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HIV/AIDS is a major cause of morbidity and mortality in Africa, and rates of retention in treatment are low. Some research has shown that mobile clinics are effective in connecting people in rural areas with health care. We compared HIV outcomes between HIV-positive patients who chose to access treatment from a regional hospital to those who chose care in one of four semi-mobile clinics closer to where they live. The subjects for this analysis were HIV-positive residents in West Pokot accessing care at one of four semi-mobile sites (Kabichbich, Chepareria, Kacheliba, and Sigor) or at the regional hospital in Kapenguria. We examined four outcome variables between the two groups: (1) retention in HIV treatment, (2) change in CD4 count, (3) adherence to ARVs, and (4) deaths. The patients who chose semi-mobile clinic care were less well educated, poorer, and sicker than those who chose to continue care in the regional hospital. There were no statistically significant differences between the groups in any of the four outcome measures. Although the population of patients attending semi-mobile clinics was on average poorer and sicker than those attending the hospital, their outcomes were similar. Care at the semi-mobile clinics did not result in significantly different outcomes from care in the district hospital. This program showed that semi-mobile clinics are a viable alternative to hospital care for very ill, isolated populations, but further measures must be taken to improve retention and adherence in these settings.

Background: Remission is the goal in depression, but in practice many patients only experience a partial response to treatment. We sought to determine the prevalence, management and subsequent outcomes of partial responder patients., Methods: Patients enrolled in the naturalistic Factors Influencing Depression Endpoints Research (FINDER) study with the Hospital Anxiety and Depression Scale depression subscale (HADS-D) score >10 at baseline who received only SSRI(s) between 0 and 3 months comprised the study cohort (n=1147). Patients were categorized as remitters, partial responders or non-responders at 3 months and then followed up at 6 months., Results: At 3 months, 29.4% of the study population were considered non-responders, 27.6% were partial responders, and 39.3% were remitters. Most partial responders at 3 months remained on the same SSRI for the next 3 months. Of the 247 partial responders at 3 months and remained on the same SSRI(s) between 3 and 6 months, 10.9% met criteria for non-response at 6 months, 32.4% remained partial responders, and 56.3% achieved remission. Quality of life outcomes for the partial responders were significantly worse than those in remission (p<0.05)., Limitations: FINDER was an observational study; the current analysis was conducted post-hoc. Multivariable methods were not applied and findings are primarily descriptive and exploratory., Conclusions: Partial response is common and patients in partial response have a poorer quality of life than those achieving remission. Despite this, the majority of partial responders continue to take the same SSRI. Our findings underscore the importance of continuing to strive for remission., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Purpose: This study intends to provide new insights into the incidence and care of mucositis by the epidemiological characterization of patients with hematological malignancy treated at our institution. It also aims to understand the effectiveness of several treatments used., Methods: This is a longitudinal observational single-center study-convenience sample-which includes malignant hematologic inpatients submitted to high-dose CT from February to August 2012. We registered epidemiological data, diagnosis, oral mucositis daily questionnaire (OMDQ), World Health Organization (WHO) oral toxicity scale, and supportive medications used for mucositis., Results: We evaluated 30 patients who had 73 episodes of hospitalization, having recorded the development of mucositis in 21.9 % (n = 16) episodes (22 patients with acute leukemia (AL) and 8 patients with non-Hodgkin lymphoma (NHL)). Grades 3-4 mucositis was reported in 4.1 % of the total episodes. The results of OMDQ showed some limitations in the quality of life, of patients with mucositis, related with the ability to eat and drink due to mouth pain (p < 0.001). In patients with NHL and AL, neutropenia entails an increased risk of mucositis (p < 0.001). Patients who did not initiate early prophylaxis with conservative measures developed mucositis earlier (p < 0.05)., Conclusions: The incidence of mucositis is high, being reported mainly in AL patients, with limitations in quality of life. Grade 4 neutropenia increases mucositis risk. Early prophylaxis with basic oral care may delay mucositis. Further studies are crucial to characterize mucositis epidemiology, physiopathology, and its management.

Introduction: Weight loss and physical activity achieved through the Diabetes Prevention Program (DPP) have been shown to reduce type 2 diabetes risk among individuals with prediabetes. The New York State Young Men's Christian Association (YMCA) delivered the 16-week evidence-based model at 14 YMCAs. A mixed methods process and outcomes evaluation was conducted., Methods: Most participants were referred by clinicians and were encouraged to achieve 5% to 7% weight loss. Participants were weighed weekly; additional data were gathered from participant surveys and focus groups and staff surveys and interviews., Results: Participants (N = 254) lost a mean of 9 pounds (P < .001), or 4.2% of body weight, by program completion; 40% achieved 5% or more weight loss and 25% achieved 7% or more weight loss. Ten months after baseline, 61% of participants reported 5% or more weight loss and 48% reported 7% or more weight loss. In multivariate models, weight loss was negatively associated with black race (16 weeks: adjusted odds ratio [AOR], 0.190, P = .002; 10 months: AOR, 0.244, P = .005) and positively associated with attendance (16 weeks: AOR, 18.699, P < .001; 10 months: AOR, 2.808, P = .024). Participants reported improvements in health and lifestyle changes after program completion. Factors contributing to program success included coaches who motivated participants, the group setting, curriculum, and program duration. However, sociodemographic diversity was limited., Conclusion: Outcomes demonstrate the potential for effectively implementing the DPP in community-based settings. Findings also suggest the need for replications among a broader population.

There are 31 million adults living with HIV-1 non-B subtypes globally, and about 10 million are on antiretroviral therapy (ART). Global evidence to guide clinical practice on ART response in HIV-1 non-B subtypes remains limited. We systematically searched 11 databases for the period 1996 to 2013 for evidence. Outcomes documented included time to development of AIDS and/or death, resistance mutations, opportunistic infections, and changes in CD4 cell counts and viral load. A lack of consistent reporting of all clinical end points precluded a meta-analysis. In sum, genetic diversity that precipitated differences in disease progression in ART-naïve populations was minimized in ART-experienced populations, although variability in resistance mutations persisted across non-B subtypes. To improve the quality of patient care in global settings, recording HIV genotypes at baseline and at virologic failure with targeted non-B subtype-based point-of-care resistance assays and timely phasing out of resistance-inducing ART regimens is recommended.

Although drug-eluting stents are increasingly used to treat coronary disease, restenosis remains the major limitation of these devices. We report a case of complete metal jacket using 17 stents for triple-vessel coronary disease in a 73-year-old man, for whom surgery would have been the best choice., (© The Author(s) 2013 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Objectives: Accumulating evidence supports a role for 2-dimensional fetal echocardiography in the first trimester of pregnancy for the identification of congenital heart defects. Our objective was to investigate the role of 4-dimensional (4D) sonography in the identification of congenital heart defects between 11 and 15 weeks of pregnancy., Methods: This study included 4 centers with expertise in first-trimester 4D fetal echocardiography. Fetuses with and without confirmed heart defects were evaluated between 11 and 15 weeks and their volume data sets were uploaded onto a centralized file transfer protocol server., Results: Forty-eight volume data sets from fetuses with normal (n = 17) and abnormal (n = 16) hearts were evaluated. Overall, the median (range) accuracy, sensitivity, and specificity, as well as the positive and negative likelihood ratios, for the identification of fetuses with congenital heart defects were 79% (77%-83%), 90% (70%-96%), 59% (58%-93%), 2.35 (2.05-9.80), and 0.18 (0.08-0.32), respectively., Conclusions: (1) Four-dimensional fetal echocardiography can be performed in the first and early second trimesters of pregnancy; and (2) 4D volume data sets obtained from fetuses between 11 and 15 weeks can be remotely acquired and accurately interpreted by different centers., (© 2014 by the American Institute of Ultrasound in Medicine.)

