Drosophila immune priming to Enterococcus faecalis relies on immune tolerance rather than resistance.

Innate immune priming increases an organism's survival of a second infection after an initial, non-lethal infection. We used Drosophila melanogaster and an insect-derived strain of Enterococcus faecalis to study transcriptional control of priming. In contrast to other pathogens, the enhanced survival in primed animals does not correlate with decreased E. faecalis load. Further analysis shows that primed organisms tolerate, rather than resist infection. Using RNA-seq of immune tissues, we found many genes were upregulated in only primed flies, suggesting a distinct transcriptional program in response to initial and secondary infections. In contrast, few genes continuously express throughout the experiment or more efficiently re-activate upon reinfection. Priming experiments in immune deficient mutants revealed Imd is largely dispensable for responding to a single infection but needed to fully prime. Together, this indicates the fly's innate immune response is plastic-differing in immune strategy, transcriptional program, and pathway use depending on infection history.

A data harmonization pipeline to leverage external controls and boost power in GWAS.

The use of external controls in genome-wide association study (GWAS) can significantly increase the size and diversity of the control sample, enabling high-resolution ancestry matching and enhancing the power to detect association signals. However, the aggregation of controls from multiple sources is challenging due to batch effects, difficulty in identifying genotyping errors and the use of different genotyping platforms. These obstacles have impeded the use of external controls in GWAS and can lead to spurious results if not carefully addressed. We propose a unified data harmonization pipeline that includes an iterative approach to quality control and imputation, implemented before and after merging cohorts and arrays. We apply this harmonization pipeline to aggregate 27 517 European control samples from 16 collections within dbGaP. We leverage these harmonized controls to conduct a GWAS of Crohn's disease. We demonstrate a boost in power over using the cohort samples alone, and that our procedure results in summary statistics free of any significant batch effects. This harmonization pipeline for aggregating genotype data from multiple sources can also serve other applications where individual level genotypes, rather than summary statistics, are required.

Comprehensive next-generation sequencing identifies novel putative pathogenic or likely pathogenic germline variants in patients with concurrent tubo-ovarian and endometrial serous and endometrioid carcinomas or precursors.

BACKGROUND: Endometrial serous carcinoma (ESC) and tubo-ovarian high-grade serous carcinoma (HGSC) are characterized by late-stage presentation and high mortality. Current guidelines for prevention recommend risk-reducing salpingo-oophorectomy (RRSO) in patients with hereditary mutations in cancer susceptibility genes. However, HGSC displays extensive genetic heterogeneity with alterations in 168 genes identified in TCGA study, but current germline testing panels are often limited to the handful of recurrently mutated genes, leaving families with rare hereditary gene mutations potentially at-risk. OBJECTIVE: To determine if there are rare germline mutations that may aid in early identification of more patients at-risk for ESC and/or HGSC by evaluating patients with concurrent ESC, HGSC or precursor lesions, and endometrial atypical hyperplasia (CAH) or low-grade endometrial endometrioid adenocarcinoma (LGEEA). METHODS: We performed targeted next-generation sequencing using TSO 500, a 523 gene panel, on formalin-fixed paraffin-embedded tumor and matched benign non-tumor tissue blocks from 5 patients with concurrent ESC, HGSC or precursor lesions, and CAH or LGEEA. RESULTS: We identified germline pathogenic, likely pathogenic or uncertain significance variants in cancer susceptibility genes in 4 of 5 patients - affected genes included GLI1, PIK3R1, FOXP1, FANCD2, INPP4B and H3F3C. Notably, none of these genes were included in the commercially available germline testing panels initially used to evaluate the patients at the time of their diagnoses. CONCLUSION: Comprehensive germline testing of patients with concurrent LGEEA or CAH and ESC, HGSC or precursor lesions may aid in early identification of relatives at-risk for cancer who may be candidates for RRSO with hysterectomy.

Validation of actigraphy sleep metrics in children aged 8 to 16 years: considerations for device type, placement and algorithms.

