The B1 H + -ATPase ( Atp6v1b1 ) Subunit in Non-Type A Intercalated Cells is Required for Driving Pendrin Activity and the Renal Defense Against Alkalosis.

SIGNIFICANCE STATEMENT: In the kidney, the B1 H + -ATPase subunit is mostly expressed in intercalated cells (IC). Its importance in acid-secreting type A ICs is evident in patients with inborn distal renal tubular acidosis and ATP6V1B1 mutations. However, the protein is also highly expressed in alkali-secreting non-type A ICs where its function is incompletely understood. We demonstrate in Atp6v1b1 knock out mice that the B1 subunit is critical for the renal response to defend against alkalosis during an alkali load or chronic furosemide treatment. These findings highlight the importance of non-type A ICs in maintaining acid-base balance in response to metabolic challenges or commonly used diuretics. BACKGROUND: Non-type A ICs in the collecting duct system express the luminal Cl - /HCO 3- exchanger pendrin and apical and/or basolateral H + -ATPases containing the B1 subunit isoform. Non-type A ICs excrete bicarbonate during metabolic alkalosis. Mutations in the B1 subunit (ATP6V1B1) cause distal renal tubular acidosis due to its role in acid secretory type A ICs. The function of B1 in non-type A ICs has remained elusive. METHODS: We examined the responses of Atp6v1b1-/- and Atp6v1b1+/+ mice to an alkali load and to chronic treatment with furosemide. RESULTS: An alkali load or 1 week of furosemide resulted in a more pronounced hypokalemic alkalosis in male ATP6v1b1-/- versus Atp6v1b1+/+ mice that could not be compensated by respiration. Total pendrin expression and activity in non-type A ICs of ex vivo microperfused cortical collecting ducts were reduced, and ß2 -adrenergic stimulation of pendrin activity was blunted in ATP6v1b1-/- mice. Basolateral H + -ATPase activity was strongly reduced, although the basolateral expression of the B2 isoform was increased. Ligation assays for H + -ATPase subunits indicated impaired assembly of V 0 and V 1 H + -ATPase domains. During chronic furosemide treatment, ATP6v1b1-/- mice also showed polyuria and hyperchloremia versus Atp6v1b1+/+ . The expression of pendrin, the water channel AQP2, and subunits of the epithelial sodium channel ENaC were reduced. CONCLUSIONS: Our data demonstrate a critical role of H + -ATPases in non-type A ICs function protecting against alkalosis and reveal a hitherto unrecognized need of basolateral B1 isoform for a proper H + -ATPase complexes assembly and ability to be stimulated.

Exploring the impact of the PNPLA3 I148M variant on primary human hepatic stellate cells using 3D extracellular matrix models.

