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Background: Protocols are an essential document for conducting randomised controlled trials (RCTs). However, the completeness of the information provided is often inadequate. To help improve the content of trial protocols, an international group of stakeholders published the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) Initiative in 2013. Presently, there is increasing use of cohorts and routinely collected data (RCD) for RCTs because these data have the potential to improve efficiencies by facilitating recruitment, simplifying, and reducing the cost of data collection. Reporting guidelines have been shown to improve the quality of reporting, but there is currently no specific SPIRIT guidance on protocols for trials conducted using cohorts and RCD. This protocol outlines steps for developing SPIRIT-ROUTINE, which aims to address this gap by extending the SPIRIT guidance to protocols for trials conducted using cohorts and RCD. Methods: The development of the SPIRIT-ROUTINE extension comprises five stages. Stage 1 consists of a project launch and a meeting to finalise the membership of the steering group and scope of the extension. In Stage 2, a rapid review will be performed to identify possible modifications to the original SPIRIT 2013 checklist. Other key reporting guidelines will be reviewed to identify areas where additional items may be needed, such as the Consolidated Standards of Reporting Trials (CONSORT) extension for trials conducted using cohorts and RCD (CONSORT-ROUTINE). Stage 3 will involve an online Delphi exercise, consisting of two rounds and involving key international stakeholders to gather feedback on the preliminary checklist items. In Stage 4, a consensus meeting of the SPIRIT-ROUTINE steering group will finalise the items to include in the extension. Stage 5 will involve the publication preparation and dissemination of the final checklist. Conclusion: The SPIRIT-ROUTINE extension will contribute to improving design of trials using cohorts and RCD and transparency of reporting.

Abstract. Antibiotic-coated intramedullary nails have been popularized in recent decades for treating long-bone infections. They are especially useful in treating diaphyseal infections requiring stability, such as those involving fractures and nonunions. The nails are made by injecting antibiotic-impregnated polymethylmethacrylate or “cement” around a metal core using a silicone tube as a mold. There are a variety of techniques that can be used to customize the nail to the affected site. Antibiotic cement has long been demonstrated as an effective local antibiotic delivery system. It is able to elute high concentrations of antibiotics while having little systemic toxicity. Several case series have reported good outcomes using this technique, defined by bone union and infection control. Further research is needed to determine the amount of weight that can safely be transferred through the nail and to optimize antibiotic elution.

The primary purpose of this study was to examine whether students’ motivation-related perceptions of mathematics courses were related to their ratings of instruction while controlling for their academic major, type of math class, and expected grade in the class. We investigated these relationships at both the student- and class-level because little is known about whether students’ motivation-related perceptions vary across mathematics courses and whether this variance is related to overall class ratings of instruction. The sample included 795 students nested within 43 different mathematics course sections. Students provided their course perceptions of autonomy, utility value, expectancies for success, situational interest, instructor caring, expected grade, and their overall perceptions of the course and instructor. Multilevel modeling techniques were used to investigate potential student- and class-level effects as well as compositional effects. Students’ class perceptions varied significantly across mathematics courses. In addition, students’ motivation-related course perceptions were positively related to their instructor and course ratings at both the student-level and class-level; however, the strength of these relationships sometimes varied across courses for some of the motivation-related perceptions. These results suggest that the motivational climate (i.e., the psychological environment) can affect students’ instructor and course ratings. Moreover, these findings suggest that instructors have some control over their instructor and course ratings through the teaching strategies that they implement. For example, they may be able to increase their ratings by implementing teaching strategies that support students’ autonomy, goals, success, interests, and relationships.

In severe viral pneumonia, including Coronavirus disease 2019 (COVID-19), the viral replication phase is often followed by hyperinflammation, which can lead to acute respiratory distress syndrome, multi-organ failure, and death. We previously demonstrated that alpha-1 adrenergic receptor (⍺1-AR) antagonists can prevent hyperinflammation and death in mice. Here, we conducted retrospective analyses in two cohorts of patients with acute respiratory distress (ARD, n = 18,547) and three cohorts with pneumonia (n = 400,907). Federated across two ARD cohorts, we find that patients exposed to ⍺1-AR antagonists, as compared to unexposed patients, had a 34% relative risk reduction for mechanical ventilation and death (OR = 0.70, p = 0.021). We replicated these methods on three pneumonia cohorts, all with similar effects on both outcomes. All results were robust to sensitivity analyses. These results highlight the urgent need for prospective trials testing whether prophylactic use of ⍺1-AR antagonists ameliorates lower respiratory tract infection-associated hyperinflammation and death, as observed in COVID-19.

Abstract Background About 70% of teachers who instruct healthcare students are considered sessional (adjunct/temporary part-time) faculty and receive limited instruction in pedagogy. Sessional faculty may feel isolated and struggle with their teacher identity, and are often assumed to vary in their commitment, motivation, and ability to teach. However, research on teaching identity, motivations, and needs of sessional faculty is lacking. The aim of this study was to compare similarities and differences between sessional and tenure-track faculty across a health science school to guide faculty development for sessional faculty. Methods We developed an online needs assessment survey, based on informal interviews and literature reviews. Seventy-eight tenure-track faculty and 160 sessional faculty completed the survey (37, 25% response rate, respectively). We used validated scales to assess intrinsic motivation, identified regulated motivation, and identification with teaching, as well as developed scales (perceived connectedness, motivated by appreciation to try new teaching method) and single items. All scales demonstrated good internal consistency. We compared sessional and tenure-track faculty using t-tests/chi-square values. Results We found similarities between sessional and tenure-track faculty in intrinsic motivation, identified regulated motivation, and identification with teaching. However, sessional faculty perceived less department connectedness and were more motivated to improve instruction if shown appreciation for trying new teaching methods. Sessional faculty agreed more that they desired pedagogy instruction before starting to teach and that teachers should invest energy in improving their teaching. Admitting to less participation in activities to enhance teaching in the last year, sessional faculty were more interested in digital formats of faculty development. Conclusion Our comparison suggested that sessional faculty value being a teacher as part of their self, similar to tenured faculty, but desired more appreciation for efforts to improve and perceived less connectedness to their university department than tenured faculty. They also preferred digital formats for pedagogy to improve accessibility, prior to and throughout their teaching career to support their development as teachers. Using this information as a guide, we provide suggestions for faculty development for sessional faculty. Supporting sessional faculty in the health sciences should improve the quality of teaching and positively affect student learning.

Abstract Purpose To inform recommendations by the Canadian Task Force on Preventive Health Care by systematically reviewing direct evidence on the effectiveness and acceptability of screening adults 40 years and older in primary care to reduce fragility fractures and related mortality and morbidity, and indirect evidence on the accuracy of fracture risk prediction tools. Evidence on the benefits and harms of pharmacological treatment will be reviewed, if needed to meaningfully influence the Task Force’s decision-making. Methods A modified update of an existing systematic review will evaluate screening effectiveness, the accuracy of screening tools, and treatment benefits. For treatment harms, we will integrate studies from existing systematic reviews. A de novo review on acceptability will be conducted. Peer-reviewed searches (Medline, Embase, Cochrane Library, PsycINFO [acceptability only]), grey literature, and hand searches of reviews and included studies will update the literature. Based on pre-specified criteria, we will screen studies for inclusion following a liberal-accelerated approach. Final inclusion will be based on consensus. Data extraction for study results will be performed independently by two reviewers while other data will be verified by a second reviewer; there may be some reliance on extracted data from the existing reviews. The risk of bias assessments reported in the existing reviews will be verified and for new studies will be performed independently. When appropriate, results will be pooled using either pairwise random effects meta-analysis (screening and treatment) or restricted maximum likelihood estimation with Hartun-Knapp-Sidnick-Jonkman correction (risk prediction model calibration). Subgroups of interest to explain heterogeneity are age, sex, and menopausal status. Two independent reviewers will rate the certainty of evidence using the GRADE approach, with consensus reached for each outcome rated as critical or important by the Task Force. Discussion Since the publication of other guidance in Canada, new trials have been published that are likely to improve understanding of screening in primary care settings to prevent fragility fractures. A systematic review is required to inform updated recommendations that align with the current evidence base.

