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Background: No evidence currently exists characterising global outcomes following major cancer surgery, including esophageal cancer. Therefore, this study aimed to characterise impact of high income countries (HIC) versus low and middle income countries (LMIC) on the outcomes following esophagectomy for esophageal cancer.Method: This international multi-center prospective study across 137 hospitals in 41 countries included patients who underwent an esophagectomy for esophageal cancer, with 90-day follow-up. The main explanatory variable was country income, defined according to the World Bank Data classification. The primary outcome was 90-day postoperative mortality, and secondary outcomes were composite leaks (anastomotic leak or conduit necrosis) and major complications (Clavien-Dindo Grade III - V). Multivariable generalized estimating equation models were used to produce adjusted odds ratios (ORs) and 95% confidence intervals (CI95%).Results: Between April 2018 to December 2018, 2247 patients were included. Patients from HIC were more significantly older, with higher ASA grade, and more advanced tumors. Patients from LMIC had almost three-fold increase in 90-day mortality, compared to HIC (9.4% vs 3.7%, p < 0.001). On adjusted analysis, LMIC were independently associated with higher 90-day mortality (OR: 2.31, CI95%: 1.17-4.55, p = 0.015). However, LMIC were not independently associated with higher rates of anastomotic leaks (OR: 1.06, CI95%: 0.57-1.99, p = 0.9) or major complications (OR: 0.85, CI95%: 0.54-1.32, p = 0.5), compared to HIC.Conclusion: Resections in LMIC were independently associated with higher 90-day postoperative mortality, likely reflecting a failure to rescue of these patients following esophagectomy, despite similar composite anastomotic leaks and major complication rates to HIC. These findings warrant further research, to identify potential issues and solutions to improve global outcomes following esophagectomy for cancer.

The number of master's degree programs in healthcare quality and safety (HQS) has increased significantly over the past decade. Academic accreditation provides assurance that educational programs are of a high quality and meet the needs of students, employers, and the general public. Under the guidance of the Commission on Accreditation of Healthcare Management Education, faculty from 9 universities collaborated in the development of criteria and related content domains to be used in the accreditation of graduate programs in HQS. Thirteen content domains were identified. Four of the content domains, safety and error science, improvement science and quality principles, evidence-based practice, and measurement and process improvement are thought to be foundational domains for graduate education in HQS. This article describes the development of the content domains and accompanying standards for accreditation of graduate programs in HQS.

Objective To evaluate outcomes before and after implementation of a risk-stratified heparin-based obstetric thromboprophylaxis protocol. Methods We performed a retrospective cohort study of all patients who delivered at our tertiary care center from 2013 to 2018. Deliveries were categorized as preprotocol (2013-2015; no standardized heparin-based thromboprophylaxis) and postprotocol (2016-2018). Patients receiving outpatient anticoagulation for active venous thromboembolism (VTE) or high VTE risk were excluded. Coprimary effectiveness and safety outcomes were postpartum VTEs and wound hematomas, respectively, newly diagnosed after delivery and up to 6 weeks postpartum. Secondary outcomes were other wound or bleeding complications, including unplanned surgical procedures (eg, hysterectomies, wound explorations) and blood transfusions. Outcomes were compared between groups, and adjusted odds ratios (aORs) and 95% CIs were calculated using the preprotocol group as reference. Results Of 24,229 deliveries, 11,799 (49%) occurred preprotocol. Although patients were more likely to receive heparin-based prophylaxis postprotocol (15.6% vs 1.2%, P Conclusion Risk-stratified heparin-based thromboprophylaxis in a general obstetric population was associated with increased wound and bleeding complications without a complementary decrease in postpartum VTE. Guidelines recommending this strategy should be reconsidered.

Context Spiritual well-being is the expression of one's spirituality as measured in the dimensions of existential and religious well-being. The Smith Cognitive Affective Model of Athletic Burnout suggests that personality factors such as spiritual well-being and the use of religious coping methods may affect burnout as well as its causes and outcomes. This has not been examined in collegiate athletic trainers (ATs). Objective To investigate the relationship between spiritual well-being and burnout in collegiate ATs. Design Cross-sectional study. Setting Web-based survey. Patients or Other Participants A total of 783 certified ATs employed full time in the collegiate setting participated. Part-time employees (eg, graduate assistants, interns) were excluded. Main Outcome Measure(s) A 100-item online questionnaire was created for this study. It used items from previously developed scales, including the Spiritual Well-Being Scale, the Brief RCOPE, the Maslach Burnout Inventory, and substance-use questions from the Monitoring the Future study. Participants were able to complete the survey in approximately 10–15 minutes. Multiple regression analyses were used to analyze survey data. We mapped all independent (existential well-being, religious well-being, positive and negative religious coping) and dependent variables (situational variables, Maslach Burnout Inventory burnout subscales, substance use, and intention to leave) onto the Smith Cognitive-Affective Model of Athletic Burnout to determine which variables altered burnout levels, substance use, and intention to leave. Tests of mediation or moderation were conducted when appropriate. Results Existential well-being was a significant positive predictor of social support and a significant negative predictor of work-family conflict, decreased sense of personal accomplishment, emotional exhaustion, depersonalization, intention to leave the profession, and binge drinking. Existential well-being also served as a mediator or moderator in several components of the model. Conclusions Existential well-being was a protective factor against burnout as well as some of the causes and effects of burnout in collegiate ATs.

Background. Dolutegravir-based 2-drug regimens (DTG 2DRs) are now accepted as alternatives to 3-drug regimens for HIV antiretroviral treatment (ART); however, literature on physician drivers for prescribing DTG 2DR is sparse. This study evaluated treatment patterns of DTG 2DR components in clinical practice in the US. Methods. This was a retrospective chart review in adult patients in care in the US with HIV-1 who received DTG 2DR prior to July 31, 2017, with follow-up until January 30, 2018. Primary objectives of the study were to determine reasons for patients initiating DTG 2DR and to describe the demographics and clinical characteristics. All analyses were descriptive. Results. Overall, 278 patients received DTG 2DR (male: 70%; mean age: 56 years). Most patients were treatment experienced (98%), with a mean 13.5 years of prior ART. DTG was most commonly paired with darunavir (55%) or rilpivirine (27%). The most common physician-reported reasons for initiating DTG 2DR were treatment simplification/streamlining (30%) and avoidance of potential long-term toxicities (20%). Before starting DTG 2DR, 42% of patients were virologically suppressed; of those, 95% maintained suppression while on DTG 2DR. Of the 50% of patients with detectable viral load before DTG 2DR, 79% achieved and maintained virologic suppression on DTG 2DR during follow-up. There were no virologic data for 8% of patients prior to starting DTG 2DR. Only 15 patients discontinued DTG 2DR, of whom 4 (27%) discontinued due to virologic failure. Conclusions. Prior to commercial availability of the single-tablet 2DRs, DTG 2DR components were primarily used in treatment-experienced patients for treatment simplification and avoidance of long-term toxicities. Many of these patients achieved and maintained virologic suppression, with low discontinuation rates.

