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Sexual dysfunction (SD) is widely reported by cancer survivors. However, this is an issue underestimated by doctors and the contribution of anticancer therapies for the development of SD in cancer survivors is understudied and poorly understood. Sexual function involves the activation of a neurovascular system that leads to penile erection in males and clitoral engorgement in females. Anticancer therapies can cause damage to the neurovascular circuit responsible for normal sexual function and thus, individual or combined therapies could play a role in the development of SD in all types of cancer survivors and not only those affected by genital cancers. In this review, the pathophysiology of SD and possible mechanisms underlying SD induced by anticancer therapies will be discussed. The effects of chemotherapy, radiotherapy and surgical interventions on the vasculature and nerves as well as their effects on sex hormones and inflammatory processes could link the biological effects of these interventions with SD. In conclusion, this review reports evidence that, despite psychological aspects and the disease itself, anticancer therapies are able to induce direct and indirect effects in males and females that could lead to SD in cancer survivors even after the end of the treatment.

Background & Hypothesis We sought to assess the reliability of 4 different shoulder arthroplasty 3-dimensional preoperative planning programs. Comparison was also made to manual measurements conducted by 2 fellowship-trained musculoskeletal radiologists. We hypothesized that there would be significant variation in measurements of glenoid anatomy affected by glenoid deformity. Methods A retrospective review of computed tomography (CT) scans of patients undergoing shoulder arthroplasty was undertaken. A total of 76 computed tomographies were analyzed for glenoid version and inclination by 4 templating software systems (VIP, Blueprint, TrueSight, ExactechGPS). Inter-rater reliability was assessed via intra-class correlation coefficient (ICC). For those shoulders with glenohumeral arthritis (58/76), ICC was also calculated when sub-grouping by modified Walch classification. Lin's concordance correlation coefficient was calculated for each system with 2 musculoskeletal-trained radiologists’ measurements. Results Measurements of glenoid version and inclination differed between at least 2 programs by 5o-10o in 75% and 92% of glenoids respectively, and by >10o in 18% and 45% respectively. ICC was excellent for version but only moderate for inclination. ICC was highest among Walch A glenoids for both version (near excellent) and inclination (good), and lowest among Walch D for version (near poor) and Walch B for inclination (moderate). When measuring version, VIP had the highest concordance with manual measurement; Blueprint had the lowest. For inclination Blueprint had the highest concordance; ExactechGPS had the lowest. Discussion & Conclusion Despite overall high reliability for measures of glenoid version between 4 frequently utilized shoulder arthroplasty templating softwares, this reliability is significantly affected by glenoid deformity. The programs were overall less reliable when measuring inclination, and a similar trend of decreasing reliability with increasing glenoid deformity emerged that was not statistically significant. Concordance with manual measurement is also variable. Further research is needed to understand how this variability should be accounted for during shoulder arthroplasty preoperative planning. Level of Evidence Level III; Retrospective Comparative Study

Background The global distribution of melioidosis is under considerable scrutiny, with both unmasking of endemic disease in African and Pacific nations and evidence of more recent dispersal in the Americas. Because of the high incidence of disease in tropical northern Australia, The Darwin Prospective Melioidosis Study commenced in October, 1989. We present epidemiology, clinical features, outcomes, and bacterial genomics from this 30-year study, highlighting changes in the past decade. Methods The present study was a prospective analysis of epidemiological, clinical, and laboratory data for all culture-confirmed melioidosis cases from the tropical Northern Territory of Australia from Oct 1, 1989, until Sept 30, 2019. Cases were identified on the basis of culture-confirmed melioidosis, a laboratory-notifiable disease in the Northern Territory of Australia. Patients who were culture-positive were included in the study. Multivariable analysis determined predictors of clinical presentations and outcome. Incidence, survival, and cluster analyses were facilitated by population and rainfall data and genotyping of Burkholderia pseudomallei, including multilocus sequence typing and whole-genome sequencing. Findings There were 1148 individuals with culture-confirmed melioidosis, of whom 133 (12%) died. Median age was 50 years (IQR 38–60), 48 (4%) study participants were children younger than 15 years of age, 721 (63%) were male individuals, and 600 (52%) Indigenous Australians. All but 186 (16%) had clinical risk factors, 513 (45%) had diabetes, and 455 (40%) hazardous alcohol use. Only three (2%) of 133 fatalities had no identified risk. Pneumonia was the most common presentation occurring in 595 (52%) patients. Bacteraemia occurred in 633 (56%) of 1135 patients, septic shock in 240 (21%) patients, and 180 (16%) patients required mechanical ventilation. Cases correlated with rainfall, with 80% of infections occurring during the wet season (November to April). Median annual incidence was 20·5 cases per 100 000 people; the highest annual incidence in Indigenous Australians was 103·6 per 100 000 in 2011–12. Over the 30 years, annual incidences increased, as did the proportion of patients with diabetes, although mortality decreased to 17 (6%) of 278 patients over the past 5 years. Genotyping of B pseudomallei confirmed case clusters linked to environmental sources and defined evolving and new sequence types. Interpretation Melioidosis is an opportunistic infection with a diverse spectrum of clinical presentations and severity. With early diagnosis, specific antimicrobial therapy, and state-of-the-art intensive care, mortality can be reduced to less than 10%. However, mortality remains much higher in the many endemic regions where health resources remain scarce. Genotyping of B pseudomallei informs evolving local and global epidemiology. Funding The Australian National Health and Medical Research Council.

