. “These figures look encouraging, and are similar to those for treatment of mild hypertension, which is widely accepted as a primary-care task,” they noted in their comment.But the evidence the meta-analysis provides in favor of statin treatment does not make treatment a slam-dunk, the comment authors warned. First, an LDL cholesterol reduction of 1 mmol/L (39 mg/dL) can be hard to achieve in people without evidence of cardiovascular disease, although they note that the evidence presented also gives reassurance about prescription of higher statin doses to “achieve greater benefit and dissipate uncertainty about any potential serious adverse risks of statins.”In addition, expansion of routine statin use for primary prevention to people with a 5-year risk for cardiovascular disease of less than 10% would sharply boost statin prescribing, and might potentially deflect attention away from aggressive statin treatment of higher-risk patients. An even better solution would be more aggressive dietary measures to lower LDL cholesterol, Dr. Ebrahim and Dr. Casas suggested, but they acknowledged that taking such steps on a national basis is hard. Still, a practical solution would be “to use age as the only indicator for statin prescription, as was originally proposed for the polypill,” they suggested, “because most people older than 50 years are likely to be at greater than 10% 10-year risk of cardiovascular disease.”Some members of the study-writing committee said that they received reimbursement of costs to participate in scientific meetings from the pharmaceutical industry. Two of the authors received honoraria from Solvay for lectures related to the meta-analysis. Dr. Ebrahim and Dr. Casas said that they had no disclosures.http://www.medconnect.me/tabid/92/ct1/c45573/Meta-Analysis-Shows-Statins-Effective-for-Primary-Prevention/Default.aspx2012-05-16The antipsychotic olanzapine trounced standard therapy for breakthrough chemotherapy-induced nausea and vomiting in a clinical trial that could change the way some cancer patients are treated. In the double-blind phase III study, 30 (71%) of 42 patients, who received olanzapine (Zyprexa) had no emesis, compared with 12 (32%) of 38 patients who received metoclopramide (P less than .01) during a 72-hour observation period after highly emetic chemotherapy. In addition, 28 (67%) patients on olanzapine had no nausea, compared with 9 (24%) of those patients on metoclopramide (P less than .01), said Dr. Rudolph M. Navari, who presented the study during a press briefing in advance of the annual meeting of American Society of Clinical Oncology, June 1-5, in Chicago. Dr. Navari is the director of the Harper Cancer Institute at Indiana University in South Bend.ASCO president-elect Dr. Sandra M. Swain, medical director of the Cancer Institute at Washington Hospital Center, called the findings “a great step forward for quality of life for our patients. “This is a huge advance,” said Dr. Swain, a breast cancer expert, who comoderated the teleconference. “We’ve come a long way to really treat and cure these patients ... these side effects can be intolerable to patients. Sometimes patients will opt out of curative treatment, and we certainly don’t want that, when we know we’ve made advances.”The researchers included chemotherapy-naive patients who received highly emetogenic chemotherapy: more than 70 mg/m2 cisplatin, or more than 50 mg/m2 doxorubicin and more than 600 mg/m2 cyclophosphamide.Patients who developed breakthrough emesis or nausea despite guideline-directed prophylaxis were randomized to receive olanzapine or metoclopramide. Pre-chemotherapy prophylaxis included intravenous dexamethasone (12 mg), intravenous palonosetron (0.25 mg), and intravenous fosaprepitant (150 mg); post-chemotherapy prophylaxis was daily oral dexamethasone (8 mg, days 2-4).Patients received 10 mg oral olanzapine for 3 days or 10 mg oral metoclopramide three times daily for 3 days. Patients were monitored for emesis and nausea for the 72 hours after the initiation of therapy. In addition, nausea was measured by patients on a visual analog scale (0-10), with 0 being no nausea and 10 being maximal nausea.Patients in the two groups were similar for age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, and diagnosis (5 bladder cancers, 40 breast cancers, 8 lymphomas, and 27 lung cancers).“Both olanzapine and metoclopramide were well tolerated with no grade 3 or 4 toxicities,” said Dr. Navari. No central nervous system toxicities were observed in either group.Olanzapine is indicated for treatment of psychosis and is associated with weight gain, but the side effect should not be a problem for cancer patients.“The side effect of weight gain occurs in patients, who receive the drug for 3 to 6 to 9 months,” Dr. Ravari noted. “So using it for a short period of 3-4 days once a month – we did not see that in the current study, nor did we see that in previous studies.”Dr. Navari had previously reported that patients receiving highly emetogenic chemotherapy were about twice as likely not to experience any delayed nausea with an olanzapine regimen compared with a standard aprepitant (Emend) regimen (68% vs. 37%) in a phase III clinical trial. The two regimens worked similarly well for preventing acute nausea and for preventing both acute and delayed vomiting, that study found (Support. Oncol. 2011;9:188-95). ASCO presented a preview of some meeting highlights with many of the abstracts being posted online as of 6 p.m. EST at www.asco.org.The authors reported that they have nothing to disclose. http://www.medconnect.me/tabid/92/ct1/c45572/Olanzapine-Overcomes-Chemotherapy-Induced-Vomiting-and-Nausea/Default.aspx2012-05-16Drinking at least one cup of coffee daily may be linked to reduced mortality risks, and people who consume more may enjoy even lower risks, according to a report examining coffee consumption among more than 400,000 people in the May 17 issue of the New England Journal of Medicine.Compared with men who didn’t drink coffee, those who drank six or more cups per day had a 10% lower risk of death during a median follow-up of 14 years. Compared with women who didn’t drink coffee, those who drank six or more cups per day had a 15% lower risk, reported Neal D. Freedman, Ph.D., of the U.S. National Cancer Institute’s Division of Cancer Epidemiology and Genetics, and his associates.The benefit of coffee consumption was similar between people who predominantly drank decaffeinated and those who predominantly drank caffeinated coffee, so caffeine does not appear to be the component of the beverage that improves mortality, they said.In previous studies, coffee drinking has been linked to lower rates of diabetes, inflammatory diseases, and stroke. But studies examining a link with heart disease have produced mixed results, and “associations with cancer have generally been null,” the researchers noted. Thus, coffee’s association with total mortality has been mixed. Dr. Freedman and his colleagues used data from the U.S. National Institutes of Health–AARP Diet and Health Study to assess the relationship between coffee drinking and both total and cause-specific mortality. The NIH-AARP study involved more than 617,000 subjects aged 50-71 years who were followed from baseline (1995-1996) through 2008, so it had ample power to detect even modest associations, the investigators noted.For the Diet and Health Study, subjects residing in six states and two cities answered a comprehensive questionnaire about diet and lifestyle at baseline. Dr. Freedman and his associates assessed a subgroup of 229,119 men and 173,141 women from this study population, after excluding those with cancer, heart disease, stroke, or inadequate information on coffee drinking and cigarette smoking.A total of 33,731 men and 18,784 women died during follow-up. The researchers found a modest inverse association between coffee drinking and total mortality for both sexes (N. Engl. J. Med. 2012;366:1891-1904). This association was dose dependent. Hazard ratios for death from any cause among men who drank coffee, compared with men who did not, were 0.99 for less than one cup per day, 0.94 for one cup, 0.90 for two to three cups, 0.88 for four to five cups, and 0.90 for six or more cups. Hazard ratios among women who drank coffee, compared with women who did not, were 1.01 for less than one cup per day, 0.95 for one cup, 0.87 for two to three cups, 0.84 for four to five cups, and 0.85 for six or more cups.These hazard ratios are similar to those found in several larger, more recent studies, including the Nurses’ Health Study and the Health Professionals Follow-up Study, the investigators said.In an analysis of the data stratified by the predominant type of coffee consumed, the link between intake and mortality was similar for caffeinated and decaffeinated coffee. This suggests that the mortality benefit is due to some compound contained in coffee other than caffeine, such as antioxidants.The association also persisted across numerous subgroups of study participants, regardless of age; body mass index; the presence or absence of diabetes; concomitant alcohol consumption; high or low intake of red meat, white meat, fruit, and vegetables; and use or nonuse of hormone replacement therapy. The strongest inverse associations between coffee drinking and total mortality were found among people who had never smoked (compared with current smokers) and those who reported having very good to excellent overall health (compared with poor to fair health). When cause-specific mortality was examined, coffee intake was inversely related to most major causes of death in both men and women. Higher coffee consumption was linked to lower mortality due to heart disease, respiratory disease, stroke, injuries and accidents, diabetes, and infections. However, coffee did not protect against cancer mortality in women, and it showed a borderline positive association with cancer mortality in men. “Given the observational nature of our study, it is not possible to conclude that the inverse relationship between coffee consumption and mortality reflects cause and effect,” the investigators said.Nevertheless, “our results provide reassurance with respect to the concern that coffee drinking might adversely affect health.”This study was supported by the U.S. National Institutes of Health, the U.S. National Cancer Institute, and the NCI’s Division of Cancer Epidemiology and Genetics. No financial conflicts of interest were reported. http://www.medconnect.me/tabid/92/ct1/c45571/More-Coffee-It-May-Extend-Your-Life/Default.aspx2012-05-16The U.S. Food and Drug Administration reviewed new drug applications significantly faster, and approved more new drugs first, than did its European and Canadian counterparts between 2001 and 2010. These and other findings of practices at the three agencies raise question about whether speeding the review process further in the renewal of the Prescription Drug User Fee Act (PDUFA) is justified, according to Nicholas Downing, of Yale University, New Haven, Connecticut, and his associates. The findings were published May 16 in the New England Journal of Medicine.Passed in 1992, PDUFA authorizes the FDA to collect fees from companies for each new drug application filed; the fees are used to speed of the review process, which includes hiring extra staff members. The law is reauthorized every 5 years, including this year (PDUFA V).Previous renewals have identified areas of specific emphasis, such as drug safety and postmarketing surveillance (in 2007). This year, the FDA has worked with the pharmaceutical industry on how to make the new drug and biologic approval process more effective and efficient, and how to increase the number of agents approved in a single review cycle. The emphasis reflects “a response to criticism that the FDA has focused on safety at the expense of timely reviews,” the researchers noted. But their findings “contradict recent criticisms of the speed of review by the FDA and lead to question about whether the speed of the review process is justified as an emphasis for PDUFA V, particularly since the FDA continues to outpace its European and Canadian peers.” Mr. Downing and his colleagues used publicly available information from the FDA, the European Medicines Agency (EMA) and Health Canada for 2001-2010 to compare the speed of review of new prescription drugs and biologics; they excluded reformulated drugs and combination drugs (N. Engl. J. Med. 2012 May 16 [doi:10.1056/NEJMsa1200223]). Until their review, little objective information has been available regarding the time it takes the FDA to review applications for new therapeutic agents, and how that review time compares with those of agencies in other countries, they noted. Of the 510 applications for new drugs that were approved during this time, 225 were approved by the FDA, 186 by the EMA, and 99 by Health Canada. Of these drugs, 289 were considered unique new therapeutic agents, including 72 that were approved by all three agencies. There were no significant differences in the therapeutic drug class reviewed or whether a priority review was used between the three agencies, with one exception: the proportion of orphan products approved by the EMA was significantly higher than that of the FDA (28% vs. almost 17%).Of the 289 new agents, 190 were approved in the United States and in Europe. Of these, 121 64%) were approved in the United States first. Of the 154 that were approved in the United States and in Canada, 132 (86%) were first approved in the United States. Most of the new agents were approved within a single cycle, but the rate was highest at the EMA (96%) compared with 62% at the FDA and 69% at Health Canada. The median time to complete the first review (the number of days from the time the application was submitted to the date the agency notified the applicant of its decision) was 303 days for FDA-approved applications, 366 days for the EMA, and 352 days for Health Canada – a statistically significant difference across the agencies. For the 72 new agents approved by all three agencies, the median time of the first review was about 100 days faster at the FDA: 254 days, compared with a median of 356 days at the EMA and 346 days at Health Canada. The study was supported by the Pew Charitable Trusts. The authors disclosed no relevant conflicts of interest.http://www.medconnect.me/tabid/92/ct1/c45570/U-S-FDA-s-New-Drug-Approvals-Outpace-Canada-Europe/Default.aspx2012-05-16BELLEVUE, WASHINGTON (EGMN) – If a child has had abdominal pain for 4-6 weeks without constipation, it’s almost always functional abdominal pain.That “somewhat bold thesis” explains nearly all childhood abdominal pain, Dr. Tyler Burpee said at the annual meeting of the North Pacific Pediatric Society.Functional GI disorders, although frequently misdiagnosed, account for 2%-4% of general pediatric visits and more than half of consultations with pediatric gastroenterologists. These patients are suffering, and have lower quality-of-life scores compared with patients who have asthma or migraines, studies have shown.When patients with functional GI disorders don’t meet criteria for functional dyspepsia, irritable bowel syndrome, or abdominal migraine, they fall into the catch-all diagnostic subcategory of functional abdominal pain, the most common type in children. Diagnostic criteria include continuous or episodic abdominal pain occurring at least weekly for at least 2 months with no evidence of an inflammatory, anatomical, metabolic, or neoplastic process that explains the symptoms.When parents (and even some physicians) hear the diagnosis of functional abdominal pain, they commonly misinterpret it to mean, “It’s all in your head,” said Dr. Burpee, a pediatric gastroenterologist at St. Luke’s Children’s Hospital, Boise, Idaho. He explains to parents and the child that the transmission of pain from the gut to the brain is incredibly complex, with more nerves in the gut than in the brain or the spinal cord. Functional abdominal pain “means that there’s not something we can see, like an ulcer, but there’s something abnormal happening in the gut,” he said.There’s no cookie-cutter work-up for these patients because their symptoms and characteristics vary so widely, he said. Physicians often order an ultrasound of the abdomen or pelvis, but there’s no evidence that this is helpful in diagnosing functional abdominal pain. The predictive value of blood tests has not been well studied. Esophagogastroduodenoscopy (EGD) should not be ordered unless the patient exhibits “alarm symptoms,” Dr. Burpee said, which can include involuntary weight loss or growth failure, dysphagia, frequent vomiting, chronic and severe diarrhea, nocturnal symptoms (especially bowel movements), persistent right upper quadrant or right lower quadrant pain, or rectal bleeding without constipation. A recent study of 301 patients found that negative EGD results do not improve outcomes with functional GI disorders (Clin. Pediatr. 2011;50:396-401).There are many useful treatments for functional abdominal pain in children, but antibiotics probably are not on that list. “I don’t think antibiotics are ready for prime time,” he said.Cognitive-behavioral therapy (CBT) and hypnotherapy have the most positive evidence behind them, but other helpful treatments may include peppermint oil, probiotics, the alteration of parenting techniques, and possibly tricyclic antidepressants, placebo pills, or biofeedback.Parents who tried to distract their child’s attention from abdominal pain made the child feel better than did parents who offered solicitous attention (“Where is the pain? How much does it hurt?”) in a prospective study of 223 children with and without functional abdominal pain. In fact, children’s symptom complaints nearly doubled under conditions of parent attention, and were reduced by half under conditions of parent distraction. However, parents in the study feared that the distraction strategy would do more harm than giving attention (Pain 2006;122:43-52). A separate study of CBT randomized 200 children with functional abdominal pain and their parents to three sessions of either education (the control group) or CBT for training in relaxation, modifying responses to illness/wellness, and altering dysfunctional thoughts about symptoms. Decreases in pain and GI symptoms were significantly greater in the CBT group during 6 months of follow-up. Parents in the CBT group were significantly more likely to decrease their solicitous responses to the child’s symptoms (Am. J. Gastroenterol. 