PURPOSE The diagnosis of monoamine-related psychiatric disorders is based on the phenomenological evaluation of symptoms and behavior by trained clinicians. The CEST technique can be sensitive to monoamines such as serotonin. This study quantifies the CEST properties of the compounds in the serotonin biosynthesis pathway with the goal of developing noninvasive techniques aimed at advancing the diagnostic assessment of serotonin dysfunction. METHODS Saturation transfer-weighted images of L-tryptophan, 5-hydroxytryptophan, serotonin, 5-hydroxyindoleacetic acid, and melatonin phantoms were acquired over a range of saturation amplitudes and frequency offsets along with observed T1 , T2 , and B1 efficiency maps at physiological temperature and pH of 5.5, 6.7, and 7.4. The CEST and MT data were fitted to a three-pool Bloch-McConnell model of exchange to estimate the model parameters. RESULTS At a pH of 5.5, tryptophan, 5-hydroxytryptophan and serotonin exhibited significant CEST contrast at resonance frequency offset, Δω between 2.64 ppm and 2.71 ppm, and magnetization transfer ratio asymmetry amplitudes up to 20% per 30 mM. At a pH of 7.4, all molecules exhibited significant CEST contrast between 5.11 ppm and 5.47 ppm, and magnetization transfer ratio asymmetry amplitudes up to 9.5% per 30 mM. At a pH of 6.7, all studied compounds except melatonin exhibited a CEST peak from each of the preceding two pHs. CONCLUSION At a pH of 5.5, tryptophan, 5-hydroxytryptophan, and serotonin CEST contrast originates from the NH3+ side chain, whereas at a pH of 7.4, CEST contrast is due to the chemical exchange between water and the NH proton on the indole ring. The data in this study could be used to inform future investigations aimed at detecting and measuring in vivo serotonin.

Objective To identify the causes, effects, and prevalence of burnout in athletic trainers (ATs) identified in the literature. Data Sources EBSCO: SPORTDiscus and OneSearch were accessed, using the search terms athletic trainer AND burnout. Study Selection Studies selected for inclusion were peer reviewed, published in a journal, and written in English and investigated prevalence, causes, effects, or alleviation of AT burnout. Data Extraction The initial search yielded 558 articles. Articles that did not specifically involve ATs were excluded from further inspection. The remaining 83 full-text articles were reviewed. Of these 83 articles, 48 examined prevalence, causes, effects, or alleviation of AT burnout. An evaluation of the bibliographies of those 48 articles revealed 3 additional articles that were not initially identified but met the inclusion criteria. In total, 51 articles were included in data collection. Data Synthesis Articles were categorized based on investigation of prevalence, causes, effects, or alleviation of burnout. Articles were also categorized based on which subset of the athletic training population they observed (ie, athletic training students, certified graduate assistants, high school or collegiate staff members, academic faculty). Conclusions Burnout was observed in all studied subsets of the population (ie, students, graduate assistants, staff, faculty), and multiple causes of burnout were reported. Suggested causes of burnout in ATs included work-life conflict and organizational factors such as poor salaries, long hours, and difficulties dealing with the “politics and bureaucracy” of athletics. Effects of burnout in ATs included physical, emotional, and behavioral concerns (eg, intention to leave the job or profession).

Single-tablet regimens (STRs) can improve antiretroviral therapy (ART) adherence; however, the relationship between long-term adherence and patient healthcare resource utilization (HRU) is unclear. The objective of this study was to assess long-term ART adherence among people living with HIV (PLHIV) using STRs and multi-tablet regimens (MTRs) and compare HRU over time by adherence.This retrospective study analyzed medical and pharmacy claims (Optum Clinformatics Data Mart Database). Included PLHIV were aged ≥18 years, had ≥1 medical claim with an HIV diagnosis, and had pharmacy claims for a complete STR or MTR. Adherence was analyzed as the proportion of days covered (PDC), stratified as ≥95%, very high; 90-95%, high; 80-90%, moderate;80%, low. Cumulative all-cause and HIV-related HRU were calculated across 4 years. Among PLHIV with ≥4-year follow-up, HRU was assessed by adherence.Among 15,153 PLHIV included, 63% achieved PDC ≥90% during Year 1. Among the subgroup of PLHIV with ≥4-year follow-up (ART adherence showed room for improvement, particularly over the long term. PLHIV receiving STRs exhibited higher adherence vs those receiving MTRs; this difference increased over time. The proportion of PLHIV with higher HRU was significantly higher among those with lower adherence and became greater over time. Interventions and alternative therapies to improve adherence among PLHIV should be explored.

Negative urgency – acting rashly in response to negative emotions – is a risk factor for central adiposity. We examine whether the relationship between negative urgency and waist-to-height ratio (WHtR) is mediated by eating behaviors (emotional eating, external eating, and cognitive restraint) and moderated by depressive symptom severity, factors that could be targeted to reduce risk associated with negative urgency. Using baseline data from the Nathan Kline Institute-Rockland Sample (N = 872; mean age = 42.4 years, SD = 15.3; 65% female; 27% non-White; mean body mass index = 27.9 kg/m(2), SD = 5.9), we conducted a series of mediation and moderated mediation analyses controlling for age, sex, race, and socioeconomic status. Overall, there was a positive association between negative urgency and WHtR. Emotional eating (ab = 0.02, SE = 0.003, 95% CI [0.02, 0.03]) and uncontrolled eating (ab = 0.008, SE = 0.002, 95% CI [0.004, 0.01]) were partial mediators of the relationship between negative urgency and WHtR, while cognitive restraint was not. In a parallel mediation model, emotional eating remained significant, while uncontrolled eating did not. Depressive symptom severity moderated the indirect effect of negative urgency on WHtR through emotional eating (b(int) = −0.08, p < .001) but not the direct effect of negative urgency on WHtR. Our results indicate that emotional eating is a viable potential mechanism explaining the relationship between negative urgency and WHtR, and the indirect effect of negative urgency on WHtR through emotional eating becomes stronger as depressive symptom severity decreases.