OBJECTIVE: To describe the protocol and statistical analysis plan for the Treatment of Invasively Ventilated Adults with Early Activity and Mobilisation (TEAM III) trial. DESIGN: An international, multicentre, parallel-group, randomised controlled phase 3 trial. SETTING: Intensive care units (ICUs) in Australia, New Zealand, Germany, Ireland, the United Kingdom and Brazil. PATIENTS: 750 adult patients expected to receive mechanical ventilation for more than 48 hours. INTERVENTIONS: Early activity and mobilisation delivered to critically ill patients in an ICU for up to 28 days compared with standard care. MAIN OUTCOME MEASURES: The primary outcome is the number of days alive and out of hospital at 180 days after randomisation. Secondary outcomes include ICU-free days, ventilator-free days, delirium-free days, all-cause mortality at 28 and 180 days after randomisation, and functional outcome at 180 days after randomisation. RESULTS: Recruitment at 46 research sites passed 576 patients in March 2021. Final collection of all 180-day outcome data for the target of 750 patients is anticipated by May 2022. CONCLUSIONS: Consistent with international guidelines, a detailed protocol and prospective analysis plan has been developed for the TEAM III trial. This plan specifies the statistical models for evaluating primary and secondary outcomes, defines covariates for adjusted analyses, and defines methods for exploratory analyses. Application of this protocol and statistical analysis plan to the forthcoming TEAM III trial will facilitate unbiased analyses of the clinical data collected. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03133377.

Concussions and chronic traumatic encephalopathy (CTE) related to professional football has received much attention within emergency care and sports medicine. Research suggests that some of this may be due to a greater likelihood of initial helmet contact (IHC), however this association has not been studied across all age groups. This study aims to investigate the association between player age and IHC in American football.Retrospective review of championship games between 2016 and 2018 at 6 levels of amateur tackle football as well as the National Football League (NFL). Trained raters classified plays as IHC using pre-specified criteria. A priori power analysis established the requisite impacts needed to establish non-inferiority of the incidence rate of IHC across the levels of play.Thirty-seven games representing 2912 hits were rated. The overall incidence of IHC was 16% across all groups, ranging from 12.6% to 18.9%. All but 2 of the non-NFL divisions had a statistically reduced risk of IHC when compared with the NFL, with relative risk ratios ranging from 0.55-0.92. IHC initiated by defensive participants were twice as high as offensive participants (RR 2.04, p0.01) while 6% [95% CI 5.4-7.2] of all hits were helmet-on-helmet contact.There is a high rate of IHC with a lower relative risk of IHC at most levels of play compared to the NFL. Further research is necessary to determine the impact of IHC; the high rates across all age groups suggests an important role for education and prevention.

A systematic review of publications addressing change in vitamin D status (25-hydroxyvitamin D (25OHD)) after exposure to UV radiation identified 2001 independent peer-reviewed publications. Of these, 21 used artificial sources of UV radiation, met all inclusion criteria and were quality assured; 13 publications used solar radiation and met sufficient inclusion criteria to be retained as supporting evidence; 1 further included publication used both solar and artificial sources. The review consistently identified that low dose, sub-erythemal doses are more effective for vitamin D synthesis than doses close to a minimum erythema dose; increasing skin area exposed increases the amount of vitamin D synthesised although not necessarily in a linear manner; constant dosing leads to a dose-dependent plateau in 25OHD, and dose–response is greatest at the start of a dosing regime; there is a large interpersonal variation in response to UV exposure. Fourteen of the studies using artificial sources of radiation were used to determine a dose–response relationship for change in 25OHD on whole-body exposure to repeated sub-erythemal doses of UV radiation, taking the form Δ25OHD (nmol/L) = A ln(standard vitamin D dose) + B. This helps quantify our understanding of UV as a source of vitamin D and enables exposure regimes for safe synthesis of vitamin D to be assessed. Specific studies of people with pigmented skin (Fitzpatrick skin types 5 and 6) were rare, and this dose–response relationship is only applicable to white-skinned individuals as skin type is a determinant of response to UV radiation. Findings provide information for vitamin D guidance updates.