2010;105:946-56). Hypnotherapy appeared to be astoundingly successful in a study that randomized 51 patients to standard medical therapy or six 50-minute sessions of gut-directed hypnotherapy over a 3-month period. Decreases in the frequency and intensity of abdominal pain were significantly greater in the hypnotherapy group. Rates of clinical remission (defined as at least an 80% decrease in pain intensity and frequency scores) were 25% in the control group and 85% with hypnotherapy – which is “incredible success” in functional abdominal pain, Dr. Burpee said.The caveat is that the study used one very experienced hypnotherapist, but Seattle Children’s Hospital has begun treating functional abdominal pain and Dr. Burpee has worked with several individual hypnotherapists, both with “incredible success,” he said. Hypnotherapy is safe, he added.Another benign therapy showing promise is peppermint oil. A 2-week period of treatment decreased pain severity by 19% in patients who were randomized to placebo, and by 75% in patients randomized to take enteric-coated peppermint oil capsules (0.2 mL) three times per day, a study of 42 children with irritable bowel syndrome found (J. Pediatr. 2001;138:125-8). The study has limitations, but “it’s a good proof of concept” that also may apply to functional abdominal pain, Dr. Burpee said. An 8-week period of probiotic therapy with Lactobacillus GG significantly reduced the frequency and severity of abdominal pain, with no significant effects from placebo, in a randomized study of 141 children with irritable bowel syndrome or functional abdominal pain. Benefits persisted for another 8 weeks of follow-up (Pediatrics 2010;126:e1445-52). There is excellent evidence supporting biofeedback treatment for chronic headaches, and although there are no data for treating abdominal pain, biofeedback seems to work, Dr. Burpee said.Both amitriptyline and placebo significantly relieved pain and produced a sense of improvement in a 4-week randomized study of 83 children with functional GI disorders. Results did not differ significantly between groups, however, which led the investigators to conclude that both the tricyclic antidepressant and placebo were effective (Gastroenterology 2009;137:1261-9). “I think most of the things we do with fiber etc. are placebo,” Dr. Burpee said. Amitriptyline might be a good choice in a child who has a lot of anxiety around functional abdominal pain, he suggested.In the latest and probably largest study of antibiotics to treat functional abdominal pain, 1,260 patients were randomized to rifaximin (55 mg three times a day) or placebo for 2 weeks. The proportions of patients who reported relief from pain for at least 2 of the 4 weeks following the start of treatment were 40% with rifaximin and 31% with placebo (N. Engl. J. Med. 2011;364:22-32). Although the difference between groups was statistically significant, “I’m not really sure of the clinical value of 40% vs. 31% when treating an individual patient,” and the antibiotic is very expensive – probably $600 for the treatment course used in the study, Dr. Burpee said. “Irritable bowel syndrome is not a one-and-done thing,” he added, noting that “2 weeks of treatment is probably not a great idea.”There are no great data to support treating functional abdominal pain with acupuncture, Dr. Burpee said. A review of the literature reported about a 30%-40% success rate with real vs. sham acupuncture (Gastroenterol. Clin. North Am. 2011;40:245-53). Dr. Burpee reported having no relevant financial disclosures. http://www.medconnect.me/tabid/92/ct1/c45569/Pediatic-Abdominal-Pain-Without-Constipation-Likely-Functional-/Default.aspx2012-05-16MONTEREY, CALIFORNIA (EGMN)–Women have a substantially elevated risk of postpartum hemorrhage after a first occurrence, a prospective population-based cohort study has shown.The study of more than half a million primiparas and roughly 1 million deliveries in Sweden found that women who had postpartum hemorrhage in their first pregnancy were more than three times as likely to have this complication again in their second pregnancy. Risk increased with the severity of hemorrhage in the first pregnancy and with the number of affected pregnancies.In additional findings, a history of postpartum hemorrhage due to one etiology, for example, uterine atony or retained placenta, increased the risk not only of a recurrence of hemorrhage due to the same etiology but also of occurrence of hemorrhage due to other etiologies.“The fact that a history of postpartum hemorrhage of one subtype confers risk of other subtypes in a subsequent pregnancy suggests that there are likely shared pathological features across the different etiologies, and I think this is going to be a very interesting area to examine in the future,” commented lead investigator Dr. Brian T. Bateman, an anesthesiologist at Harvard Medical School, Boston, at the annual meeting of the Society for Obstetric Anesthesia and Perinatology.“We could speculate that it might be undiagnosed coagulopathy that explains the shared risk or perhaps characteristics of labor, placentation, or other factors. Given the strong pattern of recurrence, perhaps these are even genetic in nature,” he added. In upcoming research, the investigators will look further into possible explanations. “We are planning to collect a series of women with recurrent hemorrhage, particularly women with hemorrhage from discordant causes, and examine in real granular detail what might be mediating these effects that we are observing at the population level,” Dr. Bateman explained. “We are also in the process of conducting familial aggregation studies to determine whether there is a genetic component to postpartum hemorrhage risk.”Session attendee Dr. Richard M. Smiley of Columbia University in New York questioned the reliability of coding of postpartum hemorrhage etiologies in the register used for the study. “It’s really intriguing, the cross-risk, if you will. ... With all due respect to the Swedish database, what’s the chance that that is just miscoded – that a woman bleeds maybe from the same cause, but someone needs to put a cause down on the chart or in the coding system, and they have to pick something, and they pick the wrong thing?” he asked.“There was a study out of the same database last year looking at the role of obesity as a risk factor for postpartum hemorrhage, and they found when they looked at the risk of postpartum hemorrhage from retained placenta or from laceration, there was no effect of body mass index in those categories, but a very, very strong effect on risk of atony, suggesting that there is some specificity in the way that these codes are being applied,” Dr. Bateman replied. Previous research has shown that postpartum hemorrhage is a risk factor for the same complication in subsequent pregnancies, he noted, giving some background to the study. However, “less is known about whether risk accumulates with multiple affected pregnancies and whether the severity of prior postpartum hemorrhage has additional predictive value, and if risk of recurrence varies according to postpartum hemorrhage subtype.” The investigators analyzed data from the Swedish Medical Birth Register. They included 538,332 primiparous women who delivered between 1997 and 2009, and followed this group through 2009, identifying a total of 914,933 subsequent deliveries.Overall, 5.5% of the women had physician-diagnosed postpartum hemorrhage (an estimated blood loss of greater than 1 L) in their first pregnancy. The rate of this complication in a second pregnancy was higher when the first pregnancy was affected, and the rate was especially high in a third pregnancy when both a first and second pregnancy were affected.Relative to their counterparts who did not have postpartum hemorrhage in their first pregnancy, women who had postpartum hemorrhage that was not severe, meaning it did not require transfusion, had increased risks of both nonsevere and severe postpartum hemorrhage in a second pregnancy (relative risk, 3.2 and 3.4, respectively).The respective elevations of risks were even greater in women who had severe postpartum hemorrhage in their first pregnancy (RR, 4.2 and 6.9), “suggesting that severity of hemorrhage does add additional predictive value and can be potentially helpful in triaging high-risk patients,” Dr. Bateman said. Additional analyses showed that postpartum hemorrhage in the first pregnancy due to one etiology increased the risk of postpartum hemorrhage in the second pregnancy due to both that etiology and others. “These findings are really quite surprising and are novel,” he commented.For example, women who had hemorrhage due to uterine atony in their first pregnancy had a 3.9-fold higher risk of hemorrhage due to uterine atony in their second pregnancy. But they also had increased risks of postpartum hemorrhage due to retained placenta (3.1-fold), laceration (1.7-fold), and delayed postpartum hemorrhage (1.8-fold). When the investigators repeated analyses but excluded women with stable risk factors that might be present across the reproductive years, such as fibroids, inherited coagulopathy, and cesarean delivery, the elevated risks of a recurrence of postpartum hemorrhage were essentially unchanged. “This argues that recurrence is mediated by some other factor,” maintained Dr. Bateman.Dr. Bateman disclosed that he had no conflicts of interest related to the research.http://www.medconnect.me/tabid/92/ct1/c45567/Prior-Postpartum-Hemorrhage-Raises-Risk-of-Another/Default.aspx2012-05-16BOSTON (EGMN) – Although it ranks behind hypertrophic cardiomyopathy as a cause of sudden cardiac death in children and young adults, the Wolff-Parkinson-White electrocardiogram pattern warrants monitoring and, in some cases, intervention, according to authors of a consensus statement announced at the annual meeting of the Heart Rhythm Society. The Pediatric and Congenital Electrophysiology Society (PACES) and the Heart Rhythm Society (HRS) issued an expert consensus statement on the care of young, asymptomatic patients with the Wolff-Parkinson-White (WPW) electrocardiographic patterns, caused by an accessory cardiac electrical pathway.The statement is intended as a guideline for clinicians who treat patients aged 8-21 years who have the WPW pattern but are otherwise asymptomatic, said lead author Dr. Mitchell I. Cohen, chief of pediatric cardiology and director of pediatric electrophysiology at Phoenix Children’s Hospital. An estimated 65% of young patients with WPW are asymptomatic, Dr. Cohen said in a briefing. In those patients, “essentially one of three things can happen: They may remain asymptomatic; they may develop an arrhythmia that can be managed with medication or ablation; or, more concerning, they may have a life-threatening event and die suddenly. The incidence of sudden death is quite rare, but it’s not zero,” he said.The consensus panel, comprising both pediatric and adult electrophysiologists, estimates the prevalence of the WPW to range from 1 to 3 per 1,000. The incidence of sudden death from WPW, including resuscitated sudden cardiac death (SCD), is about 4.5 per 1,000 patient-years, on the basis of a study of asymptomatic adults with the pattern who were followed for a mean of 38 months (J. Am. Coll. Cardiol. 2003;41:239-44).In contrast, the incidence of sudden death attributable to hypertrophic cardiomyopathy was about 7.4 per 1,000 person-years in one study. (N. Engl. J. Med. 2000;342:1778-85).Symptoms of WPW may include palpitations, dizziness, syncope, and supraventricular tachycardia. Many young patients are diagnosed only after they undergo electrocardiograms required by many school districts prior to participation in organized sports. Dr. Cohen says that although the condition can be effectively treated with catheter-based radiofrequency ablation, invasive techniques may not always be necessary or appropriate for younger patients.Specifically, the statement recommends the following for patients aged 8-21 years who have the WPW ECG pattern: • Patients should take an exercise stress test if the ambulatory ECG exhibits persistent pre-excitation. • Invasive risk stratification (transesophageal or intracardiac) should be performed to assess the shortest pre-excited RR interval in atrial fibrillation in patients in whom noninvasive testing fails to demonstrate clear and abrupt loss of pre-excitation.• Catheter ablation may be considered in young patients with a measurement of the SPERRI (Shortest Pre-Excited RR Interval) of 250 ms or less in atrial fibrillation, as they are at increased risk for SCD.• Ablation may be safely deferred in lower-risk young patients with a SPERRI longer than 250 ms in atrial fibrillation.• Catheter ablation may be considered in previously asymptomatic patients who subsequently develop cardiovascular symptoms such as syncope or palpitations.• Ablation may be considered regardless of the anterograde characteristics of the accessory pathway in asymptomatic patients with a WPW ECG pattern and structural heart disease.• Asymptomatic patients with a WPW ECG pattern and ventricular dysfunction secondary to dyssynchronous contractions, regardless of anterograde characteristics of the bypass tract, may benefit from ablation.• It is safe to prescribe medications for attention-deficit/hyperactivity disorder (ADHD) for asymptomatic patients with a WPW ECG in accordance with American Heart Association guidelines, which state that ADHD medications may be used in this setting after cardiac evaluation and with intermittent monitoring and supervision by a pediatric cardiologist.The consensus statement has been endorsed by the governing bodies of the PACES, the HRS, the American College of Cardiology Foundation, the American Heart Association, the American Academy of Pediatrics, and the Canadian Heart Rhythm Society. Dr. Cohen reported having no relevant disclosures. http://www.medconnect.me/tabid/92/ct1/c45566/Guidance-Offered-on-Children-With-Wolff-Parkinson-White-Syndrome-/Default.aspx2012-05-16The risk of developing progressive multifocal leukoencephalopathy from natalizumab therapy appears to be greater than previously thought, being greatest in multiple sclerosis patients with certain risk factors, according to an updated analysis.The analysis provides an algorithm that might help clinicians hone in on which patients are least or most likely to develop PML, and give them support in discussing risks and benefits, said Dr. Gary Bloomgren and his coauthors, all of whom work for Biogen Idec, which makes natalizumab (Tysabri).The algorithm took into account anti-JC virus antibody status; whether there was prior use of immunosuppressants; and duration of treatment. Positive anti-JC status, prior immunosuppressant use and longer treatment all have been previously identified as PML risk factors. But there has not been a physician-friendly way to stratify risk.PML is an opportunistic brain infection caused by the JC virus. Previous estimates had put the incidence at about 1 case per 1,000. In April 2011, the U.S. Food and Drug Administration reported that 102 cases of PML had been reported among 82,732 patients treated with natalizumab worldwide.But now that risk is 2.1 per 1,000, given that there have been 212 confirmed cases of PML among the 99,571 patients worldwide who have been treated with natalizumab, Dr. Bloomgren and his colleagues reported May 16 in the New England Journal of Medicine. The incidence of PML rises to as much as 11.1 per 1,000 in multiple sclerosis patients who are positive for anti-JC virus antibodies, who have taken immunosuppressants before starting natalizumab, and who have taken the drug for 25-48 months. Although this is a longer period of follow-up than has been reported previously, there were not enough data to calculate the risk beyond 4 years of treatment.In January of this year, the FDA warned that anti–JC virus–positive status was associated with an increased risk, in addition to the other known risk factors for PML. The agency also estimated the incidence of PML for patients with those risk factors at 11.1 per 1,000.Dr. Bloomgren and his associates based their calculations on data from Biogen Idec’s safety database, from clinical trials such as the Tysabri Global Observational Program in Safety study (TYGRIS-U.S. and TYGRIS–Rest of World) and from AFFIRM and STRATIFY-1. Data from an independent Swedish registry of patients with multiple sclerosis were also used (N. Engl. J. Med. 2012;366:1870-80).The algorithm can help stratify risk and assist physicians in deciding whether to use natalizumab, the authors said. Avoiding PML is of great importance. The Biogen Idec researchers said that of the 212 confirmed PML cases, 46 of the patients had died, and that 23 of the 58 survivors for whom data was available had severe disability. They noted that their risk estimates were limited by several factors, including the assumption that anti–JC-positive status was clearly associated with development of PML. This assumption was based on the fact that all 54 patients identified in the postmarketing setting had been anti–JC-positive before their PML diagnosis. But blood samples were not available for all patients with PML, and the anti-JC virus assay – which is now commercially available – has a small, but perceptible false negative rate.In a commentary accompanying the study, Dr. Allan H. Ropper said that MS patients who test negative for anti-JC antibodies ostensibly can be reassured that it is safe to take natalizumab. But he noted that there are “basic limitations to serologic tests for JC virus, since there is no standard by which to judge the absence of the virus” (N. Engl. J. Med. 2012;366:1938-9).Also, the seroprevalance of the virus increases with age, and patients can undergo seroconversion at any time, said Dr. Ropper, a neurologist at Brigham and Women’s Hospital, Boston. He urged retesting for any patients undergoing natalizumab therapy. While it is not entirely clear why natalizumab is associated with PML, it appears that it may reactivate the JC virus and that it might possibly cause the emergence of a mutation in the virus that leads to the emergency of PML.Dr. Ropper disclosed no financial conflicts, but reported that he is the associate editor of the New England Journal of Medicine.http://www.medconnect.me/tabid/92/ct1/c45565/Algorithm-May-Help-Cut-PML-Risk-With-Natalizumab/Default.aspx2012-05-16MONTEREY, CALIFORNIA (EGMN) – A new model may help take the guesswork out of identifying placenta accreta before cesarean delivery, possibly sparing some women unnecessary interventions such as general anesthesia, placement of large-bore IV lines, and elective hysterectomy.A study team led by Dr. Carolyn F. Weiniger, an obstetrical anesthesiologist at the Hadassah Hebrew University Medical Center in Jerusalem, reviewed data for 46,623 women who were delivered at the center over a 9-year period. They identified 92 women with antenatally suspected placenta accreta, of whom only 52 (56%) were confirmed to have had the condition at the time of surgery, she reported at the annual meeting of the Society for Obstetric Anesthesia and Perinatology. At a maximal-sensitivity cut-off, a predictive model based on just three clinical factors that would be assessed in any woman evaluated for suspected placenta accreta – the presence of placenta previa (yes vs. no), the number of previous cesarean deliveries, and ultrasound suspicion of accreta (high vs. low) – identified 100% of the women who were confirmed to have the condition. The trade-off was a low specificity of 25%. However, at the optimal cut-off, the model still identified 94% of the women who were confirmed to have placenta accreta, and specificity was better (53%). The investigators developed a nomogram based on the model that should be easy to apply clinically, according to Dr. Weiniger. “This nomogram could be a laminated card which a physician could sit with at his desk when faced with a suspected placenta accreta patient, to decide whether she is above or below our cut point, whether we think she actually does or does not have placenta accreta,” she explained.Although the study involves one of the largest series of patients with placenta accreta, it still had a fairly small sample size, she acknowledged. “In order to validate such data, a multicenter study would be appropriate.”