BACKGROUND: Actigraphy is often used to measure sleep in pediatric populations, despite little confirmatory evidence of the accuracy of existing sleep/wake algorithms. The aim of this study was to determine the performance of 11 sleep algorithms in relation to overnight polysomnography in children and adolescents. METHODS: One hundred thirty-seven participants aged 8-16 years wore two Actigraph wGT3X-BT (wrist, waist) and three Axivity AX3 (wrist, back, thigh) accelerometers over 24-h. Gold standard measures of sleep were obtained using polysomnography (PSG; Embletta MPRPG, ST + Proxy and TX Proxy) in the home environment, overnight. Epoch by epoch comparisons of the Sadeh (two algorithms), Cole-Kripke (three algorithms), Tudor-Locke (four algorithms), Count-Scaled (CS), and HDCZA algorithms were undertaken. Mean differences from PSG values were calculated for various sleep outcomes. RESULTS: Overall, sensitivities were high (mean ± SD: 91.8%, ± 5.6%) and specificities moderate (63.8% ± 13.8%), with the HDCZA algorithm performing the best overall in terms of specificity (87.5% ± 1.3%) and accuracy (86.4% ± 0.9%). Sleep outcome measures were more accurately measured by devices worn at the wrist than the hip, thigh or lower back, with the exception of sleep efficiency where the reverse was true. The CS algorithm provided consistently accurate measures of sleep onset: the mean (95%CI) difference at the wrist with Axivity was 2 min (-6; -14,) and the offset was 10 min (5, -19). Several algorithms provided accurate measures of sleep quantity at the wrist, showing differences with PSG of just 1-18 min a night for sleep period time and 5-22 min for total sleep time. Accuracy was generally higher for sleep efficiency than for frequency of night wakings or wake after sleep onset. The CS algorithm was more accurate at assessing sleep period time, with narrower 95% limits of agreement compared to the HDCZA (CS:-165 to 172 min; HDCZA: -212 to 250 min). CONCLUSION: Although the performance of existing count-based sleep algorithms varies markedly, wrist-worn devices provide more accurate measures of most sleep measures compared to other sites. Overall, the HDZCA algorithm showed the greatest accuracy, although the most appropriate algorithm depends on the sleep measure of focus.

Least-cost targets and avoided fossil fuel capacity in India's pursuit of renewable energy.

India has set aggressive targets to install more than 400 GW of wind and solar electricity generation by 2030, with more than two-thirds of that capacity coming from solar. This paper examines the electricity and carbon mitigation costs to reliably operate India's grid in 2030 for a variety of wind and solar targets (200 GW to 600 GW) and the most promising options for reducing these costs. We find that systems where solar photovoltaic comprises only 25 to 50% of the total renewable target have the lowest carbon mitigation costs in most scenarios. This result invites a reexamination of India's proposed solar-majority targets. We also find that, compared to other regions and contrary to prevailing assumptions, meeting high renewable targets will avoid building very few new fossil fuel (coal and natural gas) power plants because of India's specific weather patterns and need to meet peak electricity demand. However, building 600 GW of renewable capacity, with the majority being wind plants, reduces how often fossil fuel power plants run, and this amount of capacity can hold India's 2030 emissions below 2018 levels for less than the social cost of carbon. With likely wind and solar cost declines and increases in coal energy costs, balanced or wind-majority high renewable energy systems (600 GW or ≈ 45% share by energy) could result in electricity costs similar to a fossil fuel-dominated system. As an alternative strategy for meeting peak electricity demand, battery storage can avert the need for new fossil fuel capacity but is cost effective only at low capital costs (≈ USD 150 per kWh).

Characterization of DNA-protein complexes by nanoparticle tracking analysis and their association with systemic lupus erythematosus.

