Analysis-ready VCF at Biobank scale using Zarr.

Background: Variant Call Format (VCF) is the standard file format for interchanging genetic variation data and associated quality control metrics. The usual row-wise encoding of the VCF data model (either as text or packed binary) emphasises efficient retrieval of all data for a given variant, but accessing data on a field or sample basis is inefficient. Biobank scale datasets currently available consist of hundreds of thousands of whole genomes and hundreds of terabytes of compressed VCF. Row-wise data storage is fundamentally unsuitable and a more scalable approach is needed. Results: We present the VCF Zarr specification, an encoding of the VCF data model using Zarr which makes retrieving subsets of the data much more efficient. Zarr is a cloud-native format for storing multi-dimensional data, widely used in scientific computing. We show how this format is far more efficient than standard VCF based approaches, and competitive with specialised methods for storing genotype data in terms of compression ratios and calculation performance. We demonstrate the VCF Zarr format (and the vcf2zarr conversion utility) on a subset of the Genomics England aggV2 dataset comprising 78,195 samples and 59,880,903 variants, with a 5X reduction in storage and greater than 300X reduction in CPU usage in some representative benchmarks. Conclusions: Large row-encoded VCF files are a major bottleneck for current research, and storing and processing these files incurs a substantial cost. The VCF Zarr specification, building on widely-used, open-source technologies has the potential to greatly reduce these costs, and may enable a diverse ecosystem of next-generation tools for analysing genetic variation data directly from cloud-based object stores.

Serum AZD7442 (tixagevimab-cilgavimab) concentrations and in vitroIC50 values predict SARS-CoV-2 neutralising antibody titres.

Objectives: The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) necessitates rapid methods for assessing monoclonal antibody (mAb) potency against emerging variants. Authentic virus neutralisation assays are considered the gold standard for measuring virus-neutralising antibody (nAb) titres in serum. However, authentic virus-based assays pose inherent practical challenges for measuring nAb titres against emerging SARS-CoV-2 variants (e.g. storing infectious viruses and testing at biosafety level-3 facilities). Here, we demonstrate the utility of pseudovirus neutralisation assay data in conjunction with serum mAb concentrations to robustly predict nAb titres in serum. Methods: SARS-CoV-2 nAb titres were determined via authentic- and lentiviral pseudovirus-based neutralisation assays using serological data from three AZD7442 (tixagevimab-cilgavimab) studies: PROVENT (NCT04625725), TACKLE (NCT04723394) and a phase 1 dose-ranging study (NCT04507256). AZD7442 serum concentrations were assessed using immunocapture. Serum-based half-maximal inhibitory concentration (IC50) values were derived from pseudovirus nAb titres and serum mAb concentrations, and compared with in vitro IC50 measurements. Results: nAb titres measured via authentic- and lentiviral pseudovirus-based neutralisation assays were strongly correlated for the ancestral SARS-CoV-2 virus and SARS-CoV-2 Alpha. Serum AZD7442 concentrations and pseudovirus nAb titres were strongly correlated for multiple SARS-CoV-2 variants with all Spearman correlation coefficients ≥ 0.78. Serum-based IC50 values were similar to in vitro IC50 values for AZD7442, for ancestral SARS-CoV-2 and Alpha, Delta, Omicron BA.2 and Omicron BA.4/5 variants. Conclusions: These data highlight that serum mAb concentrations and pseudovirus in vitro IC50 values can be used to rapidly predict nAb titres in serum for emerging and historical SARS-CoV-2 variants.

Estimating vaccine efficacy during open-label follow-up of COVID-19 vaccine trials based on population-level surveillance data.

