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Lutein, zeaxanthin, and meso-zeaxanthin are the only carotenoids found in the human macula and may have a role in visual function. These carotenoids are reported to protect the retina, and thus vision, as antioxidants and by acting as a blue light filter. Our objective was to determine a minimum concentration of lutein/zeaxanthin intake that is associated with a statistically significant and/or clinically important change in macular pigment optical density (MPOD) among adults with healthy eyes. We searched Ovid MEDLINE, CENTRAL, and the Commonwealth of Agriculture Bureau for English-language studies through to July 2020. Two reviewers screened results to identify studies that evaluated supplements or dietary sources of lutein/zeaxanthin on MPOD among adults with healthy eyes. One reviewer extracted data and assessed strength of evidence, which was confirmed by a second reviewer. Two independent reviewers assessed the risk of bias. Meta-analyses were stratified by total lutein/zeaxanthin dose. We included 46 studies (N = 3189 participants; mean age = 43 y; 42% male). There was no statistically significant change in MPOD among studies evaluating, Statement of Significance: We conducted a systematic review to determine the quantities of lutein/zeaxanthin intake from either dietary or supplemental sources that are associated with macular pigment optical density (MPOD) among adults with healthy eyes. We concluded that >10 mg/d of lutein/zeaxanthin can increase MPOD, but the effects at doses

BACKGROUND: Gender-affirming hormone therapy for transgender women includes estrogen and antiandrogens (cyproterone acetate, spironolactone, or gonadotropin-releasing hormone agonists). Both estrogen and antiandrogens are reported to increase prolactin levels. The objective is to systematically review the evidence of the effects of antiandrogens on prolactin levels, hyperprolactinemia, and prolactinomas among transgender women on estrogen therapy. METHODS: We searched PubMed, Embase, and PsycInfo up to May 2020. We included studies with at least 3 months follow-up that evaluated the effects of antiandrogens among transgender women and reported on prolactin levels, hyperprolactinemia, or image-confirmed prolactinomas. Two reviewers independently screened studies for eligibility, serially abstracted data, and independently assessed risk of bias and graded strength of evidence. FINDINGS: We included 17 studies (16 publications): 8 prospective cohorts, 8 retrospective cohorts, and 1 cross-sectional study, each with a moderate to serious risk of bias. Among transgender women on estrogen, prolactin levels increased by over 100% with cyproterone acetate and by up to 45% with spironolactone. However, we were unable to isolate the effects of antiandrogens from estrogen therapy. We were unable to draw conclusions about effects of antiandrogens on hyperprolactinemia and prolactinomas. INTERPRETATION: Prolactin levels may be increased in transgender women who are taking both estrogens and an antiandrogen. Future research is needed to determine the effects of different antiandrogens on prolactin levels separately from estrogen therapy. Ideally, future studies would be prospective, provide either a comparison of two different antiandrogens or compare combination of estrogen and antiandrogen therapy to estrogen alone, and control for possible confounders.

BACKGROUND Exercise testing is important in people with cystic fibrosis (pwCF). The aim was to develop an incremental maximal step test to assess exercise capacity across the range of pwCF, without floor or ceiling effects, within restrictions of space, and infection prevention. METHODS The step test was developed in adults with stable CF. Subjects assisted in selecting: step height, start rate, increments, stage and test duration parameters. Equipment to externally pace and time the test and measure exercise parameters were selected. Reasons for stopping, criteria for achieving a maximal test, and key outcome measures were determined. Documentation to record and standardize the test and instructions to set up the metronome and timer App were developed. Infection control practices were considered. RESULTS Eight subjects were recruited to develop the Alfred Step Test Exercise Protocol (A-STEP) on a 20 cm portable step. The A-STEP package included a pretest information sheet, clinical assessment and instructions, recording worksheet, and the metronome/timer instructions. The test started at 18 steps/min. Each level increased by two steps/min to a maximum of 48 steps (Level 16). Results were presented as mean (SD) [range] for: age 30.63 (5.89) [21-39] years; FEV1 58.13 (18.33) [32-89]%; levels: 10.31 (3.29) [6-15.5]. The A-STEP required space of 2 m2 and complied with current infection control guidelines. CONCLUSIONS The A-STEP is a new incremental maximal step test to assess exercise capacity in pwCF, without floor or ceiling effects. It addresses the issues of space restrictions and the need for strict infection prevention in the clinical setting.

We sought to systematically review the effect of gender-affirming hormone therapy on psychological outcomes among transgender people. We searched PubMed, Embase, and PsycINFO through June 10, 2020 for studies evaluating quality of life (QOL), depression, anxiety, and death by suicide in the context of gender-affirming hormone therapy among transgender people of any age. We excluded case studies and studies reporting on less than 3 months of follow-up. We included 20 studies reported in 22 publications. Fifteen were trials or prospective cohorts, one was a retrospective cohort, and 4 were cross-sectional. Seven assessed QOL, 12 assessed depression, 8 assessed anxiety, and 1 assessed death by suicide. Three studies included trans-feminine people only; 7 included trans-masculine people only, and 10 included both. Three studies focused on adolescents. Hormone therapy was associated with increased QOL, decreased depression, and decreased anxiety. Associations were similar across gender identity and age. Certainty in this conclusion is limited by high risk of bias in study designs, small sample sizes, and confounding with other interventions. We could not draw any conclusions about death by suicide. Future studies should investigate the psychological benefits of hormone therapy among larger and more diverse groups of transgender people using study designs that more effectively isolate the effects of hormone treatment.

OBJECTIVE: This article describes the methodology used for Pediatric Critical Care Transfusion and Anemia Expertise Initiative (TAXI) Consensus Conference. DESIGN: Consensus conference of international experts in pediatric critical care and transfusion medicine, following standards set by the Institute of Medicine, using the Research And Development/University of California, Los Angeles (RAND/UCLA) appropriateness method, modeled after the Pediatric Acute Lung Injury Consensus Conference. Topics related to red blood cell transfusion (RBC) in children with or at risk for critical illness were divided into nine subgroups with a systematic review of the literature. METHODS: The panel of 38 content and 4 methodology experts met three times over the course of two years and collaborated to develop evidence-based and when evidence was lacking, expert-based clinical recommendations as well as research priorities for RBC transfusions in critically ill children or those at risk for critical illness. Electronic searches were conducted using PubMed, Embase, and Cochrane Library (CENTRAL) databases from 1980 to May 2017. Agreement was obtained using the RAND/UCLA appropriateness method. We used a standardized data extraction form to construct evidence tables, and graded the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. MAIN RESULTS: The consensus conference resulted in 102 recommendation statements, of which 57 were clinical (20 evidence-based and 37 based on expert consensus), and 45 detailed recommendations for future research. Dissemination was done via decision tree, a primary publication listing all statements, and separate publications for each subtopic that include supporting arguments for each recommendation. CONCLUSIONS: A consensus conference of experts from around the world developed recommendations for RBC transfusions in critically ill children or children at risk for critical illness, the identification of current research gaps, and future research priorities.

