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.

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.

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.

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 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.

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.

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.

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.

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.

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.

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

OBJECTIVES: To determine the role of physical activity intensity and bout-duration in modulating associations between physical activity and cardiometabolic risk markers. METHODS: A cross-sectional study using the International Children's Accelerometry Database (ICAD) including 38,306 observations (in 29,734 individuals aged 4-18 years). Accelerometry data was summarized as time accumulated in 16 combinations of intensity thresholds (≥500 to ≥3000 counts/min) and bout-durations (≥1 to ≥10 min). Outcomes were body mass index (BMI, kg/m2), waist circumference, biochemical markers, blood pressure, and a composite score of these metabolic markers. A second composite score excluded the adiposity component. Linear mixed models were applied to elucidate the associations and expressed per 10 min difference in daily activity above the intensity/bout-duration combination. Estimates (and variance) from each of the 16 combinations of intensity and bout-duration examined in the linear mixed models were analyzed in meta-regression to investigate trends in the association. RESULTS: Each 10 min positive difference in physical activity was significantly and inversely associated with the risk factors irrespective of the combination of intensity and bout-duration. In meta-regression, each 1000 counts/min increase in intensity threshold was associated with a -0.027 (95% CI: -0.039 to -0.014) standard deviations lower composite risk score, and a -0.064 (95% CI: -0.09 to -0.038) kg/m2 lower BMI. Conversely, meta-regression suggested bout-duration was not significantly associated with effect-sizes (per 1 min increase in bout-duration: -0.002 (95% CI: -0.005 to 0.0005) standard deviations for the composite risk score, and -0.005 (95% CI: -0.012 to 0.002) kg/m2 for BMI). CONCLUSIONS: Time spent at higher intensity physical activity was the main determinant of variation in cardiometabolic risk factors, not bout-duration. Greater magnitude of associations was consistently observed with higher intensities. These results suggest that, in children and adolescents, physical activity, preferably at higher intensities, of any bout-duration should be promoted.

Descriptive epidemiology of changes in objectively measured sedentary behaviour and physical activity: six-year follow-up of the EPIC-Norfolk cohort.

BACKGROUND: Sedentary time increases and total physical activity decreases with age. The magnitude and correlates of changes in sedentary time, light-intensity physical activity (LPA), moderate-to-vigorous intensity physical activity (MVPA), and overall physical activity remain unclear. We quantified these changes and identified their individual and sociodemographic correlates. METHODS: We used data from 1259 adults (67.8 ± 6.9 years; 41.9% women) who participated in the EPIC-Norfolk Study. Activity was assessed at baseline (2004-2011) and follow-up (2012-2016) for 7 days using accelerometers. Potential correlates of change were specified a priori. We used unadjusted and adjusted sex-stratified linear regressions to identify correlates of change. RESULTS: Only 3.7% of adults met the current MVPA recommendations. Sedentary time increased by 3.0 min/day/year (SD = 12.3). LPA, MVPA, and overall PA decreased by 1.7 min/day/year (SD = 5.4), 3.0 min/day/year (SD = 6.0), and 8.8 cpm/year (SD = 18.8), respectively. Correlates of greater rates of increase in sedentary time included older age and higher BMI in men, and older age, higher BMI, smoking, and urban dwelling in women. Correlates of greater rates of decrease in physical activity included older age, higher BMI, living alone, depression, car use, and/or fair/poor self-rated health in men, and older age, higher BMI, depression, smoking, and/or urban dwelling in women (e.g. depressed women had a 1.0 min/day/year greater rate of decline in MVPA than non-depressed women, 95% CI -1.8, - 0.2). CONCLUSIONS: Most (> 95%) adults are insufficiently active. Sedentary time increases and LPA, MVPA and overall physical activity decreases over time, with more pronounced rates of change observed in specific sub-groups (e.g. among older and depressed adults). To promote active living, the correlates of these changes should be considered in future interventions.

The combination of cardiorespiratory fitness and muscle strength, and mortality risk.

Little is known about the combined associations of cardiorespiratory fitness (CRF) and hand grip strength (GS) with mortality in general adult populations. The purpose of this study was to compare the relative risk of mortality for CRF, GS, and their combination. In UK Biobank, a prospective cohort of > 0.5 million adults aged 40-69 years, CRF was measured through submaximal bike tests; GS was measured using a hand-dynamometer. This analysis is based on data from 70,913 men and women (832 all-cause, 177 cardiovascular and 503 cancer deaths over 5.7-year follow-up) who provided valid CRF and GS data, and with no history of heart attack/stroke/cancer at baseline. Compared with the lowest CRF category, the hazard ratio (HR) for all-cause mortality was 0.76 [95% confidence interval (CI) 0.64-0.89] and 0.65 (95% CI 0.55-0.78) for the middle and highest CRF categories, respectively, after adjustment for confounders and GS. The highest GS category had an HR of 0.79 (95% CI 0.66-0.95) for all-cause mortality compared with the lowest, after adjustment for confounders and CRF. Similar results were found for cardiovascular and cancer mortality. The HRs for the combination of highest CRF and GS were 0.53 (95% CI 0.39-0.72) for all-cause mortality and 0.31 (95% CI 0.14-0.67) for cardiovascular mortality, compared with the reference category of lowest CRF and GS: no significant association for cancer mortality (HR 0.70; 95% CI 0.48-1.02). CRF and GS are both independent predictors of mortality. Improving both CRF and muscle strength, as opposed to either of the two alone, may be the most effective behavioral strategy to reduce all-cause and cardiovascular mortality risk.