The treatment of geriatric acetabular fractures remains controversial. Treatment options include nonoperative management, open reduction and internal fixation (ORIF), total hip arthroplasty (THA) with or without internal fixation, and closed reduction with percutaneous pinning (CRPP). There is currently no consensus on the optimal treatment strategy for geriatric patients with acetabular fractures. The purpose of this study is to compare adverse event rates, functional and radiographic outcomes, and intraoperative results between the various treatment modalities in order to help guide surgical decision making. We performed a systematic review (registration number CRD42019124624) of observational and comparative studies including patients aged ≥ 55 with acetabular fractures. Thirty-eight studies including 3,928 patients with a mean age of 72.6 years (range 55–99 years) and a mean follow-up duration of 29.4 months met our eligibility criteria. The pooled mortality rate of all patients was 21.6% (95% confidence interval [CI] 20.9–22.4%) with a mean time to mortality of 12.6 months, and the pooled non-fatal complication rate was 24.7% (95% CI 23.9–25.5%). Patients treated with ORIF had a significantly higher non-fatal complication rate than those treated with ORIF + THA, THA alone, CRPP, or nonoperative management (odds ratios [ORs] 1.87, 2.24, 2.15, and 4.48, respectively; p

Systemic buprenorphine and topical antiseptics such as chlorhexidine are frequently used in research animals to aid in pain control and to reduce infection, respectively. These therapeutics are controversial, especially when used in wound healing studies, due to conflicting data suggesting that they delay wound healing. Low-level laser therapy (LLLT) has been used to aid in wound healing without exerting the systemic effects of therapies such as buprenorphine. We conducted 2 studies to investigate the effects of these common treatment modalities on the rate of wound healing in mice. The first study used models of punch biopsy and dermal abrasion to assess whether buprenorphine HCl or 0.12% chlorhexidine delayed wound healing. The second study investigated the effects of sustained-released buprenorphine, 0.05% chlorhexidine, and LLLT on excisional wound healing. The rate of wound healing was assessed by obtaining photographs on days 0, 2, 4, 7, and 9 for the punch biopsy model in study 1, days 0, 1, 2, 4, 6, 8, 11, and 13 for the dermal abrasion model in study 1, and days 0, 3, 6, and 10 for the mice in study 2. Image J software was used to analyze the photographed wounds to determine the wound area. When comparing the wound area on the above days to the original wound area, no significant differences in healing were observed for any of the treatment groups at any time period for either study. Given the results of these studies, we believe that systemic buprenorphine, topical chlorhexidine, and LLLT can be used without impairing or delaying wound healing in mice.

Purpose: Tumor-infiltrating lymphocytes (TIL) are strongly associated with survival in most cancers; however, the tumor-reactive subset that drives this prognostic effect remains poorly defined. CD39, CD103, and PD-1 have been independently proposed as markers of tumor-reactive CD8+ TIL in various cancers. We evaluated the phenotype, clonality, and prognostic significance of TIL expressing various combinations of these markers in high-grade serous ovarian cancer (HGSC), a malignancy in need of more effective immunotherapeutic approaches. Experimental Design: Expression of CD39, CD103, PD-1, and other immune markers was assessed by high-dimensional flow cytometry, single-cell sequencing, and multiplex immunofluorescence of primary and matched pre/post-chemotherapy HGSC specimens. Results: Coexpression of CD39, CD103, and PD-1 (“triple-positive” phenotype) demarcated subsets of CD8+ TIL and CD4+ regulatory T cells (Treg) with a highly activated/exhausted phenotype. Triple-positive CD8+ TIL exhibited reduced T-cell receptor (TCR) diversity and expressed genes involved in both cytolytic and humoral immunity. Triple-positive Tregs exhibited higher TCR diversity and a tumor-resident phenotype. Triple-positive TIL showed superior prognostic impact relative to TIL expressing other combinations of these markers. TIGIT was uniquely upregulated on triple-positive CD8+ effector cells relative to their CD4+ Treg counterparts. Conclusions: Coexpression of CD39, CD103, and PD-1 demarcates highly activated CD8+ and CD4+ TIL with inferred roles in cytolytic, humoral, and regulatory immune functions. Triple-positive TIL demonstrate exceptional prognostic significance and express compelling targets for combination immunotherapy, including PD-1, CD39, and TIGIT.