Objective:To systematically assess the effect of pharmacologic treatments of diabetic peripheral neuropathy (DPN) on pain and quality of life.Methods:We searched PubMed and Cochrane Database of Systematic Reviews for systematic reviews from 2011 to October 12, 2015, and PubMed, Embase, and the Cochrane Central Register of Controlled Trials for primary studies from January 1, 2013, to May 24, 2016. We searched Clinicaltrials.gov on March 9, 2016. Two reviewers independently evaluated studies for eligibility, serially abstracted data, and independently evaluated risk of bias and graded strength of evidence (SOE).Results:We updated a recently completed systematic review of 57 eligible studies with 24 additional published studies and 25 unpublished studies. For reducing neuropathy-related pain, the serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine (moderate SOE), the anticonvulsants pregabalin and oxcarbazepine (low SOE), the drug classes tricyclic antidepressants (low SOE) and atypical opioids (low SOE), and botulinum toxin (low SOE) were more effective than placebo. We could not draw conclusions about quality of life due to incomplete reporting. All studies were short-term (less than 6 months), and all effective drugs had more than 9% dropouts from adverse effects.Conclusions:For reducing pain, duloxetine and venlafaxine, pregabalin and oxcarbazepine, tricyclic antidepressants, atypical opioids, and botulinum toxin were more effective than placebo. However, quality of life was poorly reported, studies were short-term, drugs had substantial dropout rates, and opioids have significant risks. Future studies should evaluate longer-term outcomes, use methods and measures recommended by pain organizations, and assess patients' quality of life.

BACKGROUND: Cystic fibrosis is a life‐limiting genetic condition in which thick mucus builds up in the lungs, leading to infections, inflammation, and eventually, deterioration in lung function. To clear their lungs of mucus, people with cystic fibrosis perform airway clearance techniques daily. There are various airway clearance techniques, which differ in terms of the need for assistance or equipment, and cost. OBJECTIVES: To summarise the evidence from Cochrane Reviews on the effectiveness and safety of various airway clearance techniques in people with cystic fibrosis. METHODS: For this overview, we included Cochrane Reviews of randomised or quasi‐randomised controlled trials (including cross‐over trials) that evaluated an airway clearance technique (conventional chest physiotherapy, positive expiratory pressure (PEP) therapy, high‐pressure PEP therapy, active cycle of breathing techniques, autogenic drainage, airway oscillating devices, external high frequency chest compression devices and exercise) in people with cystic fibrosis. We searched the Cochrane Database of Systematic Reviews on 29 November 2018. Two review authors independently evaluated reviews for eligibility. One review author extracted data from included reviews and a second author checked the data for accuracy. Two review authors independently graded the quality of reviews using the ROBIS tool. We used the GRADE approach for assessing the overall strength of the evidence for each primary outcome (forced expiratory volume in one second (FEV(1)), individual preference and quality of life). MAIN RESULTS: We included six Cochrane Reviews, one of which compared any type of chest physiotherapy with no chest physiotherapy or coughing alone and the remaining five reviews included head‐to‐head comparisons of different airway clearance techniques. All the reviews were considered to have a low risk of bias. However, the individual trials included in the reviews often did not report sufficient information to adequately assess risk of bias. Many trials did not sufficiently report on outcome measures and had a high risk of reporting bias. We are unable to draw definitive conclusions for comparisons of airway clearance techniques in terms of FEV(1), except for reporting no difference between PEP therapy and oscillating devices after six months of treatment, mean difference ‐1.43% predicted (95% confidence interval ‐5.72 to 2.87); the quality of the body of evidence was graded as moderate. The quality of the body of evidence comparing different airway clearance techniques for other outcomes was either low or very low. AUTHORS' CONCLUSIONS: There is little evidence to support the use of one airway clearance technique over another. People with cystic fibrosis should choose the airway clearance technique that best meets their needs, after considering comfort, convenience, flexibility, practicality, cost, or some other factor. More long‐term, high‐quality randomised controlled trials comparing airway clearance techniques among people with cystic fibrosis are needed.

This systematic review of randomized trials examines benefits and harms of antipsychotics for prevention of delirium in adults.

The use of negative pressure wound therapy (NPWT) is increasing in both the inpatient and outpatient settings. We conducted a systematic review on the efficacy and safety of NPWT for the treatment of chronic wounds in the home setting. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature, up to June 2014. Two independent reviewers screened search results. Seven studies met our criteria for inclusion. Six of the studies compared NPWT devices to other wound care methods and one study compared two different NPWT technologies. Data were limited by variability in the types of comparator groups, methodological limitations, and poor reporting of outcomes. We were unable to draw conclusions about the efficacy or safety of NPWT for the treatment of chronic wounds in the home setting due to the insufficient evidence. Consensus is needed on the methods of conducting and reporting wound care research so that future studies are able inform decisions about the use of NPWT in the home environment for chronic wounds.

Background We investigated whether information in ClinicalTrials.gov would impact the conclusions of five ongoing systematic reviews. Method We considered five reviews that included 495 studies total. Each review team conducted a search of ClinicalTrials.gov up to the date of the review’s last literature search, screened the records using the review’s eligibility criteria, extracted information, and assessed risk of bias and applicability. Each team then evaluated the impact of the evidence found in ClinicalTrials.gov on the conclusions in the review. Results Across the five reviews, the number of studies that had both a registry record and a publication varied widely, from none in one review to 43% of all studies identified in another. Among the studies with both a record and publication, there was also wide variability in the match between published outcomes and those listed in ClinicalTrials.gov. Of the 173 total ClinicalTrials.gov records identified across the five projects, between 11 and 43% did not have an associated publication. In the 14% of records that contained results, the new data provided in the ClinicalTrials.gov records did not change the results or conclusions of the reviews. Finally, a large number of published studies were not registered in ClinicalTrials.gov, but many of these were published before ClinicalTrials.gov’s inception date of 2000. Conclusion Improved prospective registration of trials and consistent reporting of results in ClinicalTrials.gov would help make ClinicalTrials.gov records more useful in finding unpublished information and identifying potential biases. In addition, consistent indexing in databases, such as MEDLINE, would allow for better matching of records and publications, leading to increased utility of these searches for systematic review projects. Electronic supplementary material The online version of this article (10.1186/s13643-018-0726-5) contains supplementary material, which is available to authorized users.

Background Complications of chronic kidney disease (CKD) include weak bones and increased fracture risk. Purpose To review the benefits and harms of osteoporosis medications (bisphosphonates, teriparatide, raloxifene, and denosumab) compared with placebo, usual care, or active control in terms of bone mineral density (BMD), fractures, and safety in patients with CKD. Data sources PubMed and the Cochrane Central Register of Controlled Trials from December 2006 through December 2016. Study selection Paired reviewers independently screened abstracts and full-text articles for English-language, randomized, controlled trials that had at least 6 months of follow-up; evaluated osteoporosis medications among patients with CKD; and reported on BMD, fractures, or safety (mortality and adverse events). Data extraction Two reviewers serially abstracted data and independently assessed risk of bias and graded the strength of evidence (SOE). Data synthesis There were 13 trials (n = 9850) that included kidney transplant recipients (6 trials), patients who had stage 3 to 5 CKD or were receiving dialysis (3 trials), or postmenopausal women with CKD (4 trials). Evidence showed that bisphosphonates may slow loss of BMD among transplant recipients (moderate SOE), but their effects on fractures and safety in transplant recipients and others with CKD are unclear. Raloxifene may prevent vertebral fractures but may not improve BMD (low SOE). Effects of teriparatide and denosumab on BMD and fractures are unclear (very low SOE), and these medications may increase risk for some safety outcomes. Limitation Unclear rigor of evidence, possible reporting biases, and scant evidence among patients with stage 3 to 5 CKD. Conclusion Effects of osteoporosis medications on BMD, fracture risk, and safety among patients with CKD are not clearly established. Primary funding source Kidney Disease: Improving Global Outcomes.