While rapid development and roll out of COVID-19 vaccines is necessary in a pandemic, the process limits the ability of clinical trials to assess longer-term vaccine efficacy. We leveraged COVID-19 surveillance data in the U.S. to evaluate vaccine efficacy in U.S. Government-funded COVID-19 vaccine efficacy trials with a three-step estimation process. First, we used a compartmental epidemiological model informed by county-level surveillance data, a "population model", to estimate SARS-CoV-2 incidence among the unvaccinated. Second, a "cohort model" was used to adjust the population SARS-CoV-2 incidence to the vaccine trial cohort, taking into account individual participant characteristics and the difference between SARS-CoV-2 infection and COVID-19 disease. Third, we fit a regression model estimating the offset between the cohort-model-based COVID-19 incidence in the unvaccinated with the placebo-group COVID-19 incidence in the trial during blinded follow-up. Counterfactual placebo COVID-19 incidence was estimated during open-label follow-up by adjusting the cohort-model-based incidence rate by the estimated offset. Vaccine efficacy during open-label follow-up was estimated by contrasting the vaccine group COVID-19 incidence with the counterfactual placebo COVID-19 incidence. We documented good performance of the methodology in a simulation study. We also applied the methodology to estimate vaccine efficacy for the two-dose AZD1222 COVID-19 vaccine using data from the phase 3 U.S. trial (ClinicalTrials.gov # NCT04516746). We estimated AZD1222 vaccine efficacy of 59.1% (95% uncertainty interval (UI): 40.4%-74.3%) in April, 2021 (mean 106 days post-second dose), which reduced to 35.7% (95% UI: 15.0%-51.7%) in July, 2021 (mean 198 days post-second-dose). We developed and evaluated a methodology for estimating longer-term vaccine efficacy. This methodology could be applied to estimating counterfactual placebo incidence for future placebo-controlled vaccine efficacy trials of emerging pathogens with early termination of blinded follow-up, to active-controlled or uncontrolled COVID-19 vaccine efficacy trials, and to other clinical endpoints influenced by vaccination.

Prediction of cardiovascular risk factors from retinal fundus photographs: Validation of a deep learning algorithm in a prospective non-interventional study in Kenya.

AIM: Hypertension and diabetes mellitus (DM) are major causes of morbidity and mortality, with growing burdens in low-income countries where they are underdiagnosed and undertreated. Advances in machine learning may provide opportunities to enhance diagnostics in settings with limited medical infrastructure. MATERIALS AND METHODS: A non-interventional study was conducted to develop and validate a machine learning algorithm to estimate cardiovascular clinical and laboratory parameters. At two sites in Kenya, digital retinal fundus photographs were collected alongside blood pressure (BP), laboratory measures and medical history. The performance of machine learning models, originally trained using data from the UK Biobank, were evaluated for their ability to estimate BP, glycated haemoglobin, estimated glomerular filtration rate and diagnoses from fundus images. RESULTS: In total, 301 participants were enrolled. Compared with the UK Biobank population used for algorithm development, participants from Kenya were younger and would probably report Black/African ethnicity, with a higher body mass index and prevalence of DM and hypertension. The mean absolute error was comparable or slightly greater for systolic BP, diastolic BP, glycated haemoglobin and estimated glomerular filtration rate. The model trained to identify DM had an area under the receiver operating curve of 0.762 (0.818 in the UK Biobank) and the hypertension model had an area under the receiver operating curve of 0.765 (0.738 in the UK Biobank). CONCLUSIONS: In a Kenyan population, machine learning models estimated cardiovascular parameters with comparable or slightly lower accuracy than in the population where they were trained, suggesting model recalibration may be appropriate. This study represents an incremental step toward leveraging machine learning to make early cardiovascular screening more accessible, particularly in resource-limited settings.

Expert consensus guidance on respiratory physiotherapy and rehabilitation of patients with rib fractures: An international, multidisciplinary e-Delphi study.

BACKGROUND: There is limited research supporting optimal respiratory physiotherapy or physical rehabilitation strategies for patients with rib fractures. The aim of this study was to develop key recommendations for the physiotherapy management of patients with rib fractures. METHODS: A three-round modified e-Delphi survey design, using an international Delphi panel including physiotherapy clinicians, researchers and lecturers, physician associates, trauma surgeons, and intensivists, was used in this study. The draft recommendations were developed by the Steering Group, based on available research. Over three rounds, panelists rated their agreement (using a Likert scale) with regard to recommendation for physiotherapists delivering respiratory physiotherapy and physical rehabilitation to patients following rib fractures. Recommendations were retained if they achieved consensus (defined as ≥70% of panelists ≥5/7) at the end of each round. RESULTS: A total of 121 participants from 18 countries registered to participate in the study, with 87 (72%), 77 (64%), and 79 (65%) registrants completing the three rounds, respectively. The final guidance document included 18 respiratory physiotherapy and rehabilitation recommendations, mapped over seven clinical scenarios for patients (1) not requiring mechanical ventilation, (2) requiring mechanical ventilation, (3) with no concurrent fracture of the shoulder girdle complex, (4) with a concurrent fracture of the shoulder girdle complex, (5) with/without concurrent upper limb orthopedic injuries, (6) undergoing surgical stabilization of rib fractures, and (7) at hospital discharge. CONCLUSION: This guidance provides key recommendations for respiratory physiotherapy and physical rehabilitation of patients with rib fractures. It could also be used to inform future research priorities in the field. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Imaging of Light-Enhanced Extracellular Vesicle-Mediated Delivery of Oxaliplatin to Colorectal Cancer Cells via Laser Ablation, Inductively Coupled Plasma Mass Spectrometry.