BACKGROUND & AIMS: The PNPLA3 rs738409 C>G (encoding for I148M) variant is a risk locus for the fibrogenic progression of chronic liver diseases, a process driven by hepatic stellate cells (HSCs). We investigated how the PNPLA3 I148M variant affects HSC biology using transcriptomic data and validated findings in 3D-culture models. METHODS: RNA sequencing was performed on 2D-cultured primary human HSCs and liver biopsies of individuals with obesity, genotyped for the PNPLA3 I148M variant. Data were validated in wild-type (WT) or PNPLA3 I148M variant-carrying HSCs cultured on 3D extracellular matrix (ECM) scaffolds from human healthy and cirrhotic livers, with/without TGFB1 or cytosporone B (Csn-B) treatment. RESULTS: Transcriptomic analyses of liver biopsies and HSCs highlighted shared PNPLA3 I148M-driven dysregulated pathways related to mitochondrial function, antioxidant response, ECM remodelling and TGFB1 signalling. Analogous pathways were dysregulated in WT/PNPLA3-I148M HSCs cultured in 3D liver scaffolds. Mitochondrial dysfunction in PNPLA3-I148M cells was linked to respiratory chain complex IV insufficiency. Antioxidant capacity was lower in PNPLA3-I148M HSCs, while reactive oxygen species secretion was increased in PNPLA3-I148M HSCs and higher in bioengineered cirrhotic vs. healthy scaffolds. TGFB1 signalling followed the same trend. In PNPLA3-I148M cells, expression and activation of the endogenous TGFB1 inhibitor NR4A1 were decreased: treatment with the Csn-B agonist increased total NR4A1 in HSCs cultured in healthy but not in cirrhotic 3D scaffolds. NR4A1 regulation by TGFB1/Csn-B was linked to Akt signalling in PNPLA3-WT HSCs and to Erk signalling in PNPLA3-I148M HSCs. CONCLUSION: HSCs carrying the PNPLA3 I148M variant have impaired mitochondrial function, antioxidant responses, and increased TGFB1 signalling, which dampens antifibrotic NR4A1 activity. These features are exacerbated by cirrhotic ECM, highlighting the dual impact of the PNPLA3 I148M variant and the fibrotic microenvironment in progressive chronic liver diseases. IMPACT AND IMPLICATIONS: Hepatic stellate cells (HSCs) play a key role in the fibrogenic process associated with chronic liver disease. The PNPLA3 genetic mutation has been linked with increased risk of fibrogenesis, but its role in HSCs requires further investigation. Here, by using comparative transcriptomics and a novel 3D in vitro model, we demonstrate the impact of the PNPLA3 genetic mutation on primary human HSCs' behaviour, and we show that it affects the cell's mitochondrial function and antioxidant response, as well as the antifibrotic gene NR4A1. Our publicly available transcriptomic data, 3D platform and our findings on NR4A1 could facilitate the discovery of targets to develop more effective treatments for chronic liver diseases.

The incidence of subsequent contralateral hip fracture and factors associated with increased risk: the IMPACT Contralateral Fracture Study.

Patients who sustain a contralateral hip fracture experience significantly inferior outcomes; however, the incidence and predictors of contralateral hip fracture remain poorly understood. In the present study, 2.5% of patients sustained a contralateral hip fracture within 12 months, and socioeconomic deprivation was associated with reduced risk of contralateral hip fracture. INTRODUCTION: Hip fractures are associated with high morbidity and mortality, and patients that sustain a subsequent contralateral fracture experience inferior outcomes. The risk of contralateral fracture is highest within the first year; however, the incidence and associated factors remain poorly understood. The aims were to investigate (i) the incidence of a subsequent contralateral hip fracture within the first year, (ii) identify factors associated with an increased risk of contralateral fracture and (iii) compare early mortality risk after index versus contralateral hip fracture. METHODS: This study included all patients aged over 50 years admitted to NHS hospitals in Scotland between 1st March 2020 and 31st December 2020 (n = 5566) as routine activity of the Scottish Hip Fracture Audit (SHFA). Multivariate logistic regression was used to examine factors associated with 30-day mortality, and cox regression was used to identify factors associated with a contralateral fracture. RESULTS: During the study period 2.5% (138/5566) of patients sustained a contralateral hip fracture within 12 months of the index hip fracture. Socioeconomic deprivation was inversely associated with increased risk of contralateral fracture (odds ratio 2.64, p < 0.001), whilst advancing age (p = 0.427) and sex (p = 0.265) were not. After adjusting for significant cofounders, there was no significant difference in 30-day mortality following contralateral fracture compared to index fracture (OR 1.22, p = 0.433). CONCLUSION: One in 40 (2.5%) hip fracture patients sustained a contralateral fracture within 12 months of their index fracture, and deprivation was associated with a reduced risk of contralateral fracture. No difference in 30-day mortality was found.

Vaccination against COVID-19 reduced the mortality risk of COVID-positive hip fracture patients to baseline levels: the nationwide data-linked IMPACT Protect study.