Objective: To compare left myocardial performance index (MPI) values and reproducibility using different settings and ultrasound equipment in order to standardize optimal machine settings., Methods: Left MPI was prospectively evaluated by one observer performing conventional Doppler in 62 fetuses (28-36 weeks of gestational age) using different settings (changing sweep speed, gain and wall motion filter (WMF)) and two different ultrasound devices (Siemens Antares, Siemens; Voluson 730 Expert, GE Medical Systems). Intraclass coefficients of agreement (ICCs) were calculated using Bland-Altman analysis., Results: Using baseline settings on the Siemens, mean (SD) MPI was 0.44 (0.05) with an ICC of 0.81. Decreasing the sweep speed resulted in decreasing average MPI values (0.43) and decreasing ICC (0.61). Lowering gain also influenced average MPI values (0.46) and ICC (0.76). Raising gain resulted in similar MPI values (0.45) with better ICC (0.90) compared with baseline settings. Raising wall motion filter (WMF) provided the best ICC (0.94) compared with the other settings. Changing the ultrasound equipment resulted in an ICC of 0.64. The optimal settings to achieve the highest reproducibility in measurement of MPI were sweep speed 8, gain 60 dB and WMF 281 Hz for Siemens Antares and sweep speed 5, gain -10 dB and WMF 210 Hz for Voluson 730 Expert., Conclusion: Changing ultrasound settings or equipment may affect the calculation and repeatability of measurement of MPI values. Strict standardization of methods decreases the variability of this parameter for fetal cardiac function assessment., (Copyright © 2014 ISUOG. Published by John Wiley & Sons Ltd.)

Venous stenosis and occlusion are a major cause of vascular access dysfunction and failure. The HeRO Graft bypasses occlusion and traverses stenosis with outflow directly into the central venous circulation. A randomized, multicenter study was conducted to evaluate the efficacy and safety of the HeRO Graft relative to conventional AV grafts. The design was to enroll 143 patients in a 2:1 randomization ratio between HeRO and conventional AV control groups. Data on 72 subjects (52 HeRO Graft and 20 AV graft controls) were obtained. The HeRO Graft and control cohorts were comparable in baseline characteristics. Adequacy of dialysis, bacteremia rates, and adverse events were consistent between groups. Twelve month Kaplan-Meier estimates for primary and secondary patency rates were 34.8% and 67.6% in the HeRO Graft cohort, and 30.6% and 58.4% in the control cohort. There was no statistical difference in terms of patency between groups. The rates of intervention were 2.2/year for HeRO Graft and 1.6/year for the control (p = 0.100). Median days to loss of secondary patency was 238 for HeRO Graft versus 102 for the control (p = 0.032). The HeRO Graft appears to provide similar patency, adequacy of dialysis, and bacteremia rates to those of conventional AV grafts., (© 2014 Wiley Periodicals, Inc.)

Dengue (DEN) represents the most serious arthropod-borne viral disease. DEN clinical manifestations range from mild febrile illness to life-threatening hemorrhage and vascular leakage. Early epidemiological observations reported that infants born to DEN-immune mothers were at greater risk to develop the severe forms of the disease upon infection with any serotype of dengue virus (DENV). From these observations emerged the hypothesis of antibody-dependent enhancement (ADE) of disease severity, whereby maternally acquired anti-DENV antibodies cross-react but fail to neutralize DENV particles, resulting in higher viremia that correlates with increased disease severity. Although in vitro and in vivo experimental set ups have indirectly supported the ADE hypothesis, direct experimental evidence has been missing. Furthermore, a recent epidemiological study has challenged the influence of maternal antibodies in disease outcome. Here we have developed a mouse model of ADE where DENV2 infection of young mice born to DENV1-immune mothers led to earlier death which correlated with higher viremia and increased vascular leakage compared to DENV2-infected mice born to dengue naïve mothers. In this ADE model we demonstrated the role of TNF-α in DEN-induced vascular leakage. Furthermore, upon infection with an attenuated DENV2 mutant strain, mice born to DENV1-immune mothers developed lethal disease accompanied by vascular leakage whereas infected mice born to dengue naïve mothers did no display any clinical manifestation. In vitro ELISA and ADE assays confirmed the cross-reactive and enhancing properties towards DENV2 of the serum from mice born to DENV1-immune mothers. Lastly, age-dependent susceptibility to disease enhancement was observed in mice born to DENV1-immune mothers, thus reproducing epidemiological observations. Overall, this work provides direct in vivo demonstration of the role of maternally acquired heterotypic dengue antibodies in the enhancement of dengue disease severity and offers a unique opportunity to further decipher the mechanisms involved.

Patients with cholestatic diseases can present secondary hypercholesterolemia, as a result of the accumulation of lipoprotein X (Lp-X); an abnormal LDL form, considered as the biochemical parameter more sensitive and specific for the diagnosis of cholestasis intra or extrahepatic cholestasis. The aim of this clinical communication is to illustrate this association. A 54-year-old male with severe cholestatic liver disease which in turn presents a progressive total cholesterol rise and LDL with presence of lipoprotein X. Total and LDL cholesterol were down to normal, also coinciding with the improvement of cholestatic liver disease conferring cardiovascular protection pattern., (Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.)

A population pharmacokinetic analysis was conducted to characterize the pharmacokinetics of fexofenadine in Japanese pediatric patients (6 months through 16 years) with perennial allergic rhinitis or atopic dermatitis. The dataset was composed of 515 patients (including 109 adults), for a total of 1,080 concentration-time points. The analysis was performed with NONMEM using the SAEM method. Several structural models and residual error models were evaluated. The relationship between the individual estimates and the potential covariates was then investigated: demographic and pathophysiologic characteristics were tested as potential model covariates (forward selection method). The qualification of the model was performed using visual predictive check and bootstrap. A two-compartment disposition model with first-order absorption best fitted the data. The inter-individual variability was modeled through an exponential error model for all parameters (except for ka for which no inter-individual term could be estimated), while a proportional error model was used to model the residual variability. The final model included two covariates on elimination clearance and one on the intercompartmental clearance. CL/F was related to BSA and patient's age (expressed in months) Q/F was also related to BSA. Once the model was correctly qualified, exposure parameters such as Cmax and AUCτ were computed and compared between each age sub-group and between Japanese and Caucasians patients. These comparisons did not reveal any major difference (less than 50 %) between subgroups.

Despite progresses in diagnosis and treatment, pancreatic cancer continues to have the worst prognosis of all solid malignant tumors. Recent evidences suggest that the metastasis-promoting protein S100P stimulates pancreatic tumor proliferation, survival, invasion and metastasis progression through extracellular functions. Moreover, its expression is strongly correlated with poor prognosis in patients with several types of cancer although the entire molecular mechanism responsible for the diverse biological functions is not fully understood. We showed that extracellular S100P stimulates pancreatic carcinoma BxPC3 cell line by promoting cell proliferation. We also demonstrated that S100P induces, in this cell line, the phosphorylation of IκBα and the secretion of matrix metalloproteinase 9 (MMP-9). In addition, treatment with S100P protected cells from injuries induced by the cytotoxic agent Gemcitabine. On the basis of these results, we developed function-blocking anti-S100P monoclonal antibodies (mAbs) that abolished all of its in vitro activities. Furthermore, in vivo treatment with the candidate 2H8 antibody decreased tumor growth and liver metastasis formation in a subcutaneous and orthotopic BxPC3 tumor model. We conclude here that a therapeutic strategy blocking the extracellular activity of S100P by means of specific mAbs could be an attractive therapeutic approach as a single agent or in combination with target-directed or chemotherapeutic drugs to treat pancreatic cancer.

