Unmet Surgical Need among Adults in A Mixed Urban-Rural Community in Nigeria: A Survey of 1,993 Adults Using the Sosas Survey Tool.

INTRODUCTION: Community-based prevalence studies are known to be more accurate than hospital-based records. However, such community-based prevalence studies are uncommon in low- and middle-income countries including Nigeria. Allocation of resources and prioritization of health care needs by policy makers require data from such community-based studies to be meaningful and sustainable. This study aims to assess the prevalence of common surgical conditions amongst adults in Nigeria. METHODS: A descriptive cross-sectional community-based study to determine the prevalence of congenital and acquired surgical conditions in adults in a mixed rural-urban area of Lagos was conducted. The study population comprised resident members in the Ikorodu Local Government Area (LGA) of Lagos State. Data was collected using a modified version of the interviewer-administered questionnaire, the Surgeons OverSeas Assessment of Surgical Need (SOSAS) survey tool. Data was analysed using the REDCap analytic tool. RESULTS: Eight hundred and fifty-six households were surveyed with a yield of 1,992 adults. There were 95 adults who complained of surgical conditions giving a prevalence rate of 5%. Vast majority of reported conditions were acquired deformities (n=94) while only 1 congenital deformity was reported. Others included breast lumps, anterior neck swelling, and groin swellings. CONCLUSION: The most common surgical complaints in our setting among adults were acquired conditions of the extremities and open wounds/sores. With an estimated population of 90 million adults and approximately 1,200 orthopaedic and general surgeons respectively, the surgeon-to-affected population ratio is 1:10,000. There is a large gap to be filled in terms of surgical manpower development.

INTRODUCTION: Les études de prévalence communautaires sont connues pour être plus précises que les dossiers hospitaliers. Cependant, de telles études de prévalence communautaires sont rares dans les pays à revenu faible et intermédiaire, y compris le Nigeria. L'allocation des ressources et la priorisation des besoins de santé par les décideurs nécessitent des données issues de telles études communautaires pour être significatives et durables. Cette étude vise à évaluer la prévalence des affections chirurgicales courantes chez les adultes au Nigeria. MÉTHODES: Une étude descriptive transversale basée sur la communauté pour déterminer la prévalence des conditions chirurgicales congénitales et acquises chez les adultes dans une zone rurale-urbaine mixte de Lagos a été menée. La population étudiée comprenait des membres résidents de la zone de gouvernement local (LGA) d'Ikorodu, dans l'État de Lagos. Les données ont été collectées à l'aide d'une version modifiée du questionnaire administré par un enquêteur, l'outil d'enquête Surgeons OverSeas Assessment of Surgical Need (SOSAS). Les données ont été analysées à l'aide de l'outil analytique REDCap. RÉSULTATS: Huit cent cinquante-six ménages ont été enquêtés, ce qui a donné 1 992 adultes. Quatre-vingt-quinze adultes se sont plaints de conditions chirurgicales, donnant un taux de prévalence de 5 %. La grande majorité des conditions rapportées étaient des déformations acquises (n=94) tandis qu'une seule déformation congénitale a été signalée. Les autres incluaient des nodules mammaires, des gonflements antérieurs du cou et des gonflements inguinaux. CONCLUSION: Les plaintes chirurgicales les plus courantes dans notre cadre parmi les adultes étaient des conditions acquises des extrémités et des plaies ouvertes/ulcères. Avec une population estimée à 90 millions d'adultes et environ 1 200 chirurgiens orthopédiques et généralistes respectivement, le ratio chirurgien-population affectée est de 1:10,000. Il y a un grand écart à combler en termes de développement de la main-d'œuvre chirurgicale. MOTS CLÉS: Prévalence, Charge de morbidité, Chirurgie, Plaies.

Wound Healing: Cellular Review With Specific Attention to Postamputation Care.

Wound healing is crucial for survival, prevention of infection, and restoration of tissue function. The immune system drives this process with 3 main phases: inflammation, proliferation, and remodeling. Keloids and hypertrophic scars reveal disruptions in these phases, underscoring the balance needed for healing. Limb amputation, a life-changing event, demands careful consideration for healing and function. Factors such as amputation level, surgical technique, and prosthetic fitting shape outcomes, while complications such as heterotopic ossification challenge recovery. Treatment advances including statins and stem cell therapy hold promise, with dermatologists poised to contribute substantially to postamputation care.