This nationwide study used data-linked records to assess the effect of COVID-19 vaccination among hip fracture patients. Vaccination was associated with a lower risk of contracting COVID-19 and, among COVID-positive patients, it reduced the mortality risk to that of COVID-negative patients. This provides essential data for future communicable disease outbreaks. PURPOSE: COVID-19 confers a three-fold increased mortality risk among hip fracture patients. The aims were to investigate whether vaccination was associated with: i) lower mortality risk, and ii) lower likelihood of contracting COVID-19 within 30 days of fracture. METHODS: This nationwide cohort study included all patients aged > 50 years that sustained a hip fracture in Scotland between 01/03/20-31/12/21. Data from the Scottish Hip Fracture Audit were collected and included: demographics, injury and management variables, discharge destination, and 30-day mortality status. These variables were linked to government-managed population level records of COVID-19 vaccination and laboratory testing. RESULTS: There were 13,345 patients with a median age of 82.0 years (IQR 74.0-88.0), and 9329/13345 (69.9%) were female. Of 3022/13345 (22.6%) patients diagnosed with COVID-19, 606/13345 (4.5%) were COVID-positive within 30 days of fracture. Multivariable logistic regression demonstrated that vaccinated patients were less likely to be COVID-positive (odds ratio (OR) 0.41, 95% confidence interval (CI) 0.34-0.48, p < 0.001) than unvaccinated patients. 30-day mortality rate was higher for COVID-positive than COVID-negative patients (15.8% vs 7.9%, p < 0.001). Controlling for confounders (age, sex, comorbidity, deprivation, pre-fracture residence), unvaccinated patients with COVID-19 had a greater mortality risk than COVID-negative patients (OR 2.77, CI 2.12-3.62, p < 0.001), but vaccinated COVID19-positive patients were not at increased risk of death (OR 0.93, CI 0.53-1.60, p = 0.783). CONCLUSION: Vaccination was associated with lower COVID-19 infection risk. Vaccinated COVID-positive patients had a similar mortality risk to COVID-negative patients, suggesting a reduced severity of infection. This study demonstrates the efficacy of vaccination in this vulnerable patient group, and presents data that will be valid in the management of future outbreaks.

Twenty-four-hour physical behaviour profiles across type 2 diabetes mellitus subtypes.

AIM: To investigate how 24-h physical behaviours differ across type 2 diabetes (T2DM) subtypes. MATERIALS AND METHODS: We included participants living with T2DM, enrolled as part of an ongoing observational study. Participants wore an accelerometer for 7 days to quantify physical behaviours across 24 h. We used routinely collected clinical data (age at onset of diabetes, glycated haemoglobin level, homeostatic model assessment index of beta-cell function, homeostatic model assessment index of insulin resistance, body mass index) to replicate four previously identified subtypes (insulin-deficient diabetes [INS-D], insulin-resistant diabetes [INS-R], obesity-related diabetes [OB] and age-related diabetes [AGE]), via k-means clustering. Differences in physical behaviours across the diabetes subtypes were assessed using generalized linear models, with the AGE cluster as the reference. RESULTS: A total of 564 participants were included in this analysis (mean age 63.6 ± 8.4 years, 37.6% female, mean age at diagnosis 53.1 ± 10.0 years). The proportions in each cluster were as follows: INS-D: n = 35, 6.2%; INS-R: n = 88, 15.6%; OB: n = 166, 29.4%; and AGE: n = 275, 48.8%. Compared to the AGE cluster, the OB cluster had a shorter sleep duration (-0.3 h; 95% confidence interval [CI] -0.5, -0.1), lower sleep efficiency (-2%; 95% CI -3, -1), lower total physical activity (-2.9 mg; 95% CI -4.3, -1.6) and less time in moderate-to-vigorous physical activity (-6.6 min; 95% CI -11.4, -1.7), alongside greater sleep variability (17.9 min; 95% CI 8.2, 27.7) and longer sedentary time (31.9 min; 95% CI 10.5, 53.2). Movement intensity during the most active continuous 10 and 30 min of the day was also lower in the OB cluster. CONCLUSIONS: In individuals living with T2DM, the OB subtype had the lowest levels of physical activity and least favourable sleep profiles. Such behaviours may be suitable targets for personalized therapeutic lifestyle interventions.