Gastric Schwannomas (GS) are benign, slow-growing, Sub-mucosal tumours (SMT’s) that constitute 0.2% of all gastric tumours. They usually have a homogenous appearance on contrast enhanced computed tomography of the abdomen (CECT Abdomen) and rarely show malignant features such as irregular borders, calcification, local invasion and mucosal ulceration. Due to lack of mucosal changes and poor yield during Oesophago-Gastro-Duodenoscopy (OGD) and biopsy, they are often misdiagnosed as Gastro-Intestinal Stromal tumours (GISTs), a malignant SMT. Treatment options range from conservative management to major open resections and are dependent on the size and clinical presentation. Histologically, GS are spindle cells tumours with lymphoid cuffing. On Immunohistochemistry, they test positive for S100 but negative for DOG1, Smooth muscle actin and Desmin which are markers of GISTs. Here we present the case of a 61-year-old female with a 15-year history of epigastric fullness that turned out to be a 13.8cm GS originating from the greater curvature of the stomach. On CECT Abdomen, the tumour appeared heterogeneous, with multiple calcium deposits and local invasion into the transverse mesocolon. The patient underwent a Sub-total gastrectomy with en-bloc transverse colectomy. Symptoms from GS can be vague and can pose a significant diagnostic and investigative dilemma. Physicians and Surgeons should have a low threshold to investigate prolonged symptoms with CECT Abdomen. Despite their benign nature, if left undiagnosed, GS can grow to significant sizes and mimic malignant gastric tumours on conventional imaging resulting in unconventionally major resections.

Aims The long-term effect of psychiatric medication on weight loss after bariatric surgery is unknown. The aim of this study was to compare the 1 year and 5 year percentage excess weight loss (%EWL) and BMI between those prescribed and not prescribed psychiatric medication who underwent laparoscopic bariatric surgery. Methods Consecutive patients, who received identical perioperative care were selected from a prospectively maintained database. Patients who had gastric bands and revisional procedures were excluded. Patients were defined as “prescribed psychiatric medication” if prescribed antidepressant, antipsychotic or mood stabilizer at baseline and subdivided into those taking a single agent and those on two or more agents. Results Of 119 patients (58 sleeve gastrectomy, 61 gastric bypass), 46 patients were prescribed psychiatric medication (40 one agent, 6 two or more agents). At 1 year, median %EWL did not differ significantly in those taking no agent, 1 agent and 2 or more agents respectively (66.8, 63.3, 57.4, p = 0.433). At 5 years this approached, but did not reach statistical significance (56.6, 54.4, 40.6, p = 0.099). The same pattern was observed for median BMI at 5 years (35.7, 39.2, 40.7, p = 0.086). Conclusion There is no significant difference in excess weight loss or BMI at 1 year post surgery between patients prescribed psychiatric medication and those not prescribed psychiatric medication but there is a difference at 5 years, which shows a trend towards statistical significance. Such patients should receive intensive specialist bariatric psychological support for a prolonged period after surgery.

BackgroundSocial factors are recognized determinants of morbidity and mortality and also have an impact on use of medical services. Low education level and lack of social and financial resources have been associated with prolonged hospital stays while for migration factors evidence is inconclusive. The objective of this study was i) to assess the associations of social factors with length of hospital stays for chronic conditions, ii) to investigate the role of comorbidity and discharge destination in mediating these associations and iii) to identify the main drivers of length of stays. MethodsThis analysis made use of nationwide inpatient data from Swiss hospital discharge statistics that was linked on the individual level with Swiss census data. The study sample included n=141,307 records of n=92,623 inpatients aged 25 to 84 years, hospitalized between 2010 and 2016 for acute care in Switzerland with a main diagnosis of one of 15 selected chronic conditions, including cancers and cardiovascular, respiratory and musculoskeletal diseases. Cross-classified multilevel models were used to assess the impact of social factors on length of hospital stay and for mediation analysis in the retrospective inpatient cohort. FindingsThe strongest determinants of length of stay were medical factors, namely main diagnosis (up to seven days difference), comorbidities (up to 10 days) and treatment-related factors (two to three days). Also, social factors were associated with duration of hospital stays. Taking into account demographic factors, main diagnosis and clustering on patient and hospital level, patients with upper secondary and compulsory education stayed longer in hospital compared to those with tertiary education ({beta} 0.24 days, 95% CI 0.14-0.33; {beta} 0.37, 95% CI 0.27-0.47, respectively). However, these effects were almost fully mediated by burden of comorbidity. The effect of living alone on length of stay ({beta} 0.60 days, 95% CI 0.50-0.70) was partially mediated by both burden of comorbidities (33%) and discharge destination (30.4%). (Semi-) private insurance was associated with prolonged stays, but an inverse effect was observed for colon and breast cancer. Allophone patients, first generation migrants and non-EU/EFTA-nationals had also prolonged hospital stays ({beta} 0.34, 95% CI 0.13-0.55; {beta} 0.16, 95% CI 0.05-0.27; {beta} 0.22, 95% CI 0.02, 0.42, resp.). ConclusionsHospital stays could be a window of opportunity to discern patients with low health literacy who need additional instructions and support to better cope with everyday life after discharge, reducing the risks of future hospital stays. However, inpatient care in Switzerland seems to take into account rather obvious individual needs such as interpreter services or rehabilitation due to lack of language skills or lack of immediate support at home, respectively, but not necessarily more hidden needs of patients with low health literacy and less resources to assert their interests within the health system. Our findings underpin the importance of health policies promoting shared decision making and patient-centred care tailored to the differential needs of social and cultural groups.

AIM Delayed closure of ileostomy following an anterior resection for rectal cancer in the UK is common. The aims of this study were (i) to investigate the variation in patient pathways between hospitals, (ii) to identify the key learning points from units with the shortest time to closure and (iii) to develop guidance for a pathway to minimize delay in ileostomy closure. METHOD This was a mixed methods study. Thirty-eight colorectal units in the UK completed a short online survey. Nine colorectal units in Wales filled in an additional, expanded version of the survey. Semi-structured interviews were performed with clinicians from the six best performing units in terms of timely ileostomy closure. The optimal pathway suggested is based on the best evidence available and the Association of Coloproctology of Great Britain and Ireland guidelines. RESULTS Qualitative analysis revealed that 5% of units (n = 2) have a local target time for ileostomy closure. Of all units, 90% (n = 34) would consider implementing a pathway if guidelines were developed. In-depth interviews highlighted the importance of a multidisciplinary approach, a dedicated coordinator to facilitate timely booking, and consensus on whether closure should be performed before or after adjuvant chemotherapy. CONCLUSION There is a lack of national guidance in timing of contrast studies and ileostomy closure. Key aspects to consider are better information at consent regarding stoma closure timing, a dedicated person to track patients and the planning of contrast studies at discharge from initial surgery. With a dedicated approach closure of ileostomy within 10-12 weeks is feasible for most units.

