Daily Associations between Salivary Cortisol and EEG-Assessed Sleep: A 15-Day Intensive Longitudinal Study.

STUDY OBJECTIVES: Current evidence suggests that cortisol levels are bi-directionally associated with sleep. However, the daily, naturalistic cortisol-sleep associations remain unclear, as current evidence is mostly cross-sectional. This study tested whether pre-sleep cortisol predicts sleep duration and quality, and whether these sleep parameters predict the following day's diurnal cortisol slope using a 15-day intensive longitudinal design with electroencephalographic measures and saliva sampling. METHODS: Ninety-five young adults (Mage=20.48±1.59 years) provided saliva samples at awakening and pre-sleep over 14 consecutive days, providing 2,345 samples (85% viable). The Z-Machine Insight+ was used to record over 900 nights of total sleep time (TST) and sleep efficiency (SE). Multilevel models tested these data at the between- and within-person levels. RESULTS: Higher pre-sleep cortisol predicted shorter TST (p<.001) and lower SE (p<.001) at the within-person level. Individuals with shorter average TST (p =.007) or lower average SE (p<.001) had flatter diurnal cortisol slope, compared to those with longer average TST or higher average SE. Follow up analyses showed that individuals with shorter average TST (vs. longer average TST) had higher pre-sleep cortisol levels (p=.01). CONCLUSION: Our findings provide evidence that pre-sleep cortisol is associated with sleep duration and quality at the within-individual level. Furthermore, individuals with short or poor sleep had flatter diurnal cortisol slope. Although the effect sizes are small, these findings show the naturalistic associations between sleep and cortisol in a relatively healthy sample. These findings suggest that sleep maintains the regulation of the stress-response system, which is protective against mental and physical disorders.

NeuroMechanics: Electrophysiological and computational methods to accurately estimate the neural drive to muscles in humans in vivo.

The ultimate neural signal for muscle control is the neural drive sent from the spinal cord to muscles. This neural signal comprises the ensemble of action potentials discharged by the active spinal motoneurons, which is transmitted to the innervated muscle fibres to generate forces. Accurately estimating the neural drive to muscles in humans in vivo is challenging since it requires the identification of the activity of a sample of motor units (MUs) that is representative of the active MU population. Current electrophysiological recordings usually fail in this task by identifying small MU samples with over-representation of higher-threshold with respect to lower-threshold MUs. Here, we describe recent advances in electrophysiological methods that allow the identification of more representative samples of greater numbers of MUs than previously possible. This is obtained with large and very dense arrays of electromyographic electrodes. Moreover, recently developed computational methods of data augmentation further extend experimental MU samples to infer the activity of the full MU pool. In conclusion, the combination of new electrode technologies and computational modelling allows for an accurate estimate of the neural drive to muscles and opens new perspectives in the study of the neural control of movement and in neural interfacing.

Power Analysis for Human Melatonin Suppression Experiments.

In humans, the nocturnal secretion of melatonin by the pineal gland is suppressed by ocular exposure to light. In the laboratory, melatonin suppression is a biomarker for this neuroendocrine pathway. Recent work has found that individuals differ substantially in their melatonin-suppressive response to light, with the most sensitive individuals being up to 60 times more sensitive than the least sensitive individuals. Planning experiments with melatonin suppression as an outcome needs to incorporate these individual differences, particularly in common resource-limited scenarios where running within-subjects studies at multiple light levels is costly and resource-intensive and may not be feasible with respect to participant compliance. Here, we present a novel framework for virtual laboratory melatonin suppression experiments, incorporating a Bayesian statistical model. We provide a Shiny web app for power analyses that allows users to modify various experimental parameters (sample size, individual-level heterogeneity, statistical significance threshold, light levels), and simulate a systematic shift in sensitivity (e.g., due to a pharmacological or other intervention). Our framework helps experimenters to design compelling and robust studies, offering novel insights into the underlying biological variability in melatonin suppression relevant for practical applications.

Regular follow-up with cervical cytology is of questionable value following surgical treatment of microinvasive cervical cancer.