Computational approaches identify a transcriptomic fingerprint of drug-induced structural cardiotoxicity.

Structural cardiotoxicity (SCT) presents a high-impact risk that is poorly tolerated in drug discovery unless significant benefit is anticipated. Therefore, we aimed to improve the mechanistic understanding of SCT. First, we combined machine learning methods with a modified calcium transient assay in human-induced pluripotent stem cell-derived cardiomyocytes to identify nine parameters that could predict SCT. Next, we applied transcriptomic profiling to human cardiac microtissues exposed to structural and non-structural cardiotoxins. Fifty-two genes expressed across the three main cell types in the heart (cardiomyocytes, endothelial cells, and fibroblasts) were prioritised in differential expression and network clustering analyses and could be linked to known mechanisms of SCT. This transcriptomic fingerprint may prove useful for generating strategies to mitigate SCT risk in early drug discovery.

Sarcopenia prevalence using handgrip strength or chair stand performance in adults living with type 2 diabetes mellitus.

BACKGROUND: The updated European Working Group on Sarcopenia in Older People (EWGSOP2) recommends handgrip strength (HGS) and the chair stand test (CST) to assess muscle strength, with the CST being a convenient proxy for lower limb strength. However, adiposity may differentially influence these strength criteria and produce discrepant sarcopenia prevalence. OBJECTIVE: To determine the prevalence of sarcopenia using HGS or the CST, and to investigate the associations between these strength criteria and adiposity in adults with type 2 diabetes mellitus. METHODS: The EWGSOP2 definition was used to assess the prevalence of probable (low muscle strength), confirmed (plus low muscle mass) and severe (plus poor physical performance) sarcopenia. Linear regression models were used to study the association between different measures of muscle strength and adiposity. RESULTS: We used data from 732 adults with type 2 diabetes mellitus (35.7% female, aged 64 ± 8 years, body mass index 30.7 ± 5.0 kg/m2). Using the CST compared with HGS produced a higher prevalence of probable (31.7% vs. 7.1%), confirmed (5.6% vs. 1.6%) and severe (1.0% vs. 0.3%) sarcopenia, with poor agreement between strength criteria to identify probable sarcopenia. CST performance, but not HGS, was significantly associated with all measures of adiposity in unadjusted and adjusted models. CONCLUSIONS: Higher levels of adiposity may impact CST performance, but not HGS, resulting in a higher prevalence of sarcopenia in adults with type 2 diabetes mellitus. Consideration should be paid to the most appropriate measure of muscle function in this population.

3D printed temporal bones for preoperative simulation and planning.

OBJECTIVE: Demonstrate the utility of 3D printed temporal bone models in individual patient preoperative planning and simulation. METHODS: 3D models of the temporal bone were made from 5 pediatric and adult patients at a tertiary academic hospital with challenging surgical anatomy planned for cochlear implantation or exteriorization of cholesteatoma with complex labyrinthine fistula. The 3D models were created from CT scan used for preoperative planning, simulation and intraoperative reference. The utility of models was assessed for ease of segmentation and production and impact on surgery in regard to reducing intraoperative time and costs, improving safety and efficacy. RESULTS: Three patients received cochlear implants, two exteriorization of advanced cholesteatoma with fistulas (1 internal auditory canal/cochlea, 1 all three semicircular canals). Surgical planning and intraoperative referencing to the simulations by the attending surgeon and trainees significantly altered original surgical plans. In a case of X-linked hereditary deafness, optimal angles and rotation maneuvers for cochlear implant insertion reduced operating time by 93 min compared to the previous contralateral side surgery. Two cochlear implant cases planned for subtotal petrosectomy approach due to aberrant anatomy were successfully approached through routine mastoidectomy. The cholesteatoma cases were successfully exteriorized without necessitating partial labyrinthectomy or labyrinthine injury. There were no complications. CONCLUSION: 3D printed models for simulation training, surgical planning and use intraoperatively in temporal bone surgery demonstrated significant benefits in designing approaches, development of patient-specific techniques, avoidance of potential or actual complications encountered in previous or current surgery, and reduced surgical time and costs.