The Influence of Objectively Measured Physical Activity During Pregnancy on Maternal and Birth Outcomes in Urban Black South African Women.

Objectives Research indicates the beneficial effects of physical activity during pregnancy on maternal health, although controversy still exists regarding its influence on birth outcomes. Little research has been done to objectively measure physical activity during pregnancy in black African women from low-to-middle income countries. The purpose of this study was to examine the association between physical activity and maternal and birth outcomes in this unique population. Methods This observational, longitudinal study assessed total physical activity using a hip-mounted triaxial accelerometer at 14-18 weeks (second trimester, n = 120) and 29-33 weeks (third trimester, n = 90) gestation. Physical activity is expressed as gravity-based acceleration units (mg). Maternal outcomes included both weight and weight gain at 29-33 weeks gestation. Birth outcomes included gestational age, birth weight, ponderal index and Apgar score, measured within 48 h of delivery. Results There was a significant decline in physical activity from the second to the third trimester (12.8 ± 4.1 mg vs. 9.7 ± 3.6 mg, p ≤ 0.01). Physical activity at 29-33 weeks as well as a change in PA was inversely associated with weight change at 29-33 weeks (ß = - 0.24; 95% CI - 0.49; - 0.00; p = 0.05 and ß = - 0.36; 95% CI - 0.62; - 0.10; p = 0.01, respectively). No significant associations were found between physical activity and birth outcomes. Conclusions for Practice Physical activity during pregnancy may be an effective method to control gestational weight gain, whilst presenting no adverse risk for fetal development, in women from a low-income urban setting.

A chronological framework for the British Quaternary based on Bithynia opercula.

Marine and ice-core records show that the Earth has experienced a succession of glacials and interglacials during the Quaternary (last ∼2.6 million years), although it is often difficult to correlate fragmentary terrestrial records with specific cycles. Aminostratigraphy is a method potentially able to link terrestrial sequences to the marine isotope stages (MIS) of the deep-sea record. We have used new methods of extraction and analysis of amino acids, preserved within the calcitic opercula of the freshwater gastropod Bithynia, to provide the most comprehensive data set for the British Pleistocene based on a single dating technique. A total of 470 opercula from 74 sites spanning the entire Quaternary are ranked in order of relative age based on the extent of protein degradation, using aspartic acid/asparagine (Asx), glutamic acid/glutamine (Glx), serine (Ser), alanine (Ala) and valine (Val). This new aminostratigraphy is consistent with the stratigraphical relationships of stratotypes, sites with independent geochronology, biostratigraphy and terrace stratigraphy. The method corroborates the existence of four interglacial stages between the Anglian (MIS 12) and the Holocene in the terrestrial succession. It establishes human occupation of Britain in most interglacial stages after MIS 15, but supports the notion of human absence during the Last Interglacial (MIS 5e). Suspicions that the treeless 'optimum of the Upton Warren interstadial' at Isleworth pre-dates MIS 3 are confirmed. This new aminostratigraphy provides a robust framework against which climatic, biostratigraphical and archaeological models can be tested.

Steps Toward Recapitulating Endothelium: A Perspective on the Next Generation of Hemocompatible Coatings.

Endothelium, the lining in this blood vessel, orchestrates three main critical functions such as protecting blood components, modulating of hemostasis by secreting various inhibitors, and directing clot digestion (fibrinolysis) by activating tissue plasminogen activator. No other surface can perform these tasks; thus, the contact of blood and blood-contacting medical devices inevitably leads to the activation of coagulation, often causing device failure, and thromboembolic complications. This perspective, first, discusses the biological mechanisms of activation of coagulation and highlights the efforts of advanced coatings to recapitulate one characteristic of endothelium, hereafter single functions of endothelium and noting necessity of the synergistic integration of its three main functions. Subsequently, it is emphasized that to overcome the challenges of blood compatibility an endothelium-mimicking system is needed, proposing a synergy of bottom-up synthetic biology, particularly synthetic cells, with passive- and bioactive surface coatings. Such integration holds promise for developing advanced biomaterials capable of recapitulating endothelial functions, thereby enhancing the hemocompatibility and performance of blood-contacting medical devices.

Rational design and in vitro testing of new urease inhibitors to prevent urinary catheter blockage.

Catheter associated urinary tract infections (CAUTI) caused by urease-positive organisms can lead to catheter blockage: urease metabolizes urea in urine to ammonia causing an increase in pH and hence precipitation of struvite and apatite salts into the catheter lumen and bladder leading to blockage. Acetohydroxamic acid (AHA) is the only urease inhibitor currently approved for patient use, however, it is rarely used owing to its side effects. Here, we report the identification and development of new urease inhibitors discovered using a rational in silico drug design approach. A series of compounds were designed, the compounds were screened and filtered to identify three compounds which were tested in in vitro urease activity assays. N,N'-Bis(3-pyridinylmethyl)thiourea (Bis-TU) outperformed AHA in activity assays and was tested in an in vitro bladder model, where it significantly extended the lifetime of the catheter compared to AHA. Bis-TU was delivered via a diffusible balloon catheter directly to the site of activity, thus demonstrating localized drug delivery. This cost-effective drug design approach allowed the identification of a potent urease inhibitor, which could be improved through iterative repeats of the method, and the process of design could be utilized to target other diseases.

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.