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The rapid finding of effective therapeutics requires efficient use of available resources in clinical trials. Covariate adjustment can yield statistical estimates with improved precision, resulting in a reduction in the number of participants required to draw futility or efficacy conclusions. We focus on time-to-event and ordinal outcomes. When more than a few baseline covariates are available, a key question for covariate adjustment in randomised studies is how to fit a model relating the outcome and the baseline covariates to maximise precision. We present a novel theoretical result establishing conditions for asymptotic normality of a variety of covariate-adjusted estimators that rely on machine learning (e.g., ℓ1-regularisation, Random Forests, XGBoost, and Multivariate Adaptive Regression Splines [MARS]), under the assumption that outcome data are missing completely at random. We further present a consistent estimator of the asymptotic variance. Importantly, the conditions do not require the machine learning methods to converge to the true outcome distribution conditional on baseline variables, as long as they converge to some (possibly incorrect) limit. We conducted a simulation study to evaluate the performance of the aforementioned prediction methods in COVID-19 trials. Our simulation is based on resampling longitudinal data from over 1500 patients hospitalised with COVID-19 at Weill Cornell Medicine New York Presbyterian Hospital. We found that using ℓ1-regularisation led to estimators and corresponding hypothesis tests that control type 1 error and are more precise than an unadjusted estimator across all sample sizes tested. We also show that when covariates are not prognostic of the outcome, ℓ1-regularisation remains as precise as the unadjusted estimator, even at small sample sizes (n=100). We give an R package adjrct that performs model-robust covariate adjustment for ordinal and time-to-event outcomes.

Allogeneic haematopoietic cell transplantation (HCT) replaces the stem cells responsible for blood production with those harvested from a donor, and is received by 40,000 patients worldwide each year. To quantify dynamics of long-term stem cell engraftment, we sequenced whole genomes of 2,824 single-cell-derived haematopoietic colonies from blood samples of 10 donor-recipient pairs taken 9-31 years after HLA-matched sibling HCT. With younger donors, 10,000–50,000 stem cells had engrafted and were still contributing to haematopoiesis at time of sampling, but estimates were 10-fold lower with older donors. Engrafted stem cells made multilineage contributions to myeloid, B-lymphoid and T-lymphoid populations, although individual clones often showed biases towards one or other mature cell type. Recipients had lower clonal diversity than matched donors, equivalent to ~10-15 years of additional ageing, arising from up to 25-fold greater expansion of stem cell clones. An HCT-related population bottleneck alone could not explain these differences: instead, phylogenetic trees evinced two distinct modes of HCT-specific selection. In ‘pruning selection’, cell divisions underpinning recipient-enriched clonal expansions had occurred in the donor, preceding transplant – their selective advantage derived from preferential mobilisation, harvest, survival ex vivo or initial homing. In ‘growth selection’, cell divisions underpinning clonal expansion occurred through proliferative advantage in the recipient’s marrow after homing – clones with multiple driver mutations especially demonstrated this pattern. Uprooting stem cells from their native environment and transplanting them to foreign soil exaggerates selective pressures, distorting and accelerating the loss of clonal diversity compared to the unperturbed haematopoiesis of donors.

Background: Fractures of the proximal fifth metatarsal bone are common injuries in elite athletes and are associated with high rates of delayed union and nonunion. Structural features of the foot may increase fracture risk in some individuals, emphasizing the need for intervention strategies to prevent fracture. Although orthotic devices have shown promise in reducing fractures of the fifth metatarsal bone, the effect of orthosis on fifth metatarsal strains is not well understood. Purpose: To quantify the effects of different foot orthotic constructs on principal tensile strains in the proximal fifth metatarsal bone during cadaveric simulations of level walking. An additional purpose was to investigate the relationships between structural features of the foot and corresponding strains on the fifth metatarsal bone during level walking. Study Design: Controlled laboratory study. Methods: A total of 10 midtibial cadaveric specimens were attached to a 6 degrees of freedom robotic gait simulator. Strain gauges were placed at the metaphyseal-diaphyseal junction (zone II) and the proximal diaphysis (zone III) during level walking simulations using 11 different foot orthotic configurations. Images of each specimen were used to measure structural features of the foot in an axially loaded position. The peak tensile strains were measured and reported relative to the sneaker-only condition for each orthotic condition and orthotic-specific association between structural features and principal strains of both zones. Results: In total, 2 of the 11 orthotic conditions significantly reduced strain relative to the sneaker-only condition in zone II. Further, 6 orthotic conditions significantly reduced strain relative to the sneaker-only condition in zone III. Increased zone II principal strain incurred during level walking in the sneaker-only condition showed a significant association with increases in the Meary’s angle. Changes in zone III principal strain relative to the sneaker-only condition were significantly associated with increases in the Meary’s angle and fourth-fifth intermetatarsal angle. Conclusion: The use of orthotic devices reduced principal strain relative to the condition of a sneaker without any orthosis in zone II and zone III. The ability to reduce strain relative to the sneaker-only condition in zone III was indicated by increasing values of the Meary’s angle and levels of the fourth-fifth intermetatarsal angle. Clinical Relevance: Clinicians can use characteristics of foot structure to determine the proper foot orthosis to potentially reduce stress fracture risk in high-risk individuals.