Sound transmission loss of periodic Mindlin plates with non-uniformly spaced mass attachmentsa).

The sound transmission loss (STL) of wall partitions, especially in the coincidence region, is investigated. A Mindlin plate with periodically attached masses in a periodic "supercell" pattern is analyzed theoretically and experimentally for sound attenuation. Modeling the masses as points, analytical expressions for predicting the dispersion relation and frequency bandgaps of the plate are developed. The results show that varying the distances between the masses or the masses themselves can lead to the emergence of additional lower-frequency bandgaps and slightly decrease the bandwidth of the primary complete bandgap. Additionally, a triangular periodic pattern of point masses can provide a larger complete bandgap than the conventional rectangular pattern. The results are validated by numerical analyses using the wave and finite element method. Experimental testing is conducted on large-scale plates (2.4 m × 1 m) with periodically attached masses under diffuse field conditions, demonstrating the benefits of utilizing multiple scattering to increase the STL in the coincidence region of the bare plate. The proposed approach is seen to significantly increase the STL of wall partitions in the coincidence region and provides insights into the fundamental principles of sound and vibration attenuation in complex structures based on multiple scattering.

NGAL in the Development of Acute Kidney Injury in a Murine Model of Remote Ischaemic Preconditioning and Liver Ischaemia Reperfusion.

Acute kidney injury (AKI) is common following liver transplantation and is associated with liver ischeamia reperfusion (IR) injury. The purpose of this study was to use a mouse model of liver IR injury and AKI to study the role of Neutrophil Gelatinase Associated Lipocalin (NGAL), a biomarker of AKI, in liver IR injury and AKI. We demonstrate an adapted, reproducible model of liver IR injury and AKI in which remote ischemic preconditioning (RIPC) by repeated episodes of hindleg ischemia prior to liver IR reduced the severity of the IR injury. In this model, serum NGAL at 2 h post reperfusion correlated with AKI development early following IR injury. This early rise in serum NGAL was associated with hepatic but not renal upregulation of NGAL mRNA, suggesting NGAL production in the liver but not the kidney in the early phase post liver IR injury.

PCK1 is a key regulator of metabolic and mitochondrial functions in renal tubular cells.

Phosphoenolpyruvate carboxykinase 1 (PCK1 or PEPCK-C) is a cytosolic enzyme converting oxaloacetate to phosphoenolpyruvate, with a potential role in gluconeogenesis, ammoniagenesis, and cataplerosis in the liver. Kidney proximal tubule cells display high expression of this enzyme, whose importance is currently not well defined. We generated PCK1 kidney-specific knockout and knockin mice under the tubular cell-specific PAX8 promoter. We studied the effect of PCK1 deletion and overexpression at the renal level on tubular physiology under normal conditions and during metabolic acidosis and proteinuric renal disease. PCK1 deletion led to hyperchloremic metabolic acidosis characterized by reduced but not abolished ammoniagenesis. PCK1 deletion also resulted in glycosuria, lactaturia, and altered systemic glucose and lactate metabolism at baseline and during metabolic acidosis. Metabolic acidosis resulted in kidney injury in PCK1-deficient animals with decreased creatinine clearance and albuminuria. PCK1 further regulated energy production by the proximal tubule, and PCK1 deletion decreased ATP generation. In proteinuric chronic kidney disease, mitigation of PCK1 downregulation led to better renal function preservation. PCK1 is essential for kidney tubular cell acid-base control, mitochondrial function, and glucose/lactate homeostasis. Loss of PCK1 increases tubular injury during acidosis. Mitigating kidney tubular PCK1 downregulation during proteinuric renal disease improves renal function.NEW & NOTEWORTHY Phosphoenolpyruvate carboxykinase 1 (PCK1) is highly expressed in the proximal tubule. We show here that this enzyme is crucial for the maintenance of normal tubular physiology, lactate, and glucose homeostasis. PCK1 is a regulator of acid-base balance and ammoniagenesis. Preventing PCK1 downregulation during renal injury improves renal function, rendering it an important target during renal disease.