Abstract Background The association of a Classical left bundle branch block (LBBB) contraction pattern and better outcome after cardiac resynchronization therapy (CRT) has only been studied using vendor-specific software for echocardiographic speckle-tracked longitudinal strain analysis. The purpose of this study was to assess whether a Classical LBBB contraction pattern on longitudinal strain analysis using vendor-independent software is associated with clinical outcome in CRT recipients with LBBB. Methods This was a retrospective cohort study including CRT recipients with LBBB, heart failure, and left ventricular (LV) ejection fraction ≤35%. Speckle-tracked echocardiographic longitudinal strain analysis was performed retrospectively on echocardiograms using vendor-independent software. The presence of a Classical LBBB contraction pattern was determined by consensus of two readers. The primary end point was a composite of time to death, heart transplantation or LV assist device implantation. Secondary outcome was ≥15% reduction in LV end-systolic volume. Intra- and inter-reader agreement of the longitudinal strain contraction pattern was assessed by calculating Cohen’s κ. Results Of 283 included patients, 113 (40%) were women, mean age was 66 ± 11 years, and 136 (48%) had ischemic heart disease. A Classical LBBB contraction pattern was present in 196 (69%). The unadjusted hazard ratio for reaching the primary end point was 1.93 (95% confidence interval, 1.36–2.76, p

Abstract Background Peer-led support groups play an important role in supporting people with chronic diseases. They may be particularly important for people with rare diseases who typically do not have access to professional support options that focus on their disease-specific needs. Many peer-led support groups in rare diseases, however, are not sustained, and many patients do not have access to support groups. Training and education for peer support group leaders could address barriers to initiating and sustaining groups, but there is little evidence on the effectiveness of support group leader training programs. A previous systematic review evaluated the effects of training programs for peer leaders of support groups for people with medical illness on leader and support group outcomes, but it identified only one randomized controlled trial (RCT) that compared high- and low-resource training programs for cancer support group leaders. The trial did not find evidence that the high-resource program was more effective, but was limited by a small sample size and serious methodological limitations. To meet the needs of people living with the rare autoimmune connective tissue disease scleroderma, the Scleroderma Patient-centered Intervention Network has partnered with patient organizations to develop the Scleroderma Support group Leader EDucation Program, and a full-scale RCT to test the effectiveness of the program is planned. To verify the need for such a trial, we updated the previous systematic review. Updated evidence Review methods for the update were unchanged from the initial review. The updated database search yielded 1504 unique citations in addition to the 9757 assessed for eligibility in the previous review. All additional citations identified in the updated search were excluded at the title and abstract review stage. Conclusions Our systematic review update found that there is presently insufficient evidence on the effectiveness of training and support programs for peer leaders of disease-based support groups, highlighting the need for well-designed and rigorously conducted RCTs to examine the effects of training for peer leaders of support groups, especially in a rare disease context. The Scleroderma Patient-centered Intervention Network’s trial of the Scleroderma Support group Leader EDucation Program will serve as such a trial. Systematic review registration PROSPERO CRD42018096369

Abstract Background Depression symptom questionnaires are commonly used to assess symptom severity and as screening tools to identify patients who may have depression. They are not designed to ascertain diagnostic status and, based on published sensitivity and specificity estimates, would theoretically be expected to overestimate prevalence. Meta-analyses sometimes estimate depression prevalence based on primary studies that used screening tools or rating scales rather than validated diagnostic interviews. Our objectives were to determine classification methods used in primary studies included in depression prevalence meta-analyses, if pooled prevalence differs by primary study classification methods as would be predicted, whether meta-analysis abstracts accurately describe primary study classification methods, and how meta-analyses describe prevalence estimates in abstracts. Methods We searched PubMed (January 2008–December 2017) for meta-analyses that reported pooled depression prevalence in the abstract. For each meta-analysis, we included up to one pooled prevalence for each of three depression classification method categories: (1) diagnostic interviews only, (2) screening or rating tools, and (3) a combination of methods. Results In 69 included meta-analyses (81 prevalence estimates), eight prevalence estimates (10%) were based on diagnostic interviews, 36 (44%) on screening or rating tools, and 37 (46%) on combinations. Prevalence was 31% based on screening or rating tools, 22% for combinations, and 17% for diagnostic interviews. Among 2094 primary studies in 81 pooled prevalence estimates, 277 (13%) used validated diagnostic interviews, 1604 (77%) used screening or rating tools, and 213 (10%) used other methods (e.g., unstructured interviews, medical records). Classification methods pooled were accurately described in meta-analysis abstracts for 17 of 81 (21%) prevalence estimates. In 73 meta-analyses based on screening or rating tools or on combined methods, 52 (71%) described the prevalence as being for “depression” or “depressive disorders.” Results were similar for meta-analyses in journals with impact factor ≥ 10. Conclusions Most meta-analyses combined estimates from studies that used screening tools or rating scales instead of diagnostic interviews, did not disclose this in abstracts, and described the prevalence as being for “depression” or “depressive disorders ” even though disorders were not assessed. Users of meta-analyses of depression prevalence should be cautious when interpreting results because reported prevalence may exceed actual prevalence.

Abstract Background Newborn resuscitation is a life-saving intervention for birth asphyxia, a leading cause of neonatal mortality. Improving provider newborn resuscitation skills is critical for delivering quality care, but the retention of these skills has been a challenge. Tanzania implemented a national newborn resuscitation using the Helping Babies Breathe (HBB) training program to help address this problem. Our objective was to evaluate the effectiveness of two training approaches to newborn resuscitation skills retention implemented across 16 regions of Tanzania. Methods An initial training approach implemented included verbal instructions for participating providers to replicate the training back at their service delivery site to others who were not trained. After a noted drop in skills, the program developed structured on-the-job training guidance and included this in the training. The approaches were implemented sequentially in 8 regions each with nurses/ midwives, other clinicians and medical attendants who had not received HBB training before. Newborn resuscitation skills were assessed immediately after training and 4–6 weeks after training using a validated objective structured clinical examination, and retention, measured through degree of skills drop, was compared between the two training approaches. Results Eight thousand, three hundred and ninety-one providers were trained and assessed: 3592 underwent the initial training approach and 4799 underwent the modified approach. Immediately post-training, average skills scores were similar between initial and modified training groups: 80.5 and 81.3%, respectively (p-value 0.07). Both groups experienced statistically significant drops in newborn resuscitation skills over time. However, the modified training approach was associated with significantly higher skills scores 4–6 weeks post training: 77.6% among the modified training approach versus 70.7% among the initial training approach (p-value

Huntington's disease (HD) is a fatal genetic neurological disorder caused by a mutation in the human Huntingtin (HTT) gene. This mutation confers a toxic gain of function of the encoded mutant huntingtin (mHTT) protein, leading to widespread neuropathology including the formation of mHTT-positive inclusion bodies, gene dysregulation, reduced levels of adult dentate gyrus neurogenesis and neuron loss throughout many regions of the brain. Additionally, because HTT is ubiquitously expressed, several peripheral tissues are also affected. HD patients suffer from progressive motor, cognitive, psychiatric, and metabolic symptoms, including weight loss and skeletal muscle wasting. HD patients also show neuroendocrine changes including a robust, significant elevation in circulating levels of the glucocorticoid, cortisol. Previously, we confirmed that the R6/2 mouse model of HD exhibits elevated corticosterone (the rodent homolog of cortisol) levels and demonstrated that experimentally elevated corticosterone exacerbates R6/2 HD symptomology, resulting in severe and rapid weight loss and a shorter latency to death. Given that efficacious therapeutics are lacking for HD, here we investigated whether normalizing glucocorticoid levels could serve as a viable therapeutic approach for this disease. We tested the hypothesis that normalizing glucocorticoids to wild-type levels would ameliorate HD symptomology. Wild-type (WT) and transgenic R6/2 mice were allocated to three treatment groups: 1) adrenalectomy with normalized, WT-level corticosterone replacement (10 μg/ml), 2) adrenalectomy with high HD-level corticosterone replacement (35 μg/ml), or 3) sham surgery with no corticosterone replacement. Normalizing corticosterone to WT levels led to an improvement in metabolic rate in male R6/2 mice, as indicated by indirect calorimetry, including a reduction in oxygen consumption and normalization of respiratory exchange ratio values (p

As a result of the dependence worldwide on satellite technology, it is now necessary to use advanced multi-target tracking algorithms for space debris tracking systems to maintain custody of space objects around the earth. One principal challenge is the correct association of observations with objects. This paper presents a multi-sensor, space-debris tracking algorithm using δ-generalized labeled multi-Bernoulli (δ-GLMB) filtering. The algorithm provides a solution to the key challenges (e.g., detection uncertainty, data association uncertainty, and clutter) in multiple object tracking. An efficient implementation of the multi-sensor δ-GLMB filter is proposed. In order to avoid exhaustively computing all the terms, we propose to use the ranked assignment algorithm with an extended assignment matrix for multiple sensors to determine the most significant terms. A measurement-based birth model is used to identify the previously unknown space objects. Sensors can have the same or different observation volumes. The expectation-maximization (EM) algorithm is used to approximate densities across observation volumes. The performance is demonstrated using the simulation results.