Nanotechnology enables investigations of single biomacromolecules, but technical challenges have limited the application in liquid biopsies, for example, blood plasma. Nonetheless, tools to characterize single molecular species in such samples represent a significant unmet need with the increasing appreciation of the physiological importance of protein structural changes at nanometer scale. Mannose-binding lectin (MBL) is an oligomeric plasma protein and part of the innate immune system through its ability to activate complement. MBL also serves a role as a scavenger for cellular debris, especially DNA. This may link functions of MBL with several inflammatory diseases in which cell-free DNA now appears to play a role, but mechanistic insight has been lacking. By making nanoparticle tracking analysis possible in human plasma, we now show that superoligomeric structures of MBL form nanoparticles with DNA. These oligomers correlate with disease activity in systemic lupus erythematosus patients. With the direct quantification of the hydrodynamic radius, calculations following the principles of Taylor dispersion in the blood stream connect the size of these complexes to endothelial inflammation, which is among the most important morbidities in lupus. Mechanistic insight from an animal model of lupus supported that DNA-stabilized superoligomers stimulate the formation of germinal center B cells and drive loss of immunological tolerance. The formation involves an inverse relationship between the concentration of MBL superoligomers and antibodies to double-stranded DNA. Our approach implicates the structure of DNA-protein nanoparticulates in the pathobiology of autoimmune diseases.

Physical activity levels in asthma: relationship with disease severity, body mass index and novel accelerometer-derived metrics.

OBJECTIVES: Patients with asthma may feel limited in physical activity (PA). Reduced PA has been demonstrated in asthmatics versus healthy controls, and increasing PA associated with improved asthma outcomes. Obesity is commonly found with difficult-to-control asthma and worsens outcomes. We compared PA levels in participants with difficult-to-control asthma and elevated body mass index (BMI) (DOW group) and two mild-moderate asthma groups: one with BMI <25 kg/m2 (MHW) and one with BMI ≥25 (MOW). METHODS: This cross-sectional study used 7-day recordings from wrist-worn accelerometers to compare PA between groups. Inactive time, light (LPA), moderate-vigorous PA (MVPA) were measured, along with two novel metrics: intensity gradient (IG) reflecting PA intensity, and average acceleration (AA) reflecting PA volume. PA parameters were compared using ANOVA or Kruskall-Wallis testing. Correlation and linear regression analyses explored associations between PA parameters and asthma outcomes. As AA was the PA parameter correlated most closely with asthma-related outcomes, an exploratory analysis compared outcomes in highest and lowest AA quartiles. RESULTS: 75 participants were recruited; 57 accelerometer readings were valid and included in analysis. Inactive time was significantly higher (p < 0.001), and LPA (p < 0.007), MVPA (p < 0.001), IG (p < 0.001) and AA (p < 0.001) all significantly lower in DOW versus MHW and MOW groups, even after adjusting for age and BMI. Quartiles based on AA had significantly different asthma profiles. CONCLUSIONS: Overweight/obese participants with difficult-to-control asthma performed less PA, and activity of reduced intensity and volume. Increased AA is associated with improvement in several asthma-related outcomes. Increased PA should be recommended to relevant patients.

Comparison of physical activity metrics from two research-grade accelerometers worn on the non-dominant wrist and thigh in children.

This study compared physical activity metrics from the activPAL (AP) worn on the thigh with the ActiGraph worn on the non-dominant wrist using open-source methods. Measures included average acceleration, intensity gradient (IG) and the minimum acceleration value of the most active X mins (MX). Fifty-two children (26 boys; age: 10.4 ± 0.6 years) provided≥1 day (24 h) of concurrent wear time from the activPAL and ActiGraph. Measures tended to be lower from the activPAL versus the ActiGraph. Poor agreement was evident for average acceleration but good for the IG. For the IG, the absolute and relative zones needed to reach equivalence was 4% and 0.4 SDs, respectively and for average acceleration were 10% and 1.2 SDs, respectively. Good agreement was evident for M60, M30, M20, M15 and M10 between devices. Regardless of the reference device used, equivalent estimates for the intensity gradient, M60, M30, M20, M15 and M10 were observed with relative and absolute equivalence zones being≤4% and≤0.5 SDs, respectively. The IG, M60, M30, M20, M15 and M10 appear good candidates for comparing activity data collected from the activPAL and ActiGraph. Future research can use the AP to report on sedentary behaviours as well as PA outcomes.

