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Skeletal muscles are living tissues that can undergo large deformations in short periods of time and that can be activated to produce force. In this paper we use the principles of continuum mechanics to propose a dynamic, fully nonlinear, and three-dimensional model to describe the deformation of these tissues. We model muscles as a fiber-reinforced composite and transversely isotropic material. We introduce a flexible computational framework to approximate the deformations of skeletal muscle to provide new insights into the underlying mechanics of these tissues. The model parameters and mechanical properties are obtained through experimental data and can be specified locally. A semi-implicit in-time, conforming, finite element in space scheme is used to approximate the solutions to the governing nonlinear dynamic model. We provide a series of numerical experiments demonstrating the application of this framework to relevant problems in biomechanics and also discuss questions around model validation. [ABSTRACT FROM AUTHOR]

Background The relevance of tobacco smoking for infectious respiratory diseases (IRD) is uncertain. We investigated the associations of cigarette smoking with severe IRD resulting in hospitalization or death in UK adults. Methods We conducted a prospective study of cigarette smoking and risk of severe IRD in UK Biobank. The outcomes included pneumonia, other acute lower respiratory tract infections (OA-LRTI) and influenza. Multivariable Cox regression analyses were used to estimate hazard ratios (HRs) of severe IRD associated with smoking habits after adjusting for confounding factors. Results Among 341 352 participants with no prior history of major chronic diseases, there were 12 384 incident cases with pneumonia, 7054 with OA-LRTI and 795 with influenza during a 12-year follow-up. Compared with non-smokers, current smoking was associated with ⁓2-fold higher rates of severe IRD (HR 2.40 [2.27–2.53] for pneumonia, 1.99 [1.84–2.14] for OA-LRTI and 1.82 [95% confidence interval: 1.47–2.24] for influenza). Incidence of all severe IRDs were positively associated with amount of cigarettes smoked. The HRs for each IRD (except influenza) also declined with increasing duration since quitting. Conclusions Current cigarette smoking was positively associated with higher rates of IRD and the findings extend indications for tobacco control measures and vaccination of current smokers for prevention of severe IRD. [ABSTRACT FROM AUTHOR]

Aims/Background: Serial blood pressure surveys in cohort studies can inform public health policies to control blood pressure for prevention of cardiovascular diseases. Methods: Mean levels of systolic blood pressure (SBP) were collected in six sequential surveys, involving 38,825 individuals aged 30–79 years (51% female), between 1979 and 2015 in the Tromsø Study in Norway. Mean levels of SBP, prevalence of hypertension and use of blood pressure-lowering treatment were estimated by age, sex and calendar year of survey. Results: Age-specific mean levels of SBP in each decade of age increased by 20–25 mmHg in men and 30–35 mmHg in women and the prevalence of hypertension increased from 25% to 75% among adults aged 30–79 years. Among successive cohorts of adults aged 40–49 years at the time of the six surveys between 1979 and 2015, the mean levels of SBP declined by about 10 mmHg and the prevalence of hypertension declined from 46% to 25% in men and from 30% to 14% in women. The proportion of individuals with hypertension who were treated increased sixfold (from 7% to 42%) between 1979 and 2015, and the proportion of adults with hypertension that were successfully controlled also increased sixfold from 10% to 60% between 1979 and 2015. Conclusions: Although this study demonstrated a halving in the age-specific prevalence of hypertension in men and women and a sixfold increase in treatment and control of hypertension, the burden of hypertension remains high among older people in Norway. [ABSTRACT FROM AUTHOR]