Aim: Globally, neurodegeneration accounts for significant morbidity and mortality among the elderly. Millions of people are afflicted with neurodegenerative diseases, with the most notable cases attributed to Alzheimer’s, Huntington’s, amyotrophic lateral sclerosis and Parkinson’s diseases. Sensitive assays that can detect proteopathic anomalies indicative of early neurodegeneration have remained elusive. Therefore, there is an urgent need for sensitive diagnostic and prognostic biomarker assays that can guide the therapeutic regimen in the clinic. Materials & methods: Single molecule array digital immunoassay platform has sensitivity about 1000-fold higher than traditional ligand binding assays. Consequently, we are now beginning to implement ultrasensitive techniques in bioanalysis. Conclusion: In the current study, we evaluated single molecule array technology and report specifications to quantitate neurofilament light chain, a bona-fide biomarker for neurodegeneration. Preliminary neurofilament light screening results from 100 human geriatric cerebrospinal fluid samples displayed huge biological variation and warrants further investigation.

Adolescents face a wide array of social, emotional, and academic problems during what is often described as a challenging and complicated stage of development. Because the peer group becomes more i...

Pseudomonas aeruginosa is an opportunistic pathogen that produces numerous exoproducts during infection that help it evade the host immune system and procure nutrients from the host environment. Among these products are a family of secreted 2-alkyl-4(1H)-quinolone metabolites (AQs), which exhibit a range of biological activities. Here, we describe the validation of a liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method for quantifying multiple AQ congeners in complex biological matrices. The assay was validated for selectivity, sensitivity, linearity, accuracy, precision, carryover, dilution integrity, recovery, matrix effects, and various aspects of stability (freeze-thaw, bench-top, long-term storage, and autosampler/post-preparative). Using authentic standards for 6 distinct AQ congeners, we report accurate quantitation within a linear range between 25 and 1000 nmol/L for all of the validated AQ standards. This method was successfully applied to quantify AQ concentrations in P. aeruginosa cell culture and in the lungs of mice infected with P. aeruginosa. Further, we confirmed the presence of unsaturated forms of several AQ congeners in cell culture. Graphical abstract Electronic supplementary material The online version of this article (10.1007/s00216-019-02374-0) contains supplementary material, which is available to authorized users.

BackgroundThe aim of our study was to use a modified Delphi process to determine the research priorities among benign upper gastrointestinal (UGI) surgeons in the United Kingdom.MethodsDelphi methodology may be utilised to develop consensus opinion amongst a group of experts. Members of the Association of Upper Gastrointestinal Surgeons of Great Britain and Ireland were invited to submit individual research questions via an online survey (phase I). Two rounds of prioritisation by multidisciplinary expert healthcare professionals (phase II and III) were completed to determine a final list of high priority research questions.Results427 questions were submitted in phase I and 51 with a benign UGI focus were taken forward for prioritisation in phase II. 28 questions were ranked in phase III. A final list of 11 high priority questions had an emphasis on acute pancreatitis, Barrett’s oesophagus and benign biliary disease.ConclusionA modified Delphi process has produced a list of 11 high priority research questions in benign UGI surgery. Future studies and awards from funding bodies should reflect this consensus list of prioritised questions in the interest of improving patient care and encouraging collaborative research.

Introduction Dolutegravir (DTG), Elvitegravir (EVG), Raltegravir (RAL) and Darunavir (DRV) are commonly prescribed core agents for antiretroviral therapy (ART), and a need exists to compare their clinical effectiveness, as defined by virologic failure risks in real-world settings. Methods This observational analysis of a US clinical cohort consisted of ART-naïve people living with HIV (PLWH) in the OPERA database initiating DTG-, EVG-, RAL- or DRV-based regimens between August 2013 and July 2016, with follow-up to July 2017. PLWH were observed from first core agent initiation until core agent discontinuation, clinical activity cessation, death, or study end. Key outcomes included viral suppression (HIV RNA 200 copies/mL or a viral load > 200 copies/mL followed by discontinuation). Association between core agent and time to virologic failure was assessed with multivariate Cox proportional hazards models. Results Overall, 4049 ART-naïve PLWH initiated EVG (47.4%), DTG (34.7%), DRV (14.6%), or RAL (3.2%). DTG and EVG initiators had generally similar baseline demographics and clinical characteristics, including race, risk of infection, baseline viral load, and baseline CD4 levels. RAL and DRV initiators were older and generally sicker than DTG initiators. During follow-up, more DTG initiators achieved virologic suppression (78.7%) compared with EVG (73.6%; p

Background Despite evidence that insomnia symptoms exacerbate alcohol use disorder symptoms, there is a dearth of prospective research testing bidirectional associations between these variables. Furthermore, no studies have prospectively examined these associations among military personnel, a vulnerable population for sleep- and alcohol-related problems. Thus, the current study examined whether insomnia symptoms prospectively predicted increased alcohol use disorder symptoms among a sample of military service members and veterans over a 6-month follow-up period, as well as whether alcohol use disorder symptoms led to increases in insomnia. Method Hypotheses were tested among a sample of 274 current and past military service members who participated in a baseline and 6-month assessment using self-report measures. Results Path analyses revealed that insomnia symptoms significantly prospectively predicted increased month-6 heavy drinking and alcohol-related problems, but not days drinking or being bothered by drinking. None of the alcohol variables significantly predicted insomnia. Conclusion Results support a model in which insomnia symptoms exacerbate alcohol use disorder symptoms, specifically heavy drinking and alcohol-related problems. Future research should seek to examine these findings in diverse populations and test potential mechanisms and clinical implications of these results.

Two global epidemics, diabetes mellitus (DM) and tuberculosis (TB), have converged making their control even more challenging. We herein have reviewed metformin's (MTF) effect on patients with active and latent TB, as well as discussed its newly discovered biological mechanisms in mycobacteria. Mounting evidence suggests that MTF provides better outcomes in TB patients, especially those with DM. The mechanisms by which MTF produces its benefits are multiple. Though metformin's potential has been proven in patients with DM, larger and more thorough clinical trials, in DM and non-DM-TB patients, need to be conducted. MTF could be added to the arsenal of anti-TB drugs, aiding in the goal of TB eradication worldwide.