Background: Pelvic ring–comminuted transforaminal sacral fracture injuries are rotationally and vertically unstable and have a high rate of failure. Objective: Our study purpose was to use three-dimensional (3D) optical tracking to detect onset location of bone–implant interface failure and measure the distances and angles between screws and line of applied force for correlation to strength of pelvic fracture fixation techniques. Methods: 3D relative motion across sacral–rami fractures and screws relative to bone was measured with an optical tracking system. Synthetic pelves were used. Comminuted transforaminal sacral–rami fractures were modelled. Each pelvis was stabilised by either (1) two iliosacral screws in S1, (2) one transsacral screw in S1 and one iliosacral screw in S1 and (3) one trans-alar screw in S1 and one iliosacral screw in S1; groups 4–6 consisted of fixation groups with addition of anterior inferior iliac pelvic external fixator. Eighteen-instrumented pelvic models with right ilium fixed simulate single-leg stance. Load was applied to centre of S1 superior endplate. Five cycles of torque was initially applied, sequentially increased until permanent deformation occurred. Five cycles of axial load compression was next applied, sequentially increased until permanent deformation occurred, followed by axial loading to catastrophic failure. A Student t test was used to determine significance (p

Abstract Background Tobacco smoking is the leading cause of cancer, preventable death, and disability. Smoking cessation can increase life expectancy by nearly a decade if achieved in the third or fourth decades of life. Various stop smoking interventions are available including pharmacotherapies, electronic cigarettes, behavioural support, and alternative therapies. This protocol outlines an evidence review which will evaluate the benefits and harms of stop smoking interventions in adults. Methods The evidence review will consist of two stages. First, an overview of systematic reviews evaluating the benefits and harms of various stop smoking interventions delivered in or referred from the primary care setting will be conducted. The second stage will involve updating a systematic review on electronic cigarettes identified in the overview; randomized controlled trials will be considered for outcomes relating to benefits while randomized controlled trials, non-randomized controlled trials, and comparative observational studies will be considered for evaluating harms. Search strategies will be developed and peer-reviewed by medical information specialists. The search strategy for the updated review on e-cigarettes will be developed using that of the candidate systematic review. The MEDLINE®, PsycINFO, Embase, and the Cochrane Library electronic databases will be searched as of 2008 for the overview of reviews and from the last search date of the selected review for the updated review. Organizational websites and trial registries will be searched for unpublished or ongoing reviews/studies. Two reviewers will independently screen the title and abstracts of citations using the liberal accelerated method. Full-text screening will be performed independently by two reviewers. Extracted data will be verified by a second reviewer. Disagreements regarding full-text screening and data extraction will be resolved by consensus or third-party adjudication. The methodological quality of systematic reviews, risk of bias of randomized and non-randomized trials, and methodological quality of cohort studies will be evaluated using AMSTAR 2, the Cochrane risk of bias tool, and a modified version of the Scottish Intercollegiate Guidelines Network critical appraisal tool, respectively. The GRADE framework will be used to assess the quality of the evidence for outcomes. Discussion The evidence review will evaluate the benefits and harms of various stop smoking interventions for adults. Findings will be used to inform a national tobacco cessation guideline by the Canadian Task Force on Preventive Health Care. Systematic review registration PROSPERO (CRD42018099691, CRD42018099692)

Abstract Background In 2018, the World Health Organization reported that depression is the most common cause of disability worldwide, with over 300 million people currently living with depression. Depression affects an individual’s physical health and well-being, impacts psychosocial functioning, and has specific negative short- and long-term effects on maternal health, child health, developmental trajectories, and family health. The aim of these reviews is to identify evidence on the benefits and harms of screening for depression in the general adult population and in pregnant and postpartum women. Methods Search strategies were developed and tested through an iterative process by an experienced medical information specialist in consultation with the review team. We will search MEDLINE, Embase, PsycINFO, CINAHL, and the Cochrane Library, and a randomized controlled trial filter will be used. The general adult review will be an update of a systematic review previously used by the Canadian Task Force on Preventive Health Care for their 2013 guideline recommendation. The search strategy will be updated and will start from the last search date of the previous review (May 2012). The pregnant and postpartum review will be a de novo review with no date restriction. For both reviews, we will search for unpublished documents following the CADTH Grey Matters checklist and relevant websites. Titles and abstracts will be screened using the liberal accelerated method. Two reviewers will independently screen full-text articles for relevance using pre-specified eligibility criteria and assess the risk of bias of included studies using the Cochrane Risk of Bias tool. Outcomes of interest for the general adult population review include symptoms of depression or diagnosis of major depressive disorder, health-related quality of life, day-to-day functionality, lost time at work/school, impact on lifestyle behaviour, suicidality, false-positive result, labelling/stigma, overdiagnosis or overtreatment, and harms of treatment. Outcomes of interest for the pregnant and postpartum review include mental health outcomes (e.g. diagnosis of major depressive disorder), parenting outcomes (e.g. mother-child interactions), and infant outcomes (e.g. infant health and development). Discussion These two systematic reviews will offer informative evaluations of depression screening. The findings will be used by the Task Force to help develop guideline recommendations on depression screening in the general adult population and in pregnant and postpartum women in Canada. Systematic review registration PROSPERO (CRD42018099689, CRD42018099690)

Abstract Background The APOBEC3 (A3) family of DNA cytosine deaminases provides an innate barrier to infection by retroviruses including HIV-1. A total of five enzymes, A3C, A3D, A3F, A3G and A3H, are degraded by the viral accessory protein Vif and expressed at high levels in CD4+ T cells, the primary reservoir for HIV-1 replication in vivo. Apart from A3C, all of these enzymes mediate restriction of Vif-deficient HIV-1. However, a rare variant of human A3C (Ile188) was shown recently to restrict Vif-deficient HIV-1 in a 293T-based single cycle infection system. The potential activity of this naturally occurring A3C variant has yet to be characterized in a T cell-based spreading infection system. Here we employ a combination of Cas9/gRNA disruption and transient and stable protein expression to assess the roles of major Ser188 and minor Ile188 A3C variants in HIV-1 restriction in T cell lines. Results Cas9-mediated mutation of endogenous A3C in the non-permissive CEM2n T cell line did not alter HIV-1 replication kinetics, and complementation with A3C-Ser188 or A3C-Ile188 was similarly aphenotypic. Stable expression of A3C-Ser188 in the permissive T cell line SupT11 also had little effect. However, stable expression of A3C-Ile188 in SupT11 cells inhibited Vif-deficient virus replication and inflicted G-to-A mutations. Conclusions A3C-Ile188 is capable of inhibiting Vif-deficient HIV-1 replication in T cells. Although A3C is eclipsed by the dominant anti-viral activities of other A3s in non-permissive T cell lines and primary T lymphocytes, this enzyme may still be able to contribute to HIV-1 diversification in vivo. Our results highlight the functional redundancy in the human A3 family with regards to HIV-1 restriction and the need to consider naturally occurring variants.

Abstract. Fracture healing is a complex cascade of cellular and molecular processes. These processes require the appropriate cellular and molecular environment to ensure the restoration of skeletal stability and resolution of inflammation. In order for fracture healing to occur, the necessary building blocks for bone metabolism and synthesis must be supplied through proper nutrition. Pharmacologic therapies aimed at modulating the inflammatory response to fractures have the potential to interfere with the synthesis of molecules needed for the production of bone. Infection can interfere with, and even prevent normal fracture healing from occurring. Cellular and genetic treatment strategies are actively being developed to target deficiencies, and bridge gaps that can influence how fractures heal. Evolving technologies, including nutritional supplementation, pharmacotherapies, antibiotics, surgical techniques, as well as genetic and cellular therapies, have the potential to enhance, optimize, and even revolutionize the process of fracture healing.