Exploring the feasibility of a cluster pilot randomised control trial to improve children's 24-hour movement behaviours and dietary intake: Happy homework.

We aimed to explore the feasibility, acceptability, and potential efficacy of Happy Homework (HH); an 8-week home-focussed intervention, with the purpose of encouraging children's positive dietary behaviours and engagement in positive physical activity (PA) and sleep behaviours. We randomised four Scottish schools (n = 71 participants; 5 classrooms) to either the HH intervention (n = 2) or usual curriculum control group (n = 2). HH consisted of movement and dietary-focused parent and child tasks. Primary outcome measures were intervention feasibility, acceptability, and potential efficacy. Secondary outcomes were objectively measured PA via ActiGraph GT3X+, sedentary behaviours (SBs) and sleep duration via activPAL4™ accelerometers and dietary behaviours, fruit and vegetable consumption and screen-time via questionnaires. After controlling for pre-test levels, post intervention stepping time and sleep duration were significantly greater for the HH group in comparison to the control group. The HH group reported eating more fruit and vegetables at post-test than the control group. Participants also reported the intervention to be enjoyable and motivating. These findings provide promising evidence that given a greater sample size, better retention and the prioritisation of health and wellbeing homework, HH could enhance children's health and wellbeing.

Comparison of indirect computed tomographic lymphography and near-infrared fluorescence sentinel lymph node mapping for integumentary canine mast cell tumors.

OBJECTIVE: To compare the independent and combined use of indirect computed tomographic lymphography (ICTL) and near-infrared fluorescence (NIRF) for sentinel lymph node (SLN) mapping in dogs with integumentary mast cell tumors (MCT) and report the metastatic LN rate. STUDY DESIGN: Prospective clinical study. ANIMALS: Twenty client-owned dogs. METHODS: Dogs underwent preoperative ICTL, then intraoperative NIRF SLN mapping and excision of the anatomic lymph node (ALN) and/or SLN, and primary MCT. Technique agreement was complete if the same SLN was detected, and partial if the same SLN was detected along with additional SLN. No agreement occurred if the techniques detected different or no SLN. MCT were graded using two- and three-tier schemes, and LN were graded from HN0-3; HN2-3 were considered metastatic. RESULTS: Complete, partial, and no agreement between ICTL and NIRF was seen in 8/20 (40%), 8/20 (40%), and 4/20 (20%) dogs, respectively. Detection of ICTL-SLN and NIRF-SLN failed in 1/20 (5%) and 4/20 (20%), respectively. Tumors were grade II/low-grade in 19/20 (95%) and grade III/high-grade in 1/20 (5%) dogs. Nineteen out of 20 (95%) dogs had HN2-3 LN. CONCLUSIONS: Technique agreement of at least one SLN was seen in 16/20 (80%) dogs. Although most MCT were classified as intermediate to low grade, LN metastases were commonly detected. CLINICAL SIGNIFICANCE: Combining ICTL and NIRF for MCT SLN mapping yields high SLN detection rates. Lymph node metastasis may be more common than previously reported for intermediate to low grade MCT.

GSK137, a potent small-molecule BCL6 inhibitor with in vivo activity, suppresses antibody responses in mice.

B-cell lymphoma 6 (BCL6) is a zinc finger transcriptional repressor possessing a BTB-POZ (BR-C, ttk, and bab for BTB; pox virus and zinc finger for POZ) domain, which is required for homodimerization and association with corepressors. BCL6 has multiple roles in normal immunity, autoimmunity, and some types of lymphoma. Mice bearing disrupted BCL6 loci demonstrate suppressed high-affinity antibody responses to T-dependent antigens. The corepressor binding groove in the BTB-POZ domain is a potential target for small compound-mediated therapy. Several inhibitors targeting this binding groove have been described, but these compounds have limited or absent in vivo activity. Biophysical studies of a novel compound, GSK137, showed an in vitro pIC50 of 8 and a cellular pIC50 of 7.3 for blocking binding of a peptide derived from the corepressor silencing mediator for retinoid or thyroid hormone receptors to the BCL6 BTB-POZ domain. The compound has good solubility (128 µg/ml) and permeability (86 nM/s). GSK137 caused little change in cell viability or proliferation in four BCL6-expressing B-cell lymphoma lines, although there was modest dose-dependent accumulation of G1 phase cells. Pharmacokinetic studies in mice showed a profile compatible with achieving good levels of target engagement. GSK137, administered orally, suppressed immunoglobulin G responses and reduced numbers of germinal centers and germinal center B cells following immunization of mice with the hapten trinitrophenol. Overall, we report a novel small-molecule BCL6 inhibitor with in vivo activity that inhibits the T-dependent antigen immune response.