Extracellular vesicles (EVs) are lipid bilayer structures released by all cells that mediate cell-to-cell communication via the transfer of bioactive cargo. Because of the natural origin of EVs, their efficient uptake by recipient cells, capacity to stabilize and transport biomolecules and their potential for cell/tissue targeting and preferential uptake by cancer cells, they have enormous potential for bioengineering into improved and targeted drug delivery systems. In this work, we investigated the use of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) as a tool to measure the loading of platinum-based chemotherapeutic agents. The EV loading of oxaliplatin via co-incubation was demonstrated, and LA-ICP-MS imaging showed greater efficiency of delivery to colorectal cancer cells compared to free oxaliplatin, leading to enhanced cytotoxic effect. Further, the impact of EV co-loading with a porphyrin (C5SHU, known as 'C5') photosensitizer on oxaliplatin delivery was assessed. Fluorescence analysis using nano-flow cytometry showed dose-dependent EV loading as well as a trend towards the loading of larger particles. Exposure of OXA-C5-EV-treated colorectal cancer cells to light indicated that delivery was enhanced by both light exposure and porphyrins, with a synergistic effect on cell viability observed between oxaliplatin, EVs and light exposure after the delivery of the co-loaded EVs. In summary, this work demonstrates the utility of LA-ICP-MS and mass spectrometry imaging in assessing the loading efficiency and cellular delivery of platinum-based therapeutics, which would also be suitable for agents containing other elements, confirms that EVs are more efficient at delivery compared to free drugs, and describes the use of light exposure in optimizing delivery and therapeutic effects of EV-mediated drug delivery both in combination and independently of porphyrin-based photosensitizers.

Durability of protection and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) COVID-19 vaccine over 6 months.

BackgroundWe report updated safety, efficacy, and immunogenicity of AZD1222 (ChAdOx1 nCoV-19) from an ongoing phase 3 trial.MethodsAdults at increased risk of SARS-CoV-2 infection were randomized (2:1), stratified by age, to receive 2 doses of AZD1222 or placebo. The primary efficacy end point was confirmed SARS-CoV-2 reverse-transcriptase PCR-positive (RT-PCR-positive) symptomatic COVID-19 at 15 or more days after a second dose in baseline SARS-CoV-2-seronegative participants. The 21,634 and 10,816 participants were randomized to AZD1222 and placebo, respectively.FindingsData cutoff for this analysis was July 30, 2021; median follow-up from second dose was 78 and 71 days for the double-blind period (censoring at unblinding or nonstudy COVID-19 vaccination) and 201 and 82 days for the period to nonstudy COVID-19 vaccination (regardless of unblinding) in the AZD1222 and placebo groups, respectively. For the primary efficacy end point in the double-blind period (141 and 184 events; incidence rates: 39.2 and 118.8 per 1,000 person years), vaccine efficacy was 67.0% (P < 0.001). In the period to nonstudy COVID-19 vaccination, incidence of events remained consistently low and stable through 6 months in the AZD1222 group; for the primary efficacy end point (328 and 219 events; incidence rates: 36.4, 108.4) and severe/critical disease (5 and 13 events; incidence rates: 0.6, 6.4), respective vaccine efficacy estimates were 65.1% and 92.1%. AZD1222 elicited humoral immune responses over time, with waning at day 180. No emergent safety issues were seen.ConclusionAZD1222 is safe and well tolerated, demonstrating durable protection and immunogenicity with median follow-up (AZD1222 group) of 6 months.Trial registrationClinicalTrials.gov NCT04516746.FundingAstraZeneca; US government.

Less Is More: A Multimodal Pain Management Strategy Is Associated With Reduced Opioid Use in Hospitalized Trauma Patients.