Rationale: Not all individuals with tobacco dependence are ready to give up smoking. Research reveals behavioral differences between adults ready to discontinue tobacco use and those who are not. Thus, the interventions applied to these populations might differ. However, the evidence of using varenicline in individuals who are not ready to discontinue tobacco use is uncertain. Objectives: To determine if, in tobacco-dependent adults who report not being ready to discontinue tobacco use, clinicians should begin treatment with varenicline or wait until subjects are ready to discontinue tobacco use. Methods: We conducted a systematic review to assess the effectiveness and safety of treatment with varenicline in tobacco-dependent adults who are not ready to discontinue tobacco use. We systematically searched the Cumulative Index to Nursing and Allied Health Literature, Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials to identify randomized controlled trials comparing varenicline versus placebo for individuals who were not ready to discontinue tobacco use. Outcomes of interest include point prevalence abstinence during treatment or at six months or longer, smoking reduction, motivation to quit, adverse events, and withdrawal symptoms. Two authors independently extracted data and assessed eligibility and risk of bias using a standardized data collection form. We followed the Grading of Recommendations, Assessment, Development and Evaluations approach to assess the certainty of evidence. Results: Five trials met our inclusion criteria. All 2,616 participants were adults who were not ready to discontinue tobacco use at study entry. For 7-day point prevalence abstinence at six months or longer, high-certainty evidence suggested that varenicline increased abstinence compared with placebo (relative risk, 2.00 [95% confidence interval (CI), 1.70-2.35]; absolute risk reduction, 173 more per 1,000 [95% CI, 121 more to 234 more]). We identified moderate-certainty evidence suggesting that varenicline increased serious adverse events (relative risk, 1.75 [95% CI, 0.98-3.13]; absolute risk reduction, 12 more per 1,000 [95% CI, 0 fewer to 35 more]). For withdrawal, low-certainty evidence suggested that varenicline treatment was associated with a lower symptom score (mean difference, 1.54 points lower; 95% CI, 2.15-0.93 points lower; low certainty) assessed using the Brief Questionnaire of Smoking Urges. Conclusions: In tobacco-dependent adults who are not ready to discontinue tobacco use, initiating varenicline treatment results in a large increase in abstinence and likely results in a slight increase in serious adverse events. [ABSTRACT FROM AUTHOR]

Background: The incidence of non-communicable diseases (NCDs) is increasing in rural India. The National Family Health Survey-5 (NFHS-5) provides estimates of the burden of NCDs and their risk factors in women aged 15-49 and men aged 15-54 years. The aim of this study is to estimate the prevalence of hypertension and body-mass index (BMI) in adults aged 35-70 years in rural India and to compare these estimates, where age ranges overlap, to routinely available data.Methods: The Non-Communicable Disease in Rural India (NCDRI) Study was a cross-sectional household survey of 1005 women and 1025 men aged 35-70 conducted in Bihar in July 2019. Information was collected on personal characteristics, self-reported medical history and physical measurements (blood pressure, height and weight). Prevalence estimates for hypertension (systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg, or diagnosed and treated for hypertension), and for underweight (body-mass index < 18.5 kg/m2), normal weight (18.5-25.0 kg/m2) and overweight (≥ 25.0 kg/m2) were calculated. Where age ranges overlapped, estimates from the NCDRI Study were compared to the NFHS-5 Survey.Results: In the NCDRI Study, the estimated prevalence of hypertension was 27.3% (N = 274) in women and 27.6% (N = 283) in men aged 35-70, which was three-times higher in women and over two-times higher in men than in the NFHS-5 Survey. One-quarter (23.5%; N = 236) of women and one-fifth (20.2%; N = 207) of men in the NCDRI Study were overweight, which was approximately 1.5 times higher than in the NFHS-5 Survey. However, where age groups overlapped, similar age-standardized estimates were obtained for hypertension and weight in both the NCDRI Study and the NFHS-5 Survey.Conclusion: The prevalence of NCDs in rural India is higher than previously reported due to the older demographic in our survey. Future routine national health surveys must widen the age range of participants to reflect the changing disease profile of rural India, and inform the planning of health services. [ABSTRACT FROM AUTHOR]

Rationale: The American Thoracic Society (ATS) developed a clinical practice guideline on initiating pharmacologic treatment in tobacco-dependent adults. Controller pharmacotherapies treat tobacco dependence effectively when taken as prescribed, but relapse after pharmacologic discontinuation is common. Objectives: To evaluate the effectiveness and safety of initiating controller for an extended (>12 wk) versus a standard duration (6-12 wk) in tobacco-dependent adults. Methods: We systematically searched PubMed, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials from database inception to December 2021 to identify randomized controlled trials comparing extended versus standard duration of controllers for tobacco-dependent adults. We conducted meta-analyses using the Mantel-Haenszel method with random effects model. Outcomes of interest include point-prevalent abstinence at 1-year follow-up or longer, relapse, adverse events, quality of life, and withdrawal symptoms. Subgroup analyses were conducted according to types of treatment and duration of extended therapy when feasible. We assessed the certainty of the estimate following the grading of recommendations, assessment, development and evaluation methodology. Results: We included 13 randomized controlled trials including 8,695 participants that directly compared extended- (>12 wk) versus standard-duration controller therapy with varenicline, bupropion, or nicotine replacement therapy. Compared with standard-duration controller therapy, extended-duration controller therapy probably increased abstinence at 1-year follow-up, measured as 7-day point-prevalence abstinence (relative risk, 1.18; 95% confidence interval [CI], 1.05-1.33; moderate certainty). Extended-duration controller therapy probably reduced relapse compared with standard-duration controller therapy, assessed at 12-18 months after initiation of therapy (hazard ratio, 0.43; 95% CI, 0.29-0.64; moderate certainty). Moderate certainty evidence also suggested that extended-duration controller therapy probably did not increase risk of serious adverse events (relative risk, 1.37; 95% CI, 0.79-2.36). Conclusions: This systematic review supported the recommendation for extended-duration therapy with controllers. Further studies on optimal extended duration are warranted. [ABSTRACT FROM AUTHOR]