Over the last decade, there have been a number of new observational records of Arctic sea ice thickness produced, with improved spatiotemporal coverage, that can allow researchers to better understand the Arctic sea ice system. In this study we use a newly developed sea ice data assimilation system CICE-PDAF, to reanalyse the Arctic sea ice cover over the satellite era. In various combinations we assimilate a year-round sea ice thickness cover and a sub-grid scale sea ice thickness distribution alongside sea ice concentration observations. The assimilation of year-round sea ice thickness provides substantial improvements to the modelled sea ice thickness in comparison to independent observations. The assimilation also has significant consequences on the modelled distribution of the ice thickness across the Arctic, particularly in regions of multi-year ice, and regional model biases are reduced in the reanalyses.

Respiratory infections place a significant burden on individuals, healthcare systems and society. This short report discusses early findings from an ongoing longitudinal survey study as part of the wider Community Action on Respiratory Infections Cymru (CARI) study. An initial baseline survey was sent to a large sample of predominately older adults in Wales in December 2022 and January 2023 (n=3476) (f = 63%; white = 98%; age, M=62.94 (SD=12.83)). Follow-up ‘symptom surveys’ are being sent to random sub-samples of the overall sample at regular intervals throughout winter 2022/3. Results find that intentions to get future COVID-19 vaccinations are high, but that prevalence of infection-reducing behaviours was generally low. Additionally, although overall worry about respiratory infections was relatively low, there was greater worry about COVID-19 relative to flu and other viruses. Amongst those experiencing symptoms, flu was perceived as the most common cause, and a high temperature, continuous cough and fever were most likely to lead people to take specific precautions like taking a COVID-19 test or seeking medical advice. Findings have implications for public health, including the need to provide nuanced but clear public health information and guidance on what actions to take when people are experiencing symptoms of a respiratory illness.

Morgagni’s hernia (MH) is a congenital diaphragmatic hernia with a small percentage of cases diagnosed in adulthood. The average age of diagnosis is 57 years, with 61% being female and 10–28% being asymptomatic. It is common practice to complete surgical repair of MH regardless of symptomology or size of the defect despite a paucity of evidence. This paper highlights the potential for non-operative management as a reasonable treatment option in large asymptomatic MH. A female in her 40s was referred following an abnormal spirometry result as a part of a routine pre-employment check. She subsequently had imaging, which showed a large MH with abdominal contents within the thoracic cavity. Following discussion at a multidisciplinary team meeting, it was decided that the risk of perioperative morbidity likely exceeded the risk of strangulation while asymptomatic, and thus surveillance was recommended.

The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20–30 cancer genes1–8. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease9–13 than in normal liver13–16, which enables positive selection to shape the genomic landscape9–13. Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease. Seven of the 29 patients with liver disease had mutations in FOXO1, the major transcription factor in insulin signalling. These mutations affected a single hotspot within the gene, impairing the insulin-mediated nuclear export of FOXO1. Notably, six of the seven patients with FOXO1S22W hotspot mutations showed convergent evolution, with variants acquired independently by up to nine distinct hepatocyte clones per patient. CIDEB, which regulates lipid droplet metabolism in hepatocytes17–19, and GPAM, which produces storage triacylglycerol from free fatty acids20,21, also had a significant excess of mutations. We again observed frequent convergent evolution: up to fourteen independent clones per patient with CIDEB mutations and up to seven clones per patient with GPAM mutations. Mutations in metabolism genes were distributed across multiple anatomical segments of the liver, increased clone size and were seen in both alcohol-related liver disease and non-alcoholic fatty liver disease, but rarely in hepatocellular carcinoma. Master regulators of metabolic pathways are a frequent target of convergent somatic mutation in alcohol-related and non-alcoholic fatty liver disease. Whole-genome sequencing analysis of somatic mutations in liver samples from patients with chronic liver disease identifies driver mutations in metabolism-related genes such as FOXO1, and shows that these variants frequently exhibit convergent evolution.