INTRODUCTION: Adequate pain control is critical to the management and recovery of acutely injured patients. Opioids are associated with various adverse effects, and drug overdose is the leading cause of injury-related death in the United States. We hypothesized that a multimodal pain management protocol would reduce opioid use while still optimizing pain control. METHODS: The study included the preanalysis (August 2017-September 2018) and postanalysis (October 2018-August 2019) of a multimodal pain management strategy implemented in hospitalized adult patients admitted to the trauma service at a single American College of Surgeons-verified level-1 trauma center. Patients less than 18 y of age, pregnant patients, or imprisoned patients were excluded. The primary endpoint was opioid prescription on discharge (morphine milligram equivalent [MME]). The secondary endpoints included inpatient MMEs, nonopioid adjunct use, and pain scores. Subgroup analysis evaluating opioid use based on Injury Severity Score groups (mild, moderate, or severe) and by the Abbreviated Injury Scale body region was performed. RESULTS: There were 1755 patients in the PRE group and 1723 patients in the POST group. MMEs prescribed on discharge decreased from median 15 (interquartile range: 37.5) to 1.2 (interquartile range: 22.5) (P < 0.001). More patients in the POST group were discharged opioid-free (44% versus 37%, P < 0.001). There was a significant increase in the use of all nonopioid pain medications. Pain scores did not change. Subgroup analysis revealed a significant decrease in discharge MMEs in mild and moderate Injury Severity Score groups and in all injured body regions except the chest. CONCLUSIONS: The implementation of a multimodal pain management protocol in trauma patients targeting scheduled nonopioid medications and patient education is feasible and is associated with reduced opioid amount prescribed on discharge, without compromising pain control.

Multiple hominin dispersals into Southwest Asia over the past 400,000 years.

Pleistocene hominin dispersals out of, and back into, Africa necessarily involved traversing the diverse and often challenging environments of Southwest Asia1-4. Archaeological and palaeontological records from the Levantine woodland zone document major biological and cultural shifts, such as alternating occupations by Homo sapiens and Neanderthals. However, Late Quaternary cultural, biological and environmental records from the vast arid zone that constitutes most of Southwest Asia remain scarce, limiting regional-scale insights into changes in hominin demography and behaviour1,2,5. Here we report a series of dated palaeolake sequences, associated with stone tool assemblages and vertebrate fossils, from the Khall Amayshan 4 and Jubbah basins in the Nefud Desert. These findings, including the oldest dated hominin occupations in Arabia, reveal at least five hominin expansions into the Arabian interior, coinciding with brief 'green' windows of reduced aridity approximately 400, 300, 200, 130-75 and 55 thousand years ago. Each occupation phase is characterized by a distinct form of material culture, indicating colonization by diverse hominin groups, and a lack of long-term Southwest Asian population continuity. Within a general pattern of African and Eurasian hominin groups being separated by Pleistocene Saharo-Arabian aridity, our findings reveal the tempo and character of climatically modulated windows for dispersal and admixture.

The expansion of Acheulean hominins into the Nefud Desert of Arabia.

The Arabian Peninsula is a critical geographic landmass situated between Africa and the rest of Eurasia. Climatic shifts across the Pleistocene periodically produced wetter conditions in Arabia, dramatically altering the spatial distribution of hominins both within and between continents. This is particularly true of Acheulean hominins, who appear to have been more tethered to water sources than Middle Palaeolithic hominins. However, until recently, chrono-cultural knowledge of the Acheulean of Arabia has been limited to one dated site, which indicated a hominin presence in Marine Isotope Stages (MIS) 7-6. Here, we report the first dated Acheulean site from the Nefud Desert of northern Saudi Arabia, together with palaeoecological evidence for an associated deep, probably fresh-water, lake. The site of An Nasim features varied and often finely flaked façonnage handaxes. Luminescence ages together with geomorphological and palaeoecological evidence indicates that the associated artefacts date to MIS 9. At present, An Nasim represents the oldest yet documented Acheulean sites in Arabia, and adds to a growing picture of regionally diverse stone tool assemblages used by Middle Pleistocene hominins, and likely indicative of repeated population re-entry into the peninsula in wet 'Green Arabia' phases.

The pitfalls and virtues of population genetic summary statistics: Detecting selective sweeps in recent divergences.

During evolution, genomes are shaped by a plethora of forces that can leave characteristic signatures. A common goal when studying diverging populations is to detect the signatures of selective sweeps, which can be rather difficult in complex demographic scenarios, such as under secondary contact. Moreover, the detection of selective sweeps, especially in whole-genome data, often relies heavily on a narrow set of summary statistics that are affected by a multitude of factors, frequently leading to false positives and false negatives. Simulating genomic regions makes it possible to control these demographic and population genetic factors. We used simulations of large genomic regions to determine how different secondary contact and sympatric speciation scenarios affect the footprint of hard and soft selective sweeps in the presence of varying degrees of gene flow and recombination. We explored the ability of an array of population genetic summary statistics to detect the footprints of these selective sweeps under specific demographies. We focussed on metrics that do not require phased data or ancestral sequences and therefore have wide applicability. We found that a newly developed beta diversity measure, B¯GD utperformed all other metrics in detecting selective sweeps and that FST also performed well. High accuracy was also found in Δπ and genotype distance-derived metrics. The performance of most metrics strongly depended on factors such as the presence of an allopatric phase, migration rates, recombination, population growth, and whether the sweep was hard or soft. We provide suggestions for locating and analysing the response to selective sweeps in whole-genome data.