Purpose: To identify cost drivers of open biceps tenodesis, arthroscopic biceps tenodesis, and arthroscopic SLAP repair in the setting of isolated SLAP tears and to perform a direct cost comparison between the procedures. Methods: The 2014 State Ambulatory Surgery and Services Databases from 6 US states were used. Cases with Current Procedural Terminology codes 23430 (tenodesis of long tendon of biceps), 29807 (shoulder arthroscopy, repair of SLAP lesion), and 29828 (shoulder arthroscopy, biceps tenodesis) were selected, excluding patients who were >50 years old or had a concomitant rotator cuff repair. Generalized linear models were used to model costs based on surgical and patient variables. Results: The mean patient age was 41.8 years for open biceps tenodesis, 31.6 for arthroscopic SLAP repair, and 41.3 for arthroscopic biceps tenodesis (P < .001). Open biceps tenodesis had cost reductions of $5,664 over arthroscopic biceps tenodesis (P = .001) and $2,320 over arthroscopic SLAP repair (P = .043). Male sex was associated with $3,798 more in costs (P < .001), presence of ≥1 comorbidities added $1,829 (P = .002), and each minute in the operating room added $37 (P < .001). Operative time for open biceps tenodesis averaged 114 minutes, and both arthroscopic procedures averaged 94 minutes (P < .001). Low-volume facilities were associated with $5,536 higher costs for arthroscopic biceps tenodesis (P = .001). Conclusion: In patients aged ≤50 years with isolated SLAP tears, open biceps tenodesis provides cost savings over arthroscopic methods of treatment. There was no significant cost difference between arthroscopic SLAP repairs and arthroscopic biceps tenodesis. Given the increased emphasis on cost containment, surgeons should be aware of the procedural costs associated with the treatment of SLAP tears. Level of Evidence: III, retrospective cohort study.

Purpose: To describe which patients are the most likely to undergo surgical management within the same calendar year as their emergency department visit for anterior shoulder instability. Methods: The State Emergency Department Databases and State Ambulatory Surgery and Services Databases from Florida were used. All patients presenting to the emergency department for anterior shoulder subluxation or dislocation between January 1 and September 30, 2017, were selected. Bivariate analysis was performed for associations with demographic variables. A binary logistic regression was performed with all significant factors to assess which were predictors of undergoing surgery the same calendar year. Results: While controlling for all significant factors, we found that patients with recurrent dislocations were 3.14 times more likely to have surgery within the same year (P = .037). Patients younger than 40 years were also 2.04 times more likely to have surgery than those aged 40 years or older (P < .001). White patients were 2.47 times more likely to have surgery than black patients (P < .001). On bivariate analysis, there was an association between greater income quartile and higher odds of undergoing surgery within 30 days. Conclusions: Following an emergency department visit for acute shoulder instability, the following variables were associated with undergoing surgical stabilization within the same calendar year: previous dislocation, age younger than 40, and white race. Patients living in the greatest income quartile of patients had a significantly greater percentage of patients having surgery within 30 days. This demonstrates that disparities and barriers to care may exist for patients with shoulder instability. Level of Evidence: Level III, Retrospective Comparative Study.

Background: The COVID-19 (2019 novel coronavirus disease) pandemic is deeply concerning because of its massive mortality and morbidity, creating adverse perceptions among patients likely to impact on their overall medical care. Thus, we evaluated the impact of the COVID-19 pandemic on the pattern of primary care consultations within a Shanghai health district.Methods: A retrospective observational cohort study was performed, with data analyzed concerning the pattern of patient visits to general practitioners within the Tongren Hospital network (the sole provider of general practice to the population of 700,000). Data from all general practice consultations for adults were collected for the first 6 months of 2020, which included a 60-day lockdown period (January 24–March 24, 2020) and compared to corresponding data from the first 6 months of 2019. We evaluated changes to the numbers and patterns of primary care consultations, including subgroup analysis based on age, sex, and primary diagnosis.Results: A substantial reduction in patient visits, associated with increased median age, was observed during the first wave of the pandemic in the first 6 months of 2020, compared to the same interval during 2019. Additionally, reduced reappointments and waiting times, but increased costs per visit were observed. When analyzed by primary disease diagnosis, patient visits were reduced for all the major systems. The most striking visit reductions were in cardiovascular, respiratory, endocrine, and gastrointestinal diseases. However, psychological disorders were increased following lockdown, but there was also a dramatic fall in consultations for depression. Reduced monthly patient numbers correlated with both rate of reappointment and average waiting time during the first 6 months of both 2019 and 2020, but an inverse correlation was observed between cost per visit and monthly patient numbers. Specifically during the lockdown period, there was ~50% reduced patient visits.Conclusions: The lockdown has had a serious impact on patients' physical and psychological health. Our analysis provides objective health-related data that may inform the current controversy concerning the balance between the detrimental effects of the use of lockdown vs. the use of a more targeted approach to eliminate viral transmission. These data may improve decision-making in medical practice, policy, and education.

Introduction The high placebo response in depression treatment trials is a major contributing factor for randomised control trial failure to establish efficacy of novel or repurposed treatments in treatment-resistant depression (TRD) and major depressive disorder in general. Though there have been a number of meta-analyses and primary research studies evaluating the placebo response in non-TRD, placebo response in TRD is poorly understood. It is important to understand the placebo response of TRD as treatments are only moderately effective and up to 1/3 of patients will experience TRD.Methods and analysis We will conduct a search of electronic databases (MEDLINE and PsychINFO) from inception to 24th January 2020 including randomised, placebo-controlled trials of pharmacological, somatic and psychological interventions for adults with TRD. TRD will be defined as a failure to respond to at least two interventions of adequate dose or duration. We will also search reference lists from review articles. We will perform several meta-analyses to quantify the placebo response for each treatment modality. Regression analysis will explore potential contributing demographic and clinical variables to the placebo response. We will use Cochrane risk of bias tool.Ethics and dissemination There is no research ethics board approval required. The dissemination plan is to publish results in a peer-reviewed academic journal.PROSPERO registration number 190 465.

Purpose: To evaluate the presence of sex-specific analysis (SSA) in abstracts accepted for podium presentation at the Arthroscopy Association of North America (AANA) and American Orthopaedic Society for Sports Medicine (AOSSM) annual meetings from 2016 to 2019. Methods: Abstracts accepted for podium presentation at the AANA and AOSSM annual meetings from 2016 to 2019 were selected for review. Studies that included sex as a variable in a multifactorial statistical model were considered to have performed adequate SSA. Secondary data collected included whether the abstract had a female lead or senior author, the degrees of the female authors, and the anatomic focuses of studies with SSA. Results: Of the 891 total abstracts accepted for podium presentation at the AANA and AOSSM annual meetings from 2016 to 2019, 90 (10%) included SSA. There were 284 AANA abstracts, 24 (8%) of which reported SSA. Of the 607 AOSSM abstracts, 66 (11%) reported SSA. There were 43 female first authors (15%) and 33 female senior authors (12%) of the AANA abstracts compared with 92 female first authors (15%) and 39 female senior authors (6%) of the AOSSM abstracts. Of the 891 total abstracts, 135 (15%) listed a female lead author and 72 (8%) had a female senior author. Of the 135 female first authors, 92 (68%) had an M.D., whereas 40 of the 72 female senior authors (56%) had an M.D. Analysis of all abstracts combined showed a positive correlation between SSA and a female first author (Pearson correlation coefficient = 0.035, P = .147), as well as between SSA and a female senior author (Pearson correlation coefficient = 0.052, P = .059). Conclusions: From 2016 to 2019, only 10% of abstracts accepted for podium presentation at the AANA and AOSSM annual meetings included SSA. Altogether, women represented 15% of first authors and 8% of senior authors. Clinical Relevance: This study highlights the low percentage of SSA in abstracts presented at the AANA and AOSSM annual meetings from 2016 to 2019. Future studies should attempt to perform SSA when relevant to better evaluate differences in outcomes between male and female patients.