OBJECTIVE The study explored the impacts of an economic crisis – the UK’s ‘cost of living crisis’ – on mental and physical health from the perspectives of people themselves. It also explored how people coping with this crisis, and as a secondary objective, explored if, and if so how, the COVID-19 pandemic was shaping, their experiences or views of the cost of living crisis.DESIGN This qualitative study consisted of online focus groups carried out between September 14th- 29th 2022. Data were analysed using a thematic approach.SETTING Focus groups took place via (Zoom) videoconferencing.PARTICIPANTS Participants (n= 28) were all UK adults, recruited as part of the Public Views during the Covid Pandemic (PVCOVID) study.RESULTS Most participants, and particularly those on low or insecure income or living in deprived communities, felt that the cost of living crisis was having negative impact on their mental and emotional health and wellbeing. Analysis generated five main themes, three related to why the cost of living crisis was affecting their health: (1) Anxiety over an uncertain future; (2) Worry about others; (3) A loss of control and two related to the ways in which people were coping, or trying to cope, with the crisis: (1) Resilience and Family and community support. CONCLUSIONS. This study found that the cost of living crisis is having significant impacts on health, particularly on the mental health of those on low- or insecure-incomes or from deprived communities. Further research and policy investment is needed to explore ways to provide emotional as well as practical/financial support for those most vulnerable to economic crises.

This study examines language ideologies and communicative practices in the multilingual Vaupes region of northwestern Amazonia. Following a comparative overview of the Vaupes as a ‘small-scale’ language ecology, it discusses claims from existing ethnographic work on the region in light of data from a corpus of video-recordings of sociolinguistic interviews and spontaneous everyday conversations. It shows how a practice-based and interdisciplinary approach combining language documentation methodology and ethnographic, structural linguistic, and interactional perspectives can contribute to understanding of macro and micro aspects of multilingualism, thus contributing to future work on the Vaupes, typologies of small-scale multilingual ecologies, and language contact research.

The purpose of this inquiry is to explore the family members’ experience in a family with a breast cancer survivor. This study examined family role shifts. Our research originated from two focus gr...

The magnitude of the electrostatic potential at the surface of a mixed ionic-electronic conducting (MIEC) solid-oxide cell (SOC) electrode is dependent on the intrinsic dipole moment of adsorbed gas species. Using density functional theory, we have investigated the electrostatic nature of hydroxyl adsorbates and the kinetics of electron transfer in the water electrolysis reaction at the pristine ceria-gas interface. First principles data ware used in a generalised kinetic model to predict reaction kinetics near equilibrium and under an applied overpotential. The mechanistic understanding gained from this model is widely applicable to a range of MIEC systems and provides a basis upon which the operating conditions can be tailored.

Background: The Lapidus procedure and scarf osteotomy are indicated for the operative treatment of hallux valgus; however, no prior studies have compared outcomes between the procedures. The aim of this study was to compare clinical and radiographic outcomes between patients with symptomatic hallux valgus treated with the modified Lapidus procedure versus scarf osteotomy. Methods: This retrospective cohort study included patients treated by 1 of 7 fellowship-trained foot and ankle surgeons. Inclusion criteria were age older than 18 years, primary modified Lapidus procedure or scarf osteotomy for hallux valgus, minimum 1-year postoperative Patient-Reported Outcomes Measurement Information System (PROMIS) scores, and minimum 3-month postoperative radiographs. Revision cases were excluded. Clinical outcomes were assessed using 6 PROMIS domains. Pre- and postoperative radiographic parameters were measured on anteroposterior (AP) and lateral weightbearing radiographs. Statistical analysis utilized targeted minimum-loss estimation (TMLE) to control for confounders. Results: A total of 136 patients (73 Lapidus, 63 scarf) with an average of 17.8 months of follow-up were included in this study. There was significant improvement in PROMIS physical function scores in the modified Lapidus (mean change, 5.25; P < .01) and scarf osteotomy (mean change, 5.50; P < .01) cohorts, with no significant differences between the 2 groups ( P = .85). After controlling for bunion severity, the probability of having a normal postoperative intermetatarsal angle (IMA; Conclusion: Although the modified Lapidus procedure led to a higher probability of achieving a normal IMA, both procedures yielded similar improvements in 1-year patient-reported outcome measures. Level of Evidence: Level III, retrospective cohort.