“Have you changed your practice ... based on your nomogram?” asked Dr. Vilma E. Ortiz, session moderator and an anesthesiologist at the Massachusetts General Hospital in Boston.“We have just created the nomogram, just finished analyzing the statistics. We haven’t yet had an accreta patient,” Dr. Weiniger replied. “But I think as we become much more experienced at managing these patients, in patients who we feel comfortable [that they] have got no risk or low suspicion [of accreta], we will do regional anesthesia.”During the study period, her center’s management in cases of suspected accreta typically included general anesthesia, the booking of an ICU bed, the insertion of two large-bore IVs, and the placement of loops on the internal iliac vessels to aid with hemostasis. It did not include planned cesarean hysterectomy. “Surgeons were not aware of our primary study outcome [that is, the rate of surgically diagnosed accreta among all cases of antenatally suspected accreta] in order to avoid bias,” she noted.A comparison of the 52 women with and 40 women without surgically confirmed accreta showed that they were statistically indistinguishable with respect to many clinical factors. But they differed significantly on the number of previous cesarean deliveries, the presence of placenta previa, and the presence of ultrasound signs of accreta. The predictive model based on these three factors had an area under the receiver operating characteristic curve of 0.846, according to Dr. Weiniger. “When we tried to add maternal age and antenatal bleeding, because [these factors have been found to be predictive] in previous studies, it did not improve the area under the curve.”Giving some examples using the new nomogram, she noted that a woman having two previous cesarean deliveries who has placenta previa and a high-suspicion ultrasound would have a probability score approaching 80%, which falls well above cut points based on both 100% and 94% model sensitivity. “So she would be classified as having placenta accreta and would require massive hemorrhage preparation for surgery.” In contrast, a woman having two previous cesarean deliveries who does not have placenta previa and has a low-suspicion ultrasound would have a probability score of almost 0%, which falls well below the cut points, and she would be classified as not having placenta accreta. “So we could manage her with regional anesthesia and maybe not do preparations for massive hemorrhage,” Dr. Weiniger commented.Finally, a woman having two previous cesarean deliveries who has a low-suspicion ultrasound but does have placenta previa would have a probability score of about 20%. This score falls above the cut point corresponding to 100% sensitivity, “so if that was the clinician’s practice, that patient would have massive hemorrhage preparations,” she said. “But if we were using the 94% sensitivity, the optimal cut point, she would be right on that, so it would be equivocal as to whether we would classify her as having massive transfusion requirements or not. Possibly, the state of her airway would define how we would manage such a patient.”Dr. Weiniger disclosed no relevant conflicts of interest.http://www.medconnect.me/tabid/92/ct1/c45563/New-Model-Developed-for-Identifying-Placenta-Accreta/Default.aspx2012-05-16BOSTON (EGMN) – Ablation bested antiarrhythmic drugs at reducing the incidence of time to first recurrence of atrial arrhythmias in patients with paroxysmal atrial fibrillation, results of a randomized, multicenter trial showed.In the study, radiofrequency catheter–based pulmonary vein isolation was associated with a 44% relative risk reduction, compared with antiarrhythmics drugs in the primary end point of time to first recurrence of symptomatic or asymptomatic atrial fibrillation (AF), atrial tachyarrhythmia (AT), or atrial flutter (AFL), reported Dr. Carlos A. Morillo, coprincipal investigator of the RAAFT-2 (Radiofrequency Ablation vs. Antiarrhythmic Drugs as First-Line Treatment of Symptomatic Atrial Fibrillation) study at the annual meeting of the Heart Rhythm Society.“Radiofrequency catheter pulmonary vein isolation achieved a significant reduction in all primary efficacy outcomes and most secondary outcomes with similar rates of success," said Dr. Morillo, a professor of cardiology at McMaster University in Hamilton, Ontario.“It certainly is very impressive that in these patients who for the first time have atrial fibrillation, they can do better with a strategy of ablation as a first-line therapy, compared to antiarrhythmic drugs. It’s only one trial, however, and it has to be validated, and we have to see how it carries forward, not only at the 1- or 2-year mark but over the long term,” Dr. Richard I. Fogel of the St. Vincent Medical Group, Indianapolis, commented in an interview.Dr. Fogel moderated the late-breaking abstract session at which these data were presented but was not involved in the study.Previous studies have shown that ablation of atrial fibrillation results in about a 66% relative risk reduction in recurrence, but most studies have focused on patients with atrial fibrillation refractory to one or more antiarrhythmic drugs, Dr. Morillo noted. The RAAFT-2 investigators enrolled 127 patients with symptomatic, recurrent paroxysmal AF lasting more than 30 seconds who had at least four episodes within the prior 6 months, with at least one of the episodes documented by Holter monitor, 12-lead ECG, event monitor, or rhythm strip.In the intention-to-treat population, 66 patients (mean age, 56.3 years) were assigned to receive ablation, and 61 (mean age, 54.3 years) were allocated to receive antiarrhythmic drugs for treatment and follow-up, including flecainide (Tambocor), propafenone (Rythmol), dronedarone (Multaq), amiodarone (Cordarone), dofetilide (Tikosyn), and sotalol (Betapace).About three-fourths of patients in each group were men, and about 87% had paroxysmal AF, with the remaining patients having persistent AF.Among patients assigned to ablation, the mean number of AF episodes before enrollment was 47.7, and among patients assigned to antiarrhythmic drugs, enrollment was 33.In the ablation group, 65 of 66 had the ablation performed. During follow-up one patient was lost to follow-up, nine received a second ablation, and seven were crossed over to antiarrhythmic drugs. In the drug group, 60 of 61 were started on drugs. One patient in this group was also lost follow-up, 36 discontinued antiarrhythmic drugs, and 26 were crossed over to ablation. At 2-year follow-up, 72% of patients in the antiarrhythmic drug group reached the primary efficacy outcome (time to first recurrence of symptomatic or asymptomatic AF/AT/AFL), compared with 55% in the catheter ablation group, for a statistically significant risk reduction of 44%. Looking at symptomatic AF/AT/AFL only, the proportion of patients with a first recurrence at 2 years was 59% and 47% for the ablation and medical therapy groups, respectively, for a significant 48% relative risk reduction.In an analysis conducted to determine whether the interventions reduced the frequency of the primary outcome, the authors compared the percentage of transtelephonic monitor (TTM) transmissions indicating any recurrence of the arrhythmias. In all, 6.6% of transmissions in catheter ablation patients showed recurrence, compared with 14.7% of transmission from the antiarrhythmic drug group, yielding a highly significant risk reduction of 66% (P = .0001).“Of note, when we excluded the transtelephonic monitor, we couldn’t show any [significant] difference in recurrence of the primary outcome – 31% in the antiarrhythmic drug and 24% in the catheter ablation – highlighting the need of very strict monitoring in these patients to be able to define a successful outcome.”Reported patient quality of life in both groups improved over baseline, and was not significantly different between the groups.For the primary safety end point, there were no deaths in either group at 2 years. Cardiac tamponade was seen in 6.2% of patients in the ablation group, and severe pulmonary stenosis of 70% or greater in 1.5%. There were no cases of atrioesophageal fistula, thromboembolism, vascular complications, or phrenic nerve injury.For patients on antiarrhythmic drugs, syncope occurred in 3.3%, atrial flutter with 1:1 conduction in 1.6%, and other significant advents leading to discontinuation of drug therapy in 14.3%.The trial was sponsored by the Population Health Research Institute and McMaster University and Hamilton Health Sciences. It was supported by grant-in-aid from Biosense Webster. Dr. Morillo disclosed receiving consulting fees/honoraria/research grants from and/or being on a speakers bureau for Boehringer Ingelheim, Sanofi, Medtronic, Merck, St. Jude Medical, Boston Scientific, and Biosense Webster. Dr. Fogel disclosed that he has received grants for clinical research and educational activities from St. Jude Medical, Medtronic, and Guidant, and owns stock in Medtronic and Guidant. http://www.medconnect.me/tabid/92/ct1/c45562/Ablation-Safe-Effective-for-First-Line-Atrial-Fib-Treatment/Default.aspx2012-05-16GLASGOW, SCOTLAND (EGMN) – The presence of specific autoantibodies may help to predict which patients with systemic sclerosis are likely to develop cancer within a few years of their diagnosis, according to the findings of a U.K.-based registry study. Development of malignancy within 3 years of a diagnosis of scleroderma was positively correlated with the presence of antinuclear antibodies (ANA) directed against RNA polymerase (RNAP) III in more than half (55.3%) of the patients studied (n = 154). Anticentromere antibodies (ACA) were found in almost a quarter (23.4%) of patients, and 13.6% had antitopoisomerase I (ATA) or anti-Scl70 (antibodies).Furthermore, patients with anti-RNAP III antibodies had an almost threefold increased risk of cancer compared with patients with ACA (hazard ratio [HR] 2.907; 95% confidence interval [CI] 1.69-4.99, P less than .0001).“We think that patients who develop scleroderma and cancer can be divided into two different groups,” trainee dermatologist Dr. Pia Moinzadeh of the University of Cologne, Germany, said at the annual meeting of the British Society for Rheumatology. “The first group are those who develop scleroderma and cancer in a very close temporal relationship, and we saw that these patients are most frequently anti-RNA polymerase positive. So scleroderma in these patients can be considered a paraneoplastic disease.”The other group includes patients who develop cancer after a delay of several years from the onset of systemic sclerosis.Several epidemiological studies have shown an increased risk of malignancy in patients with systemic sclerosis compared with the general population (Br. J. Dermatol. 2010;163:800-6), Dr. Moinzadeh observed.This includes increases in breast, lung, and hematologic malignancies (Ann. Rheum. Dis. 2003;62:728-31) in 3%-11% of scleroderma cases (South. Med. J. 2008;101:59-62).“Late onset of scleroderma has been recognized as a significant risk factor for malignancies, and recent reports have also shown a close and, at times, concurrent onset of scleroderma and cancer,” Dr. Moinzadeh added (Clin. Rheumatol. 2004;23:516-22; Curr. Opin. Rheumatol. 2011;23:530-5).The aim of the current study (Rheumatology 2012;51:[suppl. 3]abstract O42) was to determine the risk of cancer and its association with autoantibodies in a large U.K. cohort. Dr. Moinzadeh performed the research while working at the Royal Free Hospital in London with Dr. Voon Ong and colleagues. Of 2,177 patients with systemic sclerosis, 154 (7.1%) had a history of cancer. The majority (85.1%) of the patients who developed malignancy were female with a median age of 53 years. Almost two-thirds (63.3%) of the patients had limited disease, and 34.4% had diffuse systemic sclerosis. Anti-RNAP, ACA, and Scl70 were detected in 26.6%, 26%, and 18.2% of patients, respectively.The most common type of cancer was breast cancer (42%), followed by hematologic malignancies (12%), gastrointestinal tumors (11%), gynecologic cancers (11%), and lung cancer (10.4%). “We found no differences in gender, age, and disease subsets between patients with and without cancer,” Dr. Moinzadeh said. “When we looked closer at the autoantibody subgroups we saw that the overall frequency to develop cancer was significantly higher in the group of patients who were positive for anti-RNA polymerase antibodies compared with the ones which had anticentromere antibodies.”Differences were seen in the frequency of autoantibodies by tumor type. For example, a higher frequency of anti-RNAP antibodies than the other autoantibodies was seen in breast cancer patients, Scl70 was associated with lung cancer, and ACA with gastrointestinal tumors.While further research is needed to confirm whether anti-RNAP antibodies could be a marker for early cancer in patients with scleroderma, Dr. Moinzadeh noted there were several “red flags” that could perhaps signal if patients were likely to have “paraneoplastic scleroderma.”These red flags included older age (older than 65 years) of scleroderma onset, male gender, contractural arthropathy or palmar fibrosis, lack of ANA antibodies, and no sign of Raynaud’s phenomenon.“This is a retrospective study, so we are going to do a prospective study in collaboration with Johns Hopkins University School of Medicine,” said coinvestigator Dr. Voon Ong, a consultant rheumatologist at the Royal Free Hospital. The collaboration is necessary given that scleroderma is rare, regardless of its association with cancer.Dr. Moinzadeh and Dr. Ong reported that they had no financial disclosures.http://www.medconnect.me/tabid/92/ct1/c45561/Scleroderma-Malignancy-Risk-Linked-to-Antinuclear-Antibodies-/Default.aspx2012-05-16After initially turning it down – and being pressured to reevaluate by the U.K. Department of Health – the clinical effectiveness agency for England and Wales has decided to recommend abiraterone, in combination with glucocorticoids, as a second-line treatment for metastatic prostate cancer. The National Institute for Health and Clinical Excellence announced on May 16 that its new draft guidance recommending abiraterone (Zytiga, Janssen) for castration-resistant prostate cancer came in response to both a new manufacturer pricing agreement and additional information on how many patients were likely to be eligible for treatment. In February, NICE had deemed abiraterone, which has been shown to prolong survival by a median 4.6 months, not cost-effective at an estimated £63,200 per quality-adjusted life year. The following month, the U.K. Department of Health asked NICE to reevaluate its decision with regard to its estimates of the number of men eligible to be treated with abiraterone. NICE evaluates differently end-of-life treatments for patients with a life expectancy of less than 2 years, depending on the size of the population affected. A revised pricing scheme in addition to revised estimates of the population eligible for abiraterone treatment lowered NICE’s estimates to £46,800 per QALY, just under its threshold for an end-of-life treatment in a small population.Abiraterone works by blocking androgen synthesis in the adrenal glands, prostate tissue, and prostate tumors. It is indicated for men whose disease has progressed following docetaxel-containing chemotherapy regimens, and who have been deemed “castration resistant” because their tumors do not respond to androgen-deprivation treatments that may or may not include surgical castration.The list price of abiraterone is £2,930 for a 30-day supply of 120 tablets; NICE did not disclose the new discounted price. It is taken as a single dose of 1,000 mg daily, in four tablets. In a manufacturer-sponsored randomized controlled trial (n = 1,195), subjects receiving abiraterone plus prednisone or prednisolone saw a median overall survival gain of 14.8 months compared with 10.9 months for those taking placebo plus either prednisone or prednisolone after 1 year follow-up (HR 0.65; 95% confidence interval, 0.54-0.77; P less than .001).The trial (N. Engl. J. Med. 2011;364:1995-2005) was stopped due to significant evidence of benefit, but follow-up continued, and an updated analysis after 20.2 months showed that median survival continued to be significantly longer in the abiraterone group than the prednisolone group (15.8 months compared with 11.2 months; HR 0.74; 95% CI 0.64 to 0.86).In its earlier draft guidance NICE had estimated the number of men eligible for second-line treatment with abiraterone to be at least 3,500 in 2011. The revised estimate suggests that only 2,500 would have been eligible – a small population, by NICE’s calculations, and therefore meeting its cost-effectiveness criteria for an end-of-life treatment.http://www.medconnect.me/tabid/92/ct1/c45559/NICE-Reverses-Course-on-Abiraterone/Default.aspx2012-05-16DESTIN, FLA. (EGMN) –Management of lupus nephritis during pregnancy gets close attention in ACR’s new nephritis guidelines.No treatment is necessary in pregnant women with prior lupus nephritis who have no current evidence of systemic or renal disease activity, while those with mild systemic activity may be treated with hydroxychloroquine, according to the guidelines, which are published in the June issue of Arthritis Care & Research.