Category: Ankle Introduction/Purpose: Biologic fixation of total joint replacements by bone ingrowth requires minimal bone-implant micromotion [1]. Computational finite element (FE) models used to evaluate the interaction between implant and bone typically only consider simplified loading conditions based on the peak compressive force which occurs near toe-off [2,3]. However, a previous study focused on cementless knee replacements demonstrated that peak micromotion during activity cycles occurred with sub-maximal forces and moments [4]. Our objective was to calculate multi-axial loading at the ankle joint throughout level walking and evaluate tibial fixation of ankle replacements under these loading conditions. We hypothesized that peak micromotion would occur with sub-maximal loads and moments instead of at the instant of peak compressive load. Methods: Our validated six-degree-of-freedom robotic simulator utilizes in vivo data from human subjects to replicate the individual bone kinematics in cadaveric specimen throughout activity [5]. We rigidly fixed retro-reflective markers using bone pins to the tibia, talus, and calcaneus bones of three cadaveric specimens to record individual bone kinematics using motion capture cameras. We recorded the ground reaction and muscle-tendon forces during the simulated stance phase of level walking. Musculoskeletal models were then developed in OpenSim using the specimen-specific morphology and implant position from CT- scans and from the simulator outputs to determine the loading profile at the ankle joint during stance. The calculated loads were then applied to specimen-specific finite element models to evaluate the bone-implant interaction. Peak micromotion at each time point of loading was measured and compared to the loading profile to determine if it corresponded with the peak compressive load. Results: For all specimens, the peak compressive load at the ankle joint was accompanied by multi-axial moments and relatively small shear forces (Figure 1). The peak compressive load for each specimens was between 750 N and 850 N and occurred during 75-80% of gait. The largest moment experienced by all specimens was an internal moment late in stance. The peak micromotion for each specimen did not correspond to the instance of peak compressive load, as indicated in Figure 1. Instead, peak micromotion occurred at 54%, 88%, and 96% of gait. For each specimen, these instances corresponded to the combination of a sub-maximal compressive load with high eversion and internal moments. Conclusion: We have developed a workflow to calculate ankle joint loads corresponding to cadaveric simulations that reproduce a daily activity based on in vivo data. The specimen-specific, multi-axial loading profile at the ankle for our initial results suggests that peak micromotion at the bone-implant interface of the tibial implant does not coincide with the peak compressive force. The instant of peak compressive load may not capture the worst-case scenario for the interaction between the implant and the bone. Instead, the multi-axial forces and moments at the ankle joint throughout activity should be considered when evaluating implant fixation.

Treatment of rifampin-monoresistant/multidrug-resistant Tuberculosis (RR/MDR-TB) requires long treatment courses, complicated by frequent adverse events and low success rates. Incidence of RR/MDR-TB in Canada is low and treatment practices are variable due to the infrequent experience and challenges with drug access. We undertook a retrospective cohort study of all RR/MDR-TB cases in Alberta, Canada from 2007-2017 to explore the epidemiology and outcomes in our low incidence setting. We performed a descriptive analysis of the epidemiology, treatment regimens and associated outcomes, calculating differences in continuous and discrete variables using Student's t and Chi-squared tests, respectively. We identified 24 patients with RR/MDR-TB. All patients were foreign-born with the median time to presentation after immigration being 3 years. Prior treatment was reported in 46%. Treatment was individualized. All patients achieved sputum culture conversion within two months of treatment initiation. The median treatment duration after culture conversion was 18 months (IQR: 15-19). The mean number of drugs utilized during the intensive phase was 4.3 (SD: 0.8) and during the continuation phase was 3.3 (SD: 0.9) and the mean adherence to medications was 95%. Six patients completed national guideline-concordant therapy, with many patients developing adverse events (79%). Treatment success (defined as completion of prescribed therapy or cure) was achieved in 23/24 patients and no acquired drug resistance or relapse was detected over 1.8 years of median follow-up. Many cases were captured upon immigration assessment, representing important prevention of community spread. Despite high rates of adverse events and short treatment compared to international guidelines, success in our cohort was very high at 96%. This is likely due to individualization of therapy, frequent use of medications with high effectiveness, intensive treatment support, and early sputum conversion seen in our cohort. There should be ongoing exploration of treatment shortening with well-tolerated, efficacious oral agents to help patients achieve treatment completion.

Background ECG abnormalities are associated with adverse outcomes in the general population, but their prognostic significance in severe mental illness (SMI) remains unexplored. We investigated associations between no, minor, and major ECG abnormalities and fatal cardiovascular disease (CVD) among patients with SMI compared with controls without mental illness. Methods and Results We cross‐linked data from Danish nationwide registries and included primary care patients with digital ECGs from 2001 to 2015. Patients had SMI if they were diagnosed with schizophrenia, bipolar disorder, or severe depression before ECG recording. Controls were required to be without any prior mental illness or psychotropic medication use. Fatal CVD was assessed using hazard ratios (HRs) with 95% CIs and standardized 10‐year absolute risks. Of 346 552 patients, 10 028 had SMI (3%; median age, 54 years; male, 45%), and 336 524 were controls (97%; median age, 56 years; male, 48%). We observed an interaction between SMI and ECG abnormalities on fatal CVD (P

Introduction With 70.8 million people displaced worldwide, there is an increasing need for medical professionals to provide medical care to refugees. Insufficient training on refugee health poses a barrier to effective care delivery. Methods This workshop addressed common challenges in providing family-centered pediatric refugee care in community settings as well as barriers related to policy changes. Presentations covered prearrival experiences, medical screening, and trauma-based care. In small groups, participants discussed cases that featured medical, behavioral health, social, and cultural factors impacting the provision of family-centered pediatric care that was culturally respectful and included shared decision-making. After the breakout session, each small group informed the larger group of topics discussed. Facilitators identified themes and reinforced key learning points. At the workshop's conclusion, participants were guided to create their own personalized action plan. Results This workshop was presented at two international conferences to more than 47 participants, including clinicians, nurse practitioners, pediatric residents, and medical students. Evaluations were completed by 34 individuals. Participants' overall comfort level with taking care of refugee patients increased from 3.3 to 4.0 (on a 5-point scale, p = .24) during the 3-hour version of the workshop and from 3.8 to 4.0 (p = .43) in the 1-hour version of the workshop. Mean overall ratings of the 3- and 1-hour workshop versions on conference-administered evaluations were 4.8 and 4.2, respectively, on a 5-point scale. Discussions This workshop was well received and equipped participants with knowledge, tools, and strategies regarding pediatric refugee health in a community setting.

The COVID-19 outbreak has become a pandemic. The outbreak was able to be controlled in China by mid-April through the implementation of critical measures; however, significant reverse transmission has resulted in hot spots perturbing prevention and control. To date, there have only been a total of 92 indigenous COVID-19 cases confirmed in the Gansu Province, which is considered to be a consequence of the strict screening approach applied during the outbreak. The emergency response level to COVID-19 were able to be decreased from high to low, despite some relatively minor reverse transmission cases from other countries in March 2020. The stringent preparative measures undertaken by the Gansu authorities, involving high-level, streamlined cooperation between the transportation, quarantine, and medical resource departments, have underpinned this success. There has been an emergence of clusters of freshly infected COVID-19 patients in the Jilin Province in northeast China. The single largest cluster has been in Shulan of the Jilin Province, involving 43 confirmed infections. A strict lockdown was implemented immediately. The source of the current outbreak of COVID-19 is suggested to be travelers returning from Russia. The current strategy from the Chinese authorities is aimed at preventing reverse transmission via international importation to avert a rebound of COVID-19 in China. These data highlight the need for an exceptionally high level of vigilance and for a pre-emptive response that is informative for the development of policy to prevent a second and further waves of infections in general.