Background Ductal adenocarcinoma is an uncommon prostate cancer variant. Previous studies suggest that ductal variant histology may be associated with worse clinical outcomes, but these are difficult to interpret. To address this, we performed an international, multi-institutional study to describe the characteristics of ductal adenocarcinoma, particularly focussing on the effect of presence of ductal variant cancer on metastasis-free survival. Methods Patients with ductal variant histology from two institutional databases who underwent radical prostatectomies were identified and compared with an independent acinar adenocarcinoma cohort. After propensity score matching, the effect of the presence of ductal adenocarcinoma on time to biochemical recurrence, initiation of salvage therapy and the development of metastatic disease was determined. Deep whole-exome sequencing was performed for selected cases (n = 8). Results A total of 202 ductal adenocarcinoma and 2037 acinar adenocarcinoma cases were analysed. Survival analysis after matching demonstrated that patients with ductal variant histology had shorter salvage-free survival (8.1 versus 22.0 months, p = 0.03) and metastasis-free survival (6.7 versus 78.6 months, p Conclusions The presence of any ductal variant adenocarcinoma at the time of prostatectomy portends a worse clinical outcome than pure acinar cancers, with significantly shorter times to initiation of salvage therapies and the onset of metastatic disease. These features appear to be driven by uncoupling of chromosomal duplication from cell division, resulting in widespread copy number aberration with specific gain of genes implicated in treatment resistance.

BACKGROUND Retinopathy of prematurity (ROP) is a common disorder among premature infants associated with significant morbidity. The current standard of care includes laser ablation therapy when needed. While intravitreal bevacizumab (IVB) injections have emerged as a new therapy for ROP, so have concerns about the systemic effects of the bevacizumab (Avastin), specifically on neurodevelopmental outcomes. PURPOSE To review the current literature on the impact of IVB on neurodevelopmental outcomes in neonates with ROP to inform nurses' knowledge and practice. METHODS A literature search was performed in the PubMed, CINAHL, and Embase databases. Eleven primary studies examining neurodevelopmental outcomes related to IVB were identified and reviewed. RESULTS Limitations of current studies, including small sample sizes, retrospective analysis subject to selection bias, and confounding factors such as sedation/anesthesia exposure, prevent robust conclusions from being drawn. However, there is not currently any clear evidence of negative neurodevelopmental impacts associated with IVB despite a sound theoretical basis for concern. IMPLICATIONS FOR PRACTICE Nurses should include all known and potential risks and benefits when counseling families and developing individualized plans of care for their neonatal patients with ROP. IMPLICATIONS FOR RESEARCH Well-designed, prospective studies examining neurodevelopmental outcomes at later time points are needed to conclusively support or disprove results of IVB therapy for ROP in the context of potential adverse effects.

Metformin reduces the incidence of placental-mediated disease (PMD) in pregnancies with and without diabetes, but the mechanism through which it exerts these effects is not yet fully understood. We performed a systematic review and meta-analysis to examine the effect of metformin on biomarkers implicated in the pathogenesis of PMD. We searched Medline, Embase and the Cochrane Library for studies of metformin and biomarkers of PMD in pregnancy. Meta-analysis was undertaken where comparable data were obtained from two or more studies. 12 studies were included in the final review. Meta-analysis of 2 studies including 323 pregnant women showed significantly reduced CRP levels following treatment with metformin compared to placebo [mean difference = −1.72, 95% CI (−2.97; −0.48); p = 0.007]. Metformin exposure was also associated with decreased levels of the inflammatory cytokines TNFα, IL-1a, IL-1b and IL-6 in serum, placenta and omental tissue taken from pregnant women. Metformin significantly decreased the release of anti-angiogenic factors sFlt-1 and sEng from ex-vivo placental and umbilical vein tissue, and increased maternal serum levels of non-phosphorylated IGFBP-1. Overall, our findings show that metformin mediates several molecular pathways implicated in the pathogenesis of pre-eclampsia and intrauterine growth retardation. Metformin therefore has exciting potential as a therapeutic, as well as preventative, agent in the treatment of PMD, which warrants further investigation.

Objective Lumbo-pelvic landmark palpation is widely used by manual practitioners as part of a clinical assessment. However, research has not clearly described or established the validity of landmark palpation as a diagnostic tool; we aimed to analyse and synthesise data on the validity of lumbo-pelvic landmark palpation compared to an imaging modality reference standard. Methods and results Nine studies met the inclusion criteria (43 practitioners assessing 364 subjects). Mean palpatory accuracy ranged from 42 to 71%; four studies reported kappa values, ranging from 0.20 (no agreement) to 0.81 (strong); two studies could not be directly compared. The use of multiple palpation techniques improved palpation accuracy, however, no specific technique or technique combination was more accurate than another. Methodological quality was assessed using the QUADAS-2 check-list tool; eight studies were rated as having a risk of bias and/or concerns regarding applicability. Conclusion The use of lumbo-pelvic landmark palpation does not reach clinically acceptable levels of validity; however, heterogeneity in the included studies’ methods and data reporting limited between trial comparisons. These results accord with other reviews and suggest the necessity of a shift away from over-reliance on landmark palpation to align manual therapy with practise guidelines.