Objective Chronic venous ulcers (CVUs) remain the leading causes for nonhealing wounds in the lower extremities. Although multilayer compression dressing remains the treatment gold standard, there are various surgical procedures aimed at healing CVUs with little or no evidence on the efficacy of these treatment methods. We conducted a systematic review of the effects of various surgical treatments for CVUs, in terms of ulcer healing rates, complete time to heal, recurrence rates, mortality, pain, and quality of life. Methods We searched MEDLINE, EMBASE, the Cochrane Central Register for Controlled Trials, and the Cumulative Index for Nursing and Allied Health Literature databases from January 1980 through July 2012. We included studies that compared a surgical procedure with multilayer compression therapy or another surgical procedure among patients with CVUs. We also included studies without a comparison group if they were of sufficient quality. Two independent reviewers screened titles, abstracts, and articles for eligibility. Two reviewers extracted data on study design, applicability, results, and quality. Results We identified 10,676 citations, of which 22 studies (23 publications) were included. Eight studies (six randomized controlled trials, two cohorts) compared a surgical procedure with compression. Fourteen studies evaluated different surgical interventions. Adding superficial vein ligation and stripping to compression did not improve wound-healing rate. However, the recurrence rate was 50% reduced when surgery corrected the underlying superficial venous pathology (moderate to high strength of evidence [SOE]). Adding subfascial endoscopic perforator surgery with superficial vein surgery to compression does not improve the healing rate of venous ulcers or reduce the recurrence rate except for medial and large ulcers (high SOE). The SOE was insufficient to support a conclusion about the effects of sclerotherapy when added to compression in healing CVUs. There was insufficient evidence on the surgical treatment of CVUs secondary to deep venous reflux and venous obstruction. We are unable to draw conclusions about the effects of surgical procedures on mortality, pain, and quality of life. Conclusions Our ability to draw conclusions on most surgical techniques is limited due to poorly designed and executed studies, with no uniformity of treatment methods, follow-up or reporting, and lack of randomization. We found some evidence to suggest superficial vein ligation and stripping may reduce the risk of wound recurrence, but these surgical techniques are infrequently performed. The newer minimally invasive techniques lack evidence. Randomized controlled trials for the endovenous procedures used today for treating CVUs are needed.

The purpose of this study was to systematically review the literature on the benefits and harms of advanced wound dressings on wound healing, mortality, quality of life, pain, condition of the wound bed, and adverse events for patients with chronic venous leg ulcers as compared with treatment with compression alone. We searched for primary studies in the databases of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and the Cumulative Index to Nursing and Allied Health Literature(®) from January 1980 through July 2012. Each study title, abstract, and full article was evaluated by two independent reviewers. Thirty-seven studies met our specific search criteria, although most evidence was of low or insufficient quality. Cellular dressings, collagen, and some antimicrobial dressings may improve healing rates of chronic venous leg ulcers vs. compression alone or other dressings. Limited data were available on other outcomes. The poor quality of the literature limits conclusions and necessitates future, well-conducted studies to evaluate the effectiveness of advanced wound dressings on chronic venous ulcers.

Background Delirium is an acute disorder marked by impairments in attention and cognition, caused by an underlying medical problem. Antipsychotics are used to prevent delirium, but their benefits and harms are unclear. Purpose To conduct a systematic review evaluating the benefits and harms of antipsychotics for prevention of delirium in adults. Data sources PubMed, Embase, CENTRAL, CINAHL, and PsycINFO from inception through July 2019, without restrictions based on study setting, language of publication, or length of follow-up. Study selection Randomized, controlled trials (RCTs) that compared an antipsychotic with placebo or another antipsychotic, and prospective observational studies with a comparison group. Data extraction One reviewer extracted data and graded the strength of the evidence, and a second reviewer confirmed the data. Two reviewers independently assessed the risk of bias. Data synthesis A total of 14 RCTs were included. There were no differences in delirium incidence or duration, hospital length of stay (high strength of evidence [SOE]), and mortality between haloperidol and placebo used for delirium prevention. Little to no evidence was found to determine the effect of haloperidol on cognitive function, delirium severity (insufficient SOE), inappropriate continuation, and sedation (insufficient SOE). There is limited evidence that second-generation antipsychotics may lower delirium incidence in the postoperative setting. There is little evidence that short-term use of antipsychotics was associated with neurologic harms. In some of the trials, potentially harmful cardiac effects occurred more frequently with antipsychotic use. Limitations There was significant heterogeneity in antipsychotic dosing, route of antipsychotic administration, assessment of outcomes, and adverse events. There were insufficient or no data available to draw conclusions for many of the outcomes. Conclusion Current evidence does not support routine use of haloperidol or second-generation antipsychotics for prevention of delirium. There is limited evidence that second-generation antipsychotics may lower the incidence of delirium in postoperative patients, but more research is needed. Future trials should use standardized outcome measures. Primary funding source Agency for Healthcare Research and Quality. (PROSPERO: CRD42018109552).

OBJECTIVE We performed a systematic review to identify which genetic variants predict response to diabetes medications. RESEARCH DESIGN AND METHODS We performed a search of electronic databases (PubMed, EMBASE, and Cochrane Database) and a manual search to identify original, longitudinal studies of the effect of diabetes medications on incident diabetes, HbA1c, fasting glucose, and postprandial glucose in prediabetes or type 2 diabetes by genetic variation. Two investigators reviewed titles, abstracts, and articles independently. Two investigators abstracted data sequentially and evaluated study quality independently. Quality evaluations were based on the Strengthening the Reporting of Genetic Association Studies guidelines and Human Genome Epidemiology Network guidance. RESULTS Of 7,279 citations, we included 34 articles (N = 10,407) evaluating metformin (n = 14), sulfonylureas (n = 4), repaglinide (n = 8), pioglitazone (n = 3), rosiglitazone (n = 4), and acarbose (n = 4). Studies were not standalone randomized controlled trials, and most evaluated patients with diabetes. Significant medication–gene interactions for glycemic outcomes included 1) metformin and the SLC22A1, SLC22A2, SLC47A1, PRKAB2, PRKAA2, PRKAA1, and STK11 loci; 2) sulfonylureas and the CYP2C9 and TCF7L2 loci; 3) repaglinide and the KCNJ11, SLC30A8, NEUROD1/BETA2, UCP2, and PAX4 loci; 4) pioglitazone and the PPARG2 and PTPRD loci; 5) rosiglitazone and the KCNQ1 and RBP4 loci; and 5) acarbose and the PPARA, HNF4A, LIPC, and PPARGC1A loci. Data were insufficient for meta-analysis. CONCLUSIONS We found evidence of pharmacogenetic interactions for metformin, sulfonylureas, repaglinide, thiazolidinediones, and acarbose consistent with their pharmacokinetics and pharmacodynamics. While high-quality controlled studies with prespecified analyses are still lacking, our results bring the promise of personalized medicine in diabetes one step closer to fruition.