This study assesses the associations between body mass index and risk of hospitalization for or death due to COVID-19, lower respiratory tract infections, and upper respiratory tract infections. [ABSTRACT FROM AUTHOR]

Cerebral palsy results from an upper motor neuron lesion and significantly affects skeletal muscle stiffness. The increased stiffness that occurs is partly a result of changes in the microstructural components of muscle. In particular, alterations in extracellular matrix, sarcomere length, fibre diameter, and fat content have been reported; however, experimental studies have shown wide variability in the degree of alteration. Many studies have reported changes in the extracellular matrix, while others have reported no differences. A consistent finding is increased sarcomere length in cerebral palsy affected muscle. Often many components are altered simultaneously, making it difficult to determine the individual effects on muscle stiffness. In this study, we use a three dimensional modelling approach to isolate individual effects of microstructural alterations typically occurring due to cerebral palsy on whole muscle behaviour; in particular, the effects of extracellular matrix volume fraction, stiffness, and sarcomere length. Causation between the changes to the microstructure and the overall muscle response is difficult to determine experimentally, since components of muscle cannot be manipulated individually; however, utilising a modelling approach allows greater control over each factor. We find that extracellular matrix volume fraction has the largest effect on whole muscle stiffness and mitigates effects from sarcomere length. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease accounts for about one-third of all premature deaths (ie, age < 70) in Cuba. Yet, the relevance of major risk factors, including systolic blood pressure (SBP), diabetes, and body-mass index (BMI), to cardiovascular mortality in this population remains unclear.Methods: In 1996-2002, 146,556 adults were recruited from the general population in five areas of Cuba. Participants were interviewed, measured (height, weight and blood pressure) and followed up by electronic linkage to national death registries until Jan 1, 2017; in 2006-08, 24,345 participants were resurveyed. After excluding all with missing data, cardiovascular disease at recruitment, and those who died in the first 5 years, Cox regression (adjusted for age, sex, education, smoking, alcohol and, where appropriate, BMI) was used to relate cardiovascular mortality rate ratios (RRs) at ages 35-79 years to SBP, diabetes and BMI; RR were corrected for regression dilution to give associations with long-term average (ie, 'usual') levels of SBP and BMI.Results: After exclusions, there were 125,939 participants (mean age 53 [SD12]; 55% women). Mean SBP was 124 mmHg (SD15), 5% had diabetes, and mean BMI was 24.2 kg/m2 (SD3.6); mean SBP and diabetes prevalence at recruitment were both strongly related to BMI. During follow-up, there were 4112 cardiovascular deaths (2032 ischaemic heart disease, 832 stroke, and 1248 other). Cardiovascular mortality was positively associated with SBP (>=120 mmHg), diabetes, and BMI (>=22.5 kg/m2): 20 mmHg higher usual SBP about doubled cardiovascular mortality (RR 2.02, 95%CI 1.88-2.18]), as did diabetes (2.15, 1.95-2.37), and 10 kg/m2 higher usual BMI (1.92, 1.64-2.25). RR were similar in men and in women. The association with BMI and cardiovascular mortality was almost completely attenuated following adjustment for the mediating effect of SBP. Elevated SBP (>=120 mmHg), diabetes and raised BMI (>=22.5 kg/m2) accounted for 27%, 14%, and 16% of cardiovascular deaths, respectively.Conclusions: This large prospective study provides direct evidence for the effects of these major risk factors on cardiovascular mortality in Cuba. Despite comparatively low levels of these risk factors by international standards, the strength of their association with cardiovascular death means they nevertheless exert a substantial impact on premature mortality in Cuba. [ABSTRACT FROM AUTHOR]