Background: Flexible endoscopy is an integral part of surgical care. Exposure to endoscopic procedures varies greatly in surgical training. The Society of American Gastrointestinal and Endoscopic Surgeons has developed the Fundamentals of Endoscopic Surgery (FES), which serves to teach and assess the fundamental knowledge and skills required to practice flexible endoscopy of the gastrointestinal tract. This report describes the validity evidence in the development of the FES cognitive examination., Methods: Core areas in the practice of gastrointestinal endoscopy were identified through facilitated expert focus groups to establish validity evidence for the test content. Test items then were developed based on the content areas. Prospective enrollment of participants at various levels of training and experience was used for beta testing. Two FES cognitive test versions then were developed based on beta testing data. The Angoff and contrasting group methods were used to determine the passing score. Validity evidence was established through correlation of experience level with examination score., Results: A total of 220 test items were developed in accordance with the defined test blueprint and formulated into two versions of 120 questions each. The versions were administered randomly to 363 participants. The correlation between test scores and training level was high (r = 0.69), with similar results noted for contrasting groups based on endoscopic rotation and endoscopic procedural experience. Items then were selected for two test forms of 75 items each, and a passing score was established., Conclusions: The FES cognitive examination is the first test with validity evidence to assess the basic knowledge needed to perform flexible endoscopy. Combined with the hands-on skills examination, this assessment tool is a key component for FES certification.

Background and Purpose: Ureteral Stent Symptoms Questionnaire (USSQ) is an intervention-specific health-related quality-of-life (HrQoL) measure. We describe development and validation of the Spanish version., Materials and Methods: We followed established methods to develop the Spanish version of the original USSQ. After pilot testing, we conducted a formal validation study; 70 patients, undergoing placement of ureteral stents, successfully completed the Spanish USSQ as well as the EuroQoL-5D (male and female), the ICIQ male and female lower urinary tract symptoms questionnaires at weeks 1 and 4 after stent insertions, and at week 4 after their removal. In addition, 40 healthy people acted as a control group and completed the same questionnaires twice at 3-week intervals. Statistical analyses were performed to evaluate reliability, validity, and sensitivity to change of the Spanish USSQ., Results: After revision of the initial two drafts after translation, back translation, and pilot testing, a final draft was developed that underwent field testing. Psychometric analyses revealed satisfactory internal consistencies (Cronbach alpha coefficients: 0.73-0. 85) and test-retest reliability (Spearman correlation coefficient: >0.6) for the domains of urinary symptom, body pain, and general health. It demonstrated satisfactory discriminant validity (sensitivity to change, p<0.01), convergent validity (good correlations between the domains of the USSQ and existing validated questionnaires), and test-retest reliability (p<0.001). Analysis of the domains of the sexual matter (21.4%) and work performance (35.7%) were limited because of the small proportion of the study population for whom it was applicable., Conclusions: Results of our development and validation study demonstrate that the new Spanish version of the USSQ is a psychometrically valid intervention-specific measurer for use in the second most common language in the world. It is a reliable outcome measure that could be used for both clinical and research purposes.

River systems connect the terrestrial biosphere, the atmosphere and the ocean in the global carbon cycle. A recent estimate suggests that up to 3 petagrams of carbon per year could be emitted as carbon dioxide (CO2) from global inland waters, offsetting the carbon uptake by terrestrial ecosystems. It is generally assumed that inland waters emit carbon that has been previously fixed upstream by land plant photosynthesis, then transferred to soils, and subsequently transported downstream in run-off. But at the scale of entire drainage basins, the lateral carbon fluxes carried by small rivers upstream do not account for all of the CO2 emitted from inundated areas downstream. Three-quarters of the world's flooded land consists of temporary wetlands, but the contribution of these productive ecosystems to the inland water carbon budget has been largely overlooked. Here we show that wetlands pump large amounts of atmospheric CO2 into river waters in the floodplains of the central Amazon. Flooded forests and floating vegetation export large amounts of carbon to river waters and the dissolved CO2 can be transported dozens to hundreds of kilometres downstream before being emitted. We estimate that Amazonian wetlands export half of their gross primary production to river waters as dissolved CO2 and organic carbon, compared with only a few per cent of gross primary production exported in upland (not flooded) ecosystems. Moreover, we suggest that wetland carbon export is potentially large enough to account for at least the 0.21 petagrams of carbon emitted per year as CO2 from the central Amazon River and its floodplains. Global carbon budgets should explicitly address temporary or vegetated flooded areas, because these ecosystems combine high aerial primary production with large, fast carbon export, potentially supporting a substantial fraction of CO2 evasion from inland waters.

The Alzheimer's disease (AD) epidemic proceeds unabated. Estimates suggest 5.4 million Americans and 36 million people worldwide have AD. No single mechanism or pathologic mediator can account for AD progression. Currently no disease modifying therapies are available. There is a large literature documenting an association among cardiovascular risk factors (CVRFs), especially diabetes and hypoxia, with increased AD incidence. CVRFs directly impair vascular function and could mediate cerebrovascular dysfunction in AD. This is important as cerebrovascular dysfunction precedes cognitive decline and onset of neurodegenerative changes in AD and AD animal models. In this review we present evidence that thrombin may be a heretofore unexplored target for AD therapy. This idea is based on the following observations. Thrombin is elevated in the brain and cerebral microvasculature in AD, is directly neurotoxic, and causes pro-inflammatory effects in endothelial cells, microglia, and astrocytes. Diabetes- and hypoxia-induced cerebrovascular effects are mediated by thrombin. Thrombin inhibitors block the effects of hypoxia on brain endothelial cells and reduce vascular inflammation in transgenic AD mice. Based on reports that reducing cerebrovascular expression of inflammatory proteins in AD mice is associated with improved cognition, we propose thrombin inhibitors could prove useful for improving cognition in AD patients. The next generation of AD therapeutics should not focus on single target drugs but rather employ a multi-component cocktail approach. We propose thrombin inhibitors be considered as potential contributors to the dementia therapy pharmacopeia. The urgent need for disease-modifying drugs in AD demands new thinking about disease pathogenesis and exploration of novel drug targets.

Background: We conducted this study to determine whether pulse oximetry and volumetric capnography (VCap) can determine the opening and closing pressures of lungs of anesthetized morbidly obese patients., Methods: Twenty morbidly obese patients undergoing laparoscopic bariatric surgery with capnoperitoneum were studied. A lung recruitment maneuver was performed in pressure control ventilation as follows: (1) During an ascending limb, the lungs' opening pressure was detected. After increasing positive end-expiratory pressure (PEEP) from 8 to 16 cm H2O, fraction of inspired oxygen (FIO2) was decreased until pulse oximetric arterial saturation (SpO2) was <92%. Thereafter, end-inspiratory pressure was increased in steps of 2 cm H2O, from 36 to a maximum of 50 cm H2O. The opening pressure was attained when SpO2 exceeded 97%. (2) During a subsequent decreasing limb, the lungs' closing pressure was identified. PEEP was decreased from 22 to 10 cm H2O in steps of 2 cm H2O. The closing pressure was determined as the PEEP value at which respiratory compliance decreased from its maximum value. We continuously recorded lung mechanics, SpO2, and VCap., Results: The lungs' opening pressures were detected at 44 (4) cm H2O (median and interquartile range) and the closing pressure at 14 (2) cm H2O. Therefore, the level of PEEP that kept the lungs without collapse was found to be 16 (3) cm H2O. Using respiratory compliance as a reference, receiver operating characteristic analysis showed that SpO2 (area under the curve [AUC] 0.80 [SE 0.07], sensitivity 0.65, and specificity 0.94), the elimination of CO2 per breath (AUC 0.91 [SE 0.05], sensitivity 0.85, and specificity 0.98), and Bohr's dead space (AUC 0.83 [SE 0.06], sensitivity 0.70, and specificity 0.95] were relatively accurate for detecting lung collapse during the decreasing limb of a recruitment maneuver., Conclusions: Lung recruitment in morbidly obese patients could be effectively monitored by combining noninvasive pulse oximetry and VCap. SpO2, the elimination of CO2, and Bohr's dead space detected the individual's opening and closing pressures.