Immune responses to COVID-19 booster vaccinations in intensively anti-CD38 antibody treated patients with ultra-high-risk multiple myeloma: results from the Myeloma UK (MUK) nine OPTIMUM trial.

Multiple myeloma (MM) and anti-MM therapy cause profound immunosuppression, leaving patients vulnerable to coronavirus disease 2019 (COVID-19) and other infections. We investigated anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies longitudinally in ultra-high-risk patients with MM receiving risk-adapted, intensive anti-CD38 combined therapy in the Myeloma UK (MUK) nine trial. Despite continuous intensive therapy, seroconversion was achieved in all patients, but required a greater number of vaccinations compared to healthy individuals, highlighting the importance of booster vaccinations in this population. Reassuringly, high antibody cross-reactivity was found with current variants of concern, prior to Omicron subvariant adapted boostering. Multiple booster vaccine doses can provide effective protection from COVID-19, even with intensive anti-CD38 therapy for high-risk MM.

First-in-human imaging using [11C]MDTC: a radiotracer targeting the cannabinoid receptor type 2.

PURPOSE: We report findings from the first-in-human study of [11C]MDTC, a radiotracer developed to image the cannabinoid receptor type 2 (CB2R) with positron emission tomography (PET). METHODS: Ten healthy adults were imaged according to a 90-min dynamic PET protocol after bolus intravenous injection of [11C]MDTC. Five participants also completed a second [11C]MDTC PET scan to assess test-retest reproducibility of receptor-binding outcomes. The kinetic behavior of [11C]MDTC in human brain was evaluated using tissue compartmental modeling. Four additional healthy adults completed whole-body [11C]MDTC PET/CT to calculate organ doses and the whole-body effective dose. RESULTS: [11C]MDTC brain PET and [11C]MDTC whole-body PET/CT was well-tolerated. A murine study found evidence of brain-penetrant radiometabolites. The model of choice for fitting the time activity curves (TACs) across brain regions of interest was a three-tissue compartment model that includes a separate input function and compartment for the brain-penetrant metabolites. Regional distribution volume (VT) values were low, indicating low CB2R expression in the brain. Test-retest reliability of VT demonstrated a mean absolute variability of 9.91%. The measured effective dose of [11C]MDTC was 5.29 µSv/MBq. CONCLUSION: These data demonstrate the safety and pharmacokinetic behavior of [11C]MDTC with PET in healthy human brain. Future studies identifying radiometabolites of [11C]MDTC are recommended before applying [11C]MDTC PET to assess the high expression of the CB2R by activated microglia in human brain.

Validation of an automated sleep detection algorithm using data from multiple accelerometer brands.