During muscle contraction, chemical energy is converted to mechanical energy when ATP is hydrolysed during cross-bridge cycling. This mechanical energy is then distributed and stored in the tissue as the muscle deforms or is used to perform external work. We previously showed how energy is distributed through contracting muscle during fixed-end contractions; however, it is not clear how the distribution of tissue energy is altered by the kinetic energy of muscle mass during dynamic contractions. In this study we conducted simulations of a 3D continuum muscle model that accounts for tissue mass, as well as force-velocity effects, in which the muscle underwent sinusoidal work-loop contractions coupled with bursts of excitation. We found that increasing muscle size, and therefore mass, increased the kinetic energy per unit volume of the muscle. In addition to greater relative kinetic energy per cycle, relatively more energy was also stored in the aponeurosis, and less was stored in the base material, which represented the intra and extracellular tissue components apart from the myofibrils. These energy changes in larger muscles due to greater mass were associated lower mass-specific mechanical work output per cycle, and this reduction in mass-specific work was greatest for smaller initial pennation angles. When we compared the effects of mass on the model tissue behaviour to that of in situ muscle with added mass during comparable work-loop trials, we found that greater mass led to lower maximum and higher minimum acceleration in the longitudinal (x) direction near the middle of the muscle compared to at the non-fixed end, which indicates that greater mass contributes to tissue non-uniformity in whole muscle. These comparable results for the simulated and in situ muscle also show that this modelling framework behaves in ways that are consistent with experimental muscle. Overall, the results of this study highlight that muscle mass is an important determinant of whole muscle behaviour. [ABSTRACT FROM AUTHOR]

Background: Vitamin D deficiency has been associated with type 1 diabetes in observational studies, but evidence from randomized controlled trials (RCTs) is lacking. The aim of this study was to test whether genetically decreased vitamin D levels are causally associated with type 1 diabetes using Mendelian randomization (MR). Methods and findings: For our two-sample MR study, we selected as instruments single nucleotide polymorphisms (SNPs) that are strongly associated with 25-hydroxyvitamin D (25OHD) levels in a large vitamin D genome-wide association study (GWAS) on 443,734 Europeans and obtained their corresponding effect estimates on type 1 diabetes risk from a large meta-analysis of 12 type 1 diabetes GWAS studies (Ntot = 24,063, 9,358 cases, and 15,705 controls). In addition to the main analysis using inverse variance weighted MR, we applied 3 additional methods to control for pleiotropy (MR-Egger, weighted median, and mode-based estimate) and compared the respective MR estimates. We also undertook sensitivity analyses excluding SNPs with potential pleiotropic effects. We identified 69 lead independent common SNPs to be genome-wide significant for 25OHD, explaining 3.1% of the variance in 25OHD levels. MR analyses suggested that a 1 standard deviation (SD) decrease in standardized natural log-transformed 25OHD (corresponding to a 29-nmol/l change in 25OHD levels in vitamin D–insufficient individuals) was not associated with an increase in type 1 diabetes risk (inverse-variance weighted (IVW) MR odds ratio (OR) = 1.09, 95% CI: 0.86 to 1.40, p = 0.48). We obtained similar results using the 3 pleiotropy robust MR methods and in sensitivity analyses excluding SNPs associated with serum lipid levels, body composition, blood traits, and type 2 diabetes. Our findings indicate that decreased vitamin D levels did not have a substantial impact on risk of type 1 diabetes in the populations studied. Study limitations include an inability to exclude the existence of smaller associations and a lack of evidence from non-European populations. Conclusions: Our findings suggest that 25OHD levels are unlikely to have a large effect on risk of type 1 diabetes, but larger MR studies or RCTs are needed to investigate small effects. Despoina Manousaki and co-workers investigate vitamin D levels and risk of type I diabetes. Author summary: Why was this study done?: Observational epidemiological studies have associated low vitamin D levels with risk of type 1 diabetes; however, these studies are susceptible to confounding and reverse causation, and thus it remains unclear whether these associations are accurate. To our knowledge, there are no randomized controlled trials published to date on this topic. If vitamin D insufficiency did cause type 1 diabetes, this would be of clinical relevance for type 1 diabetes prevention in high-risk individuals, since vitamin D insufficiency is common and safely correctable. What did researchers do and find?: We applied a Mendelian randomization study design to understand if vitamin D levels are associated with a higher risk of type 1 diabetes. This approach offers an alternative analytical technique able to reduce conventional patterns of confounding and reverse causation and reestimate observations in a framework allowing causal inference. Our study did not find evidence in support of a large effect of vitamin D levels on type 1 diabetes. However, the findings do not exclude the possibility that there may be smaller effects than we could not detect. What do these findings mean?: Our findings suggest that the previous epidemiological associations between vitamin D and type 1 diabetes could be due to confounding factors, such as latitude and exposure to sunlight. Our results do not support increasing vitamin D levels as a strategy to decrease the risk of type 1 diabetes. [ABSTRACT FROM AUTHOR]