Since 2005, the range of Burkholderia pseudomallei sequence type 562 (ST562) has expanded in northern Australia. During 2005–2019, ST562 caused melioidosis in 61 humans and 3 animals. Cases initially occurred in suburbs surrounding a creek before spreading across urban Darwin, Australia and a nearby island community. In urban Darwin, ST562 caused 12% (53/440) of melioidosis cases, a proportion that increased during the study period. We analyzed 2 clusters of cases with epidemiologic links and used genomic analysis to identify previously unassociated cases. We found that ST562 isolates from Hainan Province, China, and Pingtung County, Taiwan, were distantly related to ST562 strains from Australia. Temporal genomic analysis suggested a single ST562 introduction into the Darwin region in ≈1988. The origin and transmission mode of ST562 into Australia remain uncertain.

Purpose To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06448-5.

Considering the range of properties that various materials offer for tissue engineering it has come clear that no one size fits all, as no one material can be fully effective for all types of cell and ensuing tissues. Scaffolds need to address the delicate balance between cell-scaffold interactions and the particular requirements of different cell types. To address the specific needs for the controlled growth of tissues it is imperative to match scaffold stiffness and elasticity to cells and tissues of interest to promote regeneration success. We here report an efficient method for creating scaffolds of tunable elasticity by generating a range of composites based on e-caprolactone-D,L-lactide-based elastomer with cellulose nanocrystals (CNC). Two specific composites with different Young's modulus (E) values (∼5 MPa and ∼15 MPa) were selected and fully evaluated by tensile tests, Fourier Transform-Infrared (FT-IR), Scanning Electron Microscopy (SEM), contact angle measurements, and X-ray scattering. As a proof of concept this work studies how matching the scaffold's mechanical properties to neuroblastomas and fibroblasts cells affects cell behavior. Specifically, the composite with lower E, by design with less CNC content, is more suitable for neuroblastomas, whereas the one with higher E via higher CNC content is more suited for human dermal fibroblasts. The approach of matching cells with appropriate mechanical environments can provide important insights into fundamental cell behaviors.

Glaucoma is a disorder of all species due to a rise of intraocular pressure (IOP) beyond which is compatible with ganglion cell and axon function, often resulting in optic nerve degeneration and irreversible blindness. Glaucoma treatment with surgical intervention aimed at either reducing aqueous production, or increasing or altering aqueous outflow has evolved over preceding decades, but there remains no cure. The present article is intended to provide a concise review of glaucoma surgical therapies in veterinary ophthalmology.

Background Adequate footwear fit is critical in preventing diabetes-related foot ulcers. One important element is the toe gap, the difference between foot length and internal footwear length available to the foot. We summarised the literature on toe gaps in studies assessing footwear worn by people with diabetes, the methods used to measure both foot length and internal footwear length and identify ambiguities which may impact on toe gap assessment in clinical practice, and suggest pragmatic solutions. Methods The Google Scholar database was searched to April 2020 for peer-reviewed studies using keywords related to incorrectly fitting or ill-fitting and diabetes, foot and ulcer which returned 979 results. Included studies within this narrative review encompassed toe gap measurement to assess footwear worn by people with diabetes. Results A total of eight studies were included after full paper review. Toe gap ranges as used in assessments of footwear worn by people with diabetes vary, with a minimum of 1.0–1.6 cm and a maximum of 1.5–2.0 cm, as do methods of measuring internal footwear length. Only three published studies suggested possible measuring devices. Conclusions Toe gap ranged as used when assessing footwear fit in people with diabetes vary and a gold standard device for internal footwear length measurement has yet to emerge. International guidelines provide welcome standardisation, but further research is needed to evaluate both the effect of toe gap ranges upon pressure, plantar stress response and ulceration and available measuring devices to facilitate development of toe gap measurement protocols that may further enhance consistency in practical assessments.

OBJECTIVE To examine whether circulating metabolic responses to low-volume high-intensity interval exercise (LV-HIIE) or continuous moderate-intensity aerobic exercise (CME) differ between white Europeans and South Asians with nondiabetic hyperglycemia (NDH). RESEARCH DESIGN AND METHODS Thirteen white Europeans and 10 South Asians (combined median [interquartile range] age 67 [60–68] years, HbA1c 5.9% [5.8–6.1%] [41.0 (39.9–43.2) mmol ⋅ mol−1]) completed three 6-h conditions (sedentary control [CON], LV-HIIE, and CME) in a randomized order. Exercise conditions contained a single bout of LV-HIIE and CME, respectively (each ending at 2 h), with meals provided at 0 and 3 h. Circulating glucose (primary outcome), insulin, insulin resistance index (IRI), triglycerides, and nonesterified fatty acids were measured at 0, 0.5, 1, 2, 3, 3.5, 4, 5, and 6 h. Data were analyzed as postexercise time-averaged area under the curve (AUC) adjusted for age, sex, and preexercise AUC. RESULTS Glucose was similar in each condition and with ethnicity, with no condition-by-ethnicity interaction (P ≥ 0.28). However, insulin was lower in LV-HIIE (mean [95% CI] −44.4 [−23.7, −65.1] mU ⋅ L−1) and CME (−33.8 [−13.7, −53.9] mU ⋅ L−1) compared with CON. Insulin responses were greater in South Asians (interaction P = 0.03) such that values were similar in each ethnicity during exercise conditions, despite being 33% higher in South Asians during CON. IRI followed a similar pattern to insulin. Lipids were unaffected by exercise. CONCLUSIONS Reductions in insulin and insulin resistance after acute LV-HIIE and CME are greater in South Asians than in white Europeans with NDH. Further trials are required to examine the longer-term impact of LV-HIIE and CME on cardiometabolic health.