To evaluate the criterion validity of an automated sleep detection algorithm applied to data from three research-grade accelerometers worn on each wrist with concurrent laboratory-based polysomnography (PSG). A total of 30 healthy volunteers (mean [SD] age 31.5 [7.2] years, body mass index 25.5 [3.7] kg/m2 ) wore an Axivity, GENEActiv and ActiGraph accelerometer on each wrist during a 1-night PSG assessment. Sleep estimates (sleep period time window [SPT-window], sleep duration, sleep onset and waking time, sleep efficiency, and wake after sleep onset [WASO]) were generated using the automated sleep detection algorithm within the open-source GGIR package. Agreement of sleep estimates from accelerometer data with PSG was determined using pairwise 95% equivalence tests (±10% equivalence zone), intraclass correlation coefficients (ICCs) with 95% confidence intervals and limits of agreement (LoA). Accelerometer-derived sleep estimates except for WASO were within the 10% equivalence zone of the PSG. Reliability between data from the accelerometers worn on either wrist and PSG was moderate for SPT-window duration (ICCs ≥ 0.65), sleep duration (ICCs ≥ 0.54), and sleep onset (ICCs ≥ 0.61), mostly good for waking time (ICCs ≥ 0.80), but poor for sleep efficiency (ICCs ≥ 0.08) and WASO (ICCs ≥ 0.08). The mean bias between all accelerometer-derived sleep estimates worn on either wrist and PSG were low; however, wide 95% LoA were observed for all sleep estimates, apart from waking time. The automated sleep detection algorithm applied to data from Axivity, GENEActiv and ActiGraph accelerometers, worn on either wrist, provides comparable measures to PSG for SPT-window and sleep duration, sleep onset and waking time, but a poor measure of wake during the sleep period.

Human genetic variation and the gut microbiome in disease.

Taxonomic and functional changes to the composition of the gut microbiome have been implicated in multiple human diseases. Recent microbiome genome-wide association studies reveal that variants in many human genes involved in immunity and gut architecture are associated with an altered composition of the gut microbiome. Although many factors can affect the microbial organisms residing in the gut, a number of recent findings support the hypothesis that certain host genetic variants predispose an individual towards microbiome dysbiosis. This condition, in which the normal microbiome population structure is disturbed, is a key feature in disorders of metabolism and immunity.

Universal vote-by-mail has no impact on partisan turnout or vote share.

In response to coronavirus disease 2019 (COVID-19), many scholars and policy makers are urging the United States to expand voting-by-mail programs to safeguard the electoral process. What are the effects of vote-by-mail? In this paper, we provide a comprehensive design-based analysis of the effect of universal vote-by-mail-a policy under which every voter is mailed a ballot in advance of the election-on electoral outcomes. We collect data from 1996 to 2018 on all three US states that implemented universal vote-by-mail in a staggered fashion across counties, allowing us to use a difference-in-differences design at the county level to estimate causal effects. We find that 1) universal vote-by-mail does not appear to affect either party's share of turnout, 2) universal vote-by-mail does not appear to increase either party's vote share, and 3) universal vote-by-mail modestly increases overall average turnout rates, in line with previous estimates. All three conclusions support the conventional wisdom of election administration experts and contradict many popular claims in the media.

Technology-enhanced learning in orthopaedics: Virtual reality and multi-modality educational workshops may be effective in the training of surgeons and operating department staff.

AIM: The aims were to assess the utility of: 1) virtual reality-mediated simulation, and 2) a multi-modality 'Bootcamp' in the delivery of total knee arthroplasty (TKA) teaching to orthopaedic surgical trainees. BACKGROUND: Surgical training opportunities are diminished as a result of the COVID-19 pandemic which may result in delays to training completion and gaps in the permanent workforce. Modern and technology-enhanced learning methods have been identified as having the potential to support high-quality and sustainable education. METHODS: This mixed-methods study assessed the educational benefit of two activities designed to teach TKA to junior (ST1-3) orthopaedic trainees. A multi-modality training Bootcamp was delivered that included: virtual reality (VR) and saw-bone simulation; tutorials, and case-based symposia. The VR component was delivered to different participants (surgical trainees, scrub nurses, and consultants) on a further two separate occasions. Qualitative and quantitative data were collected pertaining to utility and performance. RESULTS: Trainees reported that the Bootcamp improved comprehension of arthroplasty principles including component alignment, knee balancing, and intraoperative strategies. Case-based discussions helped develop diagnostic and decision-making skills. The VR activity improved understanding of the surgical process map, increased ability to anticipate steps, and consider the procedure strategically. All staff groups found the VR activity beneficial and would recommend it as a useful addition to a surgical department. CONCLUSION: VR-mediated simulation could augment the education of surgical trainees and scrub team staff by improving comprehension of the surgical process map. Integrated multi-modality 'Bootcamp-style' training activities constructed around trainees' needs may provide a sustainable solution to bridge the experience gap related to reduced exposure to elective orthopaedic practice.