Purpose: To assess the safety of duloxetine with regards to bleeding-related events in patients who concomitantly did, versus did not, use nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin., Methods: Safety data from all placebo-controlled trials of duloxetine conducted between December 1993 and December 2010, and post-marketing reports from duloxetine-treated patients in the US Food and Drug Administration Adverse Event Reporting System (FAERS), were searched for bleeding-related treatment-emergent adverse events (TEAEs). The percentage of patients with bleeding-related TEAEs was summarized and compared between treatment groups in all the placebo-controlled studies. Differences between NSAID user and non-user subgroups from clinical trial data were analyzed by a logistic regression model that included therapy, NSAID use, and therapy-by-NSAID subgroup interaction. In addition, to determine if higher duloxetine doses are associated with an increased incidence of bleeding-related TEAEs, and whether the use of concomitant NSAIDs might influence the dose effect if one exists, placebo-controlled clinical trials with duloxetine fixed doses of 60 mg, 120 mg, and placebo were analyzed. Also, the incidence of bleeding-related TEAEs reported for duloxetine alone was compared with the incidence in patients treated with duloxetine and concomitant NSAIDs. Finally, the number of bleeding-related cases reported for duloxetine in the FAERS database was compared with the numbers reported for all other drugs., Results: Across duloxetine clinical trials, there was a significantly greater incidence of bleeding-related TEAEs in duloxetine- versus placebo-treated patients overall and also in those patients who did not take concomitant NSAIDS, but no significant difference was seen among those patients who did take concomitant NSAIDS. There was no significant difference in the incidence of bleeding-related TEAEs in the subset of patients treated with duloxetine 120 mg once daily versus those treated with 60 mg once daily regardless of concomitant NSAID use. The combination of duloxetine and NSAIDs was associated with a statistically significantly higher incidence of bleeding-related TEAEs compared with duloxetine alone. A similarly higher incidence of bleeding-related TEAEs was seen in patients treated with placebo and concomitant NSAIDs compared with placebo alone. Bleeding-related TEAEs reported in the FAERS database were disproportionally more frequent for duloxetine taken with NSAIDs compared with the full FAERS background, but there was no difference in the reporting of bleeding-related TEAEs when the cases reported for duloxetine taken with NSAIDs were compared against the cases reported for NSAIDs alone., Conclusion: Concomitant use of NSAIDs was associated with a higher incidence of bleeding-related TEAEs in clinical trials regardless of whether patients were taking duloxetine or placebo; bleeding-related TEAEs did not appear to increase along with duloxetine dose regardless of NSAID use. In spontaneously reported post-marketing data, the combination of duloxetine and NSAID use was not associated with an increased reporting of bleeding-related events when compared to NSAID use alone.

S100A4, a member of the S100 calcium-binding protein family secreted by tumor and stromal cells, supports tumorigenesis by stimulating angiogenesis. We demonstrated that S100A4 synergizes with vascular endothelial growth factor (VEGF), via the RAGE receptor, in promoting endothelial cell migration by increasing KDR expression and MMP-9 activity. In vivo overexpression of S100A4 led to a significant increase in tumor growth and vascularization in a human melanoma xenograft M21 model. Conversely, when silencing S100A4 by shRNA technology, a dramatic decrease in tumor development of the pancreatic MiaPACA-2 cell line was observed. Based on these results we developed 5C3, a neutralizing monoclonal antibody against S100A4. This antibody abolished endothelial cell migration, tumor growth and angiogenesis in immunodeficient mouse xenograft models of MiaPACA-2 and M21-S100A4 cells. It is concluded that extracellular S100A4 inhibition is an attractive approach for the treatment of human cancer.

A collaborative study in 10 laboratories was performed to validate an ELISA method developed for the quantitative determination of peanut protein in foods. The ELISA kit used for this study is based on rabbit polyclonal antibody. This kit does not produce any false-positive results or cross-reactivity with a broad range of peanut-free food matrixes. All participants obtained the peanut ELISA kit with standard operational procedures, a list of samples, the samples, and a protocol for recording test results. The study included 15 food samples. Three food matrix samples of zero peanut content showed peanut protein content lower than the first standard (0.10 mg/kg). Three samples with peanut declared as an ingredient revealed peanut protein content outside the calibration curve (absorbance was above the highest standard) in all laboratories, and three samples had the peanut content reported either above the highest standard or within the calibration curve, depending on the laboratory. Six samples with peanut declared as an ingredient gave the peanut protein content within the calibration curve. Only these six samples, together with a positive control sample (CS2), were used for statistical evaluation. The statistical tests (Cochran, Grubbs, and Mandel) and analysis of variance were used for the evaluation of the collaborative study results. Repeatability and reproducibility limits, as well as an LOQ (LOQcollaborative 0.22 mg peanut proteins/kg) and an LOD (LODcollaborative 0.07 mg peanut proteinslkg) for the kit were calculated.

Objective: To assess readiness of general surgery graduate trainees entering accredited surgical subspecialty fellowships in North America., Methods: A multidomain, global assessment survey designed by the Fellowship Council research committee was electronically sent to all subspecialty program directors. Respondents spanned minimally invasive surgery, bariatric, colorectal, hepatobiliary, and thoracic specialties. There were 46 quantitative questions distributed across 5 domains and 1 or more reflective qualitative questions/domains., Results: There was a 63% response rate (n = 91/145). Of respondent program directors, 21% felt that new fellows arrived unprepared for the operating room, 38% demonstrated lack of patient ownership, 30% could not independently perform a laparoscopic cholecystectomy, and 66% were deemed unable to operate for 30 unsupervised minutes of a major procedure. With regard to laparoscopic skills, 30% could not atraumatically manipulate tissue, 26% could not recognize anatomical planes, and 56% could not suture. Furthermore, 28% of fellows were not familiar with therapeutic options and 24% were unable to recognize early signs of complications. Finally, it was felt that the majority of new fellows were unable to conceive, design, and conduct research/academic projects. Thematic clustering of qualitative data revealed deficits in domains of operative autonomy, progressive responsibility, longitudinal follow-up, and scholarly focus after general surgery education.

Objectives: To quantify the variation in rates of absence due to musculoskeletal pain across 47 occupational groups (mostly nurses and office workers) from 18 countries, and to explore personal and group-level risk factors that might explain observed differences., Methods: A standardised questionnaire was used to obtain information about musculoskeletal pain, sickness absence and possible risk factors in a cross-sectional survey of 12 416 workers (92-1017 per occupational group). Additionally, group-level data on socioeconomic variables, such as sick pay and unemployment rates, were assembled by members of the study team in each country. Associations of sickness absence with risk factors were examined by Poisson regression., Results: Overall, there were more than 30-fold differences between occupational groups in the 12-month prevalence of prolonged musculoskeletal sickness absence, and even among office workers carrying out similar occupational tasks, the variation was more than tenfold. Personal risk factors included older age, lower educational level, tendency to somatise, physical loading at work and prolonged absence for non-musculoskeletal illness. However, these explained little of the variation between occupational groups. After adjustment for individual characteristics, prolonged musculoskeletal sickness absence was more frequent in groups with greater time pressure at work, lower job control and more adverse beliefs about the work-relatedness of musculoskeletal disorders., Conclusions: Musculoskeletal sickness absence might be reduced by eliminating excessive time pressures in work, maximising employees' responsibility and control and providing flexibility of duties for those with disabling symptoms. Care should be taken not to overstate work as a cause of musculoskeletal injury.