OBJECTIVES: To assess the follow-up smears and their outcomes of patients with conservatively managed early-stage cervical cancer as per UK guidelines within our service. To evaluate whether intensive follow-up can detect pre-cancer early compared to the standard 3 yearly follow-up. STUDY DESIGN: Retrospective review. METHODS: All patients treated for early stage (stage 1A1 and 1A2) with cervical cancer from 01/2002 to 01/2020 at University Hospitals of Derby and Burton were included. Patients who had initial hysterectomy were excluded from our analysis. Review conducted using electronic patient records for treatment, histology, and follow-up smears. Number of abnormal follow-up smears and number of recurrent cervical cancers were considered the main outcome measures. RESULTS: 98 cases were identified. 81 (82.65 %) were stage 1A1 and 17 (17.35 %) were stage 1A2. 74 (75.51 %) patients had squamous histology and 24 (24.49 %) had adenocarcinomas. Median follow-up was 11.08 years (4043 days). 510 follow-up smears were performed, of which 33 (6.47 %) were abnormal. 5 of these abnormal smears showed low grade dyskaryosis (0.98 %) and 2 smears showed high grade dyskaryosis (0.39 %). The positive predictive value of follow-up smears to detect pre-cancerous changes was 5.71 %. There were no recurrent cancers detected. CONCLUSIONS: Microinvasive cervical cancer is effectively managed with conservative surgery. There were no recurrent cancers detected in our cohort during follow-up and there were only 2 high grade dyskaryoses detected (n = 2/510, 0.39 %). We therefore believe that reducing the intensity of follow up of these patients should be considered.

Hybrid immunity and SARS-CoV-2 antibodies: results of the HEROES-RECOVER prospective cohort study.

BACKGROUND: There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (SARS-CoV-2 infection or COVID-19 vaccination). From a cohort of health care personnel, first responders, and other frontline workers in six US states, we examined heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels. METHODS: Exposures included event-count (sum of infections and vaccine doses) and event-order, categorized into seven permutations of vaccination and/or infection. Outcome was level of serum binding antibodies against receptor binding domain (RBD) of the ancestral SARS-CoV-2 spike protein (total RBD-binding Ig), measured by enzyme-linked immunosorbent assay. Mean antibody levels were examined up to 365 days after each of the 1st-7th events. RESULTS: Analysis included 5,793 participants measured from August 7, 2020 to April 15, 2023. Hybrid immunity from infection before one or two vaccine doses elicited modestly superior antibody responses after the 2nd and 3rd events (compared to infections or vaccine-doses alone). This superiority was not evident after the 4th and 5th events (additional doses). Among adults infected before vaccination, adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were 1.23 (1.14-1.33), 1.09 (1.03-1.14), 0.87 (0.81-0.94), and 0.99 (0.85-1.15) after the 2nd-5th events, respectively. Post-vaccination infections elicited superior responses: adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were: 0.93 (0.75-1.17), 1.11 (1.06-1.16), 1.17 (1.11-1.24), and 1.20 (1.07-1.34) after the 2nd-5th events, respectively. CONCLUSIONS AND RELEVANCE: Findings reflecting heterogeneity in antibody levels by permutations of infection and vaccination history could inform COVID-19 vaccination policy.

Accurate detection of acute sleep deprivation using a metabolomic biomarker-A machine learning approach.

Sleep deprivation enhances risk for serious injury and fatality on the roads and in workplaces. To facilitate future management of these risks through advanced detection, we developed and validated a metabolomic biomarker of sleep deprivation in healthy, young participants, across three experiments. Bi-hourly plasma samples from 2 × 40-hour extended wake protocols (for train/test models) and 1 × 40-hour protocol with an 8-hour overnight sleep interval were analyzed by untargeted liquid chromatography-mass spectrometry. Using a knowledge-based machine learning approach, five consistently important variables were used to build predictive models. Sleep deprivation (24 to 38 hours awake) was predicted accurately in classification models [versus well-rested (0 to 16 hours)] (accuracy = 94.7%/AUC 99.2%, 79.3%/AUC 89.1%) and to a lesser extent in regression (R2 = 86.1 and 47.8%) models for within- and between-participant models, respectively. Metabolites were identified for replicability/future deployment. This approach for detecting acute sleep deprivation offers potential to reduce accidents through "fitness for duty" or "post-accident analysis" assessments.