Amphiphilic silicones for the facile dispersion of carbon nanotubes and formation of soft skin electrodes.

Flexible, dry skin electrodes represent a potentially superior alternative to standard Ag/AgCl metal electrodes for wearable devices used in long-term monitoring. Herein, such electrodes were formed using a facile method for dispersing carbon nanotubes (CNTs) in a silicone matrix using custom amphiphilic dispersive additives (DSPAs). Using only brief mixing and without the use of solvents or surface modification of CNTs, twelve poly(ethylene oxide)-silanes (PEO-SAs) of varying crosslinkability, architecture, siloxane tether length, and molar ratio of siloxane:PEO were combined with an addition cure silicone and CNTs. Nearly all PEO-SA modified silicone-CNT composites demonstrated improved conductivity compared to the unmodified composite. Best conductivities correlated to composites prepared with PEO-SAs that formed micelles of particular sizes (d ~ 200 - 300 nm) and coincided to PEO-SAs with a siloxane:PEO molar ratio of ~ 0.75 - 3.00. Superior dispersion of CNT by such PEO-SAs was exemplified by scanning electron microscopy (SEM). Advantageously, modified composites retained their moduli, rather than becoming more rigid. Resultant electrodes fabricated with modified composites showed skin-electrode impedance comparable to that of Ag/AgCl electrodes. Combined, these results demonstrate the potential of silicone-CNT composites prepared with PEO-SA DSPAs as flexible, dry electrodes as a superior alternative to traditional electrodes.

Effects of preoperative pulmonary function on perioperative outcomes after robotic-assisted pulmonary lobectomy.

INTRODUCTION: Effects of pulmonary function test (PFT) results on perioperative outcomes were investigated after robotic-assisted video-thoracoscopic (RAVT) pulmonary lobectomy. METHODS: We retrospectively analyzed 706 consecutive patients who underwent RAVT lobectomy by one surgeon over 10.8 years. Preoperative (preop) forced expiratory volume in 1 s as a percent of predicted (FEV1%) was used to group patients as having normal FEV1% (≥80%) versus reduced FEV1% (<80%). Demographics, preop comorbidities, intraoperative (intraop) and postoperative (postop) complications, perioperative outcomes, and median survival time (MST) were compared across patients with normal vs. reduced FEV1% using Chi-Square (X2), Fisher's Exact test, Student's t-test, Kruskal-Wallis test, or Kaplan-Meier analysis respectively, with significance at p ≤ 0.05. Multivariable analysis was performed for perioperative outcomes to investigate the differences across patients in the FEV1% groups. RESULTS: There were 470 patients with normal FEV1% and 236 patients with reduced FEV1%. The two FEV1% groups did not differ in intraop or postop complication rates, except for higher postop other arrhythmia requiring intervention (p = 0.004), prolonged air leak >5 days (p = 0.002), mucous plug formation (p = 0.009), hypoxia (p < 0.001), and pneumonia (p = 0.002), and total postop complications (p < 0.001) in reduced-FEV1% patients. Reduced FEV1% correlated with increased intraop estimated blood loss (p < 0.0001) and skin-to-skin operative time (p < 0.0001). Median overall survival in patients with normal FEV1% was 93.20 months (95% CI: 76.5-126.0) versus 58.9 months (95% CI: 50.4-68.4) in patients with reduced FEV1% (p = 0.0004). CONCLUSION: Patients should have PFTs conducted before surgery to determine at-risk patients. However, RAVT pulmonary lobectomy is feasible and safe even in patients with reduced FEV1%.

Anxiety and Worry about Six Categories of Climate Change Impacts.

The occurrence of severe and extreme weather events that have been attributed to a changed climate system and the widespread dissemination of the impacts of these events in the media can lead people to experience concern, worry, and anxiety, which we examined in two studies. In Study 1, we observed that people more frequently expressed worry than anxiety about the impacts of climate change in six areas. People were more frequently worried and anxious about the effects of climate change on future generations and about societal responses (or lack of a response) to climate change. The levels of anxiety that people expressed were significantly higher than the worry people reported when anxiety was their modal response. In Study 2, we observed that both climate change worry and anxiety were negatively correlated with psychological distance from climate change. Overall, climate change worry and psychological distance significantly predicted climate-sustainable behaviors. Our study was among the first to use developed measures of climate change worry, anxiety, and psychological distance to examine peoples' responses across some of the possible impact and consequence areas of climate change.