Correction to: The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study.

Unfortunately, 'Present address' was omitted from one of the addresses provided for Mark I. McCarthy (#26).

The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes: an IMI DIRECT study.

AIMS/HYPOTHESIS: It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N ≤ 920) or with recently diagnosed type 2 diabetes (cohort 2: N ≤ 435). METHODS: We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MRI, and physical activity through wrist-worn triaxial accelerometry. Results are presented as standardised beta coefficients, SE and p values, respectively. RESULTS: The TC and TC-PA models showed better fit than null models (TC: χ2 = 242, p = 0.004 and χ2 = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ2 = 180, p = 0.041 and χ2 = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. CONCLUSIONS/INTERPRETATION: These analyses partially support the mechanisms proposed in the twin-cycle model and highlight mechanistic pathways through which insulin sensitivity and liver fat mediate the association between physical activity and glycaemic control.

Correction to: Physical activity intensity, bout-duration, and cardiometabolic risk markers in children and adolescents.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Doctors Rule: An Analysis of Health Ministers' Diaries in Australia.

Limited progress in nutrition policy action is often blamed on the close relationships the food industry has with health policy decision-makers. This analysis sought to examine this belief through the analysis of health ministers' diaries. Entries were downloaded from health ministers' diaries from two states in Australia from January 2013 to June 2018. Entries were coded according to which interest group met with the minister or whether general parliamentary business was undertaken. Coding was also undertaken for any meeting topics related to nutrition policy. Analysis of health ministers' diaries found that the food industry has limited documented interaction with the two state health ministers in Australia. Instead, medical associations, private hospitals and health services, and sporting associations (rugby league associations) had the most interactions with health ministers. Poor representation was seen on nutrition issues, and there was an apparent lack of nutrition advocates interacting with the health ministers. There are opportunities for nutrition advocates to increase their level of interaction with state health ministers. This could include building alliances with medical associations, as they are in a powerful position, to advocate directly to health ministers. Health ministers' diaries can provide valuable insights into who is meeting officially with ministers. However, there are also limitations with the dataset.

Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium.

AIMS/HYPOTHESIS: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up). METHODS: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at ~18 months (both cohorts) and at ~48 months (cohort 1) or ~36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe. RESULTS: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean ± SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m2; fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m2; fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l. CONCLUSIONS/INTERPRETATION: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.

Specific physical activities, sedentary behaviours and sleep as long-term predictors of accelerometer-measured physical activity in 91,648 adults: a prospective cohort study.

BACKGROUND: The evidence for the prospective relationships between specific physical activities (PA), sedentary behaviours (SB) and sleep on subsequent total PA levels is scarce. The purpose of this study was to examine prospective associations of self-reported PA, SB and sleep, and changes in these with subsequent accelerometer-measured PA. METHODS: A sub-sample of 91,648 UK Biobank participants reported moderate-to-vigorous PA (MVPA), lifestyle activities, TV viewing, computer use and sleep through screen-based questionnaires at baseline (2006-2010), and provided valid accelerometry data (dominant wrist-worn for 7 days between 2013 and 2015). A further sub-sample of 7709 participants repeated the screen-based questionnaires between 2012 and 2013. RESULTS: In both women (n = 51,545) and men (n = 40,103), positive associations were observed between all self-reported measures of PA at baseline (MVPA, lifestyle/job-related activities, active transporting modes) and accelerometer-measured PA levels at follow-up (median 5.7 years); an exception was 'walking/standing at work' in women. Sedentary time at work, TV viewing and computer use were inversely associated with PA at follow-up. Sleeping either more or less than 7 h/day at baseline was associated with lower PA at follow-up (except for ≤6 h/day in men). In the repeat self-report sub-sample (median 4.3 years), relatively higher physical activity at follow-up was observed in those who maintained or achieved favourable levels of MVPA, walking for pleasure, strenuous sports, other exercises, heavy DIY (in women), heavy physical work, and walking/standing at work (in women), sedentary time at work, getting about methods (in women), commuting methods (in women), TV viewing, computer use or sleep. CONCLUSIONS: Initial levels of PA, SB and sleep, and changes in these variables were generally associated with subsequent accelerometer-measured PA in the expected directions, suggesting these specific behaviours all contribute to the total volume of physical activity over time and could thus be targets for intervention.