Objective To ensure appropriate allocation of research funds, we need methods for identifying high-priority research needs. We developed and pilot tested a process to identify needs for primary clinical research using a systematic review in gestational diabetes mellitus. Study Design and Setting We conducted eight steps: abstract research gaps from a systematic review using the Population, Intervention, Comparison, Outcomes, and Settings (PICOS) framework; solicit feedback from the review authors; translate gaps into researchable questions using the PICOS framework; solicit feedback from multidisciplinary stakeholders at our institution; establish consensus among multidisciplinary external stakeholders on the importance of the research questions using the Delphi method; prioritize outcomes; develop conceptual models to highlight research needs; and evaluate the process. Results We identified 19 research questions. During the Delphi method, external stakeholders established consensus for 16 of these 19 questions (15 with “high” and 1 with “medium” clinical benefit/importance). Conclusion We pilot tested an eight-step process to identify clinically important research needs. Before wider application of this process, it should be tested using systematic reviews of other diseases. Further evaluation should include assessment of the usefulness of the research needs generated using this process for primary researchers and funders.

Background People with cystic fibrosis experience chronic airway infections as a result of mucus build up within the lungs. Repeated infections often cause lung damage and disease. Airway clearance therapies aim to improve mucus clearance, increase sputum production, and improve airway function. The active cycle of breathing technique (also known as ACBT) is an airway clearance method that uses a cycle of techniques to loosen airway secretions including breathing control, thoracic expansion exercises, and the forced expiration technique. This is an update of a previously published review. Objectives To compare the clinical effectiveness of the active cycle of breathing technique with other airway clearance therapies in cystic fibrosis. Search methods We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched the reference lists of relevant articles and reviews. Date of last search: 25 April 2016. Selection criteria Randomised or quasi-randomised controlled clinical studies, including cross-over studies, comparing the active cycle of breathing technique with other airway clearance therapies in cystic fibrosis. Data collection and analysis Two review authors independently screened each article, abstracted data and assessed the risk of bias of each study. Main results Our search identified 62 studies, of which 19 (440 participants) met the inclusion criteria. Five randomised controlled studies (192 participants) were included in the meta-analysis; three were of cross-over design. The 14 remaining studies were cross-over studies with inadequate reports for complete assessment. The study size ranged from seven to 65 participants. The age of the participants ranged from six to 63 years (mean age 22.33 years). In 13 studies, follow up lasted a single day. However, there were two long-term randomised controlled studies with follow up of one to three years. Most of the studies did not report on key quality items, and therefore, have an unclear risk of bias in terms of random sequence generation, allocation concealment, and outcome assessor blinding. Due to the nature of the intervention, none of the studies blinded participants or the personnel applying the interventions. However, most of the studies reported on all planned outcomes, had adequate follow up, assessed compliance, and used an intention-to-treat analysis. Included studies compared the active cycle of breathing technique with autogenic drainage, airway oscillating devices, high frequency chest compression devices, conventional chest physiotherapy, and positive expiratory pressure. Preference of technique varied: more participants preferred autogenic drainage over the active cycle of breathing technique; more preferred the active cycle of breathing technique over airway oscillating devices; and more were comfortable with the active cycle of breathing technique versus high frequency chest compression. No significant difference was seen in quality of life, sputum weight, exercise tolerance, lung function, or oxygen saturation between the active cycle of breathing technique and autogenic drainage or between the active cycle of breathing technique and airway oscillating devices. There was no significant difference in lung function and the number of pulmonary exacerbations between the active cycle of breathing technique alone or in conjunction with conventional chest physiotherapy. All other outcomes were either not measured or had insufficient data for analysis. Authors' conclusions There is insufficient evidence to support or reject the use of the active cycle of breathing technique over any other airway clearance therapy. Five studies, with data from eight different comparators, found that the active cycle of breathing technique was comparable with other therapies in outcomes such as participant preference, quality of life, exercise tolerance, lung function, sputum weight, oxygen saturation, and number of pulmonary exacerbations. Longer-term studies are needed to more adequately assess the effects of the active cycle of breathing technique on outcomes important for people with cystic fibrosis such as quality of life and preference.

Identification of unanswered research questions about the management of gestational diabetes mellitus (GDM) is necessary to focus future research endeavors. We developed a process for elucidating the highest priority research questions on GDM.Using a systematic review on GDM as a starting point, we developed an eight-step process: (1) identification of research gaps, (2) feedback from the review's authors, (3) translation of gaps into researchable questions using population, intervention, comparators, outcomes, setting (PICOS) framework, (4) local institutions' stakeholders' refinement of research questions, (5) national stakeholders' use of Delphi method to develop consensus on the importance of research questions, (6) prioritization of outcomes, (7) conceptual framework, and (8) evaluation.We identified 15 high priority research questions for GDM. The research questions focused on medication management of GDM (e.g., various oral agents vs. insulin), delivery management for women with GDM (e.g., induction vs. expectant management), and identification of risk factors for, prevention of, and screening for type 2 diabetes in women with prior GDM. Stakeholders rated the development of chronic diseases in offspring, cesarean delivery, and birth trauma as high priority outcomes to measure in future studies.We developed an eight-step process using a multidisciplinary group of stakeholders to identify 15 research questions of high clinical importance. Researchers, policymakers, and funders can use this list to direct research efforts and resources to the highest priority areas to improve care for women with GDM.

PurposeThis study examined demographic and rehabilitation service variables affecting employment outcomes of people with spinal cord injury (SCI) receiving services from state vocational rehabilitation agencies. A secondary purpose was to determine whether there are disparities in services and outcomes between European American and Hispanic clients.MethodThe sample included 3,119 European Americans and 395 Hispanics who were closed either as rehabilitated (Status 26) or not rehabilitated (Status 28) by their state vocational rehabilitation agencies in the fiscal year 2005. The dependent variable is employment outcomes. The predictor variables include a set of personal characteristic variables and rehabilitation service variables.ResultsLogistic regression analysis results indicated that education, on-the-job training, job search assistance, job placement assistance, on-the-job support, maintenance services, assistive technology and other services were significant predictors of successful employment outcomes for individuals with SCI. European Americans were more likely to receive assistive technology services, and Hispanics were more likely to receive support services related to basic living needs.ConclusionsAssistive technology services, basic support services, and job placement support services were found to contribute significantly to successful rehabilitation outcomes. Minor disparities in case expenditures and service patterns were found between Hispanic and European American clients.

We thank Parsons et al. for their interest in our article.1 Parsons et al. indicated concern regarding our reference to reporting bias for pregabalin and note Pfizer's commitment to publishing company-sponsored research. We appreciate this and have included all available data that met eligibility criteria in our analysis. The results of our search for each drug—including counts of studies completed without available result—can be found in table e-2.1 Concerning the published pooled analysis,2 this included studies that did not meet our eligibility criteria. As a result, the pooled analysis was not included in our review.

We conducted a systematic review to estimate benefits and harms of the choice of timing of induction or elective cesarean delivery based on estimated fetal weight or gestational age in women with gestational diabetes mellitus (GDM).An electronic literature search was performed using MEDLINE, EMBASE, the Cumulative Index to Nursing and Allied Health Literature, and The Cochrane Central Register of Controlled Trials from inception to January 2007.Two investigators independently reviewed titles and abstracts, assessed article quality, and abstracted data. Maternal outcomes included cesarean delivery and operative vaginal delivery. Neonatal outcomes included birth weight, macrosomia, large for gestational age, shoulder dystocia, birth trauma, neonatal intensive care admissions, and perinatal mortality.Five studies met our inclusion criteria: one randomized controlled trial (RCT) and four observational studies. The RCT (n=200) compared the effect of labor induction at term with expectant management. The proportion of newborns with birth weight greater than the 90th percentile was significantly greater in the expectant-management group (23% compared with 10% with active induction, P=.02); there were no significant differences in rates of cesarean delivery, shoulder dystocia, neonatal hypoglycemia, or perinatal deaths. The four observational studies suggest a potential reduction in macrosomia and shoulder dystocia with labor induction and cesarean delivery for estimated fetal weight indications, but there was insufficient evidence to assess other clinical outcomes.Active rather than expectant management of labor at term for women with GDM may reduce rates of macrosomia and related complications. Further RCTs and observational studies with a broader range of outcomes are needed for sufficient evidence to inform clinical practice.

