On the genes, genealogies, and geographies of Quebec.

Population genetic models only provide coarse representations of real-world ancestry. We used a pedigree compiled from 4 million parish records and genotype data from 2276 French and 20,451 French Canadian individuals to finely model and trace French Canadian ancestry through space and time. The loss of ancestral French population structure and the appearance of spatial and regional structure highlights a wide range of population expansion models. Geographic features shaped migrations, and we find enrichments for migration, genetic, and genealogical relatedness patterns within river networks across regions of Quebec. Finally, we provide a freely accessible simulated whole-genome sequence dataset with spatiotemporal metadata for 1,426,749 individuals reflecting intricate French Canadian population structure. Such realistic population-scale simulations provide opportunities to investigate population genetics at an unprecedented resolution.

Kinesiophobia and associated factors among patients with chronic non-specific low back pain.

PURPOSE: This study determined the association between kinesiophobia and age, body mass index, highest educational status, self-efficacy, pain intensity, and disability in chronic non-specific low back pain (CNSLBP) patients. Predictors of kinesiophobia were also assessed. METHODS: This cross-sectional design utilised 224 CNSLBP patients in tertiary hospitals in Nigeria. The Tampa Scale of Kinesiophobia, Oswestry Disability Index, Pain Self-Efficacy Questionnaire, and Numerical Pain Rating Scale were used to assess kinesiophobia, disability, self-efficacy, and pain intensity respectively. Spearman's correlation and multiple regression analysis determined the association between the variables of interest and the predictors of kinesiophobia, respectively. RESULTS: Most of the participants reported a high level of kinesiophobia (92%), low level of self-efficacy (68.8%), moderate pain intensity (58.0%), and moderate disability (57.1%). A significant positive weak correlation was observed between kinesiophobia and pain intensity (r = 0.138, p = 0.040). Gender, self-efficacy, pain intensity, and disability significantly predicted the extent of kinesiophobia (p < 0.05). CONCLUSION: The increased levels of kinesiophobia are a cause for concern and highlight the need for kinesiophobia and related factors to be closely monitored and incorporated into preventive and curative rehabilitation programmes for CNSLBP patients to minimise the negative impact on rehabilitation outcomes.Implications for RehabilitationPatients with chronic non-specific low back pain (CNSLBP) have high levels of kinesiophobia, which could predispose them to avoidance behaviours, physical inactivity, and deterioration of health, all of which, if not addressed, may result in poor rehabilitation outcomes, setting off a viscious cycle.Regular kinesiophobia assessments could indicate areas of rehabilitation concern, allowing health care providers to better target rehabilitation programs and improve rehabilitation outcomes.Pain severity, self-efficacy, and disability should be frequently assessed and included when planning rehabilitation programs, to reduce the detrimental impact on kinesiophobia.In patients with CNSLBP, graded exposure therapy to movement is necessary to prevent and reduce kinesiophobia, thereby increasing compliance during rehabilitation programs.

Prevalence, pattern and predictors of work-related musculoskeletal disorders among oil workers in Nigeria.

BACKGROUND: Work-related musculoskeletal disorders (WMSD) account for a loss of GDP in most countries. The oil sector is the largest and most economically relevant industry in Nigeria, yet the impact of WMSD on workers in this industry is unknown. OBJECTIVE: To assess the prevalence, pattern and predictors of WMSD among oil workers in Nigeria. METHODS: This exploratory study was conducted in oil producing companies in Nigeria. Nordic Musculoskeletal Questionnaire was used to assess WMSD, while risk factors and demographic variables were obtained through an interview. Obtained data were analysed using descriptive statistics, Chi-square and logistic regression at α=0.05RESULTS:A total of 198 (138 male, 60 female) oil workers aged 40.3±10.1 years participated in this study. The prevalence of WMSD was 88.8%, and was most common around the low-back (51.5%), and neck (44.4%) regions. There was a significant association between WMSD and each of duration of service (X2 = 45.44, p = 0.020), awkward neck postures at work (X2 = 12.46, p = 0.006), inadequate training on injury prevention (X2 = 11.98, p = 0.007), and continuing to work while feeling discomfort (X2 = 10.83, p = 0.013). Post-hoc analysis revealed that being a male oil worker (OR = 1.17, p = 0.037) and continuing to work while feeling discomfort or pain (OR = 2.23, p = 0.048) were the significant predictors of WMSD. CONCLUSIONS: Approximately nine in every ten oil workers in Nigeria have a WMSD. Male gender and work persistence amidst discomfort or pain are the predictors of WMSD among oil workers in Nigeria. Ergonomics training and evaluation programme is recommended for workers in this industry.