“There are good data suggesting hydroxychloroquine controls lupus in women who are pregnant, resulting in fewer flares” Dr. Bevra H. Hahn said at the Congress of Clinical Rheumatology. Dr. Hahn, professor of medicine and chief of the division of rheumatology at the University of California, Los Angeles, led the ACR core working group that helped with development of the guidelines.In patients with clinically active nephritis or with substantial extrarenal disease activity, glucocorticoids may be prescribed at doses necessary to control disease activity (Arthritis Care Res. 2012;64:797-08). “I start at 0.5 mg/kg per day,” Dr. Hahn said of glucocorticoids under these circumstances. She noted that only steroids that are metabolized by placental enzymes should be used so that the drug does not reach the fetus.She and her coauthors cautioned, however, that high-dose glucocorticoid therapy is associated with a high risk of maternal complications – including hypertension and diabetes mellitus – in patients with systemic lupus erythematosus (SLE). They also stress that mycophenolate mofetil, cyclophosphamide, and methotrexate should be avoided in pregnancy, because they are established human teratogens.Azathioprine, though listed as pregnancy category D indicating teratogenic risk, has been shown in cross-sectional studies to be associated with very low risk of fetal abnormalities and can be added if necessary, according to the task force panel charged with developing the guidelines. The azathioprine dose, however, should not exceed 2 mg/kg per day in pregnant women, Dr. Hahn said. The task force has recommended that pregnant patients with a persistently active nephritis and documented or suspected class III or IV disease with crescents may be candidates for delivery after 28 weeks if the fetus is viable. The recommendations with respect to pregnancy were based on level C evidence, indicating they were based on consensus, expert opinion, and case series.For women with SLE and nephritis who are not pregnant, but who have concerns about fertility preservation, the task force panel recommended that mycophenolate mofetil was preferable to cyclophosphamide for induction therapy, because cyclophosphamide has been shown to cause permanent infertility in both women and men.For example, one study showed that 6 months of high-dose intravenous cyclophosphamide with a cumulative dose of 4.4 g-10 g was associated with sustained amenorrhea in about 10% of young women, and the risk increased with age. However, the physician should be certain the patient is not pregnant before prescribing mycophenolate mofetil or mycophenolic acid, and treatment should be stopped for at least 6 weeks before pregnancy is attempted.The guidelines were sponsored by the American College of Rheumatology via a competitive grant mechanism. Dr. Hahn has received consultant fees, speaking fees, and/or honoraria from UCB and Abbott and has served on the data and safety monitoring board for Anthera. The complete list of disclosures for the guideline authors is available with the full text of the article. http://www.medconnect.me/tabid/92/ct1/c45558/ACR-Gives-Special-Consideration-to-Pregnancy-in-Nephritis-Guidelines/Default.aspx2012-05-16DALLAS (EGMN) – In a surprising twist, multidrug resistance and antibiotic appropriateness were not correlated with mortality in a retrospective analysis of critically ill patients infected with Acinetobacter bacillus.Acinetobacter infections among critically ill patients are increasing and have been associated with mortality rates of 26%-68%. The mortality rates are thought to be driven by high rates of multidrug resistance and subsequent delays in appropriate antimicrobial therapy, Claire Murphy, Pharm.D., explained at the annual meeting of the Surgical Infection Society.She presented data on 156 surgical and medical ICU patients with at least one positive Acinetobacter culture and associated clinical symptoms who were admitted to an ICU between January 2006 and December 2009. In-hospital mortality was 35%.Patients who died had significantly higher APACHE II (Acute Physiology and Chronic Health Evaluation II) II scores than did survivors (22.3 vs. 19.5; P = .02), and were more likely to be surgical patients (50% vs. 33.3%; P = .04) and to be in an immunosuppressed state (33.3% vs. 16.7%; P = .02). Survivors were significantly younger (53 years vs. 59 years; P = .006), and – inexplicably – more likely to have prior colonization or infection with methicillin-resistant Staphylococcus aureus (4% vs. 2%; P = .04), said Dr. Murphy of the department of surgery at the Ohio State University, Columbus.Respiratory infections were the most common source of Acinetobacter for all patients. Survivors were more likely to have respiratory sources of infection (82.5% vs. 67%; P = .02), whereas nonsurvivors had a higher incidence of Acinetobacter bacteremia, including both secondary and catheter-related bacteremias (43% vs. 8%; P less than .001).Multidrug resistance rates were similar among survivors and nonsurvivors at 64% and 70.4%, respectively, although there was a slight trend toward increased resistance among nonsurvivors for cefepime (Maxipime), impinem (Primaxin IV/Primaxin IM), and tigecycline (Tygacil), she said.Rates of appropriate empirical antibiotic coverage were not significantly different, at 18.5% among nonsurvivors and 28.4% among survivors, although survivors were more likely to receive a broad-spectrum carbapenem as empirical therapy (33% vs. 17%; P = .02).ICU stay, hospital length of stay, and duration of mechanical ventilation were also similar.In a multivariate analysis that was adjusted for potential confounders, the independent predictors of mortality were bacteremia (odds ratio, 14.1; P less than .001), immunosuppression (OR, 2.76; P = .04), and higher severity of illness by APACHE II score (OR, 1.1; P = .002). The use of the carbapenem antibiotic imipenem as directed therapy was protective (OR, 0.29; P = .012).“A carbapenem should be considered for [empirical] therapy in ICU patients at risk for Acinetobacter infection,” Dr. Murphy said.Invited discussant Dr. Nicholas Namias, chief of trauma and professor of surgery at the University of Miami Health System, observed that the 35% mortality rate was disturbingly high, but not unexpected. He asked whether the use of carbapenems was forced, in a sense, by the susceptibility pattern of the isolate, and whether patients might have done better if they had been given an antibiotic like colistin.Dr. Murphy agreed that the choice of carbapenem was directed by susceptibility patterns, and remarked that clinicians tend to lean toward a carbapenem because they’re more comfortable administering and dosing a carbapenem (particularly in complex cases, such as obese patients or those on renal replacement therapy) than colistin. Dr. Namias also asked how empirical therapy is selected, and how the results might look if only carbapenem-resistant patients were included in the analysis. Dr. Murphy replied that the hospital does not have a fixed rotation, but reviews its ICU-specific antibiograms on an annual basis to determine its standard empirical therapy.The investigators plan to study outcomes in carbapenem-resistant patients, said Dr. Murphy, but she pointed out that more than half of the patients in the current study were carbapenem resistant. She suggested that a carbapenem may still be beneficial in this setting because there are in vitro data showing synergy between carbapenems and other antibiotics, including colistin, tigecycline, and amikacin. Extended infusions of impinem were not used during the study period, although the hospital recently began using 4-hour infusions of doripenem (Doribax).The authors reported no relevant conflicts of interest.http://www.medconnect.me/tabid/92/ct1/c45547/Multidrug-Resistance-Not-Linked-to-Acinetobacter-Related-Deaths/Default.aspx2012-05-15PHILADELPHIA (EGMN) – Seeking to address issues of stigma surrounding bipolar disorder among patients and health care providers, a group of Canadian researchers and patient advocates commissioned a play aimed at giving a human face to someone who has succeeded at living with bipolar disorder.The result was “That’s Just Crazy Talk,��� an hour-long, one-woman performance by actor and playwright Victoria Maxwell, which premiered in performances in Vancouver and Toronto last July, was reprised several more times last year and this year, and is now available on DVD.The show’s development also was part of a research project that measured the impact that seeing a performance had on stigmatized feelings among people with bipolar disorder, the health care providers who deal with bipolar patients, and people with relatives or friends with bipolar disorder.Survey results showed that seeing the show reduced stigma, especially among health care professionals, Dr. Sagar V. Parikh said at the annual meeting of the American Psychiatric Association.The researchers surveyed 84 health care providers who deal with bipolar patients, both before and after the providers saw a performance. The providers’ average scores, as measured on a standard inventory known as the Day’s Mental Illness Stigma Scale (J. Applied Social Psych. 2007;37:2191-219), fell significantly in several categories, including treatability, relationship disturbance, and hygiene. The magnitude of the average effect size in these domains was comparable to the effect of “8 weeks of treatment with a mildly or moderately effective intervention, such as an antidepressant, or psychotherapy,” said Dr. Parikh, a professor of psychiatry at the University of Toronto. The responses of patients with bipolar disorder and those of their family members or friends were not as robust, but their stigma levels also seemed to be reduced when they saw the play.“People said that the play made them think again about decisions they had made about treatment, how to handle treatment at work or in relationships, and how to deal with stigmatizing comments,” he said in an interview. “We think we have an intervention that works.”“That’s Just Crazy Talk” was commissioned by Dr. Parikh and his associates using funds provided by the Canadian Institutes of Health Research, and with the participation of the Collaborative Research Team to Study Bipolar Disorder, and the Canadian Network for Mood and Anxiety Treatments. The project grew out of a desire to address the stigmas surrounding bipolar disorder, and a hunch that this could be done through a patient’s story told in a comedic and dramatic way. Victoria Maxwell’s prior work served as a catalyst for the concept. Ms. Maxwell is a bipolar disorder patient who had, for several years, incorporated stories about her illness and dealing with it into her performances.“We knew of her and her work, which made us think of this project,” Dr. Parikh said. Plus, “we had the idea that a personal story could have an impact. Someone’s individual story is often very compelling. We have seen a number of shows and movies where mental illness is portrayed in various ways. “We were struck that something via theater might be a powerful way to tell this story, and we had the happy circumstance of knowing of Victoria Maxwell. We approached her about creating a play centered on her struggles. For artistic reasons, we deliberately did not give her a list of things to say, but after her play was written we compared it with the key issues. We were prepared to say that some things might need strengthening, but that wasn’t necessary. She dealt with relationships, job discrimination, treatment, [and] adverse effects, and she models how a patient can negotiate a treatment plan that works. She talks about how she deals with life.” A discussion period between the audience and Ms. Maxwell has followed each performance.After the initial performances and Dr. Parikh’s assessments last summer, Ms. Maxwell performed her show several more times last year, and this year in Toronto and Vancouver, with additional performances scheduled for later this year and in other sites such as Ottawa and Boston. Also, in April the Collaborative Research Team to Study Bipolar Disorder began making available a DVD of the performance; the first public screening of the DVD occurred in Toronto in early May. The DVD comes with an associated discussion guide, and a future edition of the DVD will include a separate video of a postperformance discussion session.Dr. Parikh said he had no disclosures. http://www.medconnect.me/tabid/92/ct1/c45546/New-Play-About-Bipolar-Disorder-Reduces-Stigma/Default.aspx2012-05-15SAN DIEGO (EGMN)–Gynecologic surgery patients at the highest risk for postoperative complications who wore an abdominopelvic compression binder for 24 hours after surgery had significantly improved ambulation compared with those who did not wear the binder, results from a randomized trial showed.“The goals of postoperative pain management include early return of normal functions and minimal impact on ambulation,” Dr. James Brian Szender said at the annual meeting of the American College of Obstetricians and Gynecologists. “Strategies that decrease morphine use, while at the same time increasing ambulation, have the potential to decrease postoperative pneumonia, prevent thromboembolic events, and lessen postoperative ileus.”Dr. Szender, a third-year resident in the department of obstetrics and gynecology at the University of Texas, and his associates at the Brooke Army Medical Center, both in San Antonio, enrolled 75 patients in a randomized trial to determine the impact of a neoprene abdominopelvic binder on postoperative morphine use, pain, and ambulation in the first 24 hours after abdominal gynecologic surgery. The binder is made by GemTech Medical and is known as the Mott compression garment. Patients were excluded from the study if they received an epidural injection, ketorolac, or oral analgesia, or if they were allergic to morphine.The binder, which varies in size and retails for about $125, was placed on patients in the OR and remained in place until 24 hours after surgery. It is believed to reduce shear forces at the surgical incision, thereby causing less discomfort when the patient sits, stands, or walks. Patients received a standardized morphine regimen for the first 24 hours; study variables (including age, weight, incision type, total morphine use, postoperative pain score, and total number of ambulatory events) were collected after 24 hours.Of the 75 patients, 36 received binders and 39 did not. The mean age of the study participants was 45 years and their mean weight was 78 kg. Spearman rank correlation identified a group of patients at high risk for decreased ambulation: those with vertical skin incisions, those older than age 50, and those with gynecologic cancer.Dr. Szender reported that compared with nonuse of the compression binder, use of the binder increased the number of ambulatory events in the first 24 hours after surgery by 200% in patients with vertical skin incisions, by 150% in those older than age 50, and by 74% in those who had undergone surgery for gynecologic cancer. The researchers observed no statistically significant differences between the two groups in the amount of morphine used or in pain scores. However, “when patient variables were stratified by age, older patients used less morphine, had lower pain, got up earlier, and walked more when they had the binder on,” Dr. Szender said.He added that the binders “were liked [and] well tolerated, and patient compliance was 100%.”GemTech Medical provided the binders used in the study. Dr. Szender said that he had no relevant financial conflicts to disclose. http://www.medconnect.me/tabid/92/ct1/c45545/Binder-Helps-Subset-of-Gynecologic-Surgery-Patients/Default.aspx2012-05-15GLASGOW, SCOTLAND (EGMN) – Five-year mortality following the diagnosis of systemic rheumatoid vasculitis hovers around 60%, according to an analysis of 34 cases identified in a British-based patient registry.Although the annual incidence of SRV has reportedly been decreasing since the 1990s, these data suggest it remains a problem despite the introduction of modern immunosuppressive therapies and the use of earlier and more aggressive treatment for rheumatoid arthritis, Dr. Eleana Ntatsaki, a rheumatology specialist trainee at Norfolk and Norwich (England) University Hospital, said at the annual meeting of the British Society for Rheumatology.The Norfolk Vasculitis Register (NORVASC) is a prospective patient registry established in 1988 to log cases of vasculitis that occur in the county of Norfolk, England. This is a region particularly well suited to epidemiological study, as it is an isolated geographical area with a stable and well-defined population. This is also one of the reasons the Norfolk Arthritis Register (NOAR) is situated in this part of the country.Between Jan. 1, 2001, and Dec. 31, 2010, a total of 34 cases were reviewed in detail, with 18 patients (10 men) confirmed as having SRV according to previously published criteria (Am. J. Med. 1984;76:377-84), chart review, and independent physician assessment.The median age of confirmed cases at diagnosis was 72 years and the average disease duration before SRV diagnosis was nearly 16 years. All patients were rheumatoid factor positive, 13 had documented erosive disease, and three had rheumatoid nodules.All patients had been treated with steroids, a median of two prior DMARDs had been used (methotrexate in 65% of patients), and two patients had received biologic agents. SRV had been treated with intravenous cyclophosphamide (median six cycles) in all but one patient.The average annual incidence of SRV was calculated to be 3.9 per million (95% confidence interval [CI], 2.3-6.2). This was substantially lower than the 9.1 per million (95% CI, 6.8-12.0) seen in a reference population of 47 patients who developed the complication between 1998 and 2000.The average annual incidence rates in 2001-2010 were 4.5 (95% CI, 2.2-8.3) for men and 3.4 (95% CI, 1.4-6.6) for women. In 1998-2000, the rates were 8.9 (95% CI, 5.7-13.1) for men and 8.7 (95% CI, 5.6-12.8) for women.No statistically significant differences were found in the number of patients experiencing systemic, cutaneous, neurologic, pulmonary, renal, ophthalmic, or gastrointestinal manifestations between the two time periods.Mortality rates at 1 year were also similar between the cohorts, at 12% for 2001-2010 and 14% for 1998-2000. Five-year mortality rates were 60% and 51%, respectively.