In this study we examined how the strain energies within a muscle are related to changes in longitudinal force when the muscle is exposed to an external transverse load. We implemented a three-dimensional (3D) finite element model of contracting muscle using the principle of minimum total energy and allowing the redistribution of energy through different strain energy-densities. This allowed us to determine the importance of the strain energy-densities to the transverse forces developed by the muscle. We ran a series of in silica experiments on muscle blocks varying in initial pennation angle, muscle length, and external transverse load. As muscle contracts it maintains a near constant volume. As such, any changes in muscle length are balanced by deformations in the transverse directions such as muscle thickness or muscle width. Muscle develops transverse forces as it expands. In many situations external forces act to counteract these transverse forces and the muscle responds to external transverse loads while both passive and active. The muscle blocks used in our simulations decreased in thickness and pennation angle when passively compressed and pushed back on the load when they were activated. Activation of the compressed muscle blocks led either to an increase or decrease in muscle thickness depending on whether the initial pennation angle was less than or greater than 15°, respectively. Furthermore, the strain energy increased and redistributed across the different strain-energy potentials during contraction. The volumetric strain energy-density varied with muscle length and pennation angle and was reduced with greater transverse load for most initial muscle lengths and pennation angles. External transverse load reduced the longitudinal muscle force for initial pennation angles of β0 = 0°. Whereas for pennate muscle (β0 > 0°) longitudinal force changed (increase or decrease) depending on the muscle length, pennation angle and the direction of the external load relative to the muscle fibres. For muscle blocks with initial pennation angles β0 ≤ 20° the reduction in longitudinal muscle force coincided with a reduction in volumetric strain energy-density. [ABSTRACT FROM AUTHOR]

Background: Patients and clinicians can choose from several treatment options to address acute pain from non-low back, musculoskeletal injuries.Purpose: To assess the comparative effectiveness of outpatient treatments for acute pain from non-low back, musculoskeletal injuries by performing a network meta-analysis of randomized clinical trials (RCTs).Data Sources: MEDLINE, EMBASE, CINAHL, PEDro (Physiotherapy Evidence Database), and Cochrane Central Register of Controlled Trials to 2 January 2020.Study Selection: Pairs of reviewers independently identified interventional RCTs that enrolled patients presenting with pain of up to 4 weeks' duration from non-low back, musculoskeletal injuries.Data Extraction: Pairs of reviewers independently extracted data. Certainty of evidence was evaluated by using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach.Data Synthesis: The 207 eligible studies included 32 959 participants and evaluated 45 therapies. Ninety-nine trials (48%) enrolled populations with diverse musculoskeletal injuries, 59 (29%) included patients with sprains, 13 (6%) with whiplash, and 11 (5%) with muscle strains; the remaining trials included various injuries ranging from nonsurgical fractures to contusions. Topical nonsteroidal anti-inflammatory agents (NSAIDs) proved to have the greatest net benefit, followed by oral NSAIDs and acetaminophen with or without diclofenac. Effects of these agents on pain were modest (around 1 cm on a 10-cm visual analogue scale, approximating the minimal important difference). Regarding opioids, compared with placebo, acetaminophen plus an opioid improved intermediate pain (1 to 7 days) but not immediate pain (≤2 hours), tramadol was ineffective, and opioids increased the risk for gastrointestinal and neurologic harms (all moderate-certainty evidence).Limitations: Only English-language studies were included. The number of head-to-head comparisons was limited.Conclusion: Topical NSAIDs, followed by oral NSAIDs and acetaminophen with or without diclofenac, showed the most convincing and attractive benefit-harm ratio for patients with acute pain from non-low back, musculoskeletal injuries. No opioid achieved benefit greater than that of NSAIDs, and opioids caused the most harms.Primary Funding Source: National Safety Council. (PROSPERO: CRD42018094412). [ABSTRACT FROM AUTHOR]

This study of Canadian university teacher militancy explores the dynamics and strategies of resistance in the neoliberal university. While responses to the neoliberal reorientation of higher education are complex, uneven, and sometimes contradictory, the authors demonstrate how neoliberalization has fostered greater conflict, more militancy, more strikes, and greater politicization of unions representing university teachers. The authors argue that these expressions of university teacher militancy are primarily driven by external pressures rather than internal forces and are further complicated by divisions between workers within the context of established university hierarchies. [ABSTRACT FROM AUTHOR]