Objective: To examine the role of spiritual well-being as a mediator and moderator between perceived uncertainty and psychosocial adaptation to multiple sclerosis (MS). Participants and Design: Fifty individuals (40 women, 10 men) diagnosed with multiple sclerosis. Main Outcome Measures: Selfreport measures on illness uncertainty, spiritual (religious and existential) well-being, and psychosocial adjustment to illness were analyzed by a series of hierarchical multiple regression analyses. Results: Both uncertainty and spiritual well-being independently predicted psychosocial adjustment to MS after the influence of demographic and disability-related variables were considered. Spiritual well-being demonstrated a mediator effect but, mostly, failed to show a moderator effect. Conclusion: Spiritual well-being exerts an appreciable influence on adaptation to MS and also acts to mitigate the impact of uncertainty on adaptation. Rehabilitation psychologists may wish to consider its beneficial role as part of their clinical work. Multiple sclerosis (MS), one of the most common disabling diseases of young adults, is an inflammatory demyelinating disorder of the central nervous system with an estimated prevalence of about 250,000‐350,000 individuals in the United States (Devins & Shnek, 2000; Kalb, 1996; Schapiro, 1998). First symptoms usually appear at the young adult age, but the disease may also become evident later in life. The course of MS is highly variable and makes studies of etiology and possible mechanisms of treatment challenging. Because of MS’s highly variable clinical course, individual outcomes cannot be reliably predicted. For many individuals, MS starts with a relapsing‐remitting pattern with episodic exacerbations of neurological dysfunction, which remit completely or partially. Over the years, for most individuals, the disease develops into the secondary progressive form with accumulated disability (Lublin & Reingold, 1996).

This study examined the relationships among four predictors (functional limitations, perceived visibility of condition, and two disability-associated affective responses— anxiety and depression), coping strategies, and two outcome measures of psychosocial adaptation to disability (disability-specific psychosocial adjustment and life satisfaction). Based on responses from 121 university students with disabilities, two models (additive and mediational) were tested to investigate the contribution of coping strategies to psychosocial adaptation to disability. The findings of this exploratory study suggest that coping strategies add significantly to the variance in both outcome measures after controlling for the contribution of disability-related factors. The role of coping strategies as mediators between the set of predictor and outcome variables was mostly unsupported in this sample, however. Reasons for the latter finding are briefly outlined, along with the implications for rehabilitation research and practice.

We systematically reviewed the effectiveness and safety of continuous subcutaneous insulin infusion (CSII) with insulin analogs compared with multiple daily injections (MDI) in pregnant women with diabetes mellitus. We searched Medline®, Embase®, and the Cochrane Central Register of Controlled Trials through May 2013. Studies comparing CSII with MDI in pregnant women with diabetes mellitus were included. Studies using regular insulin CSII were excluded. We conducted meta-analyses where there were two or more comparable studies based on the type of insulin used in the MDI arm. Seven cohort studies of pregnant women with type 1 diabetes reported improvement in hemoglobin A1c (HbA1c) in both groups. Meta-analysis showed no difference in maternal and fetal outcomes for CSII versus MDI. Results were similar when CSII was compared with MDI with insulin analogs or regular insulin. Studies had moderate to high risk bias with incomplete descriptions of study methodology, populations, treatments, follow up, and outcomes. We conclude that observational studies reported similar improvements in HbA1c with CSII and MDI during pregnancy, but evidence was insufficient to rule out possible important differences between CSII and MDI for maternal and fetal outcomes. This highlights the need for future studies to examine the effectiveness and safety of CSII with insulin analogs and MDI in pregnant women with diabetes mellitus.

Vitamin D (2012) [11] 26 22 Total 143 106 It is important that guidelines are based on a transparent, systematic assessment of evidence as they are used by clinicians to inform decisions about patient management and treatment. In 2011, the Institute of Medicine (IOM) revised their definition of a clinical practice guideline emphasizing the need to use systematic reviews (SRs) in developing guidelines [1]. However, SRs often identify a lack of evidence, or find that it is conflicting or of poor quality. There are no standards for guideline panels on drafting recommendations when there is insufficient or inconclusive evidence. Some organizations opt for a non-recommendation (i.e., a neutral statement neither for nor against an intervention) [2,3]. However, this not always satisfactory and does not provide the requisite guidance to clinicians. Others may draft consensus-based recommendations. Clinicians need to be able to recognize and interpret recommendations made with insufficient evidence. We show how one organization reacted to insufficient evidence, and provide guidance on assessing the trustworthiness of a guideline. We reviewed a set of evidence-based guidelines developed by the Cystic Fibrosis Foundation (CFF) estimating the proportion of recommendations for which there was insufficient evidence and noting the subsequent actions taken by the guideline panel [4]. As of 2013, 7 of the CFF’s 31 guidelines were based on systematic reviews (evidence-based guidelines). We abstracted 143 recommendations from these 7 guidelines [5–11]. Of these 143, 37 were identified a priori as having a limited body of evidence and no SR was conducted. For the remaining 106 recommendations, the relevant guideline panel commissioned a SR to address the question (Table 1). For 75 (71%) of these 106, there was insufficient evidence from the SR to inform a recommendation (Table 2). Only one guideline, on airway

Inflectional morphology lies at the intersection of phonology, syntax and the lexicon, three language domains that are differentially impacted in the three main variants of primary progressive aphasia (PPA). To characterize spared and impaired aspects of inflectional morphology in PPA, we elicited inflectional morphemes in 48 individuals with PPA and 13 healthy age-matched controls. We varied the factors of regularity, frequency, word class, and lexicality, and used voxel-based morphometry to identify brain regions where atrophy was predictive of deficits on particular conditions. All three PPA variants showed deficits in inflectional morphology, with the specific nature of the deficits dependent on the anatomical and linguistic features of each variant. Deficits in inflecting low-frequency irregular words were associated with semantic PPA, with lexical/semantic deficits, and with left temporal atrophy. Deficits in inflecting pseudowords were associated with non-fluent/agrammatic and logopenic variants, with phonological deficits, and with left frontal and parietal atrophy.

This article begins by reviewing the literature on the concept of psychosocial adaptation to impairment among persons with epilepsy. Particular attention is devoted to those roots reasoned to lie at the base of psychosocial problems manifested by people with epilepsy. The research literature on coping with epilepsy is then reviewed in two areas: (a) general coping styles and their relationship to psychosocial adaptation, and (b) specific coping strategies and their association with adaptation to epilepsy. Next, clinical implications of these findings are briefly outlined. The article concludes with a discussion of research limitations identified in the conceptualization and measurement of coping, followed by suggestions for future research on coping and adaptation to epilepsy.