Efficient ancestry and mutation simulation with msprime 1.0.

Stochastic simulation is a key tool in population genetics, since the models involved are often analytically intractable and simulation is usually the only way of obtaining ground-truth data to evaluate inferences. Because of this, a large number of specialized simulation programs have been developed, each filling a particular niche, but with largely overlapping functionality and a substantial duplication of effort. Here, we introduce msprime version 1.0, which efficiently implements ancestry and mutation simulations based on the succinct tree sequence data structure and the tskit library. We summarize msprime's many features, and show that its performance is excellent, often many times faster and more memory efficient than specialized alternatives. These high-performance features have been thoroughly tested and validated, and built using a collaborative, open source development model, which reduces duplication of effort and promotes software quality via community engagement.

Ergonomic assessment of work-related musculoskeletal disorder and its determinants among commercial mini bus drivers and driver assistants (mini bus conductors) in Nigeria.

INTRODUCTION: Work-related musculoskeletal disorder (WMSD) is a leading causes of occupational injury and disability among drivers and workers in the transport industry. This study evaluated the ergonomically assessed WMSD and its determinants among Nigerian commercial mini bus drivers (BD) and mini bus conductors (BC). METHOD: A total of 379 participants (BD = 200, BC = 179) were purposively sampled for this exploratory cross-sectional study. Participants' WMSD and work related variables were respectively assessed using the standardized Nordic questionnaire and a content-validated, Driving Work Station Assessment (DWSA) form. Data were analyzed descriptively and inferentially using chi-square and logistic regression. The level of significance was set at α = 0.05. RESULTS: The participants were aged between 20 and 66 years, with a mean age of 33.26±10.76years (BD = 38.42±10.22years, BC = 27.50±8.13years); most of whom consumed alcohol (84.4%) and experienced severe job stress (73.4%). There was a high prevalence (95.8%; BD = 94.5%, BC = 97.8%) of WMSDs, the lower back (66.8%) and upper back (54.1%) had the highest regional prevalence of WMSD. The BC (BC vs BD) had significantly (p<0.05) higher prevalence of Neck (47.7% vs 21.5%) and upper back (80.4% vs 30.5%) WMSDs. Conversely, the BD (BD vs BC) had significantly (p<0.05) higher prevalence of low-back (85.0% vs 46.4%), knee (25.0% vs 9.5%), elbow (11.5% vs 3.9%), and wrist (10.5% vs 3.4%) WMSD. There was a significant association between WMSD and each of work duration (X2 = 11.634, p = 0.009), work frequency (X2 = 8.394, p = 0.039), job dissatisfaction (X2 = 10.620, p = 0.001) and job stress (X2 = 16.879, p = 0.001). Working beyond 4days/week (OR = 10.019, p = 0.001), job dissatisfaction (OR = 1.990, p = 0.031), constrained working postures (OR = 5.324, p = 0.003) and fatigue (OR = 4.719, p = 0.002) were the predictors of WMSD. CONCLUSION: Job stress, work duration and work frequency, posture and fatigue are important determinants of WMSDs among mini bus drivers and their assistants in Nigeria. Ergonomics training intervention for this population is recommended.

Lessons Learned from Bugs in Models of Human History.