Advanced bioengineering of female germ cells to preserve fertility.

Oogenesis and folliculogenesis are considered as complex and species-specific cellular differentiation processes, which depend on the in vivo ovarian follicular environment and endocrine cues. Considerable efforts have been devoted to driving the differentiation of female primordial germ cells toward mature oocytes outside of the body. The recent experimental attempts have laid stress on offering a suitable microenvironment to assist the in vitro folliculogenesis and oogenesis. Despite developing a variety of bioengineering techniques and generating functional mature gametes through in vitro oogenesis in earlier studies, we still lack knowledge of appropriate microenvironment conditions for building biomimetic culture systems for female fertility preservation. Therefore, this review paper can provide a source for a large body of scientists developing cutting-edge in vitro culture systems for female germ cells or setting up the next generation of reproductive medicine as feasible options for female infertility treatment. The focal point of this review outlines advanced bioengineering technologies such as 3D biofabricated hydrogels/scaffolds and microfluidic systems utilized with female germlines for fertility preservation through in vitro folliculogenesis and oogenesis.

Early Warning Diagnostics for Emerging Infectious Diseases in Developing into Late-Stage Pandemics.

The spread of infectious diseases due to travel and trade can be seen throughout history, whether from early settlers or traveling businessmen. Increased globalization has allowed infectious diseases to quickly spread to different parts of the world and cause widespread infection. Posthoc analysis of more recent outbreaks-SARS, MERS, swine flu, and COVID-19-has demonstrated that the causative viruses were circulating through populations for days or weeks before they were first detected, allowing disease to spread before quarantines, contact tracing, and travel restrictions could be implemented. Earlier detection of future novel pathogens could decrease the time before countermeasures are enacted. In this Account, we examined a variety of novel technologies from the past 10 years that may allow for earlier detection of infectious diseases. We have arranged these technologies chronologically from pre-human predictive technologies to population-level screening tools. The earliest detection methods utilize artificial intelligence to analyze factors such as climate variation and zoonotic spillover as well as specific species and geographies to identify where the infection risk is high. Artificial intelligence can also be used to monitor health records, social media, and various publicly available data to identify disease outbreaks faster than traditional epidemiology. Secondary to predictive measures is monitoring infection in specific sentinel animal species, where domestic animals or wildlife are indicators of potential disease hotspots. These hotspots inform public health officials about geographic areas where infection risk in humans is high. Further along the timeline, once the disease has begun to infect humans, wastewater epidemiology can be used for unbiased sampling of large populations. This method has already been shown to precede spikes in COVID-19 diagnoses by 1 to 2 weeks. As total infections increase in humans, bioaerosol sampling in high-traffic areas can be used for disease monitoring, such as within an airport. Finally, as disease spreads more quickly between humans, rapid diagnostic technologies such as lateral flow assays and nucleic acid amplification become very important. Minimally invasive point-of-care methods can allow for quick adoption and use within a population. These individual diagnostic methods then transfer to higher-throughput methods for more intensive population screening as an infection spreads. There are many promising early warning technologies being developed. However, no single technology listed herein will prevent every future outbreak. A combination of technologies from across our infection timeline would offer the most benefit in preventing future widespread disease outbreaks and pandemics.

Palliative paramedicine: Comparing clinical practice through guideline quality appraisal and qualitative content analysis.