GTP cyclohydrolase I feedback regulatory protein (GFRP) mediates the feedback inhibition of GTP cyclohydrolase I activity by (6 R )- l -erythro-5,6,7,8-tetrahydrobiopterin (BH 4 ) through protein complex formation. Since guanine and BH 4 have a common pyrimidine ring structure, we examined the inhibitory effect of guanine and its analogs on the enzyme activity. Guanine, 8-hydroxyguanine, 8-methylguanine, and 8-bromoguanine inhibited the enzyme activity in a GFRP-dependent and pH-dependent manner and induced complex formation between GTP cyclohydrolase I and GFRP. The type of inhibition by this group is a mixed type. All these properties were shared with BH 4 . In striking contrast, inhibition by 8-azaguanine and 8-mercaptoguanine was GFRP-independent and pH-independent. The type of inhibition by 8-azaguanine and 8-mercaptoguanine was a competitive type. The two compounds did not induce complex formation between the enzyme and GFRP. These results demonstrate that guanine compounds of the first group bind to the BH 4 -binding site of the GTP cyclohydrolase I/GFRP complex, whereas 8-azaguanine and 8-mercaptoguanine bind to the active site of the enzyme. Finally, the possible implications in Lesch–Nyhan syndrome and Parkinson diseases of the inhibition of GTP cyclohydrolase I by guanine and 8-hydroxyguanine are discussed.

The mechanism of arsine (AsH3) toxicity is not completely understood. In this investigation, the toxicity of AsH3 and AsH3-produced hemolytic products was determined in primary culture of renal cortical epithelial cells and in the in situ isolated rat kidney. The objective of this study was to model kidney dysfunction caused by AsH3 exposure. The hypothesis was that unchanged AsH3 and AsH3-produced hemolysate that may contain arsenite (As(III)) as metabolite are both responsible for renal toxicity. Toxicity in isolated cells was determined by 2, 3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxa nilide inner salt (XTT) bioreduction, intracellular potassium (K+), and lactate dehydrogenase (LDH) leakage. Data from XTT bioreduction showed that most toxicity occurred at 1 hour and was independent of the arsenic species. At 4 hours, the observed toxicity depended on the arsenic species and was generated by As(III). In the isolated cells, the As(III)-spiked hemolysate produced similar toxicities with regard to intracellular K and LDH. The AsH3-hemolysate only affected LDH at 1 hour. Unchanged AsH3 was very toxic to the isolated rat kidney. In this system, after 10 minutes exposure to AsH3, the effects of toxicity were observed mainly in the glomerular and peritubular endothelial cells. Tubular epithelial cells also presented early signs of toxicity. The AsH3-hemolysate was not toxic after a 1 -minute exposure. These data suggested that early cytotoxicity caused by unchanged AsH3 results in kidney dysfunction, produced by AsH3, and later by the formation of a hemolysate that may contain As(III). These data may be important in understanding the renal toxic effects after AsH3 intoxication.

Objective:Mental stress has been shown to produce intestinal disease, but the effects of a mild environmental stress on intestinal physiology have not been elucidated. This study was performed to d...

Objective:This study was performed to determine the effects of environmental stress on the leakage to albumin and architecture of microvessels in the rat mesentery. Methods:One group of rats (Group A, n= 6) were examined immediately upon arrival at the animal care facility. Groups B (n= 24) and C (n= 32) were housed in rooms with high and low personnel activity, respectively, for up to 7 weeks. Group D (n=18) was housed in the high activity room for 2, 3, or 4 weeks followed by the low activity room. Results:Rats in the low activity room for 3–4 weeks showed robust microvascular networks within 25% to 50% of the mesenteric windows (each window consisting of the tissue extending between two adjacent feeding arterioles in the mesentery), whereas rats in Group B only showed fragile vessels at the edges of the mesenteric windows within fat deposits. Groups A and C demonstrated little mesenteric fat and few fragile vessels, in contrast to group B. Group D showed increased mesenteric networks and decreased mese...

Abstract Local infusion of agents through perforated catheters may reduce neointimal formation following vascular angioplasty. Such treatment will succeed only if the drug is retained within the arterial intima long enough to promote repair. Drugs will be dispersed throughout the wall predominantly by transmural convection instead of diffusion if the Peclet number, Pe=J(1-ς f )/P, is greater than unity, where J is the transmural fluid flow per unit surface area and ς f and P are the reflection and permeability coefficients to the drug, respectively. Although the targets of local drug delivery will be atherosclerotic vessels, little is known about the transport properties of these vessels. Accordingly, we evaluated the effects of hypercholesterolemia and atherosclerosis on J per unit pressure (hydraulic conductance, L p ) and on ultrastructure in femoral arteries. Measurements were made at 30, 60, and 90 mm Hg in anesthetized New Zealand white rabbits fed a normal diet (n=6) and after 3 weeks of lipid feeding (n=19). Atherosclerosis was induced in six lipid-fed animals by air desiccation of a femoral artery. Hydraulic conductance was significantly greater in vessels from hypercholesterolemic than from normal animals and decreased with pressure only in hypercholesterolemic arteries. Atherosclerosis did not augment hydraulic conductance compared with hypercholesterolemia alone. Electron microscopic examination demonstrated damaged endothelium in hypercholesterolemic arteries and both altered endothelium and less tightly packed medial tissue, compared with controls, in atherosclerotic vessels, at least at lower pressures. Peclet numbers for macromolecules exceeded unity for all three groups of arteries and reached 0.3 to 0.4 for molecules as small as heparin. Thus, convection plays a dominant role in the distribution of macromolecular agents following local delivery and may result in their rapid transport to the adventitia in the femoral artery.

Background To identify demographic and clinical characteristics associated with cases of hepatosplenic T-cell lymphoma (HSTCL) in patients with Crohn’s disease, and to assess strength of evidence for a causal relationship between medications and HSTCL in Crohn’s disease. Methods We identified cases of HSTCL in Crohn’s disease in studies included in a comparative effectiveness review of Crohn’s disease medications, through a separate search of PubMed and Embase for published case reports, and from the Food and Drug Administration (FDA) Adverse Event Reporting System (AERS). We used three causality assessment tools to evaluate the relationship between medication exposure and HSTCL. Results We found 37 unique cases of HSTCL in patients with Crohn’s disease. Six cases were unique to the published literature and nine were unique to AERS. Cases were typically young (

Background Clinicians and patients need updated evidence on the comparative effectiveness and safety of diabetes medications to make informed treatment choices. Purpose To evaluate the comparative effectiveness and safety of monotherapy (thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose cotransporter 2 [SGLT-2] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) and selected metformin-based combinations in adults with type 2 diabetes. Data sources English-language studies from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, indexed from inception through March 2015 (MEDLINE search updated through December 2015). Study selection Paired reviewers independently identified 179 trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations. Data extraction Two reviewers independently assessed study quality and serially extracted data and graded the strength of evidence. Data synthesis Cardiovascular mortality was lower for metformin versus sulfonylureas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or of low strength. Reductions in hemoglobin A1c values were similar across monotherapies and metformin-based combinations, except that DPP-4 inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP-1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors. Limitation Most studies were short, with limited ability to assess rare safety and long-term clinical outcomes. Conclusion The evidence supports metformin as first-line therapy for type 2 diabetes, given its relative safety and beneficial effects on hemoglobin A1c, weight, and cardiovascular mortality (compared with sulfonylureas). On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies. Primary funding source Agency for Healthcare Research and Quality.