A pilot multi-institutional study to evaluate the accuracy of a supine MRI based guidance system, the Breast Cancer Locator™, in patients with palpable breast cancer.

BACKGROUND: Evaluate whether the Breast Cancer Locator™ (BCL), a novel guidance system based on supine MRI images, can be safely and effectively deployed by several surgeons at multiple sites. METHODS: Patients with palpable breast cancer underwent supine MRI at their local institution. A three dimensional (3D) digital image of the tumor in the breast was derived from supine MRI images and used to generate 1) an interactive 3D virtual image of the tumor in the breast (Visualizer) and 2) a plastic bra-like form that allowed the surgeon to place a central wire and bracketing wires in the breast (BCL). The primary objective was to determine the proportion of patients who had the central localization wire deployed within the cancer on specimen mammogram. RESULTS: Fourteen patients were enrolled at 4 different sites by 6 surgeons. BCLs were successfully manufactured for all patients. The central wire was deployed within the tumor on specimen mammogram in 12 of the 13 patients who had a central wire placed (92%). The cancer was excised with negative margins in 14/14 cases (100%). No adverse events occurred. CONCLUSIONS: Supine MRI image acquisition was accomplished successfully across multiple sites. Multiple surgeons utilized the BCL system to localize cancers accurately and safely.

Complete Genome Sequence of Finnry, a Subcluster L3 Mycobacteriophage from Charleston, South Carolina.

Subcluster L3 bacteriophage Finnry was isolated from soil collected in Charleston, South Carolina, using Mycobacterium smegmatis mc2155 as a host. The genome of this temperate siphovirus is 75,632 bp long (130 predicted protein-coding genes, 9 tRNAs, and no transfer-messenger RNAs), and BLASTn alignment revealed 99.86% identity with the genome of L3 mycobacteriophage Samty.

Guiding equitable prioritisation of COVID-19 vaccine distribution and strategic deployment in South Africa to enhance effectiveness and access to vulnerable communities and prevent waste.

BACKGROUND: In South Africa (SA), >2.4 million cases of COVID­19 and >72 000 deaths were recorded between March 2020 and 1 August 2021, affecting the country's 52 districts to various extents. SA has committed to a COVID­19 vaccine roll-out in three phases, prioritising frontline workers, the elderly, people with comorbidities and essential workers. However, additional actions will be necessary to support efficient allocation and equitable access for vulnerable, access-constrained communities. OBJECTIVES: To explore various determinants of disease severity, resurgence risk and accessibility in order to aid an equitable, effective vaccine roll-out for SA that would maximise COVID­19 epidemic control by reducing the number of COVID­19 transmissions and resultant deaths, while at the same time reducing the risk of vaccine wastage. METHODS: For the 52 districts of SA, 26 COVID­19 indicators such as hospital admissions, deaths in hospital and mobility were ranked and hierarchically clustered with cases to identify which indicators can be used as indicators for severity or resurgence risk. Districts were then ranked using the estimated COVID­19 severity and resurgence risk to assist with prioritisation of vaccine roll-out. Urban and rural accessibility were also explored as factors that could limit vaccine roll-out in hard-to-reach communities. RESULTS: Highly populated urban districts showed the most cases. Districts such as Buffalo City, City of Cape Town and Nelson Mandela Bay experienced very severe first and second waves of the pandemic. Districts with high mobility, population size and density were found to be at highest risk of resurgence. In terms of accessibility, we found that 47.2% of the population are within 5 km of a hospital with ≥50 beds, and this percentage ranged from 87.0% in City of Cape Town to 0% in Namakwa district. CONCLUSIONS: The end goal is to provide equal distribution of vaccines proportional to district populations, which will provide fair protection. Districts with a high risk of resurgence and severity should be prioritised for vaccine roll-out, particularly the major metropolitan areas. We provide recommendations for allocations of different vaccine types for each district that consider levels of access, numbers of doses and cold-chain storage capability.

Is General Anesthesia for Endovascular Thrombectomy Helpful or Harmful?