Simulation plays a central role in population genomics studies. Recent years have seen rapid improvements in software efficiency that make it possible to simulate large genomic regions for many individuals sampled from large numbers of populations. As the complexity of the demographic models we study grows, however, there is an ever-increasing opportunity to introduce bugs in their implementation. Here, we describe two errors made in defining population genetic models using the msprime coalescent simulator that have found their way into the published record. We discuss how these errors have affected downstream analyses and give recommendations for software developers and users to reduce the risk of such errors.

Prevalence of work-related musculoskeletal symptoms and associated risk factors among domestic gas workers and staff of works department in Enugu, Nigeria: a cross-sectional study.

BACKGROUND: The impact of work-related musculoskeletal symptoms (WMSS) permeates various occupations. OBJECTIVE: To compare WMSS and associated risk factors among domestic gas workers (DGWs) and staff of Works Department (SWD) in Enugu. METHODS: One-hundred adults (DGW = 50, SWD = 50) participated in this cross-sectional study. The Nordic Musculoskeletal Questionnaire and a demographics questionnaire were used to assess the prevalence of WMSS and related risk factors. Data were analysed using independent t-test or Mann-Whitney U, chi-square, and logistic regression at p < 0.05. RESULTS: The DGWs (86%) had a significantly (χ2 = 24.45, p < 0.001) higher WMSS than the SWD (38%). Lower-back (54%) and shoulder (52%) were the most affected body parts among the DGWs in comparison to the hips/thighs (20%) among the SWD. Work-related factors such as daily work-duration (χ2 = 75.44, p < 0.001), lifting training (χ2 = 96.24, p < 0.001), and use of personal protective equipment (PPE) of facemask (χ2 = 100.0, p < 0.001) and gloves (χ2 = 96.09, p < 0.001) were significantly associated with general WMSS among the DGWs. However, diastolic blood pressure (DBP) (OR = 1.29, p = 0.018), work duration > 8 h/day (OR = 0.001, p = 0.028), female gender (OR = 6.98-10.26, p < 0.05), sleep duration < 6 h/day (OR = 0.56-0.73, p < 0.05) and poor exercise behaviour (OR = 0.15, p = 0.013) were the identified independent risk factors of WMSS among DGWs, while DBP (OR = 0.99, p = 0.012) and female gender (OR = 6.47, p = 0.032) were the only identified independent risk factors for SWD. CONCLUSION: WMSS is significantly higher among DGWs than the SWD. High DBP, female gender, working beyond 8 h per day, sleeping less than 6 h per day, and insufficient exercise increase the risks of WMSDs, especially among the DGWs. To mitigate the adverse effects of WMSDs, SWD and DGWs require break and leave periods, PPE and assistive devices, exercise, medical check-up, and workplace ergonomics.

Pragmatic Solutions for Stroke Recovery and Improved Quality of Life in Low- and Middle-Income Countries-A Systematic Review.

Background: Given the limited healthcare resources in low and middle income countries (LMICs), effective rehabilitation strategies that can be realistically adopted in such settings are required. Objective: A systematic review of literature was conducted to identify pragmatic solutions and outcomes capable of enhancing stroke recovery and quality of life of stroke survivors for low- and middle- income countries. Methods: PubMed, HINARI, and Directory of Open Access Journals databases were searched for published Randomized Controlled Trials (RCTs) till November 2018. Only completed trials published in English with non-pharmacological interventions on adult stroke survivors were included in the review while published protocols, pilot studies and feasibility analysis of trials were excluded. Obtained data were synthesized thematically and descriptively analyzed. Results: One thousand nine hundred and ninety six studies were identified while 347 (65.22% high quality) RCTs were found to be eligible for the review. The most commonly assessed variables (and outcome measure utility) were activities of daily living [75.79% of the studies, with Barthel Index (37.02%)], motor function [66.57%; with Fugl Meyer scale (71.88%)], and gait [31.12%; with 6 min walk test (38.67%)]. Majority of the innovatively high technology interventions such as robot therapy (95.24%), virtual reality (94.44%), transcranial direct current stimulation (78.95%), transcranial magnetic stimulation (88.0%) and functional electrical stimulation (85.00%) were conducted in high income countries. Several traditional and low-cost interventions such as constraint-induced movement therapy (CIMT), resistant and aerobic exercises (R&AE), task oriented therapy (TOT), body weight supported treadmill training (BWSTT) were reported to significantly contribute to the recovery of motor function, activity, participation, and improvement of quality of life after stroke. Conclusion: Several pragmatic, in terms of affordability, accessibility and utility, stroke rehabilitation solutions, and outcome measures that can be used in resource-limited settings were found to be effective in facilitating and enhancing post-stroke recovery and quality of life.