Longitudinal parental perception of COVID-19 vaccines for children in a multi-site, cohort study.

OBJECTIVES: Pediatric COVID-19 vaccine hesitancy and uptake is not well understood. Among parents of a prospective cohort of children aged 6 months-17 years, we assessed COVID-19 vaccine knowledge, attitudes, and practices (KAP), and uptake over 15 months. METHODS: The PROTECT study collected sociodemographic characteristics of children at enrollment and COVID-19 vaccination data and parental KAPs quarterly. Univariable and multivariable logistic regression models were used to test the effect of KAPs on vaccine uptake; McNemar's test for paired samples was used to evaluate KAP change over time. RESULTS: A total of 2,837 children were enrolled, with more than half (61 %) vaccinated by October 2022. Positive parental beliefs about vaccine safety and effectiveness strongly predicted vaccine uptake among children aged 5-11 years (aOR 13.1, 95 % CI 8.5-20.4 and aOR 6.4, 95 % CI 4.3-9.6, respectively) and children aged 12+ years (aOR 7.0, 95 % CI 3.8-13.0 and aOR 8.9, 95 % CI 4.4-18.0). Compared to enrollment, at follow-up parents (of vaccinated and unvaccinated children) reported higher self-assessed vaccine knowledge, but more negative beliefs towards vaccine safety, effectiveness, and trust in government. Parents unlikely to vaccinate their children at enrollment reported more positive beliefs on vaccine knowledge, safety, and effectiveness at follow-up. CONCLUSION: The PROTECT cohort allows for an examination of factors driving vaccine uptake and how beliefs about COVID-19 and the COVID-19 vaccines change over time. Findings of the current analysis suggest that these beliefs change over time and policies aiming to increase vaccine uptake should focus on vaccine safety and effectiveness.

Genome-wide association analysis of composite sleep health scores in 413,904 individuals.

Recent genome-wide association studies (GWASs) of several individual sleep traits have identified hundreds of genetic loci, suggesting diverse mechanisms. Moreover, sleep traits are moderately correlated, and together may provide a more complete picture of sleep health, while also illuminating distinct domains. Here we construct novel sleep health scores (SHSs) incorporating five core self-report measures: sleep duration, insomnia symptoms, chronotype, snoring, and daytime sleepiness, using additive (SHS-ADD) and five principal components-based (SHS-PCs) approaches. GWASs of these six SHSs identify 28 significant novel loci adjusting for multiple testing on six traits (p<8.3e-9), along with 341 previously reported loci (p<5e-08). The heritability of the first three SHS-PCs equals or exceeds that of SHS-ADD (SNP-h2=0.094), while revealing sleep-domain-specific genetic discoveries. Significant loci enrich in multiple brain tissues and in metabolic and neuronal pathways. Post GWAS analyses uncover novel genetic mechanisms underlying sleep health and reveal connections to behavioral, psychological, and cardiometabolic traits.

Effectiveness of Bivalent mRNA COVID-19 Vaccines in Preventing SARS-CoV-2 Infection in Children and Adolescents Aged 5 to 17 Years.