“Modern immunosuppression therapy seems to be associated with a decrease in the incidence” of systemic rheumatoid vasculitis, said Dr. Ntatsaki, “but has had no significant influence on clinical features, or outcome.”Whether the decrease in incidence can truly be attributed to methotrexate or improvements in RA treatment in general is questionable, suggested Dr. Deborah Symmons, professor of rheumatology and musculoskeletal epidemiology at the University of Manchester (England).This decline in the incidence of rheumatoid vasculitis is not necessarily because rheumatoid arthritis treatments have improved, she said. “Perhaps it is just the natural history of rheumatoid arthritis that vasculitis is becoming rare. Clearly when people do get it they do just as badly as they ever did, and perhaps all this about methotrexate is completely coincidental.”Dr. Ntatsaki reported having no financial disclosures.http://www.medconnect.me/tabid/92/ct1/c45544/Rheumatoid-Vasculitis-5-Year-Mortality-Is-60-/Default.aspx2012-05-15NEW ORLEANS (EGMN) – The total defined daily dose of antiepileptic drugs was the best predictor of medication side effects in a clinical prediction rule developed from a single-center, cross-sectional study of 801 patients with epilepsy.The finding stands in contrast to a previous study that found overall antiepileptic drug (AED) burden, also calculated by defined daily dose (DDD), was not a significant predictor of the risk of side effects (Epilepsia 2010;51:797-804). But the lead author of the current study, Jonathan Dykeman, and his associates used recursive partitioning to develop a clinical decision model that classifies patients into subgroups based on their risk of side effects, whereas the earlier report used standard multivariate linear progression to model patients’ scores on the Adverse Event Profile questionnaire. Disentangling the number of AEDs a person used from the overall AED burden on standard linear regression is not easy because the two are highly correlated, he said.The investigators aim to help guide therapy and clinical decision making with their clinical prediction rule. “To our knowledge, there isn’t a clinical prediction rule that’s used because a lot of the focus is on reduction of seizures,” said Mr. Dykeman, an MD/PhD student in the department of clinical neurosciences at the University of Calgary (Alta.) at the annual meeting of the American Academy of Neurology.Drug burden was high in the group of 801 patients; they took 17 different AEDs, and there were 132 possible combinations of drugs. Instead of modeling that complex scenario, Mr. Dykeman and his colleagues converted AED burden into the World Health Organization’s definition of DDD, which is the average total that a person would take in 1 day for the drug’s main indication. The investigators also included a number of other characteristics that broadly fit into the categories of AED type, sociodemographic factors, and clinical factors. Patients reported side effects during clinical interviews.The recursive partitioning method hierarchically organized the risk factors associated with side effects from strongest to weakest. Overall, 18% of the cohort experienced side effects. A DDD of greater than 3.5 was the best predictor of side effects. Of 46 patients with a DDD greater than 3.5, 33% reported side effects, compared with 17% of 755 patients with a lower DDD.A history of psychiatric treatment with medication or counseling also carried about a threefold higher risk for side effects than did the absence of such history. Among patients with the higher DDD, side effects occurred in 8 (57%) of 14 patients with a history of psychiatric treatment, compared with 22% of low DDD patients without a history of psychiatric treatment.“We have a side study going that’s going to try to tease out whether that’s an interaction with the psychiatric drugs or the fact that they have a psychiatric illness,” Mr. Dykeman said in an interview.Also, side effects reportedly occurred significantly less often among patients on a low DDD with a history of a learning disability (9% of 111) than in patients without such history (18% of 644). “We highly suspect this is related more to the reporting of side effects than actually the occurrence of side effects,” said Mr. Dykeman. It might have been more difficult to convey that the patients were having side effects because of their learning disorders as opposed to not actually having them, he said.The group of patients without learning disabilities could be further partitioned for side-effect risk based on whether they used topiramate (35% of 37) or not (17% of 607). Age was used to further refine the risk for side effects among patients who did not take topiramate. Patients aged 45 years or younger (6 of 27, or 22%) had a lower risk for side effects, compared with patients older than 45 years (7 of 10, or 70%).Mr. Dykeman said the conclusions that can be drawn from the study are limited by the lack of ascertainment of self-reported side effects, the cross-sectional nature of the data, and the small sizes of subgroups used in comparisons. Next, the researchers plan to validate their ascertainment of side effects against the Adverse Event Profile questionnaire and conduct the same analysis in a larger, external set of patients at another tertiary referral center before testing it in the general epilepsy population.None of the authors had relevant disclosures. http://www.medconnect.me/tabid/92/ct1/c45543/Prediction-Rule-Targets-Side-Effects-of-Antiepileptic-Drugs/Default.aspx2012-05-15GLASGOW (EGMN) – Urine analysis might help to predict if patients with rheumatoid arthritis are likely to respond to biologic treatments, the results of a small metabolomics study suggest.Pretreatment levels of histamine, glutamine, xanthurenic acid, and ethanolamine were consistently correlated to response to anti–tumor necrosis factor–alpha (anti-TNF-alpha) therapy at 12 weeks in the 36-patient evaluation.Further research is needed, of course, before any practical application of the research can be confirmed, but the finding does raise the possibly that a simple urine-based dipstick test could one day be available in the physician’s office.“TNF has huge effects on metabolism,” said Dr. Sabrina Kapoor at the annual meeting of the British Society for Rheumatology. These include effects on rheumatoid cachexia, angiogenesis, the acute phase response, and the recruitment of leukocytes to sites of inflammation.“Metabolomics assess many metabolites together in biological samples, such as urine or blood,” explained Dr. Kapoor, an Arthritis U.K. clinical research fellow in the Rheumatology Research Group at the University of Birmingham (England). The questions were, could such metabolites be found in the urine of patients with arthritic disease, and if they were present, did the metabolites change in response to treatment?Dr. Kapoor and her associates obtained frozen urine samples from 16 patients with RA and 20 with psoriatic arthritis (PsA). The samples had been taken during a randomized, three-center clinical study investigating patient responses to treatment with infliximab or etanercept (Rheumatology 2012;51[suppl.3]:abstract O15). Nuclear magnetic resonance (NMR) spectroscopy was used to analyze the metabolomic profiles of the urine samples that were taken before and 12 weeks after anti-TNF treatment. All patients in the study received methotrexate and had a disease duration of more than 6 months. RA patients were rheumatoid factor (RF) positive, anti–cyclic citrullinated protein (CCP) antibody positive, or both, and had a DAS28 (Disease Activity Score based on a 28-joint count) greater than 4. PsA patients were negative for RF and anti-CCP antibodies, with three or more swollen or tender joints.Only the samples from the patients with RA could be linked to treatment effect. All the patients with PsA had a good response to treatment according to EULAR criteria (defined as improvement in two or more of the following: tender joint score, swollen joint score, patient global score, and physician global score).Changes in the DAS28 were used to identify patients with RA who did (n = 7) or did not (n = 9) respond to anti-TNF therapy at 12 weeks. Good responders were those who achieved a DAS28 lower than 3.2, or an improvement in score greater than 1.2.The baseline clinical characteristics of “good responders” and “not good responders” were similar: The mean age was about 50 years, all patients were women, and all had a similar history of steroid or nonsteroidal anti-inflammatory drug use. RA patients who responded well to anti-TNF therapy had a distinct metabolomic profile compared with those who did not exhibit a good response to treatment. “There was a significant [P = .04]correlation between baseline metabolomic profiles in the urine samples and the extent of change in DAS28,” Dr. Kapoor said.Baseline metabolomic analysis of the urine in RA patients had 85.9% sensitivity and 85.7%, specificity to detect treatment response.“Urine is actually a cleaner biofluid than other biofluids, such as serum,” Dr. Kapoor noted in the discussion that followed her presentation, noting that there are fewer proteins involved that could interfere with the NMR. The samples tested were randomly obtained, but there is no evidence that any special collection protocols (such as early-morning collection or dietary restrictions) would be needed, she said. There is also no suggestion that urine would need handling in a particular way, although perhaps antibacterial treatment might be needed to keep specimens fresh. These data, of course, need to be confirmed in a much larger, independent cohort of patients before any subsequent investigation of specific collection or storage requirements.Dr. Kapoor had no financial disclosures. Merck sponsored the original study, but the company did not sponsor the metabolomics analysis reported here. http://www.medconnect.me/tabid/92/ct1/c45542/Could-a-Urine-Test-Predict-Response-to-Biologics-/Default.aspx2012-05-15GLASGOW, SCOTLAND (EGMN) – Patients who smoke are substantially less likely to respond to biologic treatment for rheumatoid arthritis than are those who have never smoked. The percentage of current smokers who responded to treatment with anti–tumor necrosis factor-alpha (anti-TNF-alpha) drugs at 6 months was just 27%, compared with 90% of never smokers and 63% of ex-smokers in a retrospective study of 359 patients.Similarly poor response to rituximab was seen in patients who were current smokers, with respective response rates for current, ex-, and never smokers of 20%, 68%, and 98%.A response was defined as a mean change in 28-joint disease activity score (DAS28) of 1.2 or greater, according to the U.K. National Clinical for Health and Clinical of Excellence (NICE) definition.This begs the controversial question of whether current smokers should be given treatment with biologic agents unless they quit smoking, said Dr. Abdul Khan, a rheumatology specialist trainee at St. George’s Hospital in London, speaking at the annual meeting of the British Society for Rheumatology. Working with Dr. David L. Scott, Dr. Khan assessed whether two simple pretreatment biomarkers – rheumatoid factor (RF) and smoking status – could help predict the response to biologic therapy for RA (Rheumatology 2012;51:iii41-2, abstract O40). They studied 209 patients treated with anti-TNFs and 150 treated with rituximab. The mean age of patients was 56 years for the anti-TNF treated patients and 61 years for the rituximab group. The mean disease duration was 8 years and 13 years, respectively, and 61% and 53% were RF positive. Primary outcome assessments included the 6-month change in DAS28 and calculation of NICE responders (DAS28 change greater than or equal to 1.2). Smoking status was assessed as being current, previous, or never. Dr. Khan observed that a more detailed evaluation of smoking history might be warranted in future investigations, such as the calculation of pack years. RF status was determined, and anticitrullinated protein autoantibody (ACPA) positivity was determined for patients receiving rituximab therapy.The mean change in DAS28 scores after 6 months’ anti-TNF therapy for never smokers was 2.6. For current smokers, the mean change was just 0.9 and for ex-smokers, it was 1.39. Corresponding figures for rituximab were 2.92, 0.63, and 1.49.RF status predicted responses to rituximab but not to anti-TNFs, with a mean change of 2.14 for RF-positive patients and 0.98 for RF-negative patients treated with rituximab after 6 months. Combining RF and ACPA status showed significant effects with regards to response to rituximab – 80% of never but only 22% of current smokers responded to treatment at 6 month if they were positive for both RF and ACPA“Smoking and rheumatoid factor/ACPA status had an additive effect on DAS28 responses,” Dr. Khan reported. Of 55 never smokers, 46 were RF/ACPA positive and nine were negative and almost all (98%) were NICE responders, with the mean fall in DAS28 score of 2.77. Strikingly different results were seen for current smokers, however, with 50% of RF-positive patients responding, compared with 3% of RF-negative patients. Previous smokers showed intermediate response rates between those of current and never smokers.Aside from the other well-documented health risks of smoking – including an increased risk of cardiovascular and pulmonary complications such as chronic obstructive pulmonary disease and lung cancer – these data suggest that patients with RA would do well to give up smoking if they currently smoke.Indeed, in a press statement, Dr. Scott, professor of rheumatology at King’s College in London, suggested that “these findings show what a dramatic effect modifying your lifestyle, such as giving up smoking, can have on treatment outcomes.”Dr. Khan noted that they also raise an ethical dilemma for clinicians. “The balance of evidence suggests that biologics are unlikely to be cost effective in RA patients who continue to smoke.“This observation creates a complex ethical dilemma which needs to be addressed.” Dr. Khan and Dr. Scott had no financial disclosures. http://www.medconnect.me/tabid/92/ct1/c45541/Smokers-Less-Likely-to-Respond-to-Biologic-Treatment-for-RA/Default.aspx2012-05-15KISSIMMEE, FLORIDA (EGMN) – Treatment with a 2,940 Er:YAG ablative fractional laser led to a clinically significant reduction of third-degree burn scars in a prospective study of 11 patients. Clinical and histologic findings from the laser study provide important clues as to the mechanism of action and appropriate treatment intervals, Dr. Jill S. Waibel reported at the meeting. Scars from fire or thermal injury are among the worst that are seen in clinical practice, and although fractional laser therapy is emerging as the preferred treatment for these injuries, a better understanding of the optimal laser wavelengths, clinical response patterns, scar tissue response, and histologic changes will improve outcomes.Patients in this study underwent three ablative treatments at 4-week intervals, and – based on blinded evaluation by independent investigators – were found to have an overall modified Manchester score of 2.3 out of 3 points, indicating moderate to excellent improvement. The scores for dyschromia, hypertrophy reduction, vascularity, and scar texture improvement were 1.7, 1.9, 2.0, and 2.0, respectively, indicating mild to moderate improvement, said Dr. Waibel, a physician in private practice in Miami.The patients, who had third-degree burn scars over an average of 80% of their body, were treated with one pass at depths ranging from 400 to 800 microns, depending on scar thickness and density. Biopsies were performed at baseline and at 3 months after the final treatment. On biopsies taken at baseline, the scars were noted to have thickened, homogenized, dystrophic collagen structures; and on biopsies taken 3 months after the final treatment, a decrease in these dystrophic fibers was seen, she said. Dr. Waibel hypothesized that scar improvement resulted from the complete replacement of ablated zones by newly synthesized collagen and that the collagen remodeling led to more normal-appearing skin. She noted that the erbium laser is “very powerful” and caused a great deal of erythema in two patients, leading her to “turn the power down” over the course of the study. Although no worsening of scars was seen, the increased vascularity in the two patients suggested that intervals longer than 4 weeks between treatments – perhaps to between 2 and 3 months - may be warranted.Although additional study is needed, the findings suggest that the 2,940 Er:YAG laser is effective for clinically improving burn scars through vaporization and by inducing an organized wound-healing response; this histologic healing response may lead to the improvement that is seen clinically, she concluded. This study was funded by Sciton. Dr. Waibel said she had no other relevant financial disclosures.http://www.medconnect.me/tabid/92/ct1/c45540/Ablative-Laser-Effectively-Remodeled-Scar-Collagen/Default.aspx2012-05-15Routine exercise stress echocardiography may not be warranted in asymptomatic patients after coronary revascularization because even though it may identify those at high risk, this does not improve patient outcomes, according to a report published online May 14 in Archives of Internal Medicine.