Endovascular thrombectomy (EVT) has significantly improved outcomes for patients with acute ischemic stroke due to large vessel occlusion. However, despite advances, more than half of patients remain functionally dependent 3 months after their initial stroke. Anesthetic strategy may influence both the technical success of the procedure and overall outcomes. Conventionally, general anesthesia (GA) has been widely used for neuroendovascular procedures, particularly for the distal intracranial circulation, because the complete absence of movement has been considered imperative for procedural success and to minimize complications. In contrast, in patients with acute stroke undergoing EVT, the optimal anesthetic strategy is controversial. Nonrandomized studies suggest GA negatively affects outcomes while the more recent anesthesia-specific RCTs report improved or unchanged outcomes in patients managed with versus without GA, although these findings cannot be generalized to other EVT capable centers due to a number of limitations. Potential explanations for these contrasting results will be addressed in this review including the effect of different anesthetic strategies on cerebral and systemic hemodynamics, revascularization times, and periprocedural complications.

Guiding equitable prioritisation of COVID-19 vaccine distribution and strategic deployment in South Africa to enhance effectiveness and access to vulnerable communities and prevent waste

Background. In South Africa (SA), >2.4 million cases of COVID­19 and >72 000 deaths were recorded between March 2020 and 1 August 2021, affecting the country's 52 districts to various extents. SA has committed to a COVID­19 vaccine roll-out in three phases, prioritising frontline workers, the elderly, people with comorbidities and essential workers. However, additional actions will be necessary to support efficient allocation and equitable access for vulnerable, access-constrained communities. Objectives. To explore various determinants of disease severity, resurgence risk and accessibility in order to aid an equitable, effective vaccine roll-out for SA that would maximise COVID­19 epidemic control by reducing the number of COVID­19 transmissions and resultant deaths, while at the same time reducing the risk of vaccine wastage. Methods. For the 52 districts of SA, 26 COVID­19 indicators such as hospital admissions, deaths in hospital and mobility were ranked and hierarchically clustered with cases to identify which indicators can be used as indicators for severity or resurgence risk. Districts were then ranked using the estimated COVID­19 severity and resurgence risk to assist with prioritisation of vaccine roll-out. Urban and rural accessibility were also explored as factors that could limit vaccine roll-out in hard-to-reach communities. Results. Highly populated urban districts showed the most cases. Districts such as Buffalo City, City of Cape Town and Nelson Mandela Bay experienced very severe first and second waves of the pandemic. Districts with high mobility, population size and density were found to be at highest risk of resurgence. In terms of accessibility, we found that 47.2% of the population are within 5 km of a hospital with ≥50 beds, and this percentage ranged from 87.0% in City of Cape Town to 0% in Namakwa district. Conclusions. The end goal is to provide equal distribution of vaccines proportional to district populations, which will provide fair protection. Districts with a high risk of resurgence and severity should be prioritised for vaccine roll-out, particularly the major metropolitan areas. We provide recommendations for allocations of different vaccine types for each district that consider levels of access, numbers of doses and cold-chain storage capability.

Microbial community succession on submerged vertebrate carcasses in a tidal river habitat: Implications for aquatic forensic investigations.

Death investigations in aquatic ecosystems are challenging due to abiotic and biotic factors that may influence the estimation of a postmortem submersion interval (PMSI). In this study, we examined bacterial changes throughout the decomposition process on porcine carcasses submerged in a tidal-influenced river and identified predictors of epinecrotic community succession. Fetal porcine (Sus scrofa) carcasses (N = 6) were submerged with epinecrotic samples collected every 3 days (6 collections) over a period of 19 days (~7415 accumulated degree hours (ADH)). Amplicon sequencing was performed using the Illumina MiSeq platform (16S V4 region, 2 × 250 bp format) to identify changes in bacterial relative abundance and diversity. To match bacterial succession with rough taphonomy, carcasses were visually assessed at each sampling time point to determine the decomposition stage. Notably, the three most abundant families were Moraxellaceae, Burkholderiaceae (Proteobacteria), and Clostridiaceae (Firmicutes), though communities composition varied significantly across decomposition stages. Greater bacterial phylogenetic diversity was observed in in latter decomposition stages (advanced floating decay, sunken remains). Random Forest Models were built to predict ADH and explained 77%-80.8% of variation in ADH with an error rate of +/-1943.2 ADH (Root Mean Square Error) or approx. ±2.7 days at the mean water temperature of this study. This study provided a useful model that could be used to estimate a PMSI in this river system utilizing bacterial community succession, and thus, potentially improve the accuracy of such estimations to be used in the court of law.

Perioperative mortality in bariatric surgery: meta-analysis.