Importance: Bivalent mRNA COVID-19 vaccines were recommended in the US for children and adolescents aged 12 years or older on September 1, 2022, and for children aged 5 to 11 years on October 12, 2022; however, data demonstrating the effectiveness of bivalent COVID-19 vaccines are limited. Objective: To assess the effectiveness of bivalent COVID-19 vaccines against SARS-CoV-2 infection and symptomatic COVID-19 among children and adolescents. Design, Setting, and Participants: Data for the period September 4, 2022, to January 31, 2023, were combined from 3 prospective US cohort studies (6 sites total) and used to estimate COVID-19 vaccine effectiveness among children and adolescents aged 5 to 17 years. A total of 2959 participants completed periodic surveys (demographics, household characteristics, chronic medical conditions, and COVID-19 symptoms) and submitted weekly self-collected nasal swabs (irrespective of symptoms); participants submitted additional nasal swabs at the onset of any symptoms. Exposure: Vaccination status was captured from the periodic surveys and supplemented with data from state immunization information systems and electronic medical records. Main Outcome and Measures: Respiratory swabs were tested for the presence of the SARS-CoV-2 virus using reverse transcriptase-polymerase chain reaction. SARS-CoV-2 infection was defined as a positive test regardless of symptoms. Symptomatic COVID-19 was defined as a positive test and 2 or more COVID-19 symptoms within 7 days of specimen collection. Cox proportional hazards models were used to estimate hazard ratios for SARS-CoV-2 infection and symptomatic COVID-19 among participants who received a bivalent COVID-19 vaccine dose vs participants who received no vaccine or monovalent vaccine doses only. Models were adjusted for age, sex, race, ethnicity, underlying health conditions, prior SARS-CoV-2 infection status, geographic site, proportion of circulating variants by site, and local virus prevalence. Results: Of the 2959 participants (47.8% were female; median age, 10.6 years [IQR, 8.0-13.2 years]; 64.6% were non-Hispanic White) included in this analysis, 25.4% received a bivalent COVID-19 vaccine dose. During the study period, 426 participants (14.4%) had laboratory-confirmed SARS-CoV-2 infection. Among these 426 participants, 184 (43.2%) had symptomatic COVID-19, 383 (89.9%) were not vaccinated or had received only monovalent COVID-19 vaccine doses (1.38 SARS-CoV-2 infections per 1000 person-days), and 43 (10.1%) had received a bivalent COVID-19 vaccine dose (0.84 SARS-CoV-2 infections per 1000 person-days). Bivalent vaccine effectiveness against SARS-CoV-2 infection was 54.0% (95% CI, 36.6%-69.1%) and vaccine effectiveness against symptomatic COVID-19 was 49.4% (95% CI, 22.2%-70.7%). The median observation time after vaccination was 276 days (IQR, 142-350 days) for participants who received only monovalent COVID-19 vaccine doses vs 50 days (IQR, 27-74 days) for those who received a bivalent COVID-19 vaccine dose. Conclusion and Relevance: The bivalent COVID-19 vaccines protected children and adolescents against SARS-CoV-2 infection and symptomatic COVID-19. These data demonstrate the benefit of COVID-19 vaccine in children and adolescents. All eligible children and adolescents should remain up to date with recommended COVID-19 vaccinations.

Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

The changes in health service utilisation in Malawi during the COVID-19 pandemic.

INTRODUCTION: The COVID-19 pandemic and the restriction policies implemented by the Government of Malawi may have disrupted routine health service utilisation. We aimed to find evidence for such disruptions and quantify any changes by service type and level of health care. METHODS: We extracted nationwide routine health service usage data for 2015-2021 from the electronic health information management systems in Malawi. Two datasets were prepared: unadjusted and adjusted; for the latter, unreported monthly data entries for a facility were filled in through systematic rules based on reported mean values of that facility or facility type and considering both reporting rates and comparability with published data. Using statistical descriptive methods, we first described the patterns of service utilisation in pre-pandemic years (2015-2019). We then tested for evidence of departures from this routine pattern, i.e., service volume delivered being below recent average by more than two standard deviations was viewed as a substantial reduction, and calculated the cumulative net differences of service volume during the pandemic period (2020-2021), in aggregate and within each specific facility. RESULTS: Evidence of disruptions were found: from April 2020 to December 2021, services delivered of several types were reduced across primary and secondary levels of care-including inpatient care (-20.03% less total interactions in that period compared to the recent average), immunisation (-17.61%), malnutrition treatment (-34.5%), accidents and emergency services (-16.03%), HIV (human immunodeficiency viruses) tests (-27.34%), antiretroviral therapy (ART) initiations for adults (-33.52%), and ART treatment for paediatrics (-41.32%). Reductions of service volume were greatest in the first wave of the pandemic during April-August 2020, and whereas some service types rebounded quickly (e.g., outpatient visits from -17.7% to +3.23%), many others persisted at lower level through 2021 (e.g., under-five malnutrition treatment from -15.24% to -42.23%). The total reduced service volume between April 2020 and December 2021 was 8 066 956 (-10.23%), equating to 444 units per 1000 persons. CONCLUSION: We have found substantial evidence for reductions in health service delivered in Malawi during the COVID-19 pandemic which may have potential health consequences, the effect of which should inform how decisions are taken in the future to maximise the resilience of healthcare system during similar events.