“Given the very large population of post-PCI and post-CABG patients, careful consideration is warranted before the screening of asymptomatic patients is considered appropriate at any stage after revascularization,” said Dr. Serge C. Harb and his associates at the Cleveland Clinic Heart and Vascular Institute. Exercise stress echocardiography is useful in symptomatic patients after revascularization because it can identify the cause of the symptoms and allow further treatment to relieve them, which is usually highly effective. However, its role in asymptomatic patients is controversial because there is no evidence that identifying problems that cause no symptoms leads to better treatment, nor that treatment improves the course of the disease or patient outcomes. Dr. Harb and his colleagues assessed the usefulness of exercise stress echocardiography in asymptomatic patients in an observational cohort study of 2,105 consecutive patients referred for such testing to their institute in 2000-2010. Patients were referred “solely at the discretion of individual physicians treating the patient, usually on the basis of concerns regarding risk factor status or incomplete revascularization,” the researchers said.Such testing is considered inappropriate when it is done too soon after the revascularization – less than 2 years after percutaneous coronary intervention (PCI) and less than 5 years after coronary artery bypass graft surgery (CABG). In this study, 1,143 study subjects had undergone PCI (709 referred for “early” and 434 for appropriate stress echocardiography) and 962 had undergone CABG (527 referred for “early” and 435 for appropriate stress echocardiography).There were five major findings.First, only 13% of the entire study population showed evidence of ischemia on stress echocardiography – a low yield of positive findings for this expensive procedure, the authors noted.Second, abnormal results on stress echocardiography were associated with significantly higher risks of overall and cardiac mortality during a mean follow-up of 6 years. Mortality was 8.0% in patients who showed ischemia on stress testing, compared with only 4.1% in those who had no ischemia. However, identifying these high-risk patients made no difference in the eventual outcomes of the study cohort. Interestingly, there was no distinction in the prognostic usefulness of stress echocardiography between patients who underwent “early” and those who underwent appropriate testing. This suggests that these cutoff times, which were based on expert opinion, are somewhat arbitrary and not useful for prognosis, the investigators said (Arch. Intern. Med. 2012 May 14 [doi:10.1001/archinternmed.2012.1355]). Third, the main component of stress echocardiography that was found to be predictive was exercise capacity. This indicates that standard exercise testing rather than exercise echocardiography might be sufficient for risk evaluation. Fourth, when exercise echocardiography did identify evidence of ischemia in a minority of patients, the findings were not acted upon in most cases. Only 33% of the 262 patients with positive results underwent further revascularization. Thus, the test results led to repeat revascularization in only 87 patients out of 2,105 who were tested. That’s because the decision to do repeat revascularization was based more on the development of symptoms after testing rather than on the results of the test. Fifth, further revascularization procedures did not produce more favorable mortality outcomes. “Our results suggest that from a prognostic standpoint, a combination of clinical and exercise data is effective in identifying patients at highest risk, even though they are unlikely to benefit from repeat revascularization,” Dr. Harb and his associates said. Dr. Rita F. Redberg, editor of Archives of Internal Medicine, noted that the recommendation “Do not perform serial stress cardiac imaging or advanced noninvasive imaging as part of routine follow-up in asymptomatic patients” is one of the Top 5 recommendationsfor the American College of Cardiology in the American Board of Internal Medicine Foundation’s “Choosing Wisely” campaign. Dr. Redberg, who is professor of medicine and director of Women’s Cardiovascular Services at the University of California, San Francisco, also gave the recommendation a “Less Is More” designation, which highlights areas of health care with no known benefit and definite risks.“The results presented by Harb et al. make a compelling argument that routine periodic stress testing in asymptomatic patients following coronary revascularization is of little clinical benefit” and “probably not worth the effort,” said Dr. Mark. J. Eisenberg wrote in invited commentary accompanying Dr. Harb’s report (Arch. Intern. Med. 2012 May 14 [doi:10.1001/archinternmed.2012.1910]).However, the methodology did not address two issues that might bear on the appropriateness of stress echocardiography, said Dr. Eisenberg of the divisions of cardiology and clinical epidemiology at Jewish General Hospital and in the department of epidemiology, biostatistics, and occupational health at McGill University, both in Montreal. First, if the index revascularization was incomplete, treating physicians might be justified in ordering a stress test. This study did not report the rate of incomplete revascularization in the study subjects.Second, stress echocardiography is reasonable to perform before patients enter cardiac rehabilitation, and this study did not report how many of the tests in this cohort were done for that reason, Dr. Eisenberg said. Dr. Redberg has no relevant financial disclosures. Dr. Eisenberg reported no financial conflicts of interest. http://www.medconnect.me/tabid/92/ct1/c45536/Stress-Echo-in-Asymptomatic-Revascularized-Patients-Not-Useful/Default.aspx2012-05-14Exposure to “aged” secondhand smoke – even to a small amount and even for a brief time – impairs endothelial function, according to a report in the May 22 issue of the Journal of the American College of Cardiology.“Aged” secondhand smoke refers to smoke that lingers in an indoor area 30 minutes or more after a smoker has finished a cigarette, and it is known to be more toxic to the respiratory epithelium than is fresh secondhand smoke, said Dr. Paul F. Frey of the division of cardiology, San Francisco General Hospital, and his associates.The investigators performed a study to determine whether stale secondhand smoke also impairs endothelial function at the relatively low exposure levels that people are likely to encounter in the community setting. Endothelial dysfunction is a key mechanism in all stages of cardiovascular disease, they noted.The typical level of aged secondhand smoke found in smokers�� homes or in restaurants or other public venues that allow smoking is 100 mcg/m3 respirable suspended particles (RSPs), and the typical level found in bars or casinos in which smoke is more concentrated is 400 mcg/m3 RSPs. Dr. Frey and his colleagues assessed the response to 30 minutes of exposure at both of these levels, as well as to filtered smoke-free air, in 33 healthy nonsmoking adults aged 18-40 years. All the study participants reported no exposure to secondhand smoke during the month preceding the study. None of them had conditions that could adversely affect endothelial function such as diabetes, hypertension, respiratory disease, kidney disease, coronary artery disease, or heart failure.Endothelial function was assessed using high-resolution ultrasound to measure maximal percent flow-mediated dilation of the brachial artery before and after exposure.The study participants were exposed to smoke-free air (11 participants), 100 mcg/m3 RSPs (11 participants), or 400 mcg/m3 RSPs (11 participants) in a hooded device attached to a smoking machine. The secondhand smoke was aged for 60 minutes, then routed to the hood for a single 30-minute exposure time. The RSP level was monitored continuously. Endothelial function was impaired in a dose-dependent fashion at both levels of exposure to aged secondhand smoke. For every 100 mcg/m3 increase in RSP level, maximal percent flow-mediated dilation of the brachial artery decreased by 0.67%, Dr. Frey and his associates said (J. Am. Coll. Cardiol. 2012;59:1908-13).“Our research strengthens the evidence that secondhand smoke is detrimental to cardiovascular health even at very short exposures and low particulate concentrations,” they noted. The findings highlight the importance of policies that limit the public’s exposure to secondhand smoke, the researchers said.The study conditions may underestimate the effect of aged secondhand smoke in real-world settings, they added.The subjects remained at rest throughout their exposure to secondhand smoke and were exposed for only half an hour. In real-world experience, people are exposed for much longer durations and may be physically active during their exposure, which increases minute ventilation. Moreover, “our subjects were healthy and may have been less susceptible to decrements in endothelial function than patients with vascular disease who are at greater risk for secondhand smoke–induced acute cardiovascular events.” This study was supported in part by the Tobacco-Related Disease Research Program and the Flight Attendants Medical Research Institute Bland Lane Center of Excellence on Secondhand Smoke at the University of California, San Francisco. One coauthor reported ties to pharmaceutical companies that develop or market smoking-cessation medications and being a paid expert witness in litigation against tobacco companies. http://www.medconnect.me/tabid/92/ct1/c45534/Stale-Secondhand-Smoke-Impairs-Lung-Function/Default.aspx2012-05-14GLASGOW, SCOTLAND (EGMN) – Two subtypes of the anti-Ro autoantibody that are commonly associated with primary Sjögren’s syndrome could possibly help to predict disease severity and clinical outcomes.Interim data on the first 314 patients included in the UK Primary Sjögren’s Syndrome Registry (UKPSSR) showed that anti-Ro52 was associated with a reduced risk of articular manifestations, while anti-Ro60 was associated with cutaneous manifestations of the disease.Patients who were positive for either antibody were at increased risk for increased disease activity in the biological domains. Neither subtype was associated with myositis nor liver involvement, however, which is in contrast to the findings of other studies.“There has been quite a lot of controversy regarding whether there are associations [between anti-Ro] and particular clinical manifestations in primary Sjögren’s syndrome, or indeed in other autoimmune diseases,” said Dr. Wan-Fai Ng, the chief investigator for the UKPSSR and clinical senior lecturer at Newcastle (England) University.Dr. Ng presented the research on behalf of lead author Dr. Josephine Vila of Newcastle upon Tyne Hospitals NHS Foundation Trust, May 3, at the British Society for Rheumatology Annual Conference (Rheumatology. 2012;51:iii35, abstract O30).The UKPSSR is a U.K.-based cohort and biobank of more than 600 people diagnosed with primary Sjögren’s syndrome (Rheumatology. 2011;50:32-9). Patients have been recruited from 32 centers and have been assessed prospectively using standardized criteria and validated tools such as the Sjögren’s syndrome clinical activity index (SCAI) and Sjögren’s syndrome damage index (SSDI).Previous research has suggested anti-Ro 52 may be associated with an increase in muscle and liver problems, whereas anti-Ro60 may be associated with a lower likelihood of liver involvement. Anti-Ro52 has also been associated with Sjögren’s syndrome while anti-Ro60 has been associated with systemic lupus erythematosus. Conflicting data, however, led Dr. Vila and her team to explore the associations between the anti-Ro autoantibody subtypes and clinical manifestations in primary Sjögren’s syndrome using data from the UKPSSR. Anti-Ro52 and anti-Ro60 autoantibodies were measured prospectively in the serum of patients using a high-sensitivity assay. The EULAR Sjögren’s system disease activity index (ESSDAI) was then used to stratify patients according to 12 organ-specific domains, which mostly relate to clinical data (Ann. Rheum. Dis. 2010;69:1103-9). A high percentage of patients were positive for the anti-Ro52 (81%) and anti-Ro60 (82%) autoantibodies. Very few patients were positive for only one of these autoantibodies, with just eight (2.5%) patients positive only for anti-Ro52 and 10 (3.1%) positive only for anti-Ro60. Forty-nine (15.6%) were negative for both.The relative risk for articular manifestations with anti-Ro52 was 0.7 (95% confidence interval, 0.5-0.9; P = .039). There was an increased risk of biological manifestations (RR 4.6; 95% confidence interval, 2.3-9.2; P less than .0001). Patients with anti-Ro52 autoantibodies were also more likely than those without to have decreased tear expression with an abnormal Schirmer’s test (RR 1.6; 95% CI, 1.3-2.1; P less than .0001)and abnormal salivary flow (RR 1.13; 95% CI, 1.0-1.3; P = .042).Cutaneous manifestations were increased in patients positive for anti-Ro60 (RR 6.9; 95% CI, 1.0-49.3; P = .037). This autoantibody was also associated with a higher risk of biological manifestations (RR 6.2; 95% CI, 2.7-14.5; P less than .0001) and an abnormal Schirmer’s test (RR 1.4; 95% CI, 1.1-1.7; P less than .0001).In addition, anti-Ro52 was significantly associated with disease duration and fatigue (P = .034) and anti-Ro60 with ESSDAI.“We have planned to look at the other autoantibodies and disease association as well, but we’d rather do it in the entire cohort” Dr. Ng commented. Dr. Ng reported no financial disclosures or relevant conflicts of interest. The UKPSSR is funded by the UK Medical Research Council. http://www.medconnect.me/tabid/92/ct1/c45533/Joint-Involvement-Less-Common-in-Presence-of-Sjogren-s-Autoantibodies/Default.aspx2012-05-14BOSTON (EGMN) –A narrow, targeted approach to fluconazole prophylaxis prevents most cases of neonatal candidiasis among extremely low-birth-weight infants in centers with a low incidence of the fungal infection, a study has shown.Because of the high rates of mortality and neurodevelopmental impairment associated with candidiasis infection in at-risk infants, the Infectious Diseases Society of America recommends that centers with a high incidence of the infection consider routine fluconazole prophylaxis for extremely low-birth-weight neonates (less than 1,000 g at birth). The recommendation does not extend to low-incidence centers, however, because of the unknown risks for neurologic and cognitive disorders after fluconazole exposure in premature infants, said Dr. Karen M. Puopolo, a neonatologist at Brigham and Women’s Hospital in Boston. To assess the theoretical efficacy of fluconazole prophylaxis in extremely low-birth-weight (ELBW) infants in a low-incidence center, Dr. Puopolo and her colleagues reviewed the clinical details of blood culture–proven neonatal Candida infections that occurred in a single tertiary care neonatal intensive care unit (NICU) from January 2003 to October 2010. Using demographic data and antibiotic exposure information gleaned from medical and administrative records of nearly 1,400 ELBW infants, “we developed four different possible criteria for fluconazole prophylaxis, including fluconazole prophylaxis for all babies born with a birth weight less than 1,000 g, all babies born with a birth weight less than 1,000 g who also received 7 or more days of antibiotics, all babies born with a birth weight less than 750 g, and all babies born with a birth weight less than 750 g who also received 7 or more days of antibiotics,” she explained at the annual meeting of the Pediatric Academic Societies.For the number needed to treat (NNT) calculations, the investigators assumed that fluconazole prophylaxis would be 100% effective, and for the antibiotic exposure calculation, which was based on a review of antibiotic use in the NICU, they assumed that 50% of the infants with a birth weight less than 1,000 g and 80% with a birth weight less than 750 g would be treated with antibiotics for 7 or more days, Dr. Puopolo said.During the period of study, 1,381 ELBW infants were exposed to fluconazole prophylaxis, including 878 weighing less than 1,000 g at birth, of which 293 had a minimum of 7 days of antibiotic therapy, and 393 weighing less than 750 g at birth, of which 179 had a minimum of 7 days of antibiotic therapy, Dr. Puopolo said. “Twenty cases of neonatal candidiasis were identified, with 18 [3%] occurring in ELBW infants surviving beyond 72 hours of life,” she said. The mean birth weight of the infected infants was 702 g, and the mean gestational age and age at infection were 24.5 weeks and 21.4 weeks.With respect to the number needed to treat analysis, the narrowest targeted approach – routine fluconazole prophylaxis in neonates weighing less than 750 g who had been exposed to a minimum of 7 days of antibiotic therapy – was the most efficient. In this subgroup, according to Dr. Puopolo, “we would need to treat 13 infants to prevent one fungal infection.” The NNT in the 750-g, 1000-g with 7 or more days of antibiotic exposure, and 1,000-g groups were 15, 19, and 33, respectively.If this approach were applied to the number of babies in each of the four prophylaxis categories, all 18 infections would have been targeted in the most liberal exposure group, while 567 of the babies would have been unnecessarily exposed to the antifungal drug. In the increasingly narrower exposure groups, 16, 15, and 14 of the infections would have been targeted. Although 2, 3, and 4 of the infections, respectively, would have been missed in these groups, far fewer babies would have been unnecessarily exposed to fluconazole, said Dr. Puopolo.National guidelines do not recommend fluconazole prophylaxis in centers with a lower-than-average incidence of neonatal invasive Candida infections in the NICU, but “our findings suggest that individual NICUs should consider different approaches to fluconazole prophylaxis based on their incidence of candidiasis,” Dr. Puopolo said. “A narrow targeted approach can prevent most cases of neonatal candidiasis with the lowest number needed to treat.”Dr. Puopolo said she had no relevant financial disclosures. http://www.medconnect.me/tabid/92/ct1/c45532/Consider-Narrow-Fluconazole-Strategy-if-Candida-Incidence-Is-Low/Default.aspx2012-05-14BOSTON (EGMN) – A subcutaneous implantable cardioverter defibrillator that does not require a transvenous lead appears to be safe and effective for the treatment of ventricular tachyarrhythmias, according to a prospective, nonrandomized multicenter study. In the trial, the device (S-ICD system, Cameron Health) met its primary effectiveness end point of successful ventricular fibrillation – defined as two consecutive successful conversions out of a possible four attempts in the same shock polarity – in all of 304 evaluable patients, Dr. Martin C. Burke, director of the heart rhythm center at the University of Chicago, reported at the annual meeting of the Heart Rhythm Society.The rates of major complications related to device implantation were 4.4% at 30 days and 7.9% at 180 days.