Background: Angiogenesis is tightly linked to inflammation and cancer. Regulation of angiogenesis is mediated primarily through activation of receptor tyrosine kinases, thus kinase inhibitors represent a new paradigm in anti-cancer therapy. However, these inhibitors have broad effects on inflammatory processes and multiple cell types. Sunitinib is a multitarget receptor tyrosine kinase inhibitor, which has shown promise for the treatment of glioblastoma, a highly vascularized tumor. However, there is little information as to the direct effects of sunitinib on brain-derived neurons. The objective of this study is to explore the effects of sunitinib on neuronal survival as well as on the expression of inflammatory protein mediators in primary cerebral neuronal cultures., Methods: Primary cortical neurons were exposed to various doses of sunitinib. The drug-treated cultures were assessed for survival by MTT assay and cell death by lactate dehydrogenase release. The ability of sunitinib to affect NF-κB, COX2 and NOS2 expression was determined by western blot. The NF-κB inhibitors dicoumarol, SN50 and BAY11-7085 were employed to assess the role of NF-κB in sunitinib-mediated effects on neuronal survival as well as COX2 and NOS2 expression., Results: Treatment of neuronal cultures with sunitinib caused a dose-dependent increase in cell survival and decrease in neuronal cell death. Exposure of neurons to sunitinib also induced an increase in the expression of NF-κB, COX2 and NOS2. Inhibiting NF-κB blunted the increase in cell survival and decrease in cell death evoked by sunitinib. Treatment of cell cultures with both sunitinib and NF-κB inhibitors mitigated the increase in COX2 and NOS2 caused by sunitinib., Conclusions: Sunitinib increases neuronal survival and this neurotrophic effect is mediated by NF-κB. Also, the inflammatory proteins COX2 and NOS2 are upregulated by sunitinib in an NF-κB-dependent manner. These data are in agreement with a growing literature suggesting beneficial effects for inflammatory mediators such as NF-κB, COX2 and NOS2 in neurons. Further work is needed to fully explore the effects of sunitinib in the brain and its possible use as a treatment for glioblastoma. Finally, sunitinib may be useful for the treatment of a range of central nervous system diseases where neuronal injury is prominent.

Objectives: To investigate neonatal morbidity in fetuses with severe congenital diaphragmatic hernia (CDH) treated with fetoscopic endoluminal tracheal occlusion (FETO) and compare it with historical controls with less severe forms of CDH that were managed expectantly., Methods: This was a prospective, multicenter study on neonatal outcomes and prenatal predictors in 90 FETO survivors (78 left-sided, 12 right) and 41 controls from the antenatal CDH registry with either severe or moderate hypoplasia who were managed expectantly. We also investigated early neonatal morbidity indicators, including the need for patch repair, duration of mechanical ventilation and supplemental oxygen, age at full enteral feeding and incidence of pulmonary hypertension., Results: Gestational age at delivery was predictive of duration of assisted ventilation (P = 0.046), days on supplemental oxygen (P = 0.019) and age at full enteral feeding (P = 0.020). When delivery took place after 34 weeks' gestation, neonatal morbidity of FETO cases was comparable with that of expectantly managed cases with moderate hypoplasia., Conclusions: Fetal intervention for severe CDH is associated with neonatal morbidity that is comparable with that of an expectantly managed group with less severe disease., (Copyright © 2013 ISUOG. Published by John Wiley & Sons, Ltd.)

Objective: To assess the best method of combining fetal nuchal translucency (NT) and ductus venosus (DV) blood flow measurements in the detection of major cardiac defects in chromosomally normal fetuses during the first-trimester scan., Methods: During an 8-year period NT and DV blood flow were routinely assessed at 11-14 weeks' gestation. Only chromosomally normal singleton pregnancies were included in the study. When a cardiac defect was suspected, or when increased fetal NT and/or absent or reversed (AR) A-wave in the DV was observed, early fetal echocardiography was offered. Data on routine second- and third-trimester scans, neonatal follow-up or postmortem examination were obtained from hospital records. The detection and false-positive rates for all major cardiac defects were calculated for several screening strategies, including: NT or DV pulsatility index for veins (DV-PIV) above a fixed normal centile; AR A-wave; risk based on NT and DV-PIV or A-wave velocity above a fixed normal centile; and combinations of these strategies., Results: The study population included 37 chromosomally normal fetuses with a major cardiac defect and 12 799 unaffected pregnancies. Fetal NT above the 95(th) or the 99(th) centile and AR A-wave was observed in 40, 27 and 39% of the fetuses with major cardiac defects, respectively. A 47% detection rate with a 2.7% false-positive rate was obtained when AR A-wave or NT above the 99(th) centile was used as the selection criterion., Conclusions: Half of major fetal cardiac defects could be detected in the first trimester if NT and DV Doppler are used to select 2.7% of the general pregnant population for extended fetal echocardiography., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

To compare the prevalence of disabling low back pain (DLBP) and disabling wrist/hand pain (DWHP) among groups of workers carrying out similar physical activities in different cultural environments, and to explore explanations for observed differences, we conducted a cross-sectional survey in 18 countries. Standardised questionnaires were used to ascertain pain that interfered with everyday activities and exposure to possible risk factors in 12,426 participants from 47 occupational groups (mostly nurses and office workers). Associations with risk factors were assessed by Poisson regression. The 1-month prevalence of DLBP in nurses varied from 9.6% to 42.6%, and that of DWHP in office workers from 2.2% to 31.6%. Rates of disabling pain at the 2 anatomical sites covaried (r = 0.76), but DLBP tended to be relatively more common in nurses and DWHP in office workers. Established risk factors such as occupational physical activities, psychosocial aspects of work, and tendency to somatise were confirmed, and associations were found also with adverse health beliefs and group awareness of people outside work with musculoskeletal pain. However, after allowance for these risk factors, an up-to 8-fold difference in prevalence remained. Systems of compensation for work-related illness and financial support for health-related incapacity for work appeared to have little influence on the occurrence of symptoms. Our findings indicate large international variation in the prevalence of disabling forearm and back pain among occupational groups carrying out similar tasks, which is only partially explained by the personal and socioeconomic risk factors that were analysed., (Copyright © 2013 International Association for the Study of Pain. All rights reserved.)

Background: Glutamate and corticotropin releasing hormone (CRH) are pro-stress neurotransmitters and may be altered in the plasma and cerebrospinal fluid (CSF) of persons with major depressive disorder (MDD). The goal of this study was to compare the CSF levels of glutamate, glutamine and CRH between patients with depression and healthy controls., Methods: Eighteen patients with MDD and 25 healthy controls underwent a lumbar puncture (LP); CSF samples were withdrawn and assays were done for glutamine, glutamate, and CRH. Patients with MDD underwent 8 weeks of treatment with the antidepressant venlafaxine and then had a repeat LP post treatment., Results: Patients had higher baseline scores on depression and suicide rating scales and those scales improved significantly post-treatment. Higher suicidal ratings at baseline were correlated with higher glutamate levels (p=0.016). There were no significant differences between the control and patient group in any baseline CSF measures of glutamate (p=0.761), glutamine (p=0.226) or CRH (p=0.675). Despite no significant change in glutamate (p=0.358) and CRH (p=0.331) in the treatment group, there was a post-treatment decrease in glutamine (p=0.045) in patients., Limitations: There was a small sample size, age discordance between patients and controls, lack of a follow-up LP in controls, absence of dexamethasone suppression testing, and fluctuating sample sizes among various measures., Conclusion: Although no significant differences were noted between patients and controls at baseline there was an association of high CSF glutamate and suicidal ideation and lower glutamine post-treatment which may be correlated with attenuation of dysfunction in the glutamatergic system after antidepressant treatment., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: To explore the potential value of intrapulmonary artery Doppler velocimetry in predicting neonatal morbidity in fetuses with left-sided congenital diaphragmatic hernia (CDH) treated with fetoscopic tracheal occlusion (FETO)., Methods: Observed/expected lung-to-head ratio (O/E-LHR), and intrapulmonary Doppler pulsatility index and peak early-diastolic reversed flow were evaluated within 24 h before FETO in a consecutive cohort of 51 fetuses with left-sided CDH at between 24 and 33 weeks' gestation. Lung Doppler parameters were converted into Z-scores and defined as abnormal if the pulsatility index had a Z-score of > 1.0 or the peak early-diastolic reversed flow had a Z-score of > 3.5. The association of O/E-LHR and Doppler velocimetry with neonatal outcome was assessed using multiple linear or logistic regression analysis adjusted for gestational age at birth., Results: Among the 26 fetuses that survived, 18 (69.2%) had normal and eight (30.8%) had abnormal Doppler values. O/E-LHR was not associated with neonatal morbidity in surviving fetuses. Compared with the group with normal Doppler parameters, cases with abnormal intrapulmonary Doppler were associated with a significant increase in the duration of mechanical ventilation (average increase of 21.2 (95% CI, 9.99-32.5) days; P < 0.01), conventional ventilation (15.2 (95% CI, 7.43-23.0) days; P < 0.01), high-frequency ventilation (6.34 (95% CI, 0.69-11.99) days; P < 0.05), nitric oxide therapy (5.73 (95% CI, 0.60-10.9) days; P < 0.05), oxygen support (36.5 (95% CI, 16.3-56.7) days; P < 0.01), parenteral nutrition (19.1 (95% CI, 7.53-30.7) days; P < 0.01) and stay in neonatal intensive care unit (42.7 (95% CI, 22.9-62.6) days; P < 0.001), and with significantly higher rates of high-frequency ventilation (87.5 vs. 44.4%;P < 0.05), oxygen requirement at 28 days of age (75.0 vs. 11.1%; P < 0.01), gastroesophageal reflux (62.5 vs. 22.2%; P < 0.05) and tube feeding at discharge (37.5 vs. 5.56%; P < 0.05)., Conclusion: As previously reported, O/E-LHR did not predict neonatal morbidity. In contrast, intrapulmonary artery Doppler evaluation was predictive of neonatal morbidity in CDH fetuses treated with FETO., (Copyright © 2012 ISUOG. Published by John Wiley & Sons, Ltd.)