Melioidosis is a neglected tropical disease caused by the Gram-negative soil bacterium Burkholderia pseudomallei. Current antibiotic regimens used to treat melioidosis are prolonged and expensive, and often ineffective because of intrinsic and acquired antimicrobial resistance. Efforts to develop new treatments for melioidosis are limited by the risks associated with handling pathogenic B. pseudomallei, which restricts research to facilities with biosafety level three containment. Closely related nonpathogenic Burkholderia can be investigated under less stringent biosafety level two containment, and we hypothesized that they could be used as model organisms for developing therapies that would also be effective against B. pseudomallei. We used microbroth dilution assays to compare drug susceptibility profiles of three B. pseudomallei strains and five nonpathogenic Burkholderia strains. Burkholderia humptydooensis, Burkholderia thailandensis, and Burkholderia territorii had similar susceptibility profiles to pathogenic B. pseudomallei that support their potential as safer in vitro models for developing new melioidosis therapies.

Aims To (1) explore and verify differences in the plasma proteome of white European (WE) and South Asian (SA) adults with normal glycaemic control (NGC) or non-diabetic hyperglycaemia (NDH) and to (2) validate these findings using a separate WE and SA cohort at a high risk of NDH. Methods Mass spectrometry analysis was performed on fasted samples from 72 WE or SA men with NGC or NDH. These results were verified using specific biochemical assays and validated by repeating the analysis in an additional cohort of 30 WE and 30 SA adults. Proteomic results were analysed using independent samples t test and univariate analysis. The targeted assay results were analysed using generalised linear models with adjustment for appropriate covariates including age, BMI, fasting plasma glucose, high-density lipoprotein-cholesterol, triglycerides and sex. Results Only zinc-alpha-2-glycoprotein (ZAG) significantly differed between both ethnicities and glycaemic control groups. ZAG-specific biochemical assays verified the lower circulating ZAG in SAs (41.09 versus 37.07 (mg L−1); p = 0.014), but not the difference between NGC and NDH groups (p = 0.539). Validation of the ethnicity difference in a separate cohort confirmed that, after adjustment for covariates, ZAG was lower in SAs (p = 0.018). There was no association between ZAG and glycaemic control in the validation cohort. Conclusions Our analyses identified that ZAG is lower in SAs compared to WEs, but its difference between glycaemic control statuses was uncertain. Further research is needed to establish whether lower ZAG in SAs is associated with, or prognostic of, health outcomes, particularly regarding the risk of dysglycaemia.

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled “a randomized embedded multifactorial adaptive platform.” The design has five key features: 1) randomization, allowing robust causal inference; 2) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas. Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Objective We recently showed that tumors with an immunologically ‘cold’ phenotype are enriched for expression of stemness-associated genes and PVR/CD155, the ligand of the immunosuppressive molecule TIGIT. To explore the therapeutic implications of this finding, we investigated the relationship between PVR/CD155 expression, tumor-infiltrating lymphocytes (TIL), and prognosis in high-grade serous ovarian cancer (HGSC) and other cancers. Methods Expression of CD155, TIGIT, PD-1, PD-L1, and other immune markers in HGSC was assessed by high-dimensional flow cytometry, multi-color histological imaging, and/or gene expression profiling. The prognostic significance of PVR/CD155 and CD274/PD-L1 expression was assessed bioinformatically in HGSC and 32 other cancers in The Cancer Genome Atlas. Results T cells from HGSC frequently co-expressed TIGIT and PD-1, and the ratio of TIGIT to PD-1 expression increased markedly after in vitro expansion with a clinically relevant protocol. CD155 was commonly expressed on malignant epithelium in HGSC and showed a negative or non-significant association with TIL. In contrast, PD-L1 was predominantly expressed by tumor-associated macrophages and positively associated with TIL. These contrasts between CD155 and PD-L1 were seen across HGSC patients, across metastatic sites within individual patients, and even within individual tumor deposits. PVR/CD155 and CD274/PD-L1 exhibited divergent prognostic associations across diverse cancer types in TCGA, including HGSC. Conclusions CD155 and PD-L1 exhibit contrasting expression patterns, TIL associations and prognostic significance, suggesting they represent non-redundant immunosuppressive mechanisms. The CD155/TIGIT pathway represents a compelling immunotherapeutic target for HGSC and for immunologically cold tumors in general.