The purpose of the present study was to compare the endothelial actin cytoskeleton at sites of inflammation-induced macromolecular leakage with that of intact endothelium. The circulation of a selected mesenteric window of anesthetized rats was perfused for 3 min with histamine (100 microM) plus fluorescein isothiocyanate (FITC)-albumin, or FITC-albumin alone, and was fixed at physiological pressure. The vasculature was then perfusion stained with rhodamine phalloidin to label filamentous actin (F-actin) and examined with a confocal microscope. The leakage sites were divided into three categories based on the extent of FITC-albumin leakage: 1) focal leaks, 2) mid leaks, and 3) extended leaks. The leaks were identifiable with a particular endothelial cell(s), and the structure of the endothelial actin cytoskeleton was characterized at these sites. Focal leaks occurred along a small region of endothelial cell-cell contact and in most observed cases were located at a region of specific disruption of the endothelial peripheral actin rim (PAR). Mid leaks involved the disruption of one endothelial cell, and the affected cell was observed to have extended disruption of the PAR as well as increased diffuse F-actin staining throughout the cell (1.9-fold increase relative to adjacent cells). Extended leaks involved the disruption of two or more adjacent endothelial cells, and each cell exhibited an actin pattern similar to that seen at mid leaks. These results show that histamine-induced macromolecular leakage in situ is associated with significant changes in the endothelial actin cytoskeleton.

Background Clinical practice guidelines have an important role in guiding choices among the numerous medications available to treat type 2 diabetes mellitus, but little is known about their quality. Purpose To assess whether guidelines on oral medications for type 2 diabetes are consistent with a systematic review of the current evidence and whether the consistency of the guidelines depends on the quality of guideline development. Data sources MEDLINE, CINAHL, and guideline-specific databases were searched between July 2007 and August 2011, after the 2007 publication of a peer-reviewed systematic review on oral diabetes medications. Study selection Two reviewers independently screened citations to identify English-language guidelines on oral medications to treat type 2 diabetes that were applied in the United States, United Kingdom, and Canada. Data extraction Reviewers assessed whether the guidelines addressed and agreed with 7 evidence-based conclusions from the 2007 systematic review. Two reviewers independently rated guideline quality by using 2 domains from the Appraisal of Guidelines Research and Evaluation instrument. Data synthesis Of the 1000 screened citations, 11 guidelines met the inclusion criteria. Seven guidelines agreed with the conclusion that metformin is favored as the first-line agent. Ten guidelines agreed that thiazolidinediones are associated with higher rates of edema and congestive heart failure compared with other oral medications to treat type 2 diabetes. One guideline addressed no evidence-based conclusions, and 5 guidelines agreed with all 7 conclusions. The summary scores of the rigor of development (median, 28.6% [range, 16.7% to 100.0%]) and editorial independence (median, 75.0% [range, 8.3% to 100.0%]) domains varied greatly across guidelines. Guidelines that received higher quality scores contained more recommendations that were consistent with the evidence-based conclusions. Limitation Only English-language guidelines targeting users in the United States, United Kingdom, and Canada that contained recommendations on oral medications were included. Conclusion Not all practice guidelines on oral treatment of type 2 diabetes were consistent with available evidence from a systematic review. Guidelines judged to be of higher quality contained more recommendations consistent with evidence-based conclusions. The quality of guideline development processes varied substantially. Primary funding source Agency for Healthcare Research and Quality.

Background. Policymakers need estimates of the impact of tobacco control (TC) policies to set priorities and targets for reducing tobacco use. We systematically reviewed the independent effects of TC policies on smoking behavior.Methods. We searched MEDLINE (through January 2012) and EMBASE and other databases through February 2009, looking for studies published after 1989 in any language that assessed the effects of each TC intervention on smoking prevalence, initiation, cessation, or price participation elasticity. Paired reviewers extracted data from studies that isolated the impact of a single TC intervention.Findings. We included 84 studies. The strength of evidence quantifying the independent effect on smoking prevalence was high for increasing tobacco prices and moderate for smoking bans in public places and antitobacco mass media campaigns. Limited direct evidence was available to quantify the effects of health warning labels and bans on advertising and sponsorship. Studies were too heterogeneous to pool effect estimates.Interpretations. We found evidence of an independent effect for several TC policies on smoking prevalence. However, we could not derive precise estimates of the effects across different settings because of variability in the characteristics of the intervention, level of policy enforcement, and underlying tobacco control environment.

OBJECTIVE To translate the theoretical constructs from a model of resilience into a structural equation model and evaluate relationships among the model's theoretical constructs associated with resilience and the occurrence of depressive symptoms. DESIGN Quantitative descriptive research design using structural equation modeling (SEM). PARTICIPANTS Two-hundred and fifty-five individuals with SCI recruited from the Canadian Paraplegic Association (CPA). OUTCOME MEASURES Outcome was measured by the Center for Epidemiologic Studies-Depression Scale. RESULTS The resilience model fit the data relatively well: χ² (200, N = 255) = 451.57, p < .001; χ²/df = 2.26; CFI = .92, RMSEA = 0.070 (90% CI: 0.062-0.079), explaining 77% of the variance in depressive symptomatology. Severity of SCI-related stressors significantly influenced perceived stress (β = .60) and perceived stress, in turn, affected depressive symptoms (β = .66), characteristics of resilience (β = -.43), and social support (β = -.26). The resilience characteristics had an inverse relationship with depressive symptoms (β = -.29). No direct relationship was found between severity of SCI-related stressors and depressive symptoms. CONCLUSIONS Findings provide support for the resilience model and suggests characteristics of resilience "buffer" the perceptions of stress on depressive symptoms. The resilience model may be useful to guide clinical interventions designed to improve the mental health of individuals with SCI.

Given the increase in medications for type 2 diabetes mellitus, clinicians and patients need information about their effectiveness and safety to make informed choices.To summarize the benefits and harms of metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 receptor agonists, as monotherapy and in combination, to treat adults with type 2 diabetes.MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from inception through April 2010 for English-language observational studies and trials. The MEDLINE search was updated to December 2010 for long-term clinical outcomes.Two reviewers independently screened reports and identified 140 trials and 26 observational studies of head-to-head comparisons of monotherapy or combination therapy that reported intermediate or long-term clinical outcomes or harms.Two reviewers following standardized protocols serially extracted data, assessed applicability, and independently evaluated study quality.Evidence on long-term clinical outcomes (all-cause mortality, cardiovascular disease, nephropathy, and neuropathy) was of low strength or insufficient. Most medications decreased the hemoglobin A(1c) level by about 1 percentage point and most 2-drug combinations produced similar reductions. Metformin was more efficacious than the DPP-4 inhibitors, and compared with thiazolidinediones or sulfonylureas, the mean differences in body weight were about -2.5 kg. Metformin decreased low-density lipoprotein cholesterol levels compared with pioglitazone, sulfonylureas, and DPP-4 inhibitors. Sulfonylureas had a 4-fold higher risk for mild or moderate hypoglycemia than metformin alone and, in combination with metformin, had more than a 5-fold increased risk compared with metformin plus thiazolidinediones. Thiazolidinediones increased risk for congestive heart failure compared with sulfonylureas and increased risk for bone fractures compared with metformin. Diarrhea occurred more often with metformin than with thiazolidinediones.Only English-language publications were reviewed. Some studies may have selectively reported outcomes. Many studies were small, were of short duration, and had limited ability to assess clinically important harms and benefits.Evidence supports metformin as a first-line agent to treat type 2 diabetes. Most 2-drug combinations similarly reduce hemoglobin A(1c) levels, but some increased risk for hypoglycemia and other adverse events.Agency for Healthcare Research and Quality.