Total and specific immunoglobulin (Ig) E can be detected in vitro using several commercially available methods. The largest share of the global market for these methods is held by the ImmunoCAP technique (Thermo Fisher, previously Phadia), Immulite (Siemens), and Hytec-288 (Hycor). Most comparative studies examine Immulite and ImmunoCAP, which differ methodologically but use similar units of measurement relative to the same standard of total IgE (WHO IgE Standard 75/502). Despite their similarity, these kits differ in their quantification of specific IgE, which varies depending on the allergen studied.Thus, specific IgE results obtained with ImmunoCAP and Immulite are not interchangeable. It is important to bear this in mind, especially when determining cutoff points as predictors of a response to oral challenge with specific food allergens. The method used in practice must be the same as the one in the publication guiding clinical decision making. We analyze differences between ImmunoCAP and ISAC microarray, 2 methods from the same manufacturer used to detect IgE to specific proteins (purified or recombinant).The results show that the IgE values obtained with ImmunoCAP are not equivalent to the corresponding values obtained with the ISAC microarray system.

Objectives: Direct SOS-dependent regulation of qnrB genes by fluoroquinolones mediated by LexA was reported. The smaqnr gene, on the Serratia marcescens chromosome, and qnrD both contain a putative LexA box. The aim of this study was to evaluate whether smaqnr or qnrD genes are induced via SOS-dependent mechanisms, and to investigate whether other antimicrobial agents induce qnrB, qnrD and smaqnr expression., Methods: RT-PCR was used to evaluate qnrB1, qnrD and smaqnr expression. Different concentrations of ciprofloxacin, levofloxacin, moxifloxacin and ceftazidime were evaluated as inducers. Additionally, the promoter regions of qnrB1, qnrD and smaqnr were fused transcriptionally to green fluorescent protein and used in reporter gene assays. Disc diffusion assays with different antimicrobial agents were used to detect induction. Measurements of transcriptional induction by ciprofloxacin were carried out using a plate reader., Results: RT-PCR assays showed that qnrB1, qnrD and smaqnr were induced at different concentrations of ciprofloxacin, moxifloxacin, levofloxacin and ceftazidime, increasing transcription 1.5- to 16.3-fold compared with basal expression, and depending on the antimicrobial agent and promoter analysed. The reporter gene assays showed that the qnrB1, qnrD and smaqnr genes were induced by ciprofloxacin, as expected, but also by ceftazidime, ampicillin and trimethoprim in Escherichia coli wild-type strains, but not in the recA-deficient E. coli HB101. Induction was not evident for imipenem or gentamicin., Conclusions: β-Lactams and trimethoprim, along with fluoroquinolones, induce transcription of qnrB, qnrD and smaqnr genes using SOS-dependent regulation. These results show the direct SOS-dependent regulation of a low-level fluoroquinolone resistance mechanism in response to other antimicrobials.

Background: The Global Operative Assessment of Laparoscopic Skill (GOALS) is one validated metric utilized to grade laparoscopic skills and has been utilized to score recorded operative videos. To facilitate easier viewing of these recorded videos, we are developing novel techniques to enable surgeons to view these videos. The objective of this study is to determine the feasibility of utilizing widespread current consumer-based technology to assist in distributing appropriate videos for objective evaluation., Methods: Videos from residents were recorded via a direct connection from the camera processor via an S-video output via a cable into a hub to connect to a standard laptop computer via a universal serial bus (USB) port. A standard consumer-based video editing program was utilized to capture the video and record in appropriate format. We utilized mp4 format, and depending on the size of the file, the videos were scaled down (compressed), their format changed (using a standard video editing program), or sliced into multiple videos. Standard available consumer-based programs were utilized to convert the video into a more appropriate format for handheld personal digital assistants. In addition, the videos were uploaded to a social networking website and video sharing websites., Results: Recorded cases of laparoscopic cholecystectomy in a porcine model were utilized. Compression was required for all formats. All formats were accessed from home computers, work computers, and iPhones without difficulty. Qualitative analyses by four surgeons demonstrated appropriate quality to grade for these formats., Conclusions: Our preliminary results show promise that, utilizing consumer-based technology, videos can be easily distributed to surgeons to grade via GOALS via various methods. Easy accessibility may help make evaluation of resident videos less complicated and cumbersome.

Objective: To evaluate and compare the effectiveness of a 16-week multidisciplinary (exercise plus psychological therapy) and biodanza intervention in women with fibromyalgia., Patients and Methods: Thirty-eight women with fibromyalgia were distributed to a 16-week multidisciplinary (3-times/week) intervention (n=21) or Biodanza (1-time/week) intervention (n=17). We assessed tender point, body composition, physical fitness and psychological outcomes (Fibromyalgia Impact Questionnaire, the Short-Form Health Survey 36 questionnaire (SF-36), the Hospital Anxiety and Depression Scale, Vanderbilt Pain Management Inventory (VPMI), Rosenberg Self-Esteem Scale and General Self-Efficacy Scale)., Results: We observed a significant group*time interaction effect for the scales of SF-36 physical role (P=0.038) and social functioning (P=0.030) and for the passive coping scale in VPMI (P=0.043). Post hoc analysis revealed a significant improvement on social functioning (P=0.030) in the multidisciplinary group whereas it did not change in the Biodanza group. Post hoc analysis revealed a reduction in the use of passive coping (positive) (P less than 0.001) in the multidisciplinary group. There was no significant interaction or time effect in body composition and physical fitness., Conclusions: 16 weeks of multidisciplinary intervention induced greater benefits than a Biodanza intervention for social functioning and the use of passive coping strategies in women with fibromyalgia.

With 88% of HIV-1-infected individuals living in areas of high prevalence of non-B subtypes and with expanded global access to antiretroviral treatment (ART), studying disease progression amongst non-B subtypes gains relevance. Optimized clinical management is a possibility with knowledge of non-B subtype profiles at baseline, which is currently not possible due to lack of subtype-specific point-of-care assays. In a systematic review, we synthesized global evidence on differential disease progression amongst non-B subtypes in ART-naive individuals. Due to lack of consistent effect measures, we avoided pooling data and inferred patterns with respect to disease progression outcomes (ie, AIDS, Death, CD4, viral load changes). Subtypes C and D were more aggressive, followed by G, AE, and AG, and A being the least aggressive of all HIV-1 subtypes. Evidence of greater rates of disease progression in globally prevalent C and D subtypes highlight the importance of expanding early HIV detection, and determining subtype profile at baseline with CD4 staging to optimize the quality of ART delivery and care in global settings.