The ontogeny of the human haematopoietic system during fetal development has previously been characterized mainly through careful microscopic observations1. Here we reconstruct a phylogenetic tree of blood development using whole-genome sequencing of 511 single-cell-derived haematopoietic colonies from healthy human fetuses at 8 and 18 weeks after conception, coupled with deep targeted sequencing of tissues of known embryonic origin. We found that, in healthy fetuses, individual haematopoietic progenitors acquire tens of somatic mutations by 18 weeks after conception. We used these mutations as barcodes and timed the divergence of embryonic and extra-embryonic tissues during development, and estimated the number of blood antecedents at different stages of embryonic development. Our data support a hypoblast origin of the extra-embryonic mesoderm and primitive blood in humans. Whole-genome sequencing of haematopoietic colonies from human fetuses reveals the somatic mutations acquired by individual progenitors, which are used as barcodes to construct a phylogenetic tree of blood development.

Objectives The study explored public attitudes and behaviours in relation to COVID-19 two years into the pandemic. Design This Qualitative study consisted of online focus groups carried out between 15th-30th June 2022. Data were analysed using a framework approachSetting Focus groups took place via online videoconferencingParticipants Participants (n= 28) were all UK residents aged 18 years or older, representing a range of gender and ethnic backgrounds, invited from the Public Views during the Covid Pandemic (PVCOVID) study.Results Most participants reported feeling ‘back to normal’, not having thought much about COVID-19 recently, and were not wearing masks or socially distancing. Lack of media coverage was a big factor cited, as was the perception that new variants were ‘milder.’ A minority of participants were still wearing masks or socially distancing and some argued they felt ‘reconditioned’ to be more cautious or less socially active. Identifying COVID-19 symptoms, and distinguishing them from flu was challenging, with some suggesting they would test on ‘instinct’ or if they felt very unwell. Intention to take a COVID-19 test and to socially distance if unwell was generally high. There was a modest appetite for future boosters, with those already triple-jabbed suggesting they would receive another dose in future, particularly if it was officially recommended. Some participants argued they would only change their behaviour if the situation was ‘serious’ (e.g. if the death rate increased significantly). Most participants said they would adopt more caution if there was a future wave, although many argued that the lack of trust caused by UK political figures breaking rules (‘Partygate’) would harm future compliance. Conclusions. The study suggests that the ‘Living with COVID’ strategy and the relative lack of media coverage have contributed to a sense of things being ‘back to normal’. If future developments in the pandemic require behavioural change, public health policy and communication will need to overcome this perception and barriers such as a lack of trust in government and the perception of the virus as milder.

Renewable electricity-driven water splitting provides a pathway to manufacturing hydrogen as a promising alternative to fossil fuels. A typical water electrolysis device is comprised of a cathodic hydrogen evolution reaction (HER) and an anodic oxygen evolution reaction (OER). Unfortunately, the OER consumes most of the overall electricity supply while generating negligible economic value, which inhibits the large-scale deployment of the water electrolysis technology. Here, we explored alternatives to the OER and demonstrated that electrooxidation of glycerol (a cheap byproduct of biodiesel and soap production) could lower anodic electricity consumption by up to 0.27 V while producing high-value formic acid with 96.2% faradaic efficiency (FE). Further, glycerol electrooxidation was combined with the photoelectrochemical HER to diminish the electricity requirement to 1.15 V, reducing the electricity consumption by ∼30% relative to typical water electrolysis. This study suggests that solar-assisted co-electrolysis of high-volume block chemicals and water may be an energy efficient and economically viable strategy to realize the sustainable production of value-added chemicals and hydrogen energy.

Sexual double standards tend to marginalize women and restrict their sexual expression in comparison to men. Sexual attitudes can heavily influence women’s propensity to engage in sexual risk behav...