Online case-based educational meetings can increase knowledge, skills, and widen access to surgical training:The nationwideVirtualTrauma & Orthopaedic Meetingseries.

BACKGROUND: Access to surgical training is challenging for undergraduate and early postgraduate trainees due to a greater focus on developing generic knowledge and skills, and a drive to recruit greater numbers into internal medicine and primary care. COVID-19 accelerated the declining access to surgical training environments. Our aims were to: 1) establish the feasibility of an online, specialty-specific, case-based surgical training series, and 2) evaluate its suitability for meeting the needs of trainees. METHODS: A nationwide audience of undergraduate and early postgraduate trainees were invited to a series of bespoke online case-based educational meetings in Trauma & Orthopaedics (T&O) over a six month period. The six sessions, which simulated real-world clinical meetings, were constructed by Consultant sub-specialists and involved the presentation of cases by registrars, followed by structured discussion of basic principles, radiological interpretation, and management strategies. Mixed qualitative and quantitative analyses were conducted. RESULTS: There were 131 participants (59.5% male), consisting mostly of doctors in training (58%) and medical students (37.4%). The mean quality rating was 9.0/10 (SD 1.06), further supported by qualitative analysis. 98% enjoyed the sessions, 97% reported improved knowledge of T&O, and 94% reported a direct benefit to clinical practice. There was a significant improvement in knowledge of T&O conditions, management plans, and radiological interpretation (p = <0.05). CONCLUSION: Structured virtual meetings, underpinned by bespoke clinical cases, may widen access to T&O training, increase flexibility and robustness of learning opportunities, and mitigate the effects of reduced exposure on preparation for surgical careers and recruitment.

Accelerometer-Assessed Physical Activity in People with Type 2 Diabetes: Accounting for Sleep when Determining Associations with Markers of Health.

High physical activity levels during wake are beneficial for health, while high movement levels during sleep are detrimental to health. Our aim was to compare the associations of accelerometer-assessed physical activity and sleep disruption with adiposity and fitness using standardized and individualized wake and sleep windows. People (N = 609) with type 2 diabetes wore an accelerometer for up to 8 days. Waist circumference, body fat percentage, Short Physical Performance Battery (SPPB) test score, sit-to-stands, and resting heart rate were assessed. Physical activity was assessed via the average acceleration and intensity distribution (intensity gradient) over standardized (most active 16 continuous hours (M16h)) and individualized wake windows. Sleep disruption was assessed via the average acceleration over standardized (least active 8 continuous hours (L8h)) and individualized sleep windows. Average acceleration and intensity distribution during the wake window were beneficially associated with adiposity and fitness, while average acceleration during the sleep window was detrimentally associated with adiposity and fitness. Point estimates for the associations were slightly stronger for the standardized than for individualized wake/sleep windows. In conclusion, standardized wake and sleep windows may have stronger associations with health due to capturing variations in sleep durations across individuals, while individualized windows represent a purer measure of wake/sleep behaviors.

The Molecular Basis for Zinc Bioavailability.

Zinc is an essential micronutrient, and its deficiency is perhaps the most prevalent and least understood worldwide. Recent advances have expanded the understanding of zinc's unique chemistry and molecular roles in a vast array of critical functions. However, beyond the concept of zinc absorption, few studies have explored the molecular basis of zinc bioavailability that determines the proportion of dietary zinc utilized in zinc-dependent processes in the body. The purpose of this review is to merge the concepts of zinc molecular biology and bioavailability with a focus on the molecular determinants of zinc luminal availability, absorption, transport, and utilization.