Teaching biologics design using molecular modeling and simulations.

Teaching chemistry and biology students about biologics design remains challenging despite its increasing importance in pharmaceutical development. Monoclonal antibodies, commonly called mAbs, are the most popular biologics. They have been developed into drugs to treat various diseases in the past decades. Multiple challenges exist for designing proper formulations to stabilize mAbs, such as preventing aggregation and mitigating viscosity. Molecular modeling and simulations can improve pharmaceutical products by examining the interactions between mAbs and other compounds, such as excipients. To introduce students to biopharmaceuticals, eight students at the Stevens Institute of Technology participated in a semester-long course to learn the challenges of pharmaceutical development and different computational skills to study biologics design. The students started with a limited background in this field. Throughout one semester, they were introduced to various literature and software tools for modeling antibodies and studying their interactions with excipients. This paper aims to develop a course structure to be replicated at other universities and institutions to teach biopharmaceutical development to students.

Effects of the COVID-19 pandemic on the outcomes of HIV-exposed neonates: a Zimbabwean tertiary hospital experience.

INTRODUCTION: The COVID-19 pandemic has globally impacted health service access, delivery and resources. There are limited data regarding the impact on the prevention of mother to child transmission (PMTCT) service delivery in low-resource settings. Neotree ( www.neotree.org ) combines data collection, clinical decision support and education to improve care for neonates. Here we evaluate impacts of COVID-19 on care for HIV-exposed neonates. METHODS: Data on HIV-exposed neonates admitted to the neonatal unit (NNU) at Sally Mugabe Central Hospital, Zimbabwe, between 01/06/2019 and 31/12/2021 were analysed, with pandemic start defined as 21/03/2020 and periods of industrial action (doctors (September 2019-January 2020) and nurses (June 2020-September 2020)) included, resulting in modelling during six time periods: pre-doctors' strike (baseline); doctors' strike; post-doctors' strike and pre-COVID; COVID and pre-nurses' strike; nurses' strike; post nurses' strike. Interrupted time series models were used to explore changes in indicators over time. RESULTS: Of 8,333 neonates admitted to the NNU, 904 (11%) were HIV-exposed. Mothers of 706/765 (92%) HIV-exposed neonates reported receipt of antiretroviral therapy (ART) during pregnancy. Compared to the baseline period when average admissions were 78 per week (95% confidence interval (CI) 70-87), significantly fewer neonates were admitted during all subsequent periods until after the nurses' strike, with the lowest average number during the nurses' strike (28, 95% CI 23-34, p < 0.001). Across all time periods excluding the nurses strike, average mortality was 20% (95% CI 18-21), but rose to 34% (95% CI 25, 46) during the nurses' strike. There was no evidence for heterogeneity (p > 0.22) in numbers of admissions or mortality by HIV exposure status. Fewer HIV-exposed neonates received a PCR test during the pandemic (23%) compared to the pre-pandemic periods (40%) (RR 0.59, 95% CI 0.41-0.84, p < 0.001). The proportion of HIV-exposed neonates who received antiretroviral prophylaxis during admission was high throughout, averaging between 84% and 95% in each time-period. CONCLUSION: While antiretroviral prophylaxis for HIV-exposed neonates remained high throughout, concerning data on low admissions and increased mortality, similar in HIV-exposed and unexposed neonates, and reduced HIV testing, suggest some aspects of care may have been compromised due to indirect effects of the pandemic.