This article analyzes the use of several response particles in face-to-face interaction in Wa’ikhana, an East Tukano language of northwestern Amazonia. Adopting a Conversation Analysis approach, we explore details of each particle, considering their prosodic shapes, the action contexts in which they occur, and their sequential positioning, all crucial to understanding their meanings in interaction. Our analysis shows that Wa’ikhana response particles exhibit both universal and language-particular properties, thus demonstrating the contributions of data from lesser-studied languages to research on language in social interaction, and the value of an interactional approach in the study of under-described, and often endangered, indigenous languages.---------------------------------------------------------------------------------ANALISANDO PARTÍCULAS EM WA’IKHANAEste artigo analisa o uso de um conjunto de partículas responsivas em interação cotidiana em Wa’ikhana, língua da família Tukano Oriental, falada no noroeste amazônico. Adotando a abordagem da Análise de Conversação, exploramos detalhes de cada partícula, considerando sua forma prosódica, o contexto de ação em que ocorre e sua posição sequencial, todos cruciais para o entendimento do seu significado em interação. Nossa análise mostra que partículas responsivas em Wa’ikhana exibem propriedades universais e próprias, demonstrando a contribuição de dados provindos de línguas pouco conhecidas à pesquisa sobre linguagem e interação social, bem como o valor da abordagem interacional no estudo de línguas indígenas pouco estudadas e muitas vezes ameaçadas.---Original em inglês.

Genetic profiles of the bladder Depending on the environment of the individual, the human bladder can be exposed to carcinogens as they are flushed through the body. Lawson et al. and Li et al. examined the genetic composition of laser-dissected microbiopsies from normal and cancer cells collected from the urothelium, a specialized epithelium lining the lower urinary tract (see the Perspective by Rozen). These complementary studies identified the mutational landscape of bladder urothelium through various sequencing strategies and identified high mutational heterogeneity within and between individuals and tumors. Both studies identified mutational profiles related to specific carcinogens such as aristolochic acid and the molecules found in tobacco. These studies present a comprehensive description of the diverse mutational landscape of the human bladder in health and disease, unraveling positive selection for cancer-causing mutations, a diversity of mutational processes, and large differences across individuals. Science , this issue p. 75 , p. 82 ; see also p. 34

Reduction to pole and other transformations of total field magnetic intensity data are often challenging to perform at low magnetic latitudes, when remanent magnetization exists, and when large topographic relief exists. Several studies have suggested the use of inversion‐based equivalent source methods for performing such transformations under those complicating factors. However, there has been little assessment of the importance of erroneous edge effects that occur when fundamental assumptions underlying the transformation procedures are broken. In this work we propose a transformation procedure that utilizes magnetization vector inversion, inversion‐based regional field separation and equivalent source inversion on unstructured meshes. We investigated whether edge effects in transformations could be reduced by performing a regional separation procedure prior to equivalent source inversion. We applied our proposed procedure to the transformation of total field magnetic intensity to all three Cartesian magnetic field components using a complicated synthetic example based on a real geological scenario from mineral exploration. While the procedure performed acceptably on this test example, the results could be improved. We pose many questions regarding the various choices and control parameters used throughout the procedure, but we leave the investigation of those questions to future work.

The economic losses due to grapevine leafroll-associated virus 3 (GLRaV-3) are substantial and vary significantly across California grape regions. We expand a published economic model designed to estimate the losses associated with GLRaV-3 to accommodate the varied production and market conditions that prevail across these regions. This expanded model provides the basis for assessing the value of screening grapevines for GLRaV-3 across the heterogeneous production conditions that prevail in California, which may have important distributional effects in the industry with implications for producers, consumers, and other stakeholders. We estimate that the total potential value of virus screening statewide is roughly $90 million per year, or 1.6% of the estimated $5.5 billion annual value of production of the California grape industry. Nearly 80% of this accrues to regions outside the high-value North Coast winegrape region. The value of screening varies by region and grape type and according to disease management practices, with the highest value accruing to table grapes in the South Central Valley region and white wine grapes in the Central Coast region. We estimate that growers could pay between $3 and $12 per vine for virus screening at establishment, which is higher than the current market price of most vines, and still break even. If nurseries providing screened vines continue to capture only a fraction of this value through higher vine prices, the vast majority will accrue to growers and, ultimately, to consumers through lower retail prices for grapes and wine. The substantial investments in screening capacity in both the private and public sector will likely generate benefits for years to come.