Accounting for long-range correlations in genome-wide simulations of large cohorts.

Coalescent simulations are widely used to examine the effects of evolution and demographic history on the genetic makeup of populations. Thanks to recent progress in algorithms and data structures, simulators such as the widely-used msprime now provide genome-wide simulations for millions of individuals. However, this software relies on classic coalescent theory and its assumptions that sample sizes are small and that the region being simulated is short. Here we show that coalescent simulations of long regions of the genome exhibit large biases in identity-by-descent (IBD), long-range linkage disequilibrium (LD), and ancestry patterns, particularly when the sample size is large. We present a Wright-Fisher extension to msprime, and show that it produces more realistic distributions of IBD, LD, and ancestry proportions, while also addressing more subtle biases of the coalescent. Further, these extensions are more computationally efficient than state-of-the-art coalescent simulations when simulating long regions, including whole-genome data. For shorter regions, efficiency can be maintained via a hybrid model which simulates the recent past under the Wright-Fisher model and uses coalescent simulations in the distant past.

Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons.

We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.

Inferring Transmission Histories of Rare Alleles in Population-Scale Genealogies.

Learning the transmission history of alleles through a family or population plays an important role in evolutionary, demographic, and medical genetic studies. Most classical models of population genetics have attempted to do so under the assumption that the genealogy of a population is unavailable and that its idiosyncrasies can be described by a small number of parameters describing population size and mate choice dynamics. Large genetic samples have increased sensitivity to such modeling assumptions, and large-scale genealogical datasets become a useful tool to investigate realistic genealogies. However, analyses in such large datasets are often intractable using conventional methods. We present an efficient method to infer transmission paths of rare alleles through population-scale genealogies. Based on backward-time Monte Carlo simulations of genetic inheritance, we use an importance sampling scheme to dramatically speed up convergence. The approach can take advantage of available genotypes of subsets of individuals in the genealogy including haplotype structure as well as information about the mode of inheritance and general prevalence of a mutation or disease in the population. Using a high-quality genealogical dataset of more than three million married individuals in the Quebec founder population, we apply the method to reconstruct the transmission history of chronic atrial and intestinal dysrhythmia (CAID), a rare recessive disease. We identify the most likely early carriers of the mutation and geographically map the expected carrier rate in the present-day French-Canadian population of Quebec.

Genomic Insights into the Ancestry and Demographic History of South America.

South America has a complex demographic history shaped by multiple migration and admixture events in pre- and post-colonial times. Settled over 14,000 years ago by Native Americans, South America has experienced migrations of European and African individuals, similar to other regions in the Americas. However, the timing and magnitude of these events resulted in markedly different patterns of admixture throughout Latin America. We use genome-wide SNP data for 437 admixed individuals from 5 countries (Colombia, Ecuador, Peru, Chile, and Argentina) to explore the population structure and demographic history of South American Latinos. We combined these data with population reference panels from Africa, Asia, Europe and the Americas to perform global ancestry analysis and infer the subcontinental origin of the European and Native American ancestry components of the admixed individuals. By applying ancestry-specific PCA analyses we find that most of the European ancestry in South American Latinos is from the Iberian Peninsula; however, many individuals trace their ancestry back to Italy, especially within Argentina. We find a strong gradient in the Native American ancestry component of South American Latinos associated with country of origin and the geography of local indigenous populations. For example, Native American genomic segments in Peruvians show greater affinities with Andean indigenous peoples like Quechua and Aymara, whereas Native American haplotypes from Colombians tend to cluster with Amazonian and coastal tribes from northern South America. Using ancestry tract length analysis we modeled post-colonial South American migration history as the youngest in Latin America during European colonization (9-14 generations ago), with an additional strong pulse of European migration occurring between 3 and 9 generations ago. These genetic footprints can impact our understanding of population-level differences in biomedical traits and, thus, inform future medical genetic studies in the region.