The interrelationships between sleep regularity, obstructive sleep apnea, and hypertension in a middle-aged community population.

STUDY OBJECTIVES: Little is known about the interrelationships between sleep regularity, obstructive sleep apnea (OSA) and important health markers. This study examined whether irregular sleep is associated with OSA and hypertension, and if this modifies the known association between OSA and hypertension. METHODS: Six hundred and two adults (age mean(SD) = 56.96(5.51) years, female = 60%) from the Raine Study who were not evening or night shift workers were assessed for OSA (in-laboratory polysomnography; apnea-hypopnea index ≥ 15 events/hour), hypertension (doctor diagnosed, or systolic blood pressure ≥140 mmHg and/or diastolic ≥90 mmHg) and sleep (wrist actigraphy for ≥5 days). A sleep regularity index (SRI) was determined from actigraphy. Participants were categorized by tertiles as severely irregular, mildly irregular, or regular sleepers. Logistic regression models examined the interrelationships between SRI, OSA and hypertension. Covariates included age, sex, body mass index, actigraphy sleep duration, insomnia, depression, activity, alcohol, smoking, and antihypertensive medication. RESULTS: Compared to regular sleepers, participants with mildly irregular (OR 1.97, 95% confidence intervals [CI] 1.20 to 3.27) and severely irregular (OR 2.06, 95% CI: 1.25 to 3.42) sleep had greater odds of OSA. Compared to those with no OSA and regular sleep, OSA and severely irregular sleep combined had the highest odds of hypertension (OR 2.34 95% CI: 1.07 to 5.12; p for interaction = 0.02) while those with OSA and regular/mildly irregular sleep were not at increased risk (p for interaction = 0.20). CONCLUSIONS: Sleep irregularity may be an important modifiable target for hypertension among those with OSA.

Sleep regularity is a stronger predictor of mortality risk than sleep duration: A prospective cohort study.

Abnormally short and long sleep are associated with premature mortality, and achieving optimal sleep duration has been the focus of sleep health guidelines. Emerging research demonstrates that sleep regularity, the day-to-day consistency of sleep-wake timing, can be a stronger predictor for some health outcomes than sleep duration. The role of sleep regularity in mortality, however, has not been investigated in a large cohort with objective data. We therefore aimed to compare how sleep regularity and duration predicted risk for all-cause and cause-specific mortality. We calculated Sleep Regularity Index (SRI) scores from > 10 million hours of accelerometer data in 60 977 UK Biobank participants (62.8 ±â€…7.8 years, 55.0% female, median[IQR] SRI: 81.0[73.8-86.3]). Mortality was reported up to 7.8 years after accelerometer recording in 1859 participants (4.84 deaths per 1000 person-years, mean (±SD) follow-up of 6.30 ±â€…0.83 years). Higher sleep regularity was associated with a 20%-48% lower risk of all-cause mortality (p < .001 to p = 0.004), a 16%-39% lower risk of cancer mortality (p < 0.001 to p = 0.017), and a 22%-57% lower risk of cardiometabolic mortality (p < 0.001 to p = 0.048), across the top four SRI quintiles compared to the least regular quintile. Results were adjusted for age, sex, ethnicity, and sociodemographic, lifestyle, and health factors. Sleep regularity was a stronger predictor of all-cause mortality than sleep duration, by comparing equivalent mortality models, and by comparing nested SRI-mortality models with and without sleep duration (p = 0.14-0.20). These findings indicate that sleep regularity is an important predictor of mortality risk and is a stronger predictor than sleep duration. Sleep regularity may be a simple, effective target for improving general health and survival.

Motoneuron-driven computational muscle modelling with motor unit resolution and subject-specific musculoskeletal anatomy.