Most microbial pathogens have a metabolic iron requirement, necessitating the acquisition of this nutrient in the host. In response to pathogen invasion, the human host limits iron availability. Although canonical examples of nutritional immunity are host strategies that limit pathogen access to Fe(III), little is known about how the host restricts access to another biologically relevant oxidation state of this metal, Fe(II). This redox species is prevalent at certain infection sites and is utilized by bacteria during chronic infection, suggesting that Fe(II) withholding by the host may be an effective but unrecognized form of nutritional immunity. Here, we report that human calprotectin (CP; S100A8/S100A9 or MRP8/MRP14 heterooligomer) inhibits iron uptake and induces an iron starvation response in Pseudomonas aeruginosa cells by sequestering Fe(II) at its unusual His6 site. Moreover, under aerobic conditions in which the Fe(III) oxidation state is favored, Fe(II) withholding by CP was enabled by (i) its ability to stabilize this redox state in solution and (ii) the production and secretion of redox-active, P. aeruginosa–produced phenazines, which reduce Fe(III) to Fe(II). Analyses of the interplay between P. aeruginosa secondary metabolites and CP indicated that Fe(II) withholding alters P. aeruginosa physiology and expression of virulence traits. Lastly, examination of the effect of CP on cell-associated metal levels in diverse human pathogens revealed that CP inhibits iron uptake by several bacterial species under aerobic conditions. This work implicates CP-mediated Fe(II) sequestration as a component of nutritional immunity in both aerobic and anaerobic milieus during P. aeruginosa infection.

Intolerance of uncertainty (IU), defined as an inability to tolerate the unpleasant response triggered by the observed absence of information, has received increased empirical attention in recent years. The contribution of this cognitive behavioral construct to the etiology and maintenance of various anxiety disorders has become increasingly recognized. However, the relationship between IU and other affective disorders, including posttraumatic stress disorder (PTSD), remains largely unexplored. The current study sought to examine the relationship between IU and overall PTSD symptom and cluster severity using an outpatient sample of veterans (N = 116) assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fifth edition (DSM-5) PTSD symptom structure. Results revealed that IU was significantly associated with overall PTSD symptom severity, above and beyond relevant covariates. Further, IU was significantly associated with the PTSD avoidance and hyperarousal clusters. Prospective IU, rather than inhibitory IU, accounted for these unique associations. These findings add to a growing body of literature establishing IU as a transdiagnostic risk factor and point to the importance of future research on the role of IU in contributing to and/or maintaining PTSD symptoms.

Background People living with human immunodeficiency virus (PLWH) initiating antiretroviral therapy (ART) with viral loads (VLs) ≥100 000 copies/mL are less likely to achieve virologic success, but few studies have characterized real-world treatment outcomes. Methods ART-naive PLWH with VLs ≥100 000 copies/mL initiating dolutegravir (DTG), elvitegravir (EVG), raltegravir (RAL), or darunavir (DRV) between 12 August 2013 and 31 July 2017 were identified from the OPERA database. Virologic failure was defined as (i) 2 consecutive VLs ≥200 copies/mL after 36 weeks of ART; (ii) 1 VL ≥200 copies/mL with core agent discontinuation after 36 weeks; (iii) 2 consecutive VLs ≥200 copies/mL after suppression (≤50 copies/mL) before 36 weeks; or (iv) 1 VL ≥200 copies/mL with discontinuation after suppression before 36 weeks. Cox modeling estimated the association between regimen and virologic failure. Results There were 2038 ART-naive patients with high VL who initiated DTG (36%), EVG (46%), DRV (16%), or RAL (2%). Median follow-up was 18.1 (interquartile range, 12.4–28.9) months. EVG and DTG initiators were similar at baseline, but RAL initiators were older and more likely to be female with low CD4 cell counts while DRV initiators differed notably on factors associated with treatment failure. Virologic failure was experienced by 9.2% DTG, 13.2% EVG, 18.4% RAL, and 18.8% DRV initiators. Compared to DTG, the adjusted hazard ratio (95% confidence interval) was 1.46 (1.05–2.03) for EVG, 2.24 (1.50–3.34) for DRV, and 4.13 (1.85–9.24) for RAL. Conclusions ART-naive PLWH with high VLs initiating on DTG were significantly less likely to experience virologic failure compared to EVG, RAL, and DRV initiators. Antiretroviral therapy-naïve people living with HIV (PLWH) initiating therapy with viral loads ≥100,000 copies/mL varied markedly at baseline. In adjusted models, PLWH initiating dolutegravir-based regimens were less likely to experience virologic failure as compared to elvitegravir, raltegravir and darunavir initiators., Baseline characteristics of antiretroviral therapy–naive people living with HIV (PLWH) initiating 4 commonly prescribed core agents with high viral load varied markedly. In adjusted models, PLWH initiating dolutegravir-based regimens were significantly less likely to experience virologic failure as compared to elvitegravir, raltegravir, and darunavir initiators.

BACKGROUND: Dolutegravir(DTG)/lamivudine(3TC) is the first 2-drug regimen recommended as an initial treatment for people living with HIV (PLHIV). OBJECTIVE: To assess the cost-effectiveness and potential budget impact of DTG/3TC in the US healthcare setting. METHODS: A previously published hybrid decision-tree and Markov cohort state transition model was adapted to estimate the incremental costs and health outcome benefits over a patients' lifetime. DTG/3TC was compared with current standard of care in treatment naive and treatment experienced virologically suppressed PLHIV. Health states included in the model were based upon virologic response and CD4 cell count, with death as an absorbing state. Clinical data was informed by the Phase III GEMINI 1 and 2 clinical trials, a published network meta-analysis (NMA) in treatment-naive patients and the Phase III TANGO clinical trial in treatment experienced patients. Costs and utilities were informed by published data and discounted annually at a rate of 3%. A separate 5-year budget impact analysis was conducted assuming 5%-15% uptake in eligible treatment naive and 10%-30% uptake in eligible treatment experienced patients. RESULTS: In the treatment naive analyses based on GEMINI 1 and 2, DTG/3TC dominated, i.e., was less costly and more effective, than all comparators. DTG/3TC resulted in 0.083 incremental quality-adjusted life-years (QALYs) at a cost saving of $199,166 compared with the DTG + tenofovir disoproxil(TDF)/emtricitabine(FTC) comparator arm. The incremental QALY and cost savings for DTG/3TC compared with DTG/abacavir(ABC)/3TC, cobicistat-boosted darunavir(DRV/c)/tenofovir alafenamide(TAF)/FTC, and bictegravir (BIC)/TAF/FTC, based on NMA results were 0.465, 0.142, and 0.698, and $42,948, $122,846, and $44,962, respectively. In the analyses of treatment-experienced virologically suppressed patients based on TANGO, DTG/3TC offered slightly lower QALYs (-0.037) with an estimated savings of $78,730 when compared with continuation of TAF-based regimen (TBR). Sensitivity analyses demonstrated that these conclusions were relatively insensitive to alternative parameter estimates. The budget impact analysis estimated that by 5th year a total of 70,240 treatment naive patients and 1,340,480 treatment experienced patients could be eligible to be prescribed DTG/3TC. The estimated budget savings over 5 years ranged from $1.12b to $3.35b (corresponding to 27,512 to 82,536 on DTG/3TC by year 5) in the lowest and highest uptake scenarios, respectively. CONCLUSION: In conclusion, DTG/3TC with its comparable efficacy and lower drug acquisition costs, has the potential to offer significant cost savings to US healthcare payers for the initial treatment of treatment naive patients and as a treatment switching option for virologically suppressed patients. DISCLOSURES: This study was funded in full by ViiV healthcare, Brentford, UK. Medical writing to support this study was also funded in full by ViiV Healthcare, Brentford, UK. Butler, Hayward, and Jacob are employees of HEOR Ltd, the company performing this study funded by ViiV Healthcare. Anderson is an employee of GlaxoSmithKline and owns shares in the company. Punekar, Evitt, and Oglesby are employees of ViiV Healthcare and own stocks in GlaxoSmithKline.