BACKGROUND: Palliative care is an emerging scope of practice for paramedicine. The COVID-19 pandemic has highlighted the opportunity for emergency settings to deliver palliative and end-of-life care to patients wishing to avoid intensive life-sustaining treatment. However, a gap remains in understanding the scope and limitations of current ambulance services' approach to palliative and end-of-life care. AIM: To examine the quality and content of existing Australian palliative paramedicine guidelines with a sample of guidelines from comparable Anglo-American ambulance services. DESIGN: We appraised guideline quality using the AGREE II instrument and employed a collaborative qualitative approach to analyse the content of the guidelines. DATA SOURCES: Eight palliative care ambulance service clinical practice guidelines (five Australian; one New Zealand; one Canadian; one United Kingdom). RESULTS: None of the guidelines were recommended by both appraisers for use based on the outcomes of all AGREE II evaluations. Scaled individual domain percentage scores varied across the guidelines: scope and purpose (8%-92%), stakeholder involvement (14%-53%), rigour of development (0%-20%), clarity of presentation (39%-92%), applicability (2%-38%) and editorial independence (0%-38%). Six themes were developed from the content analysis: (1) audience and approach; (2) communication is key; (3) assessing and managing symptoms; (4) looking beyond pharmaceuticals; (5) seeking support; and (6) care after death. CONCLUSIONS: It is important that ambulance services' palliative and end-of-life care guidelines are evidence-based and fit for purpose. Future research should explore the experiences and perspectives of key palliative paramedicine stakeholders. Future guidelines should consider emerging evidence and be methodologically guided by AGREE II criteria.

Capturing learning from public involvement with people experiencing homelessness to help shape new physiotherapy research: Utilizing a reflective model with an under-served, vulnerable population.

INTRODUCTION: People experiencing homelessness (PEH) have poorer health than housed people but face barriers accessing care and being involved in research. As an often-ignored group, their contribution to help shape research that is for and about them is essential, as it can strengthen the research proposal, in turn facilitating research and outcomes that are relevant to this vulnerable group. METHODS: Six people with experience of homelessness attended a PPI consultation aided by Pathway, a UK homeless peer advocacy charity, which coordinates an 'Experts by Experience' group. We present reflections on conducting PPI with PEH that informed the development of a physiotherapy research proposal. Kolb's Experiential Learning Cycle guided reflections across four stages: (1) describing the PPI experience; (2) reviewing and reflecting on the PPI experience; (3) learning from the PPI experience; and (4) planning and trying out learning. RESULTS: Reflections highlighted the importance of: working closely with an advocacy organisation and leader to reach under-served people; the diversity of experiences; using familiar venues, contingency and budget planning; flexibility and 'allowing time; talking less; listening more'; planning for early and ongoing PPI, and the potential of mobile 'one-off' PPI outreach models to reach vulnerable groups. CONCLUSION: Kolb's Experiential Learning Cycle aided team reflection on feedback from PEH, which helped refine and strengthen a physiotherapy research proposal. The project was unfunded. However, a reflective model helped maximize learning and impact including for future PPI and research. The novel application of Kolb's Experiential Learning Cycle provided structure, facilitated reflection and enhanced individual and collective learning and may benefit capturing learning from PPI with other vulnerable populations. PATIENT OR PUBLIC CONTRIBUTION: We highlight how a PPI consultation with people with experience of homelessness helped shape a funding proposal. Additionally, the reflections of the experts by experience team leader are included.

A pragmatic randomised controlled trial of tailored pulmonary rehabilitation in participants with difficult-to-control asthma and elevated body mass index.