The computational simulation of human voluntary muscle contraction is possible with EMG-driven Hill-type models of whole muscles. Despite impactful applications in numerous fields, the neuromechanical information and the physiological accuracy such models provide remain limited because of multiscale simplifications that limit comprehensive description of muscle internal dynamics during contraction. We addressed this limitation by developing a novel motoneuron-driven neuromuscular model, that describes the force-generating dynamics of a population of individual motor units, each of which was described with a Hill-type actuator and controlled by a dedicated experimentally derived motoneuronal control. In forward simulation of human voluntary muscle contraction, the model transforms a vector of motoneuron spike trains decoded from high-density EMG signals into a vector of motor unit forces that sum into the predicted whole muscle force. The motoneuronal control provides comprehensive and separate descriptions of the dynamics of motor unit recruitment and discharge and decodes the subject's intention. The neuromuscular model is subject-specific, muscle-specific, includes an advanced and physiological description of motor unit activation dynamics, and is validated against an experimental muscle force. Accurate force predictions were obtained when the vector of experimental neural controls was representative of the discharge activity of the complete motor unit pool. This was achieved with large and dense grids of EMG electrodes during medium-force contractions or with computational methods that physiologically estimate the discharge activity of the motor units that were not identified experimentally. This neuromuscular model advances the state-of-the-art of neuromuscular modelling, bringing together the fields of motor control and musculoskeletal modelling, and finding applications in neuromuscular control and human-machine interfacing research.

Causal Association Between Subtypes of Excessive Daytime Sleepiness and Risk of Cardiovascular Diseases.

BACKGROUND: Excessive daytime sleepiness (EDS), experienced in 10% to 20% of the population, has been associated with cardiovascular disease and death. However, the condition is heterogeneous and is prevalent in individuals having short and long sleep duration. We sought to clarify the relationship between sleep duration subtypes of EDS with cardiovascular outcomes, accounting for these subtypes. METHODS AND RESULTS: We defined 3 sleep duration subtypes of excessive daytime sleepiness: normal (6-9 hours), short (<6 hours), and long (>9 hours), and compared these with a nonsleepy, normal-sleep-duration reference group. We analyzed their associations with incident myocardial infarction (MI) and stroke using medical records of 355 901 UK Biobank participants and performed 2-sample Mendelian randomization for each outcome. Compared with healthy sleep, long-sleep EDS was associated with an 83% increased rate of MI (hazard ratio, 1.83 [95% CI, 1.21-2.77]) during 8.2-year median follow-up, adjusting for multiple health and sociodemographic factors. Mendelian randomization analysis provided supporting evidence of a causal role for a genetic long-sleep EDS subtype in MI (inverse-variance weighted ß=1.995, P=0.001). In contrast, we did not find evidence that other subtypes of EDS were associated with incident MI or any associations with stroke (P>0.05). CONCLUSIONS: Our study suggests the previous evidence linking EDS with increased cardiovascular disease risk may be primarily driven by the effect of its long-sleep subtype on higher risk of MI. Underlying mechanisms remain to be investigated but may involve sleep irregularity and circadian disruption, suggesting a need for novel interventions in this population.

Modeling Contraception and Pregnancy in Malawi: A Thanzi La Onse Mathematical Modeling Study.

Malawi has high unmet need for contraception with a costed national plan to increase contraception use. Estimating how such investments might impact future population size in Malawi can help policymakers understand effects and value of policies to increase contraception uptake. We developed a new model of contraception and pregnancy using individual-level data capturing complexities of contraception initiation, switching, discontinuation, and failure by contraception method, accounting for differences by individual characteristics. We modeled contraception scale-up via a population campaign to increase initiation of contraception (Pop) and a postpartum family planning intervention (PPFP). We calibrated the model without new interventions to the UN World Population Prospects 2019 medium variant projection of births for Malawi. Without interventions Malawi's population passes 60 million in 2084; with Pop and PPFP interventions. it peaks below 35 million by 2100. We compare contraception coverage and costs, by method, with and without interventions, from 2023 to 2050. We estimate investments in contraception scale-up correspond to only 0.9 percent of total health expenditure per capita though could result in dramatic reductions of current pressures of very rapid population growth on health services, schools, land, and society, helping Malawi achieve national and global health and development goals.