BACKGROUND: Bariatric surgery is an established treatment for severe obesity; however, fewer than 1 per cent of eligible patients undergo surgery. The perceived risk of surgery may contribute to the low uptake. The aim of this study was to determine perioperative mortality associated with bariatric surgery, comparing different operation types and data sources. METHODS: A literature search of Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials was conducted to identify studies published between 1 January 2014 and 31 July 2020. Inclusion criteria were studies of at least 1000 patients reporting short-term mortality after bariatric surgery. Data were collected on RCTs. Meta-analysis was performed to establish overall mortality rates across different study types. The primary outcome measure was perioperative mortality. Different operation types were compared, along with study type, in subgroup analyses. The study was registered at PROSPERO (2019: CRD 42019131632). RESULTS: Some 4356 articles were identified and 58 met the inclusion criteria. Data were available on over 3.6 million patients. There were 4707 deaths. Pooled analysis showed an overall mortality rate of 0.08 (95 per cent c.i. 0.06 to 0.10; 95 per cent prediction interval 0 to 0.21) per cent. In subgroup analysis, there was no statistically significant difference between overall, 30-day, 90-day or in-hospital mortality (P = 0.29). There was no significant difference in reported mortality for RCTs, large studies, national databases or registries (P = 0.60). The pooled mortality rates by procedure type in ascending order were: 0.03 per cent for gastric band, 0.05 per cent for sleeve gastrectomy, 0.09 per cent for one-anastomosis gastric bypass, 0.09 per cent for Roux-en-Y gastric bypass, and 0.41 per cent for duodenal switch (P < 0.001 between operations). CONCLUSION: Bariatric surgery is safe, with low reported perioperative mortality rates.

Weight loss surgery helps patients with severe obesity. This study looked at the risk of dying after weight loss surgery in over 3.6 million patients. The risk was less than 1 in 1000 (0.08 per cent). The risk was lowest for gastric band and sleeve gastrectomy, then for gastric bypasses and highest for the duodenal switch operation. This shows that weight loss surgery is safe, with a low risk of dying similar to that of other common operations.

Targeting the Apoa1 locus for liver-directed gene therapy.

Clinical application of somatic genome editing requires therapeutics that are generalizable to a broad range of patients. Targeted insertion of promoterless transgenes can ensure that edits are permanent and broadly applicable while minimizing risks of off-target integration. In the liver, the Albumin (Alb) locus is currently the only well-characterized site for promoterless transgene insertion. Here, we target the Apoa1 locus with adeno-associated viral (AAV) delivery of CRISPR-Cas9 and achieve rates of 6% to 16% of targeted hepatocytes, with no evidence of toxicity. We further show that the endogenous Apoa1 promoter can drive robust and sustained expression of therapeutic proteins, such as apolipoprotein E (APOE), dramatically reducing plasma lipids in a model of hypercholesterolemia. Finally, we demonstrate that Apoa1-targeted fumarylacetoacetate hydrolase (FAH) can correct and rescue the severe metabolic liver disease hereditary tyrosinemia type I. In summary, we identify and validate Apoa1 as a novel integration site that supports durable transgene expression in the liver for gene therapy applications.

A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function.

INTRODUCTION: Delayed graft function (DGF) following renal transplantation is a manifestation of acute kidney injury (AKI) leading to poor long-term outcome. Current treatments have limited effectiveness in preventing DGF. Interleukin-18 (IL18), a biomarker of AKI, induces interferon-γ expression and immune activation. GSK1070806, an anti-IL18 monoclonal antibody, neutralizes activated (mature) IL18 released from damaged cells following inflammasome activation. This phase IIa, single-arm trial assessed the effect of a single dose of GSK1070806 on DGF occurrence post donation after circulatory death (DCD) kidney transplantation. METHODS: The 3 mg/kg intravenous dose was selected based on prior studies and physiologically based pharmacokinetic (PBPK) modeling, indicating the high likelihood of a rapid and high level of IL18 target engagement when administered prior to kidney allograft reperfusion. Utilization of a Bayesian sequential design with a background standard-of-care DGF rate of 50% based on literature, and confirmed via extensive registry data analyses, enabled a statistical efficacy assessment with a minimal sample size. The primary endpoint was DGF frequency, defined as dialysis requirement ≤7 days post transplantation (except for hyperkalemia). Secondary endpoints included safety, pharmacokinetics and pharmacodynamic biomarkers. RESULTS: GSK1070806 administration was associated with IL18-GSK1070806 complex detection and increased total serum IL18 levels due to IL18 half-life prolongation induced by GSK1070806 binding. Interferon-γ-induced chemokine levels declined or remained unchanged in most patients. Although the study was concluded prior to the Bayesian-defined stopping point, 4/7 enrolled patients (57%) had DGF, exceeding the 50% standard-of-care rate, and an additional two patients, although not reaching the protocol-defined DGF definition, demonstrated poor graft function. Six of seven patients experienced serious adverse events (SAEs), including two treatment-related SAEs. CONCLUSION: Overall, using a Bayesian design and extensive PBPK dose modeling with only a small sample size, it was deemed unlikely that GSK1070806 would be efficacious in preventing DGF in the enrolled DCD transplant population. TRIAL REGISTRATION: NCT02723786.