Background Cardiac assessment in noncardiac surgery clinical practice guidelines should be supported by the highest-quality evidence such as that offered by systematic reviews. Currently, the methodological and reporting quality of these studies remains unknown. Methods We used PubMed to search for all clinical practice guidelines related to perioperative cardiovascular patients undergoing noncardiac surgery from 2010 to 2021. The included clinical practice guidelines were analysed for all systematic reviews and meta-analyses. The primary objective of this study was to determine reporting and methodological quality using the PRISMA (Preferred Reporting Instrument for Systematic Reviews and Meta-Analyses) and AMSTAR-2 (A Measurement Tool to Assess Systematic Reviews-2) instruments. Our secondary objective was to compare systematic reviews conducted by the Cochrane Collaboration with non-Cochrane studies. Results Three clinical practice guidelines were included in our study. Within these, 78 systematic reviews were included. PRISMA completion ranged from 34.8% to 100.0% with a mean of 76.9%. AMSTAR-2 completion ranged from 15.6% to 96.9% with a mean of 58.0%. Fifty-four systematic reviews underpinned a clinical practice guidelines recommendation, of which 25 were rated ‘critically low' by AMSTAR-2 appraisal. Cochrane systematic reviews typically performed better than non-Cochrane studies, but were a minority of the included studies (10/78). Conclusion We found deficiencies in several key areas regarding the methodological and reporting qualities of systematic reviews included in cardiac assessment in noncardiac surgery clinical practice guidelines. As these clinical practice guidelines are instrumental to clinical decision-making and patient care in cardiac assessment in noncardiac surgery, we advocate for improved reporting quality among systematic reviews cited as supportive evidence for these recommendations.

To combat infections, the mammalian host limits availability of essential transition metals such as iron (Fe), zinc (Zn), and manganese (Mn) in a strategy termed “nutritional immunity”. The innate immune protein calprotectin (CP) contributes to nutritional immunity by sequestering these metals to exert antimicrobial activity against a broad range of microbial pathogens. One such pathogen is Pseudomonas aeruginosa, which causes opportunistic infections in vulnerable populations including individuals with cystic fibrosis. CP was previously shown to withhold Fe(II) and Zn(II) from P. aeruginosa and induce Fe- and Zn-starvation responses in this pathogen. In this work, we performed quantitative, label-free proteomics to further elucidate how CP impacts metal homeostasis pathways in P. aeruginosa. We report that CP induces an incomplete Fe-starvation response, as many Fe-containing proteins that are repressed by Fe limitation are not affected by CP treatment. The Zn-starvation response elicited by CP seems to be more complete than the Fe-starvation response and includes increases in Zn transporters and Zn-independent proteins. CP also induces the expression of membrane-modifying proteins, and metal-depletion studies indicate this response results from the sequestration of multiple metals. Moreover, the increased expression of membrane-modifying enzymes upon CP treatment correlates with increased resistance to polymyxin B. Thus, response of P. aeruginosa to CP treatment includes both single and multi-metal starvation responses and includes many factors related to virulence potential, broadening our understanding of this pathogen’s interaction with the host.ImportanceTransition metals are critical for growth and infection by all pathogens, and the innate immune system withholds these metals from pathogens to limit their growth in a strategy termed “nutritional immunity”. While multi-metal depletion by the host is appreciated, the majority of metal depletion studies have focused on individual metald. Here we use the innate immune protein calprotectin (CP), which complexes with several metals including iron (Fe), zinc (Zn), and manganese (Mn), and the opportunistic pathogen Pseudomonas aeruginosa to investigate multi-metal starvation. Using an unbiased label-free proteomics response, we demonstrate that multi-metal withholding by CP induces a regulatory response that is not merely additive of individual metal starvation responses, including the induction of Lipid A modification enzymes.

Objectives:. Critical care teams are encouraged to follow best practice protocols to help wean mechanically ventilated patients from the ventilator to reduce ventilator-associated events including ventilator-associated conditions, probable ventilator-associated pneumonias, and infection-related ventilator-associated conditions. Providers monitor for alerts suggestive of possible ventilator-associated events and advise when patients should undergo spontaneous breathing trials. Compliance with protocols in most units is suboptimal. Design:. Retrospective review of clinical data over 24 months. Setting:. St. Joseph Mercy Hospital Candler Hospital Medical-Surgical ICU. Patients:. All mechanically ventilated patients. Interventions:. The Respiratory Knowledge Portal was implemented in our ICU. For 13 months, Respiratory Knowledge Portal data were ported to ICU workstations (control). For the following 11 months, Respiratory Knowledge Portal data were also presented on tablet computers (intervention) for use during multidisciplinary rounds. We performed a retrospective review of Respiratory Knowledge Portal data from before and after the implementation of the tablet computers. Measurements and Main Results:. Data were collected from 337 patients (187 control group, 150 intervention group). A decrease in the occurrence of ventilator-associated events was observed during the intervention group compared with the control group. Only 2.0% of patients in the intervention group experienced any category of ventilator-associated event, while 11.2% of patients in the control group experienced one event (p = 0.003). Intervention patients experienced less ventilator-associated conditions (p = 0.002), infection-related ventilator-associated conditions (p = 0.026), and probable ventilator-associated pneumonias (p = 0.036) than control patients. Twenty-one of the 24 patients with any ventilator-associated events were in the control group. There was no significant difference between the days spent on ventilation nor hospital length of stay in the control compared with intervention group patients. Conclusions:. Fewer ventilator-associated events, ventilator-associated conditions, infection-related ventilator-associated conditions, and probable ventilator-associated pneumonias were seen during the period when Respiratory Knowledge Portal monitoring data was presented on tablet computers. There was no difference in time on ventilator nor overall length of stay.