Aims/hypothesis Early-onset adult type 2 diabetes (diagnosed between ages 18 and 39 years) is increasingly prevalent and associated with poor long-term outcomes. We hypothesised that individuals with early-onset adult type 2 diabetes were underrepresented in the prominent research trials that underpin type 2 diabetes management guidelines. Methods We reviewed the mean age of the study populations recruited to 90 prominent trials in type 2 diabetes, including 37 cardio-renal outcomes trials across a range of pharmacological, non-pharmacological and multifactorial interventions, 28 trials from the phase III programmes of three representative glucose-lowering therapies used routinely in clinical practice (empagliflozin, liraglutide and sitagliptin) and 25 prominent trials of diabetes self-management education and support or intensive lifestyle interventions (diet or supervised exercise training). We then estimated the number of individuals within these trials who were aged between 18 and 39 years. Results Across all 90 trials, the mean age of 268,978 participants was 63 years (range 51–69 years in individual trials). In 73 trials (81%), Conclusions/interpretation Guidelines for early-onset adult type 2 diabetes are extrapolated predominantly from evidence in older individuals. Strategies to support the participation of individuals with early-onset adult type 2 diabetes in future research are imperative to ensure guidelines for these high-risk individuals are evidence-based.

Mycoplasma species (spp.) bacteria can infect cell cultures, posing a potential threat to recipients of cell therapy products. Conventional Mycoplasma testing methods are highly sensitive but typically require a minimum of 28 days to produce results. This delay is problematic if rapid results are needed to inform treatment decisions. Nucleic acid amplification technique (NAT) methods have been gaining favor for Mycoplasma testing due to their speed and specificity; however, they must first be qualified as meeting or exceeding the sensitivity of the compendial method. We present herein a NAT method for the detection of Mycoplasma that circumvents the need for live Mycoplasma spp. in the test procedure by instead being qualified using Mycoplasma spp. genomic DNA. We have demonstrated a lower limit of detection that exceeds the regulatory requirements set by Health Canada. This assay is now being used to screen clinical cell therapy products manufactured at our center.

James A. Arrighi, MD, FACC, Chair Lisa A. Mendes, MD, FACC, Co-Chair Jesse E. Adams iii, MD, FACC[∗][1] John E. Brush, Jr, MD, FACC[∗][1] G. William Dec, Jr, MD, FACC Ali Denktas, MD, FACC Susan M. Fernandes, LPD, PA-C Sanjeev A. Francis, MD, FACC Rosario Freeman, MD, MS, FACC[∗][1

BackgroundCutaneous exposure to sunlight is a major source of vitamin D. Individuals with photosensitivity disorders have symptoms provoked by sunlight and may not achieve the brief sunlight exposures that convey vitamin D acquisition.ObjectiveTo explore knowledge, behaviour and attitudes towards vitamin D and its acquisition in patients with photosensitivity.MethodsPatients (n=19) diagnosed with solar urticaria, erythropoietic protoporphyria or polymorphic light eruption at a specialist photoinvestigation centre participated in semi‐structured focus groups to discuss vitamin D knowledge, acquisition behaviours, and attitudes towards vitamin D acquisition through sunlight and diet. Discussions were analysed by thematic analysis using MAXQDA11.ResultsKnowledge of vitamin D was variable. There was good awareness that sunlight exposure is an important source but knowledge of dietary sources was poor. Patients had little concern for their own vitamin D status prior to attending the photoinvestigation centre. Most patients avoided sunlight exposure, were unable to achieve the guidance on sun exposure for healthy individuals, and were aware this could affect their vitamin D status. Use of oral vitamin D supplements was common and all were willing to consider supplements if required. Patients recommended improving education of clinicians to increase patient awareness of vitamin D,ConclusionsMore targeted guidance is required on acquisition of vitamin D for patients with photosensitivity, supported by increased patient and clinician education.