HDAC Inhibition Reverses Preexisting Diastolic Dysfunction and Blocks Covert Extracellular Matrix Remodeling.

BACKGROUND: Diastolic dysfunction (DD) is associated with the development of heart failure and contributes to the pathogenesis of other cardiac maladies, including atrial fibrillation. Inhibition of histone deacetylases (HDACs) has been shown to prevent DD by enhancing myofibril relaxation. We addressed the therapeutic potential of HDAC inhibition in a model of established DD with preserved ejection fraction. METHODS: Four weeks after uninephrectomy and implantation with deoxycorticosterone acetate pellets, when DD was clearly evident, 1 cohort of mice was administered the clinical-stage HDAC inhibitor ITF2357/Givinostat. Echocardiography, blood pressure measurements, and end point invasive hemodynamic analyses were performed. Myofibril mechanics and intact cardiomyocyte relaxation were assessed ex vivo. Cardiac fibrosis was evaluated by picrosirius red staining and second harmonic generation microscopy of left ventricle (LV) sections, RNA sequencing of LV mRNA, mass spectrometry-based evaluation of decellularized LV biopsies, and atomic force microscopy determination of LV stiffness. Mechanistic studies were performed with primary rat and human cardiac fibroblasts. RESULTS: HDAC inhibition normalized DD without lowering blood pressure in this model of systemic hypertension. In contrast to previous models, myofibril relaxation was unimpaired in uninephrectomy/deoxycorticosterone acetate mice. Furthermore, cardiac fibrosis was not evident in any mouse cohort on the basis of picrosirius red staining or second harmonic generation microscopy. However, mass spectrometry revealed induction in the expression of >100 extracellular matrix proteins in LVs of uninephrectomy/deoxycorticosterone acetate mice, which correlated with profound tissue stiffening based on atomic force microscopy. ITF2357/Givinostat treatment blocked extracellular matrix expansion and LV stiffening. The HDAC inhibitor was subsequently shown to suppress cardiac fibroblast activation, at least in part, by blunting recruitment of the profibrotic chromatin reader protein BRD4 (bromodomain-containing protein 4) to key gene regulatory elements. CONCLUSIONS: These findings demonstrate the potential of HDAC inhibition as a therapeutic intervention to reverse existing DD and establish blockade of extracellular matrix remodeling as a second mechanism by which HDAC inhibitors improve ventricular filling. Our data reveal the existence of pathophysiologically relevant covert or hidden cardiac fibrosis that is below the limit of detection of histochemical stains such as picrosirius red, highlighting the need to evaluate fibrosis of the heart using diverse methodologies.

Blocking von Willebrand factor free thiols inhibits binding to collagen under high and pathological shear stress.

BACKGROUND: Von Willebrand factor (VWF) contains a number of free thiols, the majority of which are located in its C-domains, and these have been shown to alter VWF function, However, the impact of free thiols on function following acute exposure of VWF to collagen under high and pathological shear stress has not been determined. METHODS: VWF free thiols were blocked with N-ethylmaleimide and flow assays performed under high and pathological shear rates to determine the impact on platelet capture and collagen binding function. Atomic force microscopy (AFM) was used to probe the interaction of VWF with collagen and molecular simulations conducted to determine the effect of free thiols on the flexibility of the VWF-C4 domain. RESULTS: Blockade of VWF free thiols reduced VWF-mediated platelet capture to collagen in a shear-dependent manner, with platelet capture virtually abolished above 5000 s-1 and in regions of stenosis in microfluidic channels. Direct visualization of VWF fibers formed under extreme pathological shear rates and analysis of collagen-bound VWF attributed the effect to altered binding of VWF to collagen. AFM measurements showed that thiol-blockade reduced the lifetime and strength of the VWF-collagen bond. Pulling simulations of the VWF-C4 domain demonstrated that with one or two reduced disulphide bonds the C4 domain has increased flexibility and the propensity to undergo free-thiol exchange. CONCLUSIONS: We conclude that free thiols in the C-domains of VWF enhance the flexibility of the molecule and enable it to withstand high shear forces following collagen binding, demonstrating a previously unrecognized role for VWF free thiols.