Purpose To describe the implementation and initial results of using Chemical Exchange Saturation Transfer (CEST) for monitoring patients with central nervous system (CNS) tumours treated using a 1.5 tesla MR-guided radiotherapy system. Methods CNS patients were treated with up to 30 fractions (total dose up to 60 Gy) using a 1.5 T Elekta Unity MR-Linac. CEST scans were obtained in 54 subjects at one or more time points during treatment. CEST metrics, including the amide magnetization transfer ratio (MTRAmide), nuclear Overhauser effect (NOE) MTR (MTRNOE) and asymmetry, were quantified in phantoms and CNS patients. The signal was investigated between tumour and white matter, across time, and across disease categories including high- and low-grade tumours. Results The gross tumour volume (GTV) exhibited lower MTRAmide and MTRNOE and higher asymmetry compared to contralateral normal appearing white matter. Signal changes in the GTV during fractionated radiotherapy were observed. There were differences between high- and low-grade tumours, with higher CEST asymmetry associated with higher grade disease. Conclusion CEST MRI using a 1.5 T MR-Linac was demonstrated to be feasible for in vivo imaging of CNS tumours. CEST images showed tumour/white-matter contrast, temporal CEST signal changes, and associations with tumour grade. These results show promise for the eventual goal of using metabolic imaging to inform the design of adaptive radiotherapy protocols.

Background: Anastomotic leaks are associated with significant risk of morbidity, mortality and treatment costs after oesophagectomy. The aim of this study was to evaluate international variation in unit-level clinical practice and resource availability for the prevention and management of anastomotic leak following oesophagectomy.Method: The Oesophago-Gastric Anastomosis Audit (OGAA) is an international research collaboration focussed on improving the care and outcomes of patients undergoing oesophagectomy. Any unit performing oesophagectomy worldwide can register to participate in OGAA studies. An online unit survey was developed and disseminated to lead surgeons at each unit registered to participate in OGAA. High-income country (HIC) and low/middle-income country (LMIC) were defined according to the World Bank whilst unit volume were defined as < 20 versus 20-59 versus ≥60 cases/year in the unit.Results: Responses were received from 141 units, a 77% (141/182) response rate. Median annual oesophagectomy caseload was reported to be 26 (inter-quartile range 12-50). Only 48% (68/141) and 22% (31/141) of units had an Enhanced Recovery After Surgery (ERAS) program and ERAS nurse, respectively. HIC units had significantly higher rates of stapled anastomosis compared to LMIC units (66 vs 31%, p = 0.005). Routine post-operative contrast-swallow anastomotic assessment was performed in 52% (73/141) units. Stent placement and interventional radiology drainage for anastomotic leak management were more commonly available in HICs than LMICs (99 vs 59%, p < 0.001 and 99 vs 83%, p < 0.001).Conclusions: This international survey highlighted variation in surgical technique and management of anastomotic leak based on case volume and country income level. Further research is needed to understand the impact of this variation on patient outcomes.

Summary Idiopathic pulmonary fibrosis (IPF) is a progressive fatal disease affecting over 100 000 people in Europe with an increasing incidence. Available treatments offer only slowing of disease progression and are poorly tolerated by patients leading to cessation of therapy. Lung transplant remains the only cure. Therefore, alternative treatments are urgently required. The pathology of IPF is complex and poorly understood and thus creates a major obstacle to the discovery of novel treatments. Additionally, preclinical assessment of new treatments currently relies upon animal models where disparities with human lung biology often hamper drug development. At a cellular level, IPF is characterized by persistent and abnormal deposition of extracellular matrix by fibroblasts and alveolar epithelial cell injury which is seen as a key event in initiation of disease progression. In-depth investigation of the role of alveolar epithelial cells in health and disease has been impeded due to difficulties in primary cell isolation and culture ex vivo. Novel strategies employing patient-derived induced pluripotent stem cells engineered to produce type 2 alveolar epithelial cells (iAEC2) cultured as three-dimensional organoids have the potential to overcome these hurdles and inform new effective precision treatments for IPF leading to improved survival and quality of life for patients worldwide.

Summary The COVID‐19 pandemic continues to cause critical illness and deaths internationally. Up to 31 May 2020, mortality in patients admitted to intensive care units (ICU) with COVID‐19 was 41.6%. Since then, changes in therapeutics and management may have improved outcomes. Also, data from countries affected later in the pandemic are now available. We searched MEDLINE, Embase, PubMed and Cochrane databases up to 30 September 2020 for studies reporting ICU mortality among adult patients with COVID‐19 and present an updated systematic review and meta‐analysis. The primary outcome measure was death in intensive care as a proportion of completed ICU admissions, either through discharge from intensive care or death. We identified 52 observational studies including 43,128 patients, and first reports from the Middle East, South Asia and Australasia, as well as four national or regional registries. Reported mortality was lower in registries compared with other reports. In two regions, mortality differed significantly from all others, being higher in the Middle East and lower in a single registry study from Australasia. Although ICU mortality (95%CI) was lower than reported in June (35.5% (31.3–39.9%) vs. 41.6% (34.0–49.7%)), the absence of patient‐level data prevents a definitive evaluation. A lack of standardisation of reporting prevents comparison of cohorts in terms of underlying risk, severity of illness or outcomes. We found that the decrease in ICU mortality from COVID‐19 has reduced or plateaued since May 2020 and note the possibility of some geographical variation. More standardisation in reporting would improve the ability to compare outcomes from different reports.

Pseudomonas aeruginosa is an opportunistic pathogen that is frequently associated with both acute and chronic infections. P. aeruginosa possesses a complex regulatory network that modulates nutrient acquisition and virulence, but our knowledge of these networks is largely based on studies with shaking cultures, which are not likely representative of conditions during infection. Here, we provide proteomic, metabolic, and genetic evidence that regulation by iron, a critical metallonutrient, is altered in static P. aeruginosa cultures. Specifically, we observed a loss of iron-induced expression of proteins for oxidative phosphorylation, tricarboxylic acid (TCA) cycle metabolism under static conditions. Moreover, we identified type VI secretion as a target of iron regulation in P. aeruginosa cells under static but not shaking conditions, and we present evidence that this regulation occurs via PrrF small regulatory RNA (sRNA)-dependent production of 2-alkyl-4(1H)-quinolone metabolites. These results yield new iron regulation paradigms in an important opportunistic pathogen and highlight the need to redefine iron homeostasis in static microbial communities. IMPORTANCE Host-mediated iron starvation is a broadly conserved signal for microbial pathogens to upregulate expression of virulence traits required for successful infection. Historically, global iron regulatory studies in microorganisms have been conducted in shaking cultures to ensure culture homogeneity, yet these conditions are likely not reflective of growth during infection. Pseudomonas aeruginosa is a well-studied opportunistic pathogen and model organism for iron regulatory studies. Iron homeostasis is maintained through the Fur protein and PrrF small regulatory sRNAs, the functions of which are highly conserved in many other bacterial species. In the current study, we examined how static growth affects the known iron and PrrF regulons of P. aeruginosa, leading to the discovery of novel PrrF-regulated virulence processes. This study demonstrates how the utilization of distinct growth models can enhance our understanding of basic physiological processes that may also affect pathogenesis.