The Balanced Scorecard (BSC) is a validated tool to monitor enterprise performances against specific objectives. Through the choice and the evaluation of strategic Key Performance Indicators (KPIs), it provides a measure of the past company's outcome and allows planning future managerial strategies. The Fresenius Medical Care (FME) BSC makes use of 30 KPIs for a continuous quality improvement strategy within its dialysis clinics. Each KPI is monthly associated to a score that summarizes the clinic efficiency for that month. Standard statistical methods are currently used to analyze the BSC data and to give a comprehensive view of the corporate improvements to the top management. We herein propose the Self-Organizing Maps (SOMs) as an innovative approach to extrapolate information from the FME BSC data and to present it in an easy-readable informative form. A SOM is a computational technique that allows projecting high-dimensional datasets to a two-dimensional space (map), thus providing a compressed representation. The SOM unsupervised (self-organizing) training procedure results in a map that preserves similarity relations existing in the original dataset; in this way, the information contained in the high-dimensional space can be more easily visualized and understood. The present work demonstrates the effectiveness of the SOM approach in extracting useful information from the 30-dimensional BSC dataset: indeed, SOMs enabled both to highlight expected relationships between the KPIs and to uncover results not predictable with traditional analyses. Hence we suggest SOMs as a reliable complementary approach to the standard methods for BSC interpretation.

Objectives: There is a high incidence of pulmonary hypertension during the lung transplant peri-operative period, and could lead to a haemodynamic deterioration that may require the need of extracorporeal circulation. Our aim was to study the haemodynamic effects on the pulmonary and systemic circulation of the combination of inhaled nitric oxide and iloprost and oral sildenafil in patients with severe pulmonary hypertension during lung transplant surgery., Patients and Methods: Seventeen patients received 10μg of nebulised iloprost during the peri-operative period of the lung transplant when their mean pulmonary pressure exceeded 50mmHg. AU the patients received 50mg of oral sildenafil 30min before anaesthetic induction, 20ppm of inhaled nitric oxide after tracheal intubation. The haemodynamic and respiratory variables were recorded at baseline (after anaesthetic induction), prior to the administering of iloprost, and at 5 and 30min after it was given., Results: The administering of iloprost significantly reduced the pulmonary arterial pressure and significantly increases the cardiac Índex and the right ventrícular ejection fractíon. There were no signíficant changes occurred in the systemic arterial pressure., Conclusions: The triple combination significantly reduces the pulmonary pressures in the lung transplant peri-operative and should be considered when there is severe pulmonary hypertension during the surgery or during the immediate post-operative period of lung transplantation., (Copyright © 2010 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Published by Elsevier España.. All rights reserved.)

This article explores the question of how scientific uncertainty can be managed in medical decision making using the Advisory Committee on Immunization Practices as a case study. It concludes that where a high degree of technical consensus exists about the evidence and data, decision makers act according to a clear decision rule. If a high degree of technical consensus does not exist and uncertainty abounds, the decision will be based on a variety of criteria, including readily available resources, decision-process constraints, and the available knowledge base, among other things. Decision makers employ a variety of heuristic devices and techniques, thereby employing a pragmatic approach to uncertainty in medical decision making. The article concludes with recommendations for managing scientific uncertainty in medical decision making.

Background: The CUPID (Cultural and Psychosocial Influences on Disability) study was established to explore the hypothesis that common musculoskeletal disorders (MSDs) and associated disability are importantly influenced by culturally determined health beliefs and expectations. This paper describes the methods of data collection and various characteristics of the study sample., Methods/principal Findings: A standardised questionnaire covering musculoskeletal symptoms, disability and potential risk factors, was used to collect information from 47 samples of nurses, office workers, and other (mostly manual) workers in 18 countries from six continents. In addition, local investigators provided data on economic aspects of employment for each occupational group. Participation exceeded 80% in 33 of the 47 occupational groups, and after pre-specified exclusions, analysis was based on 12,426 subjects (92 to 1018 per occupational group). As expected, there was high usage of computer keyboards by office workers, while nurses had the highest prevalence of heavy manual lifting in all but one country. There was substantial heterogeneity between occupational groups in economic and psychosocial aspects of work; three- to five-fold variation in awareness of someone outside work with musculoskeletal pain; and more than ten-fold variation in the prevalence of adverse health beliefs about back and arm pain, and in awareness of terms such as "repetitive strain injury" (RSI)., Conclusions/significance: The large differences in psychosocial risk factors (including knowledge and beliefs about MSDs) between occupational groups should allow the study hypothesis to be addressed effectively.

Background: A number of studies have shown that elevated levels of inflammatory cytokines may promote depression and suicidal ideation and that neuroprotective peptides may decrease the response to stress and depression. In this study, cerebrospinal fluid (CSF) levels of three inflammatory cytokines (IL-1, IL-6, and tumor necrosis factor α (TNFα)) and two putative "resiliency" neuropeptides (brain-derived neurotrophic factor (BDNF) and neuropeptide Y (NPY)) were compared between patients with depression and healthy controls., Methods: Eighteen patients with major depression and 25 healthy controls underwent a lumbar puncture; CSF samples were withdrawn and assayed for IL-1, IL-6, TNFα, BDNF, and NPY levels. Patients with depression were then entered into an 8-week treatment protocol and had repeated lumbar puncture procedures post-treatment., Results: Contrary to prediction, we found that at baseline depressed patients had higher CSF NPY concentration compared to the normal comparison group. Within the depressed patients, we found several statistically significant correlations between elevated CSF cytokine levels and clinical severity., Conclusion: Despite the small sample size, given the challenges in obtaining CSF from patients with depression these data are of interest in confirming some aspects of the inflammatory hypothesis of depression., (© 2011 Wiley-Liss, Inc.)

Monochorionic (MC) twins represent a significant proportion of perinatal morbidity and mortality. Overall, 1 of 3 MC twin pregnancies will develop complications in relation to the MC placenta and the presence of interfetal placental anastomoses. From a clinical standpoint, these complications can be grouped into four main types of clinical problems: chronic transfusion, acute transfusion, growth discordance, and discordant malformation. Differential diagnosis of MC twin complications is still challenging due to frequent overlap of their clinical signs and the complex relationships between them. Clinical experience demonstrates that most instances of wrong management derive from failure to comply with a basic set of rules for diagnosis and management. In this review, we propose a simplified approach to the understanding of MC twin pregnancy, its potential complications, and the key concepts allowing adequate differential diagnosis and targeted management., (Copyright © 2012 S. Karger AG, Basel.)

This subgroup analysis assessed the efficacy of duloxetine in patients with chronic low back pain (CLBP) who did or did not use concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen (APAP). Data were pooled from two 13-week randomized trials in patients with CLBP who were stratified according to NSAID/APAP use at baseline: duloxetine NSAID/APAP user (n = 137), placebo NSAID/APAP user (n = 82), duloxetine NSAID/APAP nonuser (n = 206), and placebo NSAID/APAP nonuser (n = 156). NSAID/APAP users were those patients who took NSAID/APAP for at least 14 days per month during 3 months prior to study entry. An analysis of covariance model that included therapy, study, baseline NSAID/APAP use (yes/no), and therapy-by-NSAID/APAP subgroup interaction was used to assess the efficacy. The treatment-by-NSAID/APAP use interaction was not statistically significant (P = 0.31) suggesting no substantial evidence of differential efficacy for duloxetine over placebo on pain reduction or improvement in physical function between concomitant NSAID/APAP users and non-users.