Funder: European Research Council, Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1-4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.

ImportanceCommunication and adoption of modern study design and analytical techniques is of high importance for the improvement of clinical research from observational data.ObjectiveTo compare (1) a modern method for causal inference including a target trial emulation framework and doubly robust estimation to (2) approaches common in the clinical literature such as Cox proportional hazards models. To do this, we estimate the effect of corticosteroids on mortality for moderate-to-severe coronavirus disease 2019 (COVID-19) patients. We use the World Health Organization’s (WHO) meta-analysis of corticosteroid randomized controlled trials (RCTs) as a benchmark.DesignRetrospective cohort study using longitudinal electronic health record data for 28 days from time of hospitalization.SettingsMulti-center New York City hospital system.ParticipantsAdult patients hospitalized between March 1-May 15, 2020 with COVID-19 and not on corticosteroids for chronic use.InterventionCorticosteroid exposure defined as >0.5mg/kg methylprednisolone equivalent in a 24-hour period. For target trial emulation, interventions are (1) corticosteroids for six days if and when patient meets criteria for severe hypoxia and (2) no corticosteroids. For approaches common in clinical literature, treatment definitions used for variables in Cox regression models vary by study design (no time frame, one-, and five-days from time of severe hypoxia).Main outcome28-day mortality from time of hospitalization.Results3,298 patients (median age 65 (IQR 53-77), 60% male). 423 receive corticosteroids at any point during hospitalization, 699 die within 28 days of hospitalization. Target trial emulation estimates corticosteroids to reduce 28-day mortality from 32.2% (95% CI 30.9-33.5) to 25.7% (24.5-26.9). This estimate is qualitatively identical to the WHO’s RCT meta-analysis odds ratio of 0.66 (0.53-0.82)). Hazard ratios using methods comparable to current corticosteroid research range in size and direction from 0.50 (0.41-0.62) to 1.08 (0.80-1.47).Conclusion and RelevanceClinical research based on observational data can unveil true causal relationships; however, the correctness of these effect estimates requires designing the study and analyzing the data based on principles which are different from the current standard in clinical research.Key PointsQuestionHow do modern methods for causal inference compare to approaches common in the clinical literature when estimating the effect of corticosteroids on mortality for moderate-to-severe coronavirus disease 2019 (COVID-19) patients?FindingsIn an analysis using retrospective data for 3,298 hospitalized COVID-19 patients, target trial emulation using a doubly robust estimation procedure successfully recovers a randomized controlled trial (RCT) meta-analysis benchmark. In contrast, analytic approaches common in the clinical research literature generally cannot recover the benchmark.MeaningClinical research based on observational data can unveil true causal relations. However, the correctness of these effect estimates requires designing and analyzing the data based on principles which are different from the current standard in clinical research. Widespread communication and adoption of these analytical techniques are of high importance for the improvement of clinical research.

In this work we present results from a new sea ice reanalysis over the satellite era. We use a newly created sea ice data assimilation system CICE-PDAF, combining the Los Alamos Sea Ice Model (CICE) and the Parallelized Data Assimilation Framework (PDAF), to take advantage of the new observations of the sea ice cover produced in the last decade by Cryosat-2. Sea ice thickness and sea ice thickness distribution observations from Cryosat-2, alongside sea ice concentration observations, are assimilated to explore their effects on our current estimates of the Arctic sea ice cover. In particular we look at its effects on the sea ice thickness distribution. The true state of the Arctic sub-grid scale thickness distribution system is not well known, and yet it plays a key role in the dynamic and thermodynamic processes present in the model to produce a good estimate of the Arctic sea ice state. Thus by combining knowledge from state-of-the-art sea ice models with knowledge from newly developed observations we hope to produce a clearer picture of the Arctic sea ice and its thickness distribution.