Introduction: Web-based treatments can deliver broad reaching, relatively inexpensive, and clinically tested methods for smoking cessation. We performed a systematic review of randomized controlled trials (RCTs) of smoking cessation to evaluate the efficacy of Web-based interventions in adults, college students, and adolescents.Methods: MEDLINE, EMBASE, The Cochrane Library, CINAHL, and PsycINFO were searched from January 1, 1990 through February 12, 2010 for RCTs examining the efficacy of Web-based smoking cessation programs. Paired reviewers abstracted data on study design, patient characteristics, and outcomes sequentially and did quality assessments independently.Results: Twenty-one RCTs met eligibility criteria, with 15 conducted among adults. Among adults, 2 RCTs found that a multicomponent intervention with Web and non-Web–based elements was more efficacious than a self-help manual, and one of 2 RCTs found that Web-based interventions may be more effective than no treatment. Three trials provided insufficient evidence to demonstrate whether Web-based interventions were more efficacious than counseling. By contrast, tailored Web sites in 2 RCTs and greater Web site exposure in 6 of 7 RCTs were associated with higher rates of abstinence. Among college students, evidence supporting use of Web-based interventions was insufficient because the one RCT conducted was also a multicomponent intervention. Five RCTs among adolescents demonstrated mixed results, with insufficient evidence supporting their efficacy.Conclusions: Evidence supporting the use of Web-based interventions for smoking cessation is insufficient to moderate in adults and insufficient in college students and adolescents. These RCTs have, however, elucidated clinical, methodological, and statistical practices that are likely to improve future trial design and treatment delivery.

In eight anesthetized New Zealand White rabbits, the aorta was cannulated in situ for measurement of hydraulic conductance (Lp) at different pressures with and without endothelium. De-endothelialization increased Lp at > or = 75 mmHg but not at 50 mmHg. Because endothelium resists transmural water flow, the endothelium must also increase medial Lp at 50 mmHg. To determine whether this effect results from secretion of endothelial-derived relaxing factor (EDRF), Lp was measured in eight rabbits in the presence and absence of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of EDRF synthesis. At 50 mmHg L-NAME reduced Lp from 6.79 +/- 2.19 to 2.59 +/- 1.41 (SD) x 10(-8) (P < 0.05, paired Student's t test). After L-NAME was removed, Lp returned to its control value. At 125 mmHg L-NAME did not significantly change Lp, although endothelial permeability seemed to increase. L-NAME did not affect Lp of nine de-endothelialized vessels at either pressure. An additional five experiments showed that the effect of L-NAME at 50 mmHg was reversed by L-arginine. Eleven additional experiments demonstrated that NG-nitro-D-arginine methyl ester does not affect Lp at 50 mmHg. These results indicate that EDRF increases Lp of the rabbit aorta at low pressures.

The objective of this study is to systematically review methods for detecting Factor V Leiden or prothrombin G20210A. English-language literature from MEDLINE, EMBASE, The Cochrane Library, the Cumulative Index to Nursing and Allied Health Literature, PsycInfo(c), 2000-December 2008. Studies assessed methods for detection of these mutations in at least 10 human blood samples and reported concordance, discordance, or reproducibility. Two investigators abstracted data on the sample selection criteria, test operators, DNA extraction, experimental test, reference standard, commercial instruments, concordance rates, explanation of any discordance, and whether discordance resolved after repetition. We assessed strength of the evidence using the GRADE criteria. We reviewed 7,777 titles and included 66 articles. The majority of the reviewed studies used PCR-RFLP or AS-PCR as the reference standard. The studies demonstrated that commercially available and precommercial tests have high analytic validity with all having greater than 99% concordance with the reference standard. With a few exceptions, discordance resolved with repetition of the test, suggesting operator or administrative errors were responsible for the discordant results. In the quality assurance studies, greater than 98% of laboratories demonstrated high, even perfect, accuracy when asked to diagnose a sample with a known mutation. The majority of errors came from a limited number of laboratories. Although not all methods may be accurate, there is high-grade evidence that genetic tests for the detection of FVL and prothrombin G20210A have excellent analytic validity. There is high-grade evidence that most, but not all, clinical laboratories test for FVL and prothrombin G20210A accurately.

Women with a history of gestational diabetes mellitus are at high risk for type 2 diabetes mellitus. We systematically reviewed and synthesized the literature on the sensitivity, specificity, and reproducibility of postpartum screening tests for type 2 diabetes in women with prior gestational diabetes to inform screening guidelines.We searched electronic databases through October 1, 2008. Two investigators independently reviewed titles, abstracts, and articles, performed serial data abstraction, and independently assessed quality. We calculated standard errors and confidence intervals for sensitivity and specificity using the exact binomial formula.Eleven studies contained 13 evaluations of a comparison screening test with the 2-h 75-g oral glucose tolerance test (OGTT) reference. All studies used a cross-sectional study design. There were ten comparisons of a single fasting blood glucose (FBG)=7.0 mmol/L (=126 mg/dL) with the OGTT. The sensitivity ranged from 14%-100% in five studies using the 1985 World Health Organization's (WHO) criteria as the reference and from 16%-89% in five studies using the 1999 WHO criteria as the reference. Variation in the sensitivities may be due to the limited number of comparisons, differences in populations, and timing of screening. There were high losses to follow-up, limiting generalizability.When compared with the OGTT, the single FBG alone was not consistently reported to be a sensitive screening test for type 2 diabetes in women with a history of gestational diabetes. Longitudinal studies are needed to address the natural history of glucose metabolism in women with a history of gestational diabetes, the optimal approach to diagnostic testing for type 2 diabetes in this population, and the short-term and long-term outcomes of testing.

Little is known about the comparative risks and benefits of medical treatments for gestational diabetes mellitus (GDM). We conducted a systematic review of randomized controlled trials and observational studies of maternal and neonatal outcomes in women with GDM treated with oral diabetes agents compared with all types of insulin.We searched four electronic databases from inception through January 2007. Terms for GDM, insulins, and oral hypoglycemic agents were used in the search. Two investigators independently reviewed titles and abstracts, performed data abstraction on full articles, and assessed study quality.Articles were excluded if they had no comparison group or did not use a standard diagnosis of GDM (3-hour, 100-g oral glucose tolerance test or 2-hour, 75-g oral glucose tolerance test). Nine studies met our inclusion criteria, four randomized controlled trials (n=1,229 participants) and five observational studies (n=831 participants). Data were abstracted on study characteristics, gestational age at treatment, medication dosage, and length of follow-up. Outcomes included glycemic control, infant birth weight, neonatal hypoglycemia, and congenital anomalies.Two trials compared insulin to glyburide; one trial compared insulin, glyburide, and acarbose; and one trial compared insulin to metformin. No significant differences were found in maternal glycemic control or cesarean delivery rates between the insulin and glyburide groups. A meta-analysis showed similar infant birth weights between women treated with glyburide and women treated with insulin (mean difference -93 g) (95% confidence interval -191 to 5 g). There was a higher proportion of infants with neonatal hypoglycemia in the insulin group (8.1%) compared with the metformin group (3.3%) (P=.008). The rate of congenital malformations did not differ between pregnancies treated with insulin and those treated with oral agents. Observational studies were limited by selection bias and confounding.No substantial maternal or neonatal outcome differences were found with the use of glyburide or metformin compared with use of insulin in women with GDM.