“This is not a niche device. We actually implanted it in anybody who had an indication for ICD implantation that met the guidelines indications overall,” he said.Unlike ICDs with transvenous leads, however, the subcutaneous device cannot provide pacing, Dr. Burke noted.Dr. Hugh Calkins, who was not involved in the study, said in an interview that “the data look really terrific. What’s striking is that when this company started, [ICD] lead failures and lead problems weren’t paid much attention, and now this device is coming along just at a time when everyone is being reminded the implanted lead is the weak link of an implantable device of any type.”The device, if approved in the United States, would most benefit younger patients who do not need antitachycardial pacing, such as those with long QT or Brugada syndromes, or with hypertrophic cardiomyopathy, said Dr. Calkins, professor of cardiology at the Johns Hopkins Heart and Vascular Institute in Baltimore and vice president of the Heart Rhythm Society.The device involves a pulse generator implanted into the left lateral, middle axillary line with a lead tunneled across to a subxiphoid incision, then carried along the left parasternum to the sternal angle (angle of Louis) at the second intercostal space. The lead has two electrodes: one that sits at the angle, and the other down by the xiphoid process, with a coil between the electrodes where the shock vector is continued across to the casing of the generator, or vice versa.The investigators enrolled 330 patients with any standard indication for an ICD who did not require pacing. The patients came from 33 sites in the United States, New Zealand, the Netherlands, and the United Kingdom. Common comorbidities in the group included heart failure in 61%, hypertension in 58%, myocardial infarction in 41%, and diabetes in 28%. Nearly one-third of patients (29%) had undergone percutaneous revascularization, 15% had a coronary artery bypass graft, and 13% had previously had a transvenous ICD.Among the 321 patients in whom the implantation was attempted, the device was indicated for primary prevention in 79% and secondary prevention in 21%, similar to the proportion in the National Cardiovascular Data Registry, Dr. Burke said.In all but 5% of the implantations, the device was inserted using only anatomical landmarks, with no medical imaging required.Of the 321 patients, acute induction testing was not performed in 1, and was not evaluable in 16 patients, because they did not complete four required shock episodes, leaving 304 patients for the effectiveness analysis. The device successfully converted in 100% of the 304 patients. In a sensitivity analysis including 11 additional patients with incomplete testing and one or more failed shocks, the conversion rate was 96.5%.In a “worst-case” sensitivity analysis, including all nonevaluable patients, the successful conversion rate was 94.7%, above the prespecified lower boundary of a two-sided 95% confidence interval of more than 88%, Dr. Burke said.There were 109 spontaneous episodes in 16 patients, with 1 patient experiencing a ventricular fibrillation storm of 81 episodes. All the episodes converted either spontaneously after the first shock, or with 80 J of energy.The device algorithm prevents delivery of therapy for ventricular tachycardia/ventricular fibrillation rhythms that are likely to spontaneously terminate. Therapy was avoided in 63% if patients with VT/VF met criteria to charge the device without any reports of syncope, Dr. Burke said.The safety analysis showed that the rate of freedom from type I complications (device-related complications requiring invasive interaction) was 99% at 180 days, above the performance goal of 79%. The rate of freedom from all device-, labeling-, and procedure-related complications at 180 days was 92%.There were 18 suspected or confirmed infections, 14 of which were superficial or incisional infections successfully managed with antibiotics in 13 and sternal wound revision in 1, and 4 cases in which explantation of the device was required.Inappropriate shocks occurred in 38 patients, 15 with supraventricular tachycardia in the shock-only zone, and 24 patients from oversensing (1 patient had multiple events). No patient had a shock caused by a discrimination error in the conditional shock zone.Inappropriate shocks were reduced with dual-zone programming, Dr. Burke noted. The device is currently approved for marketing in Europe (CE Marking) but has not received the U.S. Food and Drug Administration’s approval.The study was funded by Cameron Health, maker of the device. Dr. Burke and his colleagues have received consulting fees, honoraria, and/or research grants from the company. Dr. Calkins reported having no relevant financial disclosures. http://www.medconnect.me/tabid/92/ct1/c45531/Subcutaneous-ICD-Passes-Efficacy-Safety-Muster/Default.aspx2012-05-14NEW ORLEANS (EGMN) – Higher vitamin D levels are associated with slightly less disability and greater preservation of gray matter in patients with multiple sclerosis, according to a 5-year observational study. The researchers assessed 25-hydroxyvitamin D levels, clinical disability, and MRI brain volumes annually in 469 patients with relapsing-remitting multiple sclerosis (MS) or clinically isolated syndrome, all members of a longitudinal MS cohort study at the University of California, San Francisco. They found that for every 10-ng/mL increase in 25-hydroxyvitamin D levels, subsequent EDSS (Expanded Disability Status Scale) scores were 0.05 points lower (95% confidence interval –0.091 to –0.003; P = .037), and subsequent normalized gray matter volume was 7 cc higher (95% CI 2.4, 11.5; P = .003). The results were adjusted for age, sex, ethnicity, smoking status, body mass index, and use of MS treatments. Based on the results and a growing body of literature suggesting a role for vitamin D in MS, lead investigator Dr. Ellen Mowry, an assistant professor of neuroimmunology at Johns Hopkins University, Baltimore, often supplements her patients to a vitamin D level of 40-60 ng/mL, which usually takes 2,000-4,000 international units a day.“The preponderance of the observational evidence is in favor of supplementing, and I think those levels are the most strongly supported by the data. Above 60 ng/mL, there are very few data to say whether or not the effect remains the same,” she said at the annual meeting of the American Academy of Neurology.Dr. Mowry said she is careful to tell her MS patients that although observational studies suggest vitamin D is safe and helpful, ongoing randomized trials may prove otherwise. The average age of patients in her study was 42 years; their median disease duration was 5 years, and about two-thirds were women. Their baseline vitamin D levels were low at around 28 ng/mL.Mean EDSS scores were about 1.5 at the start of the study, and about 2 at its end. Mean normalized gray matter volumes were 985 cc at baseline and 964 cc at the end of 4 years. Only 9% of the subjects took vitamin D supplements at the start of the study, but almost half (43%) took them at its end. Trends were favorable for an association between vitamin D levels and preservation of brain parenchymal volume, but the results were not statistically significant. The results are in line with a 2006 study that found an inverse association between vitamin D levels and the risk for developing MS (JAMA 2006;296:2832-8).Previously, Dr. Mowry and other researchers have demonstrated that vitamin D levels are inversely associated with MS relapse risk in both children and adults (Ann. Neurol. 2010;67:618-24; Ann. Neurol. 2010;68:193-203).Dr. Mowry is the principal investigator in a randomized treatment trial that will assess the impact of high- and low-dose vitamin D supplementation on attack rates, numbers of new lesions, and changes in brain volume in relapsing-remitting MS. The study was funded by a grant from the U.S. National Institutes of Health and by GlaxoSmithKline and Biogen Idec. Dr. Mowry reported receiving research support from Teva Pharmaceuticals. http://www.medconnect.me/tabid/92/ct1/c45530/Vitamin-D-Levels-Correspond-to-Disability-in-MS/Default.aspx2012-05-14BALTIMORE (EGMN)–Gastrointestinal complication rates from laparoscopic sacrocolpopexy are low, although a significant portion of these complications require readmissions and reoperations, based on the results of a retrospective analysis of 390 patients.Functional GI complications occurred in 1.8% of patients, and bowel injury occurred in 1.3% of patients. Of the seven patients with functional GI complications, four were related to the ileus/small-bowel obstruction and three had nausea and vomiting. Of the five bowel injuries, three were small-bowel injuries and two were rectal injuries, Dr. William B. Warner reported at the annual meeting of the Society of Gynecologic Surgeons.The researchers conducted a retrospective cohort study of patients at Inova Fairfax Hospital in Falls Church, Virginia, who underwent a laparoscopic sacrocolpopexy between January 2006 and August 2010. They collected demographic information, operative details, and data on intraoperative and postoperative complications.The study included 390 patients who had a mean age of 59 years, a mean body mass index of 27, and a median follow-up of 6 months. The mean hospital stay was 1.7 days, with 93% leaving on postoperative days 1 (44%) or 2 (49%). Almost three-quarters (72%) of patients had a concurrent hysterectomy.The researchers divided GI complications into two groups: functional complications (nausea/emesis, ileus and small-bowel obstruction) and bowel injury (injury to either the small bowel or rectum). A complication was considered to be functional if it involved prolonged admission (greater than 48 hours), readmission, or reoperation.There were seven functional GI complications, four of which involved ileus/small-bowel obstruction (four readmissions and one reoperation), and three cases of nausea and vomiting (two that required prolonged stay and one that required readmission). There were also five cases of bowel injury (1.3%), three of which involved the small bowel (one that was recognized and repaired intraoperatively, and two that were unrecognized, resulting in reoperation and lengthy readmission), and two rectal injuries (one that was repaired intraoperatively and one rectovaginal fistula).“We attempted to find risk factors for the most common complications,” said Dr. Warner, who is an urogynecology fellow at the Walter ReedNational Military Medical Center in Bethesda, Maryland.They found that all patients with functional GI complications had prior abdominal surgery. “This association with prior abdominal surgery was statistically significant. Interestingly, bowel injury was not associated with prior abdominal surgery,” he said at the meeting, which was jointly sponsored by the American College of Surgeons. Neither functional GI complications nor bowel injury was associated with age, body mass index, estimated blood loss, or operating room time. Most patients used oral sodium for bowel preparation. Only polypropylene mesh was used, and the peritoneum was closed over the mesh in almost all cases. Patients were given a clear liquid diet immediately after surgery and were started on regular food the following morning. The aim was to discharge patients on the first postoperative day.The authors reported that they have no relevant financial disclosures. http://www.medconnect.me/tabid/92/ct1/c45529/Laparoscopic-Sacrocolpopexy-Results-in-Few-GI-Complications/Default.aspx2012-05-14MIAMI BEACH (EGMN) – Certain clinical factors – and a scoring system that incorporates them – could help physicians in the differential diagnosis of adnexal torsion when girls present with acute abdominal pain, according to a small retrospective study. Researchers compared 45 pediatric patients who had adnexal torsion confirmed at the time of surgery vs. another 49 without this problem to determine factors associated with higher risk. Abdominal tenderness, type of pain, pain radiation, ovary size (as well presence of a mass, and its size and palpability) were found to be potential predictors. Ultimately, however, the following three combined factors emerged as significantly associated with adnexal torsion: • Presence of intermittent pain.• Absence of radiating pain.• An adnexal mass larger than 4 cm. “There was a high level of distinction as to who had ovarian torsion and who did not,” Dr. Cynthia Abraham said. “If they have these three factors, they should go straight to the OR.”In statistical terms, an area under the curve of 0.8601 on a receiver operating curve for these three factors “suggests an excellent discrimination between adnexal torsion and other causes of abdominal pain.” “This study thus demonstrates that key clinical and imaging parameters can be combined into a model that can aid in the early diagnosis of adnexal torsion,” Dr. Abraham said at a poster during the annual meeting of the North American Society for Pediatric and Adolescent Gynecology. Girls included in the study were aged 2-18 years.Even though the condition occurs in only 3% of patients with abdominal pain, adnexal torsion can be life threatening, and the differential diagnosis from other etiologies (for example, appendicitis or gastritis) is important. “The diagnosis is extremely critical and may lead to ovarian salvage,” she added. If the diagnosis is missed or delayed, tissue necrosis and a diminished future fertility could ensue.A weighted scoring system based on these factors would be helpful because “very often gynecologists are called to evaluate many patients who do not have ovarian torsion,” said Dr. Abraham, a fourth year resident at the Steven and Alexandra Cohen Children’s Medical Center of New York, New Hyde Park“Other studies have looked at physical examination and history,” Dr. Abraham said. “We looked at a score for ovarian torsion.” The scoring system is still in development. “We have not used it yet [in practice]. That is the next step.” Dr. Abraham said she had no relevant financial disclosures.http://www.medconnect.me/tabid/92/ct1/c45528/Three-Factors-Found-to-Predict-Adnexal-Torsion/Default.aspx2012-05-14People with schizophrenia are more likely to report having had a wide range of unhappy childhood experiences than are healthy, age-matched controls, a group of Australian researchers has found.Childhood adversity has been associated with higher risk for numerous adult psychiatric disorders. Childhood physical abuse, sexual abuse, neglect, and other types of abuse have been shown in a recent meta-analysis to be associated with an increase in the risk of psychosis (Schizophr. Bull. 2012 March 29 [doi:10.1093/schbul/sbs050]). This new study adds to the catalog of childhood hardships seen as bearing on risk for schizophrenia (J. Psychiatr. Res 2012;46:600-7).Ph.D. candidate Kathryn L. McCabe and her colleagues used data from 675 adults (aged 18-65 years), all of whom previously had been recruited as part of a national schizophrenia study cohort, the Australian Schizophrenia Research Bank. Of the subjects, 408 were diagnosed with schizophrenia (268 men, 140 women). The remaining 267 (116 men, 151 women) were healthy, age-matched controls. Subjects and controls completed extensive clinical interviews that included the use of a standardized childhood adversity questionnaire measuring 19 types of adversity, from sibling loss to the feeling that parents “did not do their best for me,” reported Ms. McCabe of the Schizophrenia Research Institute in Darlinghurst, New South Wales, and her colleagues. Schizophrenia subjects reported higher rates of abusive, neglectful, and dysfunctional parenting than did controls. After controlling for age, sex, and education, the researchers found that subjects with schizophrenia were significantly more likely to report experiencing childhood trauma than were controls (86.8% vs. 69.5%; odds ratio, 2.87; 95% confidence interval, 1.95-4.23; P less than .001), and to report suffering more of the types of 19 adversities listed in the questionnaire (mean, 5.4 vs. 2.3), wrote Ms. McCabe, who also is affiliated with the University of Newcastle (New South Wales). Humiliation by a parent, growing up in a household characterized by conflict, and witnessing the physical or sexual abuse of others all were associated with statistically significant increases