To examine the association between baseline glucose control and risk of COVID-19 hospitalization and in-hospital death among patients with diabetes.We performed a retrospective cohort study of adult patients in the INSIGHT Clinical Research Network with a diabetes diagnosis and haemoglobin A1c (HbA1c) measurement in the year prior to an index date of March 15, 2020. Patients were divided into four exposure groups based on their most recent HbA1c measurement (in mmol/mol): 39-46 (5.7%-6.4%), 48-57 (6.5%-7.4%), 58-85 (7.5%-9.9%), and ≥86 (10%). Time to COVID-19 hospitalization was compared in the four groups in a propensity score-weighted Cox proportional hazards model adjusting for potential confounders. Patients were followed until June 15, 2020. In-hospital death was examined as a secondary outcome.Of 168,803 patients who met inclusion criteria; 50,016 patients had baseline HbA1c 39-46 (5.7%-6.4%); 54,729 had HbA1c 48-57 (6.5-7.4%); 47,640 had HbA1c 58-85 (7.5^%-9.9%) and 16,418 had HbA1c ≥86 (10%). Compared with patients with HbA1c 48-57 (6.5%-7.4%), the risk of hospitalization was incrementally greater for those with HbA1c 58-85 (7.5%-9.9%) (adjusted hazard ratio [aHR] 1.19, 95% confidence interval [CI] 1.06-1.34) and HbA1c ≥86 (10%) (aHR 1.40, 95% CI 1.19-1.64). The risk of COVID-19 in-hospital death was increased only in patients with HbA1c 58-85 (7.5%-9.9%) (aHR 1.29, 95% CI 1.06, 1.61).Diabetes patients with high baseline HbA1c had a greater risk of COVID-19 hospitalization, although association between HbA1c and in-hospital death was less consistent. Preventive efforts for COVID-19 should be focused on diabetes patients with poor glucose control.

Background: oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. Methods: all available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki67 2wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. Findings: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki67 2wk (p2wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. Interpretation: our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse. Funding: Cancer Research UK (CRUK/07/015).

Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1-3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617F was the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617F acquisition and diagnosis was 30 years (range 11-54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.

To examine trends of population-level semen quality over a 20-year period.We performed a retrospective review of data from the andrology lab of a high volume tertiary hospital. All men with semen samples between 2000 and 2019 were included and men with azoospermia were excluded. Semen parameters were reported using the World Health Organization (WHO) 4th edition. The primary outcome of interest was changes in semen parameters over time. Generalized least squares (GLS) with restricted cubic splines were used to estimate average-monthly measurements, adjusting for age and abstinence period. Contrasts of the estimated averages based on GLS between the first and last months of collection were calculated.A total of 8,990 semen samples from subfertile non-azoospermic men were included in our study. Semen volume decreased over time and estimate average at the beginning and end were statistically different (p0.001). Similarly sperm morphology decreased over time, with a statistically significant difference between estimated averages from start to finish (p0.001). Semen pH appeared to be increasing over time, but this difference was not significant over time (p=0.060). Sperm concentration and count displayed an increase around 2003 to 2005, but otherwise remained fairly constant over time (p=0.100 and p=0.054, respectively). Sperm motility appeared to decrease over time (p0.001).In a large sample of patients presenting to a single institution for fertility assessment, some aspects of semen quality declined across more than two decades. An understanding of the etiologies and driving forces of changing semen parameters over time is warranted.

Objectives: Qualitative study exploring public attitudes to COVID-19 18 months into the pandemic, specifically focused on adherence to infection-reducing behaviours and policy measures during a period of the emergence of a new variant (Omicron)Study design: Qualitative online focus group study Methods: Focus groups were conducted with a diverse sample of 22 adults in the United Kingdom to explore their views. Data were analysed using a framework approach.Findings: Analysis revealed two main groups based on participants’ perceived concern over Omicron: variant fatigue (n=16 (73%)) and deja vu (n=6 (27%)). Those exhibiting variant fatigue reported not adopting any additional caution or infection-reducing behaviours as a result of the new variant. They tended to describe Omicron as ‘just another variant’ and expressed a need to ‘get on’ and ‘live with’ the virus. Those exhibiting deja vu suggested that Omicron was of additional concern to them and for some posed a threat not seen since ‘last year’ (second wave). No demographic patterns emerged, although there was a high amount of variant fatigue (absence of additional caution) (n=5 (83%)) amongst the unvaccinated participants. Those who were concerned about Omicron tended to report reducing social contacts. Few participants reported taking lateral flow tests regularly, except for those required to by their employers. Stated compliance with facemask rules was high. Nearly all participants stated an intention to comply with any future potential policy measures to reduce transmission of COVID-19, including more stringent measures such as lockdowns. Implications: 18 months into the pandemic, there may be habituation to the risk posed by COVID-19, despite the increased risk posed by the new variant Omicron. Due to this risk habituation (‘variant fatigue’) and due to a general decline in engagement with news related to COVID-19, many people may not be, or might be reluctant to, voluntarily adopt additional caution and infection-reducing behaviours. This poses a challenge for public health communication, since a sense of being ‘relaxed’ about, or ‘living with’ COVID-19 may undermine efforts to encourage voluntary adherence to infection-reducing behaviours. However, findings suggest that most people intend to comply (albeit reluctantly) with policy measures (as opposed to ‘advice’)- including stringent measures such as lockdown - if they were required in future.