BACKGROUND: Difficult-to-control asthma associated with elevated body mass index (BMI) is challenging with limited treatment options. The effects of pulmonary rehabilitation (PR) in this population are uncertain. METHODS: This is a randomised controlled trial of an eight-week asthma-tailored PR programme versus usual care (UC) in participants with difficult-to-control asthma and BMI ≥ 25 kg/m2. PR comprised two hours of education and supervised exercise per week, with encouragement for two individual exercise sessions. Primary outcome was difference in change in Asthma Quality of Life Questionnaire (AQLQ) in PR versus UC groups between visits. Secondary outcomes included difference in change in Asthma Control Questionnaire-6 (ACQ6), and a responder analysis comparing proportion reaching minimum clinically important difference for AQLQ and ACQ6. RESULTS: 95 participants were randomised 1:1 to PR or UC. Median age was 54 years, 60% were female and median BMI was 33.8 kg/m2. Mean  (SD) AQLQ was 3.9 (+/-1.2) and median (IQR) ACQ6 2.8(1.8-3.6). 77 participants attended a second visit and had results analysed. Median (IQR) change in AQLQ was not significantly different: 0.3 (- 0.2 to 0.6) in PR and - 0.1 (- 0.5 to 0.4) in UC, p = 0.139. Mean change in ACQ6 was significantly different: - 0.4 (95% CI - 0.6 to - 0.2) in PR and 0 (- 0.3 to + 0.3) in UC, p = 0.015, but below minimum clinically important difference. In ACQ6 responder analysis, minimum clinically important difference was reached by 18 PR participants (54.5%) versus 10 UC (22.7%), p = 0.009. Dropout rate was 31% between visits in PR group, and time to completion was significantly prolonged in PR group at 94 (70-107) days versus 63 (56-73) in UC, p < 0.001. CONCLUSIONS: PR improved asthma control and reduced perceived breathlessness in participants with difficult-to-control asthma and elevated BMI. However, this format appears to be suboptimal for this population with high drop-out rates and prolonged time to completion. Trial registration Clinicaltrials.gov. ID NCT03630432. Retrospectively registered, submitted May 26th 2017, posted August 14th 2018.

A cross-sectional study examining MRCS performance by core surgical training location.

BACKGROUND: In the UK, core surgical training (CST) is the first specialty experience that early-career surgeons receive but training differs significantly across CST deaneries. To identify the impact these differences have on trainee performance, we assessed whether success at the Membership of the Royal College of Surgeons (MRCS) examinations is associated with CST deanery. METHODS: A retrospective cohort study of UK trainees in CST who attempted MRCS between 2014 and 2020 (n = 1104). Chi-squared tests examined associations between locality and first-attempt MRCS performance. Multivariate logistic regression models identified the likelihood of MRCS success depending on CST deanery. RESULTS: MRCS Part A and Part B pass rates were associated with CST deanery (p < 0.001 and p = 0.013, respectively). Candidates that trained in Thames Valley (Odds Ratio [OR] 2.52 (95% Confidence Interval [CI] 1.00-6.42), North Central and East London (OR 2.37 [95% CI 1.04-5.40]) or South London (OR 2.36 [95% CI 1.09-5.10]) were each more than twice as likely to pass MRCS Part A at first attempt. Trainees from North Central and East London were more than ten times more likely to pass MRCS Part B at first attempt (OR 10.59 [95% CI 1.23-51.00]). However, 68% of candidates attempted Part A prior to CST and 48% attempted Part B before or during the first year of CST. CONCLUSION: MRCS performance is associated with CST deanery; however, many candidates passed the exam with little or any CST experience suggesting that some deaneries attract high academic performers. MRCS performance is therefore not a suitable marker of CST training quality.

Equivalence of activity outcomes derived from three research grade accelerometers worn simultaneously on each wrist.

This study evaluated the equivalence of activity outcomes from three accelerometer brands worn on both wrists during free living. Forty-four adults wore a GENEActiv, ActiGraph and Axivity accelerometer for 7 days. Outcomes were assessed between and within accelerometer brand and wrist location with average acceleration and the intensity gradient (IG) being of particular interest. Pairwise 95% equivalence tests and intra-class correlation coefficients (ICC) evaluated agreement. Average acceleration and the IG were largely equivalent between combinations of accelerometer device and wrists when applying a 10% equivalence zone. There was largely a lack of equivalence between pairings for time spent in acceleration values ≥100 mg. However, equivalence was largely achieved when applying an equivalence zone that encompassed values ranging from 0.3 to 0.45 SDs for IG and time spent above 100 mg and 150 mg. Agreement between pairings tended to be stronger between different brands on the non-dominant (ICCs ≥ 0.73-0.97) versus the dominant wrist (ICCs ≥ 0.57-0.97) and between wrists for the same accelerometer (ICCs ≥ 0.59-0.97) for average acceleration and the IG. These are important findings since device placement is not consistent in studies. Further work that applies an equivalence zone reflecting the variability of the outcome measure is encouraged.