Transparency in surgical randomized clinical trials: cross-sectional observational study.

BACKGROUND: RCTs provide the scientific basis upon which treatment decisions are made. To facilitate critical review, it is important that methods and results are reported transparently. The aim of this study was to explore transparency in surgical RCTs with respect to trial registration, disclosure of funding sources, declarations of investigator conflicts and data-sharing. METHODS: This was a cross-sectional review of published surgical RCTs. Ten high-impact journals were searched systematically for RCTs published in years 2009, 2012, 2015 and 2018. Four domains of transparency were explored: trial registration, disclosure of funding, disclosure of investigator conflicts, and a statement relating to data-sharing. RESULTS: Of 611 RCTs, 475 were eligible for analysis. Some 397 RCTs (83.6 per cent) were registered on a trial database, of which 190 (47·9 per cent) had been registered prospectively. Prospective registration increased over time (26 per cent in 2009, 33·0 per cent in 2012, 54 per cent in 2015, and 72·7 per cent in 2018). Funding disclosure was present in 55·0, 65·0, 69·4 and 75·4 per cent of manuscripts respectively. Conflict of interest disclosure was present in 49·5, 89·1, 94·6 and 98·3 per cent of manuscripts across the same time periods. Data-sharing statements were present in only 15 RCTs (3·2 per cent), 11 of which were published in 2018. CONCLUSION: Trial registration, disclosure of funding and disclosure of investigator conflicts in surgical RCTs have improved markedly over the past 10 years. Disclosure of data-sharing plans is exceptionally low. This may contribute to research waste and represents a target for improvement.

ANTECEDENTES: Los ensayos clínicos aleatorizados y controlados (randomized controlled trials, RCT) proporcionan la base científica para la toma de decisiones terapéuticas. Es importante que los métodos y los resultados se presenten de forma transparente para facilitar la revisión crítica. El objetivo de este estudio fue investigar la transparencia en los RCTs del ámbito quirúrgico según su registro, declaraciones de las fuentes de financiación del estudio y conflicto de interés de los investigadores, así como información referente a compartir los datos. MÉTODOS: Revisión transversal de RCTs quirúrgicos publicados. Se realizó una búsqueda sistemática de los RCTs publicados en 10 revistas de alto impacto en los años 2009, 2012, 2015 y 2018. Se exploraron cuatro dominios de transparencia: el registro de los ensayos, la declaración de los fondos utilizados, la declaración de los conflictos de los investigadores y la información referente a la forma de compartir los datos. RESULTADOS: De 611 RCTs, se incluyeron en el análisis 475. Un total de 397 (83,6%) estudios se registraron en una base de datos de ensayos clínicos, de forma prospectiva en 190 (47,9%). El registro prospectivo aumentó a lo largo del tiempo (26,0% en 2009, 33,0% en 2012, 53,5% en 2015 y 72,7% en 2018). Se mencionaban las fuentes de financiación en el 55%, 65%, 69,4% y 75,4% de los manuscritos, respectivamente. La declaración de conflictos de interés estuvo presente en el 49,5%, 89,1%, 94,6% y 98,3% de los manuscritos en esos mismos períodos de tiempo. Las declaraciones relativas a compartir los datos de la investigación constaban en solo 15 (3,2%) RCTs, 11 de los cuales fueron publicados en el 2018. CONCLUSIÓN: En los últimos 10 años ha mejorado de forma notable el registro de los ensayos y las declaraciones de las fuentes de financiación y conflicto de interés en los RCTs quirúrgicos. La declaración referente a compartir los datos es excepcionalmente baja, lo que puede contribuir al desperdicio de la investigación y constituye un objetivo de mejora.