Background Prehospital care is potentially hazardous with the possibility for patients to experience an adverse event. However, as compared to secondary care, little is known about how patient safety is managed in prehospital care settings. Objectives The objectives of this systematic review were to identify and classify the methods of measuring and monitoring patient safety that have been used in prehospital care using the five dimensions of the Measuring and Monitoring Safety (MMS) framework and use this classification to identify where there are safety ‘blind spots’ and make recommendations for how these deficits could be addressed. Methods Searches were conducted in January 2020, with no limit on publication year, using Medline, PsycInfo, CINAHL, Web of Science and Academic Search. Reference lists of included studies and existing related reviews were also screened. English-language, peer-reviewed studies concerned with measuring and monitoring safety in prehospital care were included. Two researchers independently extracted data from studies and applied a quality appraisal tool (the Quality Assessment Tool for Studies with Diverse Designs). Results A total of 5301 studies were screened, with 52 included in the review. A total of 73% (38/52) of the studies assessed past harm, 25% (13/52) the reliability of safety critical processes, 1.9% (1/52) sensitivity to operations, 38.5% (20/52) anticipation and preparedness and 5.8% (3/52) integration and learning. A total of 67 methods for measuring and monitoring safety were used across the included studies. Of these methods, 38.8% (26/67) were surveys, 29.9% (20/67) were patient records reviews, 14.9% (10/67) were incident reporting systems, 11.9% (8/67) were interviews or focus groups and 4.5% (3/67) were checklists. Conclusions There is no single method of measuring and monitoring safety in prehospital care. Arguably, most safety monitoring systems have evolved, rather than been designed. This leads to safety blind spots in which information is lacking, as well as to redundancy and duplication of effort. It is suggested that the findings from this systematic review, informed by the MMS framework, can provide a structure for critically thinking about how safety is being measured and monitored in prehospital care. This will support the design of a safety surveillance system that provides a comprehensive understanding of what is being done well, where improvements should be made and whether safety interventions have had the desired effect.

BACKGROUND. The frequency of "exhausted" or check-point-positive (PD-1(+)CTLA-4(+)) cytotoxic lymphocytes (Tex) in the tumor microenvironment is associated with response to anti-PD-1 therapy in metastatic melanoma. The current study determined whether pretreatment Tex cells in locally advanced melanoma predicted response to neoadjuvant anti-PD-1 blockade. METHODS. Pretreatment tumor samples from 17 patients with locally advanced melanoma underwent flow cytometric analysis of pretreatment Tex and regulatory T cell frequency. Patients who met the criteria for neoadjuvant checkpoint blockade were treated with either PD-1 monotherapy or PD-1/CTLA-4 combination therapy. Best overall response was evaluated by response evaluation criteria in solid tumors version 1.1, with recurrence-free survival (RFS) calculated by the Kaplan–Meier test. The incidence and severity of adverse events were tabulated by clinicians using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4. RESULTS. Of the neoadjuvant treated patients, 10 received anti-PD-1 monotherapy and 7 received anti-CTLA-4/PD-1 combination therapy. Of these 17 patients, 12 achieved a complete response, 4 achieved partial responses, and 1 exhibited stable disease. Surgery was subsequently performed for 11 of the 17 patients, and 8 attained a complete pathologic response. Median RFS and overall survival (OS) were not reached. Immune-related adverse events comprised four grade 3 or 4 events, including pneumonitis, transaminitis, and anaphylaxis. CONCLUSION. The results showed high rates of objective response, RFS, and OS for patients undergoing immune profile-directed neoadjuvant immunotherapy for locally advanced melanoma. Furthermore, the study showed that treatment stratification based upon Tex frequency can potentially limit the adverse events associated with combination immunotherapy. These data merit further investigation with a larger validation study.

Proper disinfection using adequate disinfecting agents will be necessary for infection control strategies against coronavirus disease 2019 (COVID-19). However, limited guidance exists on effective surface disinfectants or best practices for their use against severe acute respiratory coronavirus 2. We outlined a process of fully characterizing over 350 products on the Environmental Protection Agency List N, including pH, method of delivery, indication for equipment sterilization, and purchase availability. We then developed a streamlined set of guidelines to help rapidly evaluate and select suitable disinfectants from List N, including practicality, efficacy, safety, and cost/availability. This resource guides the evaluation of ideal disinfectants amidst practical considerations posed by the COVID-19 pandemic.

Summary Background Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial. Funding UK National Institute for Health Research Health Technology Assessment Programme.

Context The Smith Cognitive-Affective Model of Athletic Burnout suggests that athletic trainers (ATs) suffering from burnout may engage in substance use as a coping behavior. Increases in self-reported burnout symptoms are often associated with increases in heavy episodic drinking and tobacco use among various health care providers. However, this relationship has not been examined thoroughly. Objective To investigate the prevalence of substance use in ATs and identify relationships between symptoms of burnout and substance use among ATs. Design Cross-sectional study. Setting Web-based survey. Patients or Other Participants A total of 783 certified ATs working full time in the collegiate or university setting were sampled for this study. Graduate assistant and other part-time ATs were excluded. The survey was distributed via the National Athletic Trainers' Association membership directory e-mail broadcast service. Main Outcome Measure(s) A 100-item online questionnaire consisting of items from previously used scales was used for this study. The survey included the Maslach Burnout Inventory and questions on substance use from the Monitoring the Future study. Multiple regression analyses were performed to analyze the survey data. All independent (Maslach Burnout Inventory subscales) and dependent (use of alcohol, tobacco, and marijuana) variables were mapped to the Smith Cognitive-Affective Model of Athletic Burnout to determine which dimensions of burnout altered the odds of self-reported substance use. Results Almost half (46.3%) of participants admitted to at least 1 binge-drinking episode. However, the use of cigarettes, smokeless tobacco, marijuana, and energy drinks during the previous month was less pronounced in the sample. Emotional exhaustion (B = 0.008, P = .023) and personal accomplishment (B = −0.016, P = .02) were significantly correlated with binge drinking. Emotional exhaustion (Exp[B] = 1.017, P < .001) was also significantly positively correlated with energy-drink consumption. Conclusions Some ATs engaged in heavy episodic drinking. Emotional exhaustion and a decreased sense of personal accomplishment were significantly correlated with this behavior.