During contraction the energy of muscle tissue increases due to energy from the hydrolysis of ATP. This energy is distributed across the tissue as strain-energy potentials in the contractile elements, strain-energy potential from the 3D deformation of the base-material tissue (containing cellular and extracellular matrix effects), energy related to changes in the muscle's nearly incompressible volume and external work done at the muscle surface. Thus, energy is redistributed through the muscle's tissue as it contracts, with only a component of this energy being used to do mechanical work and develop forces in the muscle's longitudinal direction. Understanding how the strain-energy potentials are redistributed through the muscle tissue will help enlighten why the mechanical performance of whole muscle in its longitudinal direction does not match the performance that would be expected from the contractile elements alone. Here we demonstrate these physical effects using a 3D muscle model based on the finite element method. The tissue deformations within contracting muscle are large, and so the mechanics of contraction were explained using the principles of continuum mechanics for large deformations. We present simulations of a contracting medial gastrocnemius muscle, showing tissue deformations that mirror observations from magnetic resonance imaging. This paper tracks the redistribution of strain-energy potentials through the muscle tissue during fixed-end contractions, and shows how fibre shortening, pennation angle, transverse bulging and anisotropy in the stress and strain of the muscle tissue are all related to the interaction between the material properties of the muscle and the action of the contractile elements. [ABSTRACT FROM AUTHOR]

Purpose: Work-integrated learning (WIL) has emerged as a leading pedagogy that blends theory with application. In recent years, policymakers, educators and practitioners have called for a significant expansion of WIL, one which would enable every undergraduate student has at least one WIL experience during their program of study. Despite these appeals, there remains a significant divide between the aspiration of universality and the realities. Consequently, the study asks the following question: How can post-secondary institutions expand their WIL initiatives to universal levels that deliver transformative learning? Design/methodology/approach: In this exploratory study, the authors leverage research from entrepreneurship and management to develop a conceptual model of universal work-integrated learning (UWIL). Entrepreneurship and management research is relevant in this context, as the rapid introduction of a UWIL has transformative implications at the level of the individual (e.g. students, faculty), organization (e.g. processes) and the learning ecosystem (e.g. partners, policymakers) — issues at the core of research in entrepreneurship and management over the past two decades. Findings: At the core of the authors' proposal is the contention that the high-impact talent challenge and the delivery of UWIL must be reframed as not simply a challenge facing educators, but as a challenge facing the broader ecosystem of the workforce and the larger community. The authors propose the implementation of UWIL through an open innovation framework based on five strategic pillars. Originality/value: Ultimately, the findings the authors present here can be leveraged by all members of the learning ecosystem, including administrators, faculty, policymakers, accreditation bodies and community partners, as a framework for operationalizing a UWIL strategy. The study's model challenges all members of this learning ecosystem to operationalize a UWIL strategy. This entrepreneurial reframing introduces the potential for innovating the delivery of UWIL by leveraging the broader learning ecosystem to drive efficiencies and transformative learning. [ABSTRACT FROM AUTHOR]

Most replicated genetic determinants for type 1 diabetes are common (minor allele frequency [MAF] >5%). We aimed to identify novel rare or low-frequency (MAF <5%) single nucleotide polymorphisms with large effects on risk of type 1 diabetes. We undertook deep imputation of genotyped data followed by genome-wide association testing and meta-analysis of 9,358 type 1 diabetes case and 15,705 control subjects from 12 European cohorts. Candidate variants were replicated in a separate cohort of 4,329 case and 9,543 control subjects. Our meta-analysis identified 27 independent variants outside the MHC, among which 3 were novel and had MAF <5%. Three of these variants replicated with Preplication < 0.05 and Pcombined < Pdiscovery In silico analysis prioritized a rare variant at 2q24.3 (rs60587303 [C], MAF 0.5%) within the first intron of STK39, with an effect size comparable with those of common variants in the INS and PTPN22 loci (combined [from the discovery and replication cohorts] estimate of odds ratio [ORcombined] 1.97, 95% CI 1.58-2.47, Pcombined = 2.9 × 10-9). Pharmacological inhibition of Stk39 activity in primary murine T cells augmented effector responses through enhancement of interleukin 2 signaling. These findings provide insight into the genetic architecture of type 1 diabetes and have identified rare variants having a large effect on disease risk. [ABSTRACT FROM AUTHOR]