Surgical Helmets Used During Total Joint Arthroplasty Harbor Common Pathogens: A Cautionary Note.

BACKGROUND: The use of personal-protection surgical helmet/hood systems is now a part of the standard surgical attire during arthroplasty in North America. There are no protocols for the disinfection of these helmets. METHODS: This is a prospective, single-center, observational study. Helmets worn by 44 members of the surgical team and foreheads of 44 corresponding surgical personnel were swabbed at three distinct time points. In addition, 16 helmets were treated with hypochlorite spray to determine if pathogens could be eliminated. Swabs obtained were processed for culture and next-generation sequencing (NGS). RESULTS: Of the 132 helmet samples, 97 (73%) yielded bacteria on culture and 94 (71%) had evidence of bacterial-deoxyribonucleic acid (DNA) on NGS. Of the swabs sent for bacterial identification at the three time points, at least one from each helmet was positive for a pathogen(s). Of the 132 forehead samples, 124 (93%) yielded bacteria on culture and 103 (78%) had evidence of bacterial-DNA on NGS. The most commonly identified organism from helmets was Cutibacterium acnes (86/132) on NGS and Staphylococcus epidermidis (47/132) on culture. The most commonly identified organism from the foreheads of surgical personnel was Cutibacterium acnes (100/132) on NGS and Staphylococcus epidermidis (70/132) on culture. Sanitization of helmets was totally effective; no swabs taken the following morning for culture and NGS identified any bacteria. CONCLUSION: This study demonstrates that surgical helmets worn during orthopedic procedures are contaminated with common pathogens that can potentially cause surgical site infections. The findings of this study should at the minimum compel us to develop protocols for the disinfection of these helmets.

Validation of Septic Knee Monoarthritis Prediction Rule in a Lyme Disease Endemic Area.

OBJECTIVE: In Lyme disease endemic areas, Lyme and septic arthritis often present similarly. A published septic knee arthritis clinical prediction rule includes 2 high-risk predictors: absolute neutrophil count of 10,000 cells/mm3 or greater and erythrocyte sedimentation rate of 40 mm/h or greater. The objective of the study was to externally validate this prediction rule in a multicenter prospective cohort. METHODS: We enrolled a prospective cohort of children with knee monoarthritis undergoing evaluation for Lyme disease at 1 of 8 Pedi Lyme Net emergency departments located in endemic areas. We defined a case of septic arthritis with a positive synovial fluid culture or a synovial fluid white blood cell count of 50,000 or greater per high powered field with a positive blood culture and Lyme arthritis with a positive or equivocal C6 EIA, followed by a positive supplemental immunoblot. Other children were classified as having inflammatory arthritis. We report the performance of the septic arthritis clinical prediction rule in our study population. RESULTS: Of the 543 eligible children, 13 had septic arthritis (2.4%), 234 Lyme arthritis (43.1%), and 296 inflammatory arthritis (54.5%). Of the 457 children (84.2%) with available laboratory predictors, all children with septic arthritis were classified as high risk (sensitivity, 100%; 95% confidence interval [CI], 77.2%-100%; specificity, 68.1%; 95% CI, 63.6-73.3; negative predictive value, 278/278 [100%]; 95% CI, 98.6%-100%). Of the 303 low-risk children, 52 (17.2%) underwent diagnostic arthrocentesis. CONCLUSIONS: The septic knee arthritis clinical prediction rule accurately distinguished between septic and Lyme arthritis in an endemic area. Clinical application may reduce unnecessary invasive diagnostic procedures.