Abstract Prolonging chondrocyte survival is essential to ensure fresh osteochondral (OC) grafts for treatment of articular cartilage lesions. Doxycycline has been shown to enhance cartilage growth, disrupt terminal differentiation of chondrocytes, and inhibit cartilage matrix degradation. It is unknown whether doxycycline prolongs chondrocyte survival in OC grafts. We hypothesized that doxycycline protects against chondrocyte death and maintains function of articular cartilage. To test this hypothesis, we employed human and calf articular cartilages, and incubated chondrocytes isolated from cartilage or cartilage plugs with doxycycline (0, 1 or 10 μg/ml) at either 37°C or 4°C. Chondrocyte viability, apoptosis, glycosaminoglycan (GAG), collagen, and mechanical test in cartilage plugs were measured. We found that reduced chondrocyte viability, increased chondrocyte apoptosis, reduced GAG contents, and impaired equilibrium modulus in cartilage plugs were observed in a time‐dependent manner at both 37°C and 4°C. Chondrocyte viability was further reduced when the plugs were cultured at 4°C as compared to 37°C. Doxycycline prolonged viability and reduced apoptosis of chondrocytes during culture of cartilage plugs. Functionally, doxycycline protected against reduced production of GAG and collagen II as well as impaired mechanical properties in cartilage plugs during culture. Mechanistically, doxycycline increased mitochondrial respiration in cultured chondrocytes. In conclusion, preservation at 37°C is beneficial for maintaining chondrocyte viability in cartilage plugs compared to 4°C. Incubation of doxycycline protects against chondrocyte apoptosis, reduced extracellular matrix, and impaired mechanical properties in cartilage plugs. The findings provide a potential approach using doxycycline at 37°C to preserve chondrocyte viability in fresh OC grafts for treatment of articular cartilage lesions.

Background: As an emerging infectious disease, COVID-19 has garnered great research interest. We aimed to explore the differences between English language and Chinese language Medical/Scientific journals publications, particularly aiming to explore the efficacy/contents of the literature published in English and Chinese in relation to the outcomes of management and characterization of COVID-19 during the early stage of COVID-19 pandemic.Methods: Publications on COVID-19 research were retrieved from both English and Chinese databases. Bibliometric analyses were performed using VOSviewer 1.6.14, and CiteSpace V software. Network maps were generated to evaluate the collaborations between different authors, countries/provinces, and institutions.Results: A total of 143 English and 721 Chinese original research articles and reviews on COVID-19 were included in our study. Most of the authors and institutions of the papers were from China before March 1st, 2020, however, the distribution of authors and institutions were mainly in developed countries or more wealthy areas of China. The range of the keywords in English publications was more extensive than those in Chinese. Traditional Chinese Medicine was seen more frequently in Chinese papers than in English. Of the 143 articles published in English, 54 articles were published by Chinese authors only and 21 articles were published jointly by Chinese and other overseas authors.Conclusions: The publications in English have enabled medical practitioners and scientists to share/exchange information, while on the other hand, the publications in the Chinese language have provided complementary educational approaches for the local medical practitioners to understand the essential and key information to manage COVID-19 in the relatively remote regions of China, for the general population with a general level of education.

Background Left ventricular assist devices (LVADs) generate electromagnetic interference that causes high‐frequency noise artifacts on 12‐lead ECGs. We describe the causes of this interference and potential solutions to aid ECG interpretation in patients with LVAD. Methods and Results Waveform data from ECGs performed before and after LVAD implantation were passed through a fast Fourier transform to identify LVAD‐related changes in the spectral profile. ECGs recorded in 9 patients with HeartMate II, HeartMate 3, and HeartWare LVADs were analyzed to identify the LVAD model‐specific spectral patterns. Waveform data were then passed through digital low‐pass and bandstop filters and redisplayed to evaluate the effect of filtering on LVAD‐related electromagnetic interference. The spectral profile of patients with HeartMate II and HeartMate 3 LVADs demonstrated a prominent signal at the device‐specific frequency of impeller rotation. In patients with the HeartMate 3 LVAD, 2 additional peaks were observed at the frequencies equivalent to the LVAD's artificial pulsatility rotational speeds. Patients with HeartWare devices demonstrated a prominent signal peak at a frequency equal to double their LVAD's set rotational speed. Applying a low‐pass filter to a value below the observed frequency peak from the LVAD significantly improved the waveform tracing and quality of the ECG. Applying a speed‐specific bandstop filter to remove the observed LVAD frequency peak also improved the clarity of the ECG without compromising physiological high‐frequency signal components. Conclusions LVADs create impeller rotational speed‐specific electromagnetic interference that can be ameliorated by application of low‐pass or bandstop filters to improve ECG clarity.

Translational regulation of mRNAs is critically important for proper gene expression in germ cells, gametes, and embryos. The ability of the nucleus to control gene expression in these systems may be limited due to spatial or temporal constraints, as well as the breadth of gene products they express to prepare for the rapid animal development that follows. During development germ granules are hubs of post-transcriptional regulation of mRNAs. They assemble and remodel messenger ribonucleoprotein (mRNP) complexes for translational repression or activation. Recently, mRNPs have been appreciated as discrete regulatory units, whose function is dictated by the many positive and negative acting factors within the complex. Repressed mRNPs must be activated for translation on ribosomes to introduce novel proteins into germ cells. The binding of eIF4E to interacting proteins (4EIPs) that sequester it represents a node that controls many aspects of mRNP fate including localization, stability, poly(A) elongation, deadenylation, and translational activation/repression. Furthermore, plants and animals have evolved to express multiple functionally distinct eIF4E and 4EIP variants within germ cells, giving rise to different modes of translational regulation.

The overall aim of this article is to explain how the MUSIC Model of Motivation can be applied to L2 instruction in a manner that is consistent with positive psychology, which emphasizes individuals’ strengths and the conditions in which they thrive. The article begins by describing the MUSIC model, which is a research-based framework that organizes strategies that instructors can use to motivate students to engage in learning. The MUSIC model can be used by L2 instructors to create learning experiences that consider learners’ cognition, affect, needs, and desires in order to foster their motivation and engagement in L2 classes. The article also provides teaching strategies related to the MUSIC model and presents an assessment tool (the MUSIC Model of Academic Motivation Inventory) that can be used by L2 instructors to measure students’ MUSIC perceptions of their class. The assessment tool provides feedback to instructors that can be used to improve their instruction by incorporating strategies that allow their students to flourish. Examples of how the MUSIC Inventory can be used to assess L2 instruction are provided. Although researchers have examined the use of the MUSIC model in L2 classes, this research is underdeveloped, and many questions related to its use in L2 classes remain. The article concludes by proposing unanswered questions that could lead to more effective uses of the MUSIC model in L2 classes.

Objective To (1) investigate the extent to which recently published meta-analyses report trial funding, author–industry financial ties and author–industry employment from included randomised controlled trials (RCTs), comparing Cochrane and non-Cochrane meta-analyses; (2) examine characteristics of meta-analyses independently associated with reporting funding sources of included RCTs; and (3) compare reporting among recently published Cochrane meta-analyses to Cochrane reviews published in 2010.Design Review of consecutive sample of recently published meta-analyses.Data sources MEDLINE database via PubMed searched on 19 October 2018.Eligibility criteria for selecting articles We selected the 250 most recent meta-analyses listed in PubMed that included a documented search of at least one database, statistically combined results from ≥2 RCTs and evaluated the effects of a drug or class of drugs.Results 90 of 107 (84%) Cochrane meta-analyses reported funding sources for some or all included trials compared with 21 of 143 (15%) non-Cochrane meta-analyses, a difference of 69% (95% CI 59% to 77%). Percent reporting was also higher for Cochrane meta-analyses compared with non-Cochrane meta-analyses for trial author–industry financial ties (44% versus 1%; 95% CI for difference 33% to 52%) and employment (17% versus 1%; 95% CI for difference 9% to 24%). In multivariable analysis, compared with Cochrane meta-analyses, the odds ratio (OR) for reporting trial funding was ≤0.11 for all other journal category and impact factor combinations. Compared with Cochrane reviews from 2010, reporting of funding sources of included RCTs among recently published Cochrane meta-analyses improved by 54% (95% CI 42% to 63%), and reporting of trial author–industry financial ties and employment improved by 37% (95% CI 26% to 47%) and 10% (95% CI 2% to 19%).Conclusions Reporting of trial funding sources, trial author–industry financial ties and trial author–industry employment in Cochrane meta-analyses has improved since 2010 and is higher than in non-Cochrane meta-analyses.

