Key points The capillary module, consisting of parallel capillaries from arteriole to venule, is classically considered as the building block of complex capillary networks. In skeletal muscle, this structure fails to address how blood flow is regulated along the entire length of the synchronously contracting muscle fibres. Using intravital video microscopy of resting extensor digitorum longus muscle in rats, we demonstrated the capillary fascicle as a series of interconnected modules forming continuous columns that align naturally with the dimensions of the muscle fascicle. We observed structural heterogeneity for module topology, and functional heterogeneity in space and time for capillary‐red blood cell (RBC) haemodynamics within a module and between modules. We found that module RBC haemodynamics were independent of module resistance, providing direct evidence for microvascular flow regulation at the level of the capillary module. The capillary fascicle is an updated paradigm for characterizing blood flow and RBC distribution in skeletal muscle capillary networks. Abstract Capillary networks are the fundamental site of oxygen exchange in the microcirculation. The capillary module (CM), consisting of parallel capillaries from terminal arteriole (TA) to post‐capillary venule (PCV), is classically considered as the building block of complex capillary networks. In skeletal muscle, this structure fails to address how blood flow is regulated along the entire length of the synchronously contracting muscle fibres, requiring co‐ordination from numerous modules. It has previously been recognized that TAs and PCVs interact with multiple CMs, creating interconnected networks. Using label‐free intravital video microscopy of resting extensor digitorum longus muscle in rats, we found that these networks form continuous columns of linked CMs spanning thousands of microns, herein denoted as the capillary fascicle (CF); this structure aligns naturally with the dimensions of the muscle fascicle. We measured capillary‐red blood cell (RBC) haemodynamics and module topology (n = 9 networks, 327 modules, 1491 capillary segments). The average module had length 481 μm, width 157 μm and 9.51 parallel capillaries. We observed structural heterogeneity for CM topology, and functional heterogeneity in space and time for capillary‐RBC haemodynamics within a module and between modules. There was no correlation between capillary RBC velocity and lineal density. A passive inverse relationship between module length and haemodynamics was remarkably absent, providing direct evidence for microvascular flow regulation at the level of the CM. In summary, the CF is an updated paradigm for characterizing RBC distribution in skeletal muscle, and strengthens the theory of capillary networks as major contributors to the signal that regulates capillary perfusion.

Background: Many methods have been suggested for analyzing the modified Rankin Scale (mRS). However, there lacks a unified approach to analysis and sample size determination that properly uses the ordinal nature of the data. We propose a simple method for CI estimation and corresponding sample size determination. Methods: We quantify treatment effect by the win probability (WinP) that a randomly selected patient in the treatment group has an equal or a better mRS score than a patient in the control group. Thus, a win probability of 0.5 means no effect, likened to a draw in competitive sports. We estimate the win probability and its SE based on the ranks of mRS scores, where tied scores are handled by average ranks. Corresponding methods for hypothesis testing, CI estimation, and sample size determination are derived. The methods are evaluated with a simulation study based on real data from 10 randomized stroke trials that used mRS as the outcome measure. Results: Simulation results demonstrated that the methods performed very well in terms of CI coverage, tail errors, and assurance to achieving the prespecified precision. Because the methods are very simple, we implemented them in an Excel spreadsheet, requiring only user inputs on frequencies of mRS scores in 2 comparison groups. Conclusions: Sound statistical methods are important for the success of randomized stroke trials. The proposed methods and associated spreadsheet should prove useful for stroke researchers in the planning and analysis of randomized trials. Meta-analysis has also been made easy for trials with ordinal scores.

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Background Lynch Syndrome (LS) screening guidelines originally recommended colonoscopy every 1 to 2 years, beginning between the ages of 20-25 years. Recent studies have questioned the benefits of these short screening intervals in preventing colorectal cancer (CRC). Our goal is to determine how colonoscopy screening intervals impact CRC in patients with LS. Methods We analyzed the demographics, screening practices and outcomes of patients with LS identified through the clinic based Familial Gastrointestinal Cancer Registry at the Zane Cohen Centre, Sinai Health System, Toronto. Results A total of 429 patients with LS were identified with median follow-up of 9.2 years, 44 developed CRC. We found a positive trend between shorter screening intervals and the number of adenomas detected during colonoscopy. Any new adenoma detected at screening decreased 10-year CRC incidence by 11.3%. For MLH1 carriers, a screening interval of 1-2 years vs. 2-3 years led to a 20-year cumulative CRC risk reduction of 28% and 14% in females and males. For MSH2 carriers, this risk reduction was 29% and 17%, respectively, and for male MSH6 carriers 18%. Individuals without any adenomas detected (53.4% of LS carriers) had an increased 20-year CRC risk of 25.7% and 57.2% for women and men, respectively, compared to those diagnosed with adenomas at screening. Conclusions The recommended colonoscopy screening interval of 1-2 year is efficient at detecting adenomas and reducing CRC risk. The observation that 53.4% of LS patients never had an adenoma warrants further investigation about a possible adenoma-free pathway.

Even though several studies have examined various risk factors for hypertension, residential influence is poorly explored especially in the low-income countries. We aim to investigate the association between residential characteristics and hypertension in resource limited and transitional settings like Nepal. A total of 14,652 individuals aged 15 and above were selected from 2016-Nepal Demographic and Health Survey. Individuals with blood pressure ≥140/90 mmHg or a history of hypertension (as identified by physicians/health professionals) or under antihypertensive medication were defined as hypertensive. Residential characteristics were represented by area level deprivation index, with a higher score representing higher level of deprivation. Association was explored using a two-level logistic regression. We also assessed if residential area modifies the association between individual socio-economic status and hypertension. Area deprivation had a significant inverse association with the risk of hypertension. Individuals from the least deprived areas had higher odds of hypertension compared to highly deprived areas 1.59 (95% CI 1.30, 1.89). Additionally, the association between literacy a proxy of socio-economic status and hypertension varied with a place of residence. Literate individuals from highly deprived areas were likely to have a higher odds of hypertension compared to those with no formal education. In contrast, literate from the least deprived areas had lower odds of hypertension. These results identify counterintuitive patterns of associations between residential characteristics and hypertension in Nepal, as compared with most of the epidemiological data from high-income countries. Differential stages of demographic and nutritional transitions between and within the countries might explain these associations.