in risk. Having had a parent who was “not affectionate at all” was associated with an OR of 2.89 (95% CI, 1.84-4.52; P less than .001), the researchers found, whereas verbal abuse by a parent was associated with an OR of 2.32 (95% CI, 1.53-3.51; P less than .001).Severity of positive symptoms – including auditory hallucinations, delusions, and disordered thoughts – was also seen as correlating with numbers of adversities reported. No relationship was seen between reported childhood adversities and negative symptoms of schizophrenia, which have been shown in studies to antedate the onset of psychosis, the researchers wrote, “and may therefore be likely to reflect neurodevelopmental dysfunction that is a core component of the schizophrenia syndrome and less subject to environmental influences.”The researchers noted that despite their study’s limitations – which included the fact that experiences of adversity were self-reported and subject to recall bias, and also that the cohort of schizophrenia patients was relatively high functioning – “the rate of childhood adversity reported in this sample was high, suggesting greater exposure to adverse childhood events among participants with schizophrenia in comparison with healthy controls. These findings are consistent with previous research indicating that childhood adversity is related to subsequent development of a range of mental illnesses, including schizophrenia.”The research was funded by the National Health and Medical Research Council of Australia, the Pratt Foundation, Ramsay Health Care, the Viertel Charitable Foundation, and the Schizophrenia Research Institute. None of the researchers declared conflicts of interest. http://www.medconnect.me/tabid/92/ct1/c45527/Range-of-Childhood-Trauma-Linked-to-Schizophrenia-Risk/Default.aspx2012-05-14BALTIMORE (EGMN) – Researchers identified markers in two genes involved in the production of norepinephrine that significantly linked with an increased rate of suicide attempts among patients with schizophrenia in an exploratory study of 241 patients.If the findings are confirmed in expanded clinical studies, the results could advance physicians’ ability to identify patients with schizophrenia who have an elevated risk for attempting suicide, provide important leads for developing new agents to treat patients at risk for suicide, and help better target existing treatments to suicidal patients who could most benefit from them, Dr. Vincenzo De Luca said at the annual conference of the American Association of Suicidology.Elevated noradrenergic activity is associated with aggressive behavior, which led Dr. De Luca and his associates to explore the hypothesis that a link exists between genes involved in norepinephrine metabolism and suicidal behavior in patients with schizophrenia, explained Dr. De Luca, a psychiatrist at the University of Toronto. Prior work by his group led to preliminary evidence linking a marker in a gene involved in regulating the hypothalamic-pituitary-adrenal pathway to an increased risk for suicide attempts in patients with schizophrenia (J. Psychopharmacol. 2010;24:677-82).The current study involved 241 patients who met the DSM-IV criteria for schizophrenia and were recruited from several psychiatric care facilities in the Toronto area. The patients averaged 36 years old, with an average duration of illness of 16 years; 71% were men; and 80% were white. Fifty-three of the patients (22%) had a history of at least one well-documented suicide attempt, a rate that fits with prior reports of suicide attempt rates of 20%-50% among patients with schizophrenia, he said.A series of analyses showed no demographic or clinical differences between the suicide attempters and nonattempters. However, the genetic analysis showed two very statistically significant differences in the prevalence of specific genetic polymorphisms in two different genes involved in norepinephrine production. One marker was in the gene for tyrosine hydroxylase (the enzyme that converts tyrosine to dopamine), and the second marker was in the gene for dopamine beta-hydroxylase (the enzyme that converts dopamine to norepinephrine).The tyrosine hydroxylase polymorphism linked with a 3.7-fold increased rate of suicide attempts, compared with patients without the marker. And the dopamine beta-hydroxylase polymorphism linked with a 3.5-fold increased rate of suicide attempts, compared with patients who lacked this marker.If this finding is confirmed in a larger number of patients, it might mean that these markers could constitute “a predictive test to help clinicians assess a patient’s suicide risk,” Dr. De Luca said in an interview. The findings may apply not only to patients with schizophrenia, but also to patients with bipolar disorder, a possibility that also needs assessment in future clinical studies, he said. Key elements in trying to make these genetic links are having “clean,” well-characterized, and well-documented data about patients’ clinical status; their diagnosed phenotypes; their suicide-attempt histories; and their ethnicity, as well as a large number of potential genetic markers.Dr. De Luca said he had no relevant financial disclosures. http://www.medconnect.me/tabid/92/ct1/c45526/Gene-Markers-Linked-With-Suicidality-in-Schizophrenia/Default.aspx2012-05-14BOSTON (EGMN) – A screening tool designed to identify medical and psychosocial risk factors associated with poor pregnancy outcomes also seems to predict maternal traumatic pregnancy–associated death, according to Dr. Nancy S. Hardt. The Florida Healthy Start Prenatal Risk Screen has been validated for the identification of women who are at risk for preterm delivery or for delivering a low-birth-weight infant. Even low levels of risk on the screening test, which has been offered to all pregnant women in Florida at their first prenatal visit as per state legislative statute since 1991, appear to be associated with an increased likelihood of traumatic maternal death, Dr. Hardt said at the annual meeting of the Pediatric Academic Societies. “It’s possible that services targeting the reduction of adverse infant outcomes may simultaneously lower pregnant women’s risk of traumatic death,” she said. “It doesn’t take a whole lot of practice change to address some of the factors that might be putting the moms at risk, such as dispelling the myth that pregnant women shouldn’t wear seatbelts, asking patients if they feel safe in their homes, and stressing the dangers of substance use and abuse, including prescription drug use.”Dr. Hardt and her colleagues reviewed 600,000 Healthy Start screens from 1999 to 2005, as well as linked data for the concurrent period from Florida’s Enhanced Maternal Mortality Reporting Database. Of the women who died during the period of study, 144 experienced traumatic deaths. These included accidents, homicides, suicides, and drug overdoses, she said, noting that the top four causes of maternal deaths were trauma related. Specifically, the causes of death that had the greatest maternal mortality ratios were transport accidents (13.3), homicide (5.5), accidental poisoning (3.3), and suicide (2.9). “We have to go through quite a few categories of traumatic deaths before we get to the obstetric-related deaths,” such as hypertension disorders (2.7), hemorrhage (2.2), thrombotic embolism (2.2), and infection (2.0), observed Dr. Hardt, professor of pathology and ob.gyn. at the University of Florida in Gainesville. To evaluate the predictive value of the Healthy Start screen for identifying risk of traumatic death, the investigators used the same screening threshold as that used for identifying women at risk for poor pregnancy outcomes, Dr. Hardt said. “A score of 4 or higher on the [15-item] weighted measure, which includes demographic as well as environmental and social factors, indicates a positive screen for risk of preterm or low-birth-weight delivery and triggers referral to Healthy Start services,” Dr. Hardt explained. “We hypothesized that the risk factors for these infant problems would be the same as for maternal death, and as such the screening instruments would work for identifying at-risk moms.”An analysis of the data showed that as a woman’s risk score increased, the probability of traumatic death also increased. In fact, “a woman with a risk score of 4 had nearly 12 times the risk of traumatic death compared to a women with a risk score of zero, and a woman with a risk score of 9 had 52 times the risk of traumatic death compared to one who scored zero,” Dr. Hardt said. “What we observed is that with each increase in score of 1, the relative risk of death increased 1.5 to 2 times.”What this means, in terms of a prediction tool, “is that for every 100,000 women with a score of 4, expect nearly 48 traumatic maternal deaths, and for every one with a score of 9, expect 215 traumatic deaths,” according to Dr. Hardt.Many of the specific risk determinants associated with poor pregnancy outcomes are likely the same as those that are predictive of maternal traumatic death, including mental health, substance use, domestic violence, education, and employment/family income status, Dr. Hardt said. Dr. Hardt said she had no relevant financial disclosures. http://www.medconnect.me/tabid/92/ct1/c45525/Prenatal-Screen-Predicts-Maternal-Risk-of-Traumatic-Death-/Default.aspx2012-05-14MIAMI BEACH (EGMN) –A study of more than 150,000 pregnancies indicates adolescents and their newborns run an increased risk for complications. Dr. Kathy Wilson and her colleagues at Washington Hospital Center and Georgetown University Hospital, in Washington, compared peripartum outcomes among 1,312 teens aged 15 years and younger; 19,403 teens aged 16 to 19 years; and 130,453 adults aged 20-34 years. Each had a singleton pregnancy of at least 24 weeks’ gestation between 2002 and 2008. Adolescent mothers had higher rates of complications, including anemia, preterm premature rupture of membranes (PPROM), chorioamnionitis, and eclampsia, compared with adults. Anemia affected 9.4% of the teens under age 16 years and 10.2% of the older teenagers. These rates were significantly higher than was the 8.2% rate in adults.PPROM was noted in the records of 2.1% of younger teens, 2.5% of older teens, and 1.9% of adults. Chorioamnionitis occurred in 8.8% of young adolescents, 8.0% of older adolescents, and 4.8% of adults. Rates of both complications were significantly different between adolescents and adults. Other researchers have researched risks in adolescent pregnancy, but most of these studies have been small, Dr. Wilson said at the annual meeting of the North American Society for Pediatric and Adolescent Gynecology. Clinical and demographic data for the 151,476 women in this study come from the Consortium on Safe Labor, which includes electronic medical records from 19 hospitals in the United States. The consortium is sponsored by the U.S. National Institute of Child Health and Human Development.The researchers found a nonsignificant trend for higher prevalence of eclampsia in the adolescent mothers as well – 0.25% of the younger teenagers and 0.12% of the older teenagers vs. 0.008% among adult mothers.Neonates born to adolescent mothers were more likely to be delivered preterm, to be low birth weight or very low birth weight, to have lower APGAR scores, and to have higher rates of admission to a neonatal intensive care unit.Preterm births occurred in 21.1% of the teens under age 16 years, 18.3% of teens aged 16-19 years, and 16% of adults. Low birth weight infants were born to 13.1% of the younger teen mothers, 12% of the older teen mothers, and 7.8% of adult mothers. Very low birth weight infants were born to 2.7% of the young teens, 2.5% of the older teens, and 1.7% of the adults. All differences between infants born to adolescents and adults were statistically significant. Other findings include a higher percentage of 5-minute APGAR scores below 7 for neonates of younger teen mothers, 2.8%, compared with 2.3% for older teens and 2% for adult mothers. Neonatal ICU admission rates were 14.8% for the newborns of young teens, 14% for those born to older teens, and 11.8% for those born to adults. Cesarean section rate was one factor that was significantly lower among the younger adolescent mothers. Their c-section rate was 15.9%, compared with 21.1% for the older teenagers and 24.8% for the adults. Young adolescents were more likely to have public health insurance, 70.3%, compared with 66.6% of older adolescents and 39.1% of adult mothers. Dr. Wilson had no relevant financial disclosures. http://www.medconnect.me/tabid/92/ct1/c45524/Large-Database-Links-Adolescent-Pregnancy-to-More-Adverse-Events-/Default.aspx2012-05-14DALLAS (EGMN) – Unannounced surveillance detected Acinetobacter contamination in more than one-fourth of burn/trauma intensive care unit rooms tested at a Miami hospital.Although 58% of rooms housed an Acinetobacter-positive patient, 42% had patients who were negative for the aerobic gram-negative bacillus.“That’s a worrisome number because those patients are now at risk of picking up Acinetobacter from their environment,” senior author Dr. Nicholas Namias said at the annual meeting of the Surgical Infection Society.Acinetobacter has become one of the preeminent ICU pathogens and is resistant to simple cleaning and many commonly prescribed antibiotics.New acquisitions of carbapenem-resistant Acinetobacter at the University of Miami’s Jackson Memorial Hospital, where the study was conducted, were high in early 2011 at up to 13/week, but leveled off to zero in some weeks after a bundle intervention was put in place. The bundle included grouping a positive patient cohort, active surveillance of patients using rectal swab cultures, hand hygiene education, operating room interventions, and weekly environmental cleaning feedback.The 25-bed ICU was cultured weekly and the cultures subjected to pulsed field gel electrophoresis. Ultraviolet powder, invisible to the naked eye, was also placed on surfaces throughout the ICU and checked 48 hours later with ultraviolet light to see if they were cleaned.“We even went so far as to place plates on high surfaces where nobody reaches to see if Acinetobacter could grow out of thin air,” said Dr. Namias, chief of trauma and professor of surgery at the University of Miami Health System.Of the 213 rooms cultured over 15 weeks, 57 (27%) were positive for Acinetobacter. More than 90% of samples were identified as Acinetobacter baumannii. Contaminated sites included 38 bed rails (67%), 21 intravenous pumps (37%), 6 bedside tables (11%), and 3 ventilator control panels (5%).“This actually turned out to be a major issue, because once you discover they’re dirty, it becomes a big question of who’s supposed to clean them,” he said. “Understandably, environmental staff was kind of hesitant to touch IV pumps and ventilator control panels, and the nurses are probably overtrained to be cleaning bed rails and bedside tables. So you end up having to use techs, the people who go around doing urimeters and finger-prick glucose, but you have to make sure they’re trained in proper hand hygiene.” At baseline, only slightly more than 40% of surfaces had been cleaned at 48 hours – a percentage that Dr. Namias described as alarming, but typical in surveillance studies. Once the ultraviolet “spying” began, and environmental services was told that surfaces were unclean, there was a very quick response. Within 1 week, the percentage of surfaces cleaned at 48 hours rose to nearly 100%, where it has remained. “Once they know they are being watched, you can have them do the right thing,” he said.In a separate analysis, similar results were achieved in the operating room, where the percentage of surfaces cleaned at 48 hours increased from 47% to 82% after the educational and cleaning intervention.Importantly, the number of new acquisitions of Acinetobacter decreased concomitantly from 1.40 patients/week to 0.37; and from 9.2/month during the first 6 months of 2011 to 3.3/month during the last 6 months (P = .003).Invited discussant Dr. Heather Evans, a trauma and acute care surgeon and surgical intensivist with the University of Washington in Seattle, thanked the program committee for selecting the abstract for oral discussion, citing the relevance of infection-control data to the practicing clinician and to prevention efforts. She went on to ask whether the hospital regularly uses active surveillance for Acinetobacter and contact precautions when a patient is colonized and whether the hospital would presumptively put a patient on contact precautions if they reach a certain level.Dr. Namias, who acknowledged that initially he was not a believer, said the hospital continues to use active surveillance and that everyone in the burn/trauma ICU is on contact precautions.Dr. Evans also asked whether cleaning personnel can game the system, citing a recent paper by lead study author Dr. L. Silvia Munoz-Price that identified preferential cleaning of white UV powder targets among units with high levels of experience with UV powder (Infect. Control Hosp. Epidemiol. 2012;33:92-5). Dr. Namias said it’s entirely possible that personnel are gaming the system, but noted that Acinetobacter is also airborne.Finally, an audience member remarked that the open-air design of the trauma ICU, as shown in an illustration, may be contributing to the unusually high rates of contamination. Dr. Namias agreed that the unit is due for an update and said it was designed before it was known that closed units are best.Dr. Munoz-Price, medical director of infection control at Jackson Memorial, said they are currently performing multivariable analyses to better understand the factors associated with higher environmental contamination.“The control of Acinetobacter within a hospital setting deals with the interaction of patient’s bioburden, health care worker hands/uniforms, and contaminated objects in the environment,” she said in an interview. “This cycle of contamination needs to be tackled at different levels in order to sustain good outcomes.”The authors reported no relevant conflicts of interest. http://www.medconnect.me/tabid/92/ct1/c45523/Active-Surveillance-in-ICU-Cut-Acinetobacter-Contamination/Default.aspx2012-05-14