Characteristics of hardware failure in patients undergoing surgical stabilization of rib fractures: A Chest Wall Injury Society multicenter study.

BACKGROUND: Surgical stabilization of rib fractures (SSRF) is increasingly used for severe rib fractures/flail chest. There are no reports discussing mechanisms of failure of implanted hardware, its clinical presentation, or consequences. The purpose of this study was to evaluate the incidence, presenting signs, and clinical sequela of hardware failure after SSRF. METHODS: A multicenter, retrospective study was performed by a group of surgeons with a large SSRF case volume. All cases with known hardware failure from January 1, 2010, to December 31, 2017, were included. The surgeon's experience at the time of hardware implantation, specific implant used, number of failures the surgeon had experienced with the same system, and time from implantation to hardware failure were recorded. Additionally, patient demographics, including age, comorbid conditions, and number and location of rib fractures were recorded. Symptomatology associated with hardware failure and need for explant and/or reimplantation of hardware was also recorded. Nonparametric statistical tests were used to compare cohorts. RESULTS: Of 1,224 patients who underwent SSRF, 38 patients with 233 rib fractures and 279 fracture segments experienced hardware failure and were enrolled in the study. Twelve patients presented more than 3 months following injury. Median age was 54 years old and 34% were active smokers. One hundred forty-four plates were implanted with a median of four plates per patient. Median number of SSRF cases by each surgeon was 100 (range, 1-280). Fractures and hardware failure were most frequent in the anterolateral/lateral region. Hardware failure was mostly due to screw migration and plate fracture. Hardware failure was asymptomatic in 40% and presented as pain in 42% of cases. Fifty-five percent of the cases required explantation of hardware, and only 10% required SSRF again. There was no difference between the acute and chronic fracture cohorts. CONCLUSION: Hardware failure after SSRF is rare and often asymptomatic. When present, it rarely requires redo SSRF. LEVEL OF EVIDENCE: Therapeutic, level V.

Estimating energy expenditure from wrist and thigh accelerometry in free-living adults: a doubly labelled water study.

BACKGROUND: Many large studies have implemented wrist or thigh accelerometry to capture physical activity, but the accuracy of these measurements to infer activity energy expenditure (AEE) and consequently total energy expenditure (TEE) has not been demonstrated. The purpose of this study was to assess the validity of acceleration intensity at wrist and thigh sites as estimates of AEE and TEE under free-living conditions using a gold-standard criterion. METHODS: Measurements for 193 UK adults (105 men, 88 women, aged 40-66 years, BMI 20.4-36.6 kg m-2) were collected with triaxial accelerometers worn on the dominant wrist, non-dominant wrist and thigh in free-living conditions for 9-14 days. In a subsample (50 men, 50 women) TEE was simultaneously assessed with doubly labelled water (DLW). AEE was estimated from non-dominant wrist using an established estimation model, and novel models were derived for dominant wrist and thigh in the non-DLW subsample. Agreement with both AEE and TEE from DLW was evaluated by mean bias, root mean squared error (RMSE), and Pearson correlation. RESULTS: Mean TEE and AEE derived from DLW were 11.6 (2.3) MJ day-1 and 49.8 (16.3) kJ day-1 kg-1. Dominant and non-dominant wrist acceleration were highly correlated in free-living (r = 0.93), but less so with thigh (r = 0.73 and 0.66, respectively). Estimates of AEE were 48.6 (11.8) kJ day-1 kg-1 from dominant wrist, 48.6 (12.3) from non-dominant wrist, and 46.0 (10.1) from thigh; these agreed strongly with AEE (RMSE ~12.2 kJ day-1 kg-1, r ~ 0.71) with small mean biases at the population level (~6%). Only the thigh estimate was statistically significantly different from the criterion. When combining these AEE estimates with estimated REE, agreement was stronger with the criterion (RMSE ~1.0 MJ day-1, r ~ 0.90). CONCLUSIONS: In UK adults, acceleration measured at either wrist or thigh can be used to estimate population levels of AEE and TEE in free-living conditions with high precision.