Background and Aims: Recent studies have unveiled an association between ADAMTS7 gene variation and coronary artery disease (CAD) caused by atherosclerosis. We investigated if the ADAMTS7 Serine214-to-Proline substitution arising from a CAD-associated variant affected angiogenesis, since neovascularization plays an important role in atherosclerosis. Methods and Results: ADAMTS7 knockdown in vascular endothelial cells (ECs) attenuated their angiogenesis potential, whereas augmented ADAMTS7-Ser214 expression had the opposite effect, leading to increased ECs migratory and tube formation ability. Proteomics analysis showed an increase in thrombospondin-1, a reported angiogenesis inhibitor, in culture media conditioned by ECs with ADAMTS7 knockdown and a decrease of thrombospondin-1 in media conditioned by ECs with ADAMTS7-Ser214 overexpression. Cleavage assay indicated that ADAMTS7 possessed thrombospondin-1 degrading activity, which was reduced by the Ser214-to-Pro substitution. The pro-angiogenic effect of ADAMTS7-Ser214 diminished in the presence of a thrombospondin-1 blocking antibody. Conclusions: The ADAMTS7 Ser217-to-Pro substitution as a result of ADAMTS7 polymorphism affects thrombospondin-1 degradation, thereby promoting atherogenesis through increased EC migration and tube formation.

BackgroundMelioidosis is a tropical infectious disease which is being increasingly recognised throughout the globe. Infection occurs in humans and animals, typically through direct exposure to soil or water containing the environmental bacteriumBurkholderia pseudomallei. Case clusters of melioidosis have been described in humans following severe weather events and in exotic animals imported into melioidosis endemic zones. Direct transmission ofB. pseudomalleibetween animals and/or humans has been documented but is considered extremely rare. Between March 2015 and October 2016 eight fatal cases of melioidosis were reported in slender-tailed meerkats (Suricata suricatta)on display at a Wildlife Park in Northern Australia. To further investigate the melioidosis case cluster we sampled the meerkat enclosure and adjacent park areas and performed whole-genome sequencing (WGS) on all culture-positiveB. pseudomalleienvironmental and clinical isolates.ResultsWGS confirmed that the fatalities were caused by two differentB. pseudomalleisequence types (STs) but that seven of the meerkat isolates were highly similar on the whole-genome level. Used concurrently with detailed pathology data, our results demonstrate that the seven cases originated from a single original source, but routes of infection varied amongst meerkats belonging to the clonal outbreak cluster. Moreover, in some instances direct transmission may have transpired through wounds inflicted while fighting.ConclusionsCollectively, this study supports the use of high-resolution WGS to enhance epidemiological investigations into transmission modalities and pathogenesis of melioidosis, especially in the instance of a possible clonal outbreak scenario in exotic zoological collections. Such findings from an animal outbreak have important One Health implications.

Castration of male piglets in the United States is conducted without analgesics because no Food and Drug Administration (FDA) approved products are labeled for pain control in swine. The absence of approved products is primarily due to a wide variation in how pain is measured in suckling piglets and the lack of validated pain-specific outcomes individually indistinct from other biological responses, such as general stress or inflammation responses with cortisol. Simply put, to measure pain mitigation, measurement of pain must be specific, quantifiable, and defined. Therefore, given the need for mitigating castration pain, a consortium of researchers, veterinarians, industry, and regulatory agencies was formed to identify potential animal-based outcomes and develop a methodology, based on the known scientific research, to measure pain and the efficacy of mitigation strategies. The outcome-based measures included physiological, neuroendocrine, behavioral, and production parameters. Ultimately, this consortium aims to provide a validated multimodal methodology to demonstrate analgesic drug efficacy for piglet castration.Measurable outcomes were selected based on published studies suggesting their validity, reliability, and sensitivity for the direct or indirect measurement of pain associated with surgical castration in piglets. Outcomes to be considered are observation of pain behaviors (i.e. ethogram defined behaviors and piglet grimace scale), gait parameters measured with a pressure mat, infrared thermography of skin temperature of the cranium and periphery of the eye, and blood biomarkers. Other measures include body weight and mortality rate.This standardized measurement of the outcome variable's primary goal is to facilitate consistency and rigor by developing a research methodology utilizing endpoints that are well-defined and reliably measure pain in piglets. The resulting methodology will facilitate and guide the evaluation of the effectiveness of comprehensive analgesic interventions for 3- to 5-day-old piglets following surgical castration.

The COVID‐19 pandemic provides a pertinent reminder of the imperative to generate timely reliable clinical evidence. Delivery of optimal paediatric care is predicated on the availability of comprehensive, high quality, clinical evidence in a relevant population. However, over 80% of current clinical guidelines and bedside decisions are not based on direct high‐level evidence. Integration of research activities into routine clinical care is paramount to address this shortfall. Active engagement of patients, families and hospital administrations is required to reframe integrated clinical trials as a tenet of quality health‐care delivery. Current research funding in health care is 1–2 orders of magnitude below that of other industries. At an institutional level, investment in research should be prioritised with enhanced funding and supportive policies. Thoughtful integration of trials into routine bedside care will enable pragmatic research outcomes, tangible returns on financial investments and improved decision‐making for patients in the medium‐ to long‐term.