ABSTRACT While the basic mechanisms of flavivirus entry and fusion are understood, little is known about the postfusion events that precede RNA replication, such as nucleocapsid disassembly. We describe here a sensitive, conditionally replication-defective yellow fever virus (YFV) entry reporter, YFVΔSK/Nluc, to quantitively monitor the translation of incoming, virus particle-delivered genomes. We validated that YFVΔSK/Nluc gene expression can be neutralized by YFV-specific antisera and requires known flavivirus entry pathways and cellular factors, including clathrin- and dynamin-mediated endocytosis, endosomal acidification, YFV E glycoprotein-mediated fusion, and cellular LY6E and RPLP1 expression. The initial round of YFV translation was shown to require cellular ubiquitylation, consistent with recent findings that dengue virus capsid protein must be ubiquitylated in order for nucleocapsid uncoating to occur. Importantly, translation of incoming YFV genomes also required valosin-containing protein (VCP)/p97, a cellular ATPase that unfolds and extracts ubiquitylated client proteins from large complexes. RNA transfection and washout experiments showed that VCP/p97 functions at a postfusion, pretranslation step in YFV entry. Finally, VCP/p97 activity was required by other flaviviruses in mammalian cells and by YFV in mosquito cells. Together, these data support a critical role for VCP/p97 in the disassembly of incoming flavivirus nucleocapsids during a postfusion step in virus entry. IMPORTANCE Flaviviruses are an important group of RNA viruses that cause significant human disease. The mechanisms by which flavivirus nucleocapsids are disassembled during virus entry remain unclear. Here, we used a yellow fever virus entry reporter, which expresses a sensitive reporter enzyme but does not replicate, to show that nucleocapsid disassembly requires the cellular protein-disaggregating enzyme valosin-containing protein, also known as p97.

Background: Clinical trainees face challenges throughout short-term experiences in global health (STEGH) that are not routinely addressed. Objectives: Describe common professional and ethical dilemmas faced by clinical trainees and identify gaps and solutions for pre, during, and post-STEGH training and mentoring. Methods: We conducted a mixed-methods study among trainees and mentors involved in global health. The study utilized focus groups with trainees (November–December 2015) and online surveys of trainees, in-country and stateside faculty mentors (October 2016–April 2017). Results: 85% (17/20) of students reported feeling prepared for their STEGH; however, 59% (23/39) of faculty felt students were unprepared. A majority of both students (90%) and faculty (77%) stated students would likely experience an ethical dilemma during STEGH. Major themes relating to meaningful global health work were elucidated: personal and inter-professional skills; interpersonal networks and collaboration; and awareness of power dynamics and bias. Conclusions: The most common challenges faced by trainees during STEGH related to leadership, bias, ethics and interprofessional collaboration. Redirecting trainee energies from a focus on ‘doing’ and deliv­erables to attitudes (e.g., humility, professionalism) that cultivate personal and professional growth will help create lifelong global health learners and leaders.

Escherichia coli is frequently isolated from the respiratory secretions of cystic fibrosis (CF) patients yet is not considered a classical CF pathogen. Accordingly, little is known about the natural history of this organism in the CF airways, as well as the potential for patient-to-patient transmission. Patients attending the Calgary Adult CF Clinic (CACFC) between January 1983 and December 2016 with at least one E. coli-positive sputum culture were identified by retrospective review. Annual E. coli isolates from the CACFC biobank from each patient were typed by pulsed-field gel electrophoresis (PFGE) and isolates belonging to shared pulsotypes were sequenced. Single nucleotide polymorphism (SNP) and phylogenetic analysis were used to investigate the natural history of E. coli infection and identify potential transmission events. Forty-five patients with E. coli-positive sputum cultures were identified. Most patients had a single infection episode with a single pulsotype, while replacement of an initial pulsotype with a second was observed in three patients. Twenty-four had E. coli recovered from their sputum more than once and 18 patients had persistent infections (E. coli carriage >6 months with ≥3 positive cultures). Shared pulsotypes corresponded to known extraintestinal pathogenic E. coli strains: ST-131, ST-73, and ST-1193. Phylogenetic relationships and SNP distances among isolates within shared pulsotypes were consistent with independent acquisition of E. coli by individual patients. Most recent common ancestor date estimates of isolates between patients were inconsistent with patient-to-patient transmission. E. coli infection in CF is a dynamic process that appears to be characterized by independent acquisition within our patient population and carriage of unique sets of strains over time by individual patients.

Mouse models of human disease remain the bread and butter of modern biology and therapeutic discovery. Nonetheless, more often than not mouse models do not reproduce the pathophysiology of the human conditions they are designed to mimic. Naturally occurring large animal models have predominantly been found in companion animals or livestock because of their emotional or economic value to modern society and, unlike mice, often recapitulate the human disease state. In particular, numerous models have been discovered in dogs and have a fundamental role in bridging proof of concept studies in mice to human clinical trials. The present article is a review that highlights current canine models of human diseases, including Alzheimer's disease, degenerative myelopathy, neuronal ceroid lipofuscinosis, globoid cell leukodystrophy, Duchenne muscular dystrophy, mucopolysaccharidosis, and fucosidosis. The goal of the review is to discuss canine and human neurodegenerative pathophysiologic similarities, introduce the animal models, and shed light on the ability of canine models to facilitate current and future treatment trials.

Practical diets for commercial barramundi production rarely contain greater than 10% starch, used mainly as a binding agent during extrusion. Alternative ingredients such as digestible starch have shown some capacity to spare dietary protein catabolism to generate glucose. In the present study, a carnivorous fish species, the Asian seabass (Lates calcarifer) was subjected to two diets with the same digestible energy: Protein (P) – with high protein content (no digestible starch); and Starch (S) – with high digestible (pregelatinized) starch content. The effects of a high starch content diet on hepatic glycogen synthesis as well as the muscle and liver metabolome were studied using a complementary approach of 1H and 2H NMR. The hepatosomatic index was lower for fish fed high starch content diet while the concentration of hepatic glycogen was similar between groups. However, increased glycogen synthesis via the direct pathway was observed in the fish fed high starch content diet which is indicative of increased carbohydrate utilization. Multivariate analysis also showed differences between groups in the metabolome of both tissues. Univariate analysis revealed more variations in liver than in muscle of fish fed high starch content diet. Variations in metabolome were generally in agreement with the increase in the glycogen synthesis through direct pathway, however, this metabolic shift seemed to be insufficient to keep the growth rate as ensured by the diet with high protein content. Although liver glycogen does not make up a substantial quantity of total stored dietary energy in carnivorous fish, it is a key regulatory intermediate in dietary energy utilization.

Isoniazid resistant Mycobacterium tuberculosis (Hr-TB) is the most frequently encountered TB resistance phenotype in North America but limited data exist on the effectiveness of current therapeutic regimens. Ineffective treatment of Hr-TB increases patient relapse and anti-mycobacterial resistance, specifically MDR-TB. We undertook a multi-centre, retrospective review of culture-positive Hr-TB patients in Alberta, Canada (2007-2017). We assessed incidence and treatment outcomes, with a focus on fluoroquinolone (FQ)-containing regimens, to understand the risk of unsuccessful outcomes. Rates of Hr-TB were determined using the mid-year provincial population and odds of unsuccessful treatment was calculated using a Fisher's Exact test. One hundred eight patients of median age 37 years (IQR: 26-50) were identified with Hr-TB (6.3%), 98 of whom were able to be analyzed. Seven percent reported prior treatment. Rate of foreign birth was high (95%), but continent of origin did not predict Hr-TB (p = 0.47). Mean compliance was 95% with no difference between FQ and non-FQ regimens (p = 1.00). Treatment success was high (91.8%). FQ-containing regimens were frequently initiated (70%), with no difference in unsuccessful outcomes compared to non-FQ-containing regimens (5.8% vs. 13.8%, OR 0.4, 95% CI 0.1-2.3, p = 0.23). Only one patient (1%) utilizing a less common non-FQ-based regimen including two months of pyrazinamide developed secondary multidrug resistance. Unsuccessful treatment was low (

Depression is common among cardiac patients and associated with adverse cardiovascular outcomes. Bright light therapy has emerged as a promising treatment for depressive symptoms, however it has not yet been investigated in this population. We conducted a double-blind, randomized, placebo-controlled pilot trial to assess the feasibility of a larger-scale trial testing bright light therapy for depressive symptoms in cardiac patients. Patients hospitalized for an acute coronary syndrome or undergoing cardiac surgery were randomized to either bright light (10,000 lux) or dim light placebo (500 lux) lamps for 30 minutes each day over 4 weeks, beginning in-hospital. Depression was quantified using the Patient Health Questionnaire 9 (PHQ-9) and Depression Anxiety and Stress Scales (DASS-21). The Short-Form Health Survey 36 (SF-36) was used to measure quality of life. A total of 175 patients were screened and 15 were randomized (8 treatment, 7 placebo) (8.6%) over 10 months. Despite protocol amendments which broadened the inclusion criteria, the trial was terminated early for infeasibility based on the rate of enrollment (1-2 participants/month), with 39.5% of the target sample (38 participants) enrolled. Future trials should take into account the timing of the onset of depressive symptoms in these patients, and consider a less conservative approach to eligibility as well as ways to increase the acceptability of bright light therapy in hospitalized cardiac patients. Once enrolled, our findings suggest that most participants will adhere to the assigned treatment and complete follow-up.