Some evidence suggests that medications that modulate both serotonin and norepinephrine may be more effective than selective serotonin-reuptake inhibitors (SSRIs) in severe major depressive disorder (MDD). This prospective pragmatic trial tests this hypothesis. Patients with severe MDD were randomly assigned to either duloxetine (a serotonin and norepinephrine-reuptake inhibitor) or physicians' choice of four generic SSRIs. Nonblinded, flexibly dosed treatment was used to mimic clinical practice. To address potential investigator bias, the patient-reported Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR) was used as the primary efficacy outcome measure. A total of 750 outpatients (19.2%, African descent; 14.8%, Hispanic) were randomized. The primary outcome, remission at week 12 by QIDS-SR, was numerically greater for duloxetine compared with SSRIs (36 vs. 32%), but this difference was not statistically significant. Mean changes in secondary outcomes were significantly superior in favor of duloxetine for the Hamilton Depression Scale-17 item, the Brief Pain Inventory, and the Sheehan Disability Scale. Remission superiority on the QIDS-SR was not achieved. Significantly greater benefit for duloxetine compared with SSRIs was demonstrated on measures of pain and functioning. Study demographics suggest a more generalizable racial and ethnic population than is typical in randomized clinical trials.

Objective: To present the planning and medical encounters for the 2010 Paralympic Winter Games., Design: Prospective medical encounter study., Setting: 2010 Paralympic Winter Games., Participants: Athletes, coaches, officials, workforce, volunteers, and media., Assessment of Risk Factors: Sport type: alpine, Nordic, and sledge hockey and curling. Participant type: athlete, workforce, and spectators. Terrain and speed., Main Outcome Measures: Medical encounters entered in database at competitive (alpine skiing, biathlon, cross-country skiing, sledge hockey, and curling) and noncompetitive (Whistler and Vancouver Polyclinics, presentation centers, opening and closing ceremonies, media center, Paralympic Family Hotel) venues., Results: Forty-two nations participated with 1350 Paralympic athletes, coaches, and officials. There were 2590 accredited medical encounters (657 athletes, 25.4%; 682 International Federation/National Paralympic Committee officials, 26.3%; 57 IPC, 2.2%; 8 media, 0.3%; 1075 workforce, 41.5%; 111 others, 4.3%) and 127 spectator encounters for a total of 2717 encounters. During the preopening period medical services saw 201 accredited personnel. The busiest venues during the Paralympic Games were the Whistler (1633 encounters) and Vancouver (748 encounters) Polyclinics. Alpine, sledge hockey, and curling were the busiest competitive venues. The majority of medical encounters were musculoskeletal (44.6%, n = 1156). Medical services recorded 1657 therapy treatments, 977 pharmaceutical prescriptions dispensed, 204 dental treatments, 353 imaging examinations (more than 50% from alpine skiing), and 390 laboratory tests. There were 24 ambulance transfers with 7 inpatient hospitalizations for a total of 24 inpatient days and 4 outpatient visits., Conclusions: The mandate to have minimal impact on the health services of Vancouver and the Olympic Corridor while offering excellent medical services to the Games was accomplished. This data will be valuable to future organizing committees.

Objective: Painful physical symptoms are common in patients with major depressive disorder (MDD) and may predict poorer treatment outcomes. Duloxetine has demonstrated efficacy in treating both MDD and certain other painful conditions. This randomized, double-blind clinical trial assessed the effects of duloxetine in patients with both MDD and MDD-associated physical pain., Methods: Participants were outpatient adults with current MDD (DSM-IV-TR criteria; Montgomery-Åsberg Depression Rating Scale [MADRS] total score ≥20) and at least moderate pain (Brief Pain Inventory Short Form [BPI] average pain rating ≥3) and with at least one prior episode of MDD. Patients received placebo (N = 266) or duloxetine (N = 262) 60 mg once daily. This trial is registered at clinicaltrials.gov (NCT01000805)., Main Outcome Measures: Coprimary outcomes were MADRS total score (change from baseline at 8 weeks) and BPI average pain rating (overall main effect over 8 weeks). The Sheehan Disability Scale (SDS) global functional impairment score (change from baseline at 8 weeks) was used to assess functioning. Remission was defined as MADRS total score ≤12 at the 8-week endpoint. Changes were analyzed using mixed-effects model repeated measures (MMRM)., Results: Compared with placebo, duloxetine significantly improved the mean MADRS total score, BPI average pain rating, and SDS global functional impairment score (all p ≤ 0.05 for analyses described above). The remission rate was significantly greater with duloxetine compared with placebo (p = 0.001) and was greater for duloxetine-treated patients with ≥50% versus <50% improvement in BPI average pain score (p ≤ 0.001). Treatment emergent adverse events that occurred in at least 5% of duloxetine-treated patients and at twice the rate of placebo included nausea, somnolence, constipation, decreased appetite, and hyperhidrosis. Rates of discontinuation due to adverse events were greater for duloxetine than placebo (8.0% vs 3.4%, respectively; p = 0.024). This study did not address the effects of duloxetine on MDD and comorbid pain of a known origin., Conclusions: These results support the efficacy and tolerability of duloxetine in the treatment of depression and associated painful physical symptoms in patients with MDD and at least moderate MDD-associated pain.

Introduction: A novel multi-port (Triport+) and methodology were designed for single port cholecystectomy (SPC) to replicate the principles found in the gold standard 4-port laparoscopic cholecystectomy. We present the first case series utilizing the Triport+, and methodology through a single 15-mm periumbilical fascial incision., Methods: The 4 lumen multi-channel port was placed in the umbilicus through a measured 15-mm fascial incision. Instrument design and placement in the port is specific to the performance of the SPC. Retrospective review of the cases was performed., Results: 15 SPCs were performed without complications. No conversions or additional ports were required. Fascial defect size measured was 15 mm. Visualization of the critical view was obtained in each case. The mean total operative time was 36 minutes., Conclusion: The Triport+ and novel SPC methodology successfully replicate the standard of retraction and exposure in traditional 4-port laparoscopic cholecystectomy. This novel technique eliminates both instrument and hand conflict.

Objective: Painful physical symptoms are common in patients with major depressive disorder (MDD) and can negatively affect patient outcomes. Duloxetine has demonstrated efficacy in treating MDD and other certain painful conditions; this study specifically evaluated patients with both MDD and MDD-associated pain., Methods: This randomized, double-blind clinical trial enrolled adult outpatients with MDD (DSM-IV-TR criteria; Montgomery-Åsberg Depression Rating Scale [MADRS] total score ≥20) and at least moderate pain (Brief Pain Inventory, Short Form [BPI] average pain rating ≥3). Patients received placebo (N = 266) or duloxetine (N = 261) 60 mg once daily (QD) (after starting dose of 30 mg QD for 1 week). This study replicated another study evaluating MDD and MDD-associated pain., Clinical Trial Registration: Clinicaltrials.gov (NCT01070329)., Main Outcome Measures: Co-primary outcomes were the MADRS total score (change from baseline at 8 week endpoint) and BPI average pain rating (overall main effect over 8 weeks of treatment). The Sheehan Disability Scale (SDS) global functional impairment score at week 8 assessed functioning as a secondary outcome. Changes were analyzed using mixed-effects model repeated measures (MMRM), and the MADRS remission rate (total score ≤12 at 8-week endpoint) was analyzed using the Cochran-Mantel-Haenszel test., Results: Both co-primary objectives and the first two gated secondary objectives were achieved: compared with placebo, duloxetine significantly improved the mean MADRS total score, BPI average pain rating, SDS global functional impairment score, and remission of depression at 8-week endpoint (all p < 0.01). The third gated secondary objective, evaluating remission of depression at the last two non-missing visits, was not achieved. The within-group MADRS remission rate was greater for duloxetine-treated patients with ≥50% (versus <50%) improvement in BPI average pain (p < 0.001). Safety outcomes were similar to previous reports. This study did not address the effects of duloxetine on MDD and comorbid pain of a known origin., Conclusions: These results replicated findings supporting the efficacy and tolerability of duloxetine compared to placebo as treatment for depression and pain in patients with MDD and at least moderate pain associated with MDD.