A geometric comparison of single chain multi-state models of ion channel gating.

Multi-state models of ion channel gating have been used extensively, but choosing optimally small yet sufficiently complex models to describe particular experimental data remains a difficult task. In order to provide some insight into appropriate model selection, this paper presents some basic results about the behavior of solutions of multi-state models, particularly those arranged in a chain formation. Some properties of the eigenvalues and eigenvectors of constant-rate multi-state models are presented. A geometric description of a three-state chain is given and, in particular, differences between a chain equivalent to an Hodgkin-Huxley model and a chain with identical rates are analyzed. One distinguishing feature between these two types of systems is that decay from the open state in the Hodgkin-Huxley model is dominated by the most negative eigenvalue while the identical rate chain displays a mix of modes over all eigenvalues.

Chromatin decondensation and nuclear reprogramming by nucleoplasmin.

Somatic cell nuclear cloning has repeatedly demonstrated striking reversibility of epigenetic regulation of cell differentiation. Upon injection into eggs, the donor nuclei exhibit global chromatin decondensation, which might contribute to reprogramming the nuclei by derepressing dormant genes. Decondensation of sperm chromatin in eggs is explained by the replacement of sperm-specific histone variants with egg-type histones by the egg protein nucleoplasmin (Npm). However, little is known about the mechanisms of chromatin decondensation in somatic nuclei that do not contain condensation-specific histone variants. Here we found that Npm could widely decondense chromatin in undifferentiated mouse cells without overt histone exchanges but with specific epigenetic modifications that are relevant to open chromatin structure. These modifications included nucleus-wide multiple histone H3 phosphorylation, acetylation of Lys 14 in histone H3, and release of heterochromatin proteins HP1beta and TIF1beta from the nuclei. The protein kinase inhibitor staurosporine inhibited chromatin decondensation and these epigenetic modifications with the exception of H3 acetylation, potentially linking these chromatin events. At the functional level, Npm pretreatment of mouse nuclei facilitated activation of four oocyte-specific genes from the nuclei injected into Xenopus laevis oocytes. Future molecular elucidation of chromatin decondensation by Npm will significantly contribute to our understanding of the plasticity of cell differentiation.

Requirement of the protein B23 for nucleolar disassembly induced by the FRGY2a family proteins.

In Xenopus somatic cell nuclear cloning, the nucleoli of donor nuclei rapidly and almost completely disappear in egg cytoplasm. We previously showed that the germ cell-specific proteins FRGY2a and FRGY2b were responsible for this unusually drastic nucleolar disassembly. The nucleolar disassembly occurs without inhibition of pre-rRNA transcription, a well known trigger for nucleolar segregation, and the mechanism for the nucleolar disassembly by FRGY2a and FRGY2b remains largely unknown. In this study, we searched for FRGY2a-interacting proteins and investigated the functional consequences of their interactions through a series of experiments. We showed that during the nucleolar disassembly, FRGY2a localized to the nucleoli of isolated nuclei and was capable of disassembling purified nucleoli, suggesting a direct interaction between FRGY2a and nucleolar components. Using a His tag pulldown approach, we identified the abundant and multifunctional nucleolar protein B23 as a potential target of FRGY2a and its related human protein YB1. A specific interaction between FRGY2a/YB1 and B23 was confirmed by co-immunoprecipitation. Finally, B23 knockdown using short interfering RNA and a subsequent add-back experiment confirmed that B23 was necessary for nucleolar disassembly by YB1. We propose that FRGY2a and YB1 disassemble nucleoli by sequestering B23, which is associated with pre-ribosomes and other structurally important nucleolar components.