Abstract Background Randomized controlled trials (RCTs) are often complex and expensive to perform. Less than one third achieve planned recruitment targets, follow-up can be labor-intensive, and many have limited real-world generalizability. Designs for RCTs conducted using cohorts and routinely collected health data, including registries, electronic health records, and administrative databases, have been proposed to address these challenges and are being rapidly adopted. These designs, however, are relatively recent innovations, and published RCT reports often do not describe important aspects of their methodology in a standardized way. Our objective is to extend the Consolidated Standards of Reporting Trials (CONSORT) statement with a consensus-driven reporting guideline for RCTs using cohorts and routinely collected health data. Methods The development of this CONSORT extension will consist of five phases. Phase 1 (completed) consisted of the project launch, including fundraising, the establishment of a research team, and development of a conceptual framework. In phase 2, a systematic review will be performed to identify publications (1) that describe methods or reporting considerations for RCTs conducted using cohorts and routinely collected health data or (2) that are protocols or report results from such RCTs. An initial “long list” of possible modifications to CONSORT checklist items and possible new items for the reporting guideline will be generated based on the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) and The REporting of studies Conducted using Observational Routinely-collected health Data (RECORD) statements. Additional possible modifications and new items will be identified based on the results of the systematic review. Phase 3 will consist of a three-round Delphi exercise with methods and content experts to evaluate the “long list” and generate a “short list” of key items. In phase 4, these items will serve as the basis for an in-person consensus meeting to finalize a core set of items to be included in the reporting guideline and checklist. Phase 5 will involve drafting the checklist and elaboration-explanation documents, and dissemination and implementation of the guideline. Discussion Development of this CONSORT extension will contribute to more transparent reporting of RCTs conducted using cohorts and routinely collected health data.

Abstract Many medical professions require practitioners to perform visual categorizations in domains such as radiology, dermatology, and neurology. However, acquiring visual expertise is tedious and time-consuming and the perceptual strategies mediating visual categorization skills are poorly understood. In this paper, the Ease algorithm was developed to predict an item’s categorization difficulty (Ease value) based on the item’s perceptual similarity to all within-category items versus between-category items in the dataset. In this study, Ease values were used to construct an easy-to-hard and hard-to-easy training schedule for teaching melanoma diagnosis. Whereas previous visual training studies suggest that an easy-to-hard schedule benefits learning outcomes, no studies to date have demonstrated the easy-to-hard advantage with complex, real-world images. In our study, 237 melanoma and benign images were collected for training and testing purposes. The diagnostic accuracy of images was verified by an expert dermatologist. Based on their Ease values, the items were grouped into easy, medium, and hard categories, each containing an equal number of melanoma and benign lesions. During training, participants categorized images of skin lesions as either benign or melanoma and were given corrective feedback after each trial. In the easy-to-hard training condition, participants learned to categorize all the easy items first, followed by the medium items, and finally the hard items. Participants in the hard-to-easy training condition learned items in the reverse order. Post-training results showed that training in both conditions transferred to the classification of new melanoma and benign images. Participants in the easy-to-hard condition showed modest advantages both in the acquisition and retention of the melanoma diagnosis skills, but neither scheduling condition exhibited a gross advantage. The Ease values of the items predicted categorization accuracy after, but not before training, suggesting that the Ease algorithm is a promising tool for optimizing medical training in visual categorization.

Abstract Background Postpartum hemorrhage is the leading cause of maternal mortality in low- and middle-income countries. While evidence on uterine balloon tamponade efficacy for severe hemorrhage is encouraging, little is known about safety of this intervention. The objective of this study was to evaluate the safety of an ultra-low-cost uterine balloon tamponade package (named ESM-UBT) for facility-based management of uncontrolled postpartum hemorrhage (PPH) in Kenya and Sierra Leone. Methods Data were collected on complications/adverse events in all women who had an ESM-UBT device placed among 92 facilities in Sierra Leone and Kenya, between September 2012 and December 2015, as part of a multi-country study. Three expert maternal health investigator physicians analyzed each complication/adverse event and developed consensus on whether there was a potential causal relationship associated with use of the ESM-UBT device. Adverse events/complications specifically investigated included death, hysterectomy, uterine rupture, perineal or cervical injury, serious or minor infection, and latex allergy/anaphylaxis. Results Of the 201 women treated with an ESM-UBT device in Kenya and Sierra Leone, 189 (94.0%) survived. Six-week or longer follow-up was recorded in 156 of the 189 (82.5%). A causal relationship between use of an ESM-UBT device and one death, three perineal injuries and one case of mild endometritis could not be completely excluded. Three experts found a potential association between these injuries and an ESM-UBT device highly unlikely. Conclusion The ESM-UBT device appears safe for use in women with uncontrolled PPH. Trial registration Trial registration was not completed as data was collected as a quality assurance measure for the ESM-UBT kit.

Abstract Background Sepsis and septic shock occur commonly in severe burns. Acute kidney injury (AKI) is also common and often results as a consequence of sepsis. Mortality is unacceptably high in burn patients who develop AKI requiring renal replacement therapy and is presumed to be even higher when combined with septic shock. We hypothesized that high-volume hemofiltration (HVHF) as a blood purification technique would be beneficial in this population. Methods We conducted a multicenter, prospective, randomized, controlled clinical trial to evaluate the impact of HVHF on the hemodynamic profile of burn patients with septic shock and AKI involving seven burn centers in the United States. Subjects randomized to the HVHF were prescribed a dose of 70 ml/kg/hour for 48 hours while control subjects were managed in standard fashion in accordance with local practices. Results During a 4-year period, a total of nine subjects were enrolled for the intervention during the ramp-in phase and 28 subjects were randomized, 14 each into the control and HVHF arms respectively. The study was terminated due to slow enrollment. Ramp-in subjects were included along with those randomized in the final analysis. Our primary endpoint, the vasopressor dependency index, decreased significantly at 48 hours compared to baseline in the HVHF group (p = 0.007) while it remained no different in the control arm. At 14 days, the multiple organ dysfunction syndrome score decreased significantly in the HVHF group when compared to the day of treatment initiation (p = 0.02). No changes in inflammatory markers were detected during the 48-hour intervention period. No significant difference in survival was detected. No differences in adverse events were noted between the groups. Conclusions HVHF was effective in reversing shock and improving organ function in burn patients with septic shock and AKI, and appears safe. Whether reversal of shock in these patients can improve survival is yet to be determined. Trial registration Clinicaltrials.gov NCT01213914 . Registered 30 September 2010.

Major depressive disorder (MDD) and bipolar disorder (BD) are often chronic with many patients not responding to available treatments. As these mood disorders are frequently associated with metabolic dysfunction, there has been increased interest in novel treatments that would target metabolic pathways. The objectives of this scoping review were to synthesize evidence on the impact on mood symptoms of lipid lowering agents and anti-diabetics drugs, while also reviewing current knowledge on the association between mood disorders and dyslipidemia or hyperglycemia. We propose that metabolic dysfunction is prevalent in both MDD and BD and it may contribute to the development of these disorders through a variety of pathophysiological processes including inflammation, brain structural changes, hormonal alterations, neurotransmitter disruptions, alteration on brain cholesterol, central insulin resistance, and changes in gut microbiota. Current evidence is conflicting on the use of statins, polyunsaturated fatty acids, thiazolidinediones, glucagon-like peptide agonists, metformin, or insulin for the treatment of MDD and BD. Given the paucity of high-quality randomized controlled trials, additional studies are needed before any of these medications can be repurposed in routine clinical practice. Future trials need to enrich patient recruitment, include evaluations of mechanism of action, and explore differential effects on specific symptom domains such as anhedonia, suicidality, and cognition.