The 2016 International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR:RS) is a collaborative distillation of available research and consensus recommendations for the management for chronic rhinosinusitis (CRS). However, implementation of the ICAR:RS recommendations in the reality of clinical practice is not clearly defined.An anonymous, web-based survey of the American Rhinologic Society membership was performed in October, 2018. Respondents were asked about the frequency that they recommended the various treatments reviewed in ICAR:RS in the context of medical management for CRS. A 7-point Likert-type scale assessed the frequency of treatment patterns.A total of 140 members completed the survey (response rate 11.9%). Seventy-two (51.4%) were in practice for 0 to 15 years, 61 (43.6%) completed a rhinology fellowship, and 73 (52.1%) worked in private practice. Disparate treatment patterns were reported for each of the therapies assessed for CRS, including those that were "recommended" or "recommended against" in ICAR:RS. Members with15 years of experience were more likely to use nasal saline irrigation. Fellowship-trained respondents reported a greater likelihood of using nasal saline irrigation and aspirin desensitization (for patients with aspirin-exacerbated respiratory disease). Practitioners in academic medicine were more likely to utilize aspirin desensitization than those in private practice. Surgeons performing100 sinus surgeries per year were more likely to use topical antibiotics.The range of reported treatment patterns identified in this study despite the availability of the ICAR:RS recommendations may suggest the need for improved standardization of CRS management.

This paper offers an analysis of the Ford-Kavanaugh hearing by the U.S. Senate Judiciary Committee, with particular attention to the role of the Committee chairperson within this procedural infrastructure—an infrastructure that, we argue, systematically provides for and thereby implicitly legitimizes the insertion of bias in its proceedings, while nonetheless orienting to an ideology of fairness based on time limits for speaking. Focusing on the linguistic and interactional mechanisms through which chairpersons may use the ‘interstitial spaces’ that emerge within such hearings, we conclude that the structural privileges afforded to partisan chairpersons can compromise the Committee's ability to reach impartial and unbiased conclusions in its investigations, and we offer recommendations with regard to how this might be resolved.

ImportanceCommunication and adoption of modern study design and analytical techniques is of high importance for the improvement of clinical research from observational data.ObjectiveTo compare a modern method for statistical inference, including a target trial emulation framework and doubly robust estimation, with approaches common in the clinical literature, such as Cox proportional hazards models.Design, Setting, and ParticipantsThis retrospective cohort study used longitudinal electronic health record data for outcomes at 28-days from time of hospitalization within a multicenter New York, New York, hospital system. Participants included adult patients hospitalized between March 1 and May 15, 2020, with COVID-19 and not receiving corticosteroids for chronic use. Data were analyzed from October 2021 to March 2022.ExposuresCorticosteroid exposure was defined as more than 0.5 mg/kg methylprednisolone equivalent in a 24-hour period. For target trial emulation, exposures were corticosteroids for 6 days if and when a patient met criteria for severe hypoxia vs no corticosteroids. For approaches common in clinical literature, treatment definitions used for variables in Cox regression models varied by study design (no time frame, 1 day, and 5 days from time of severe hypoxia).Main Outcomes and MeasuresThe main outcome was 28-day mortality from time of hospitalization. The association of corticosteroids with mortality for patients with moderate to severe COVID-19 was assessed using the World Health Organization (WHO) meta-analysis of corticosteroid randomized clinical trials as a benchmark.ResultsA total of 3298 patients (median [IQR] age, 65 [53-77] years; 1970 [60%] men) were assessed, including 423 patients who received corticosteroids at any point during hospitalization and 699 patients who died within 28 days of hospitalization. Target trial emulation analysis found corticosteroids were associated with a reduced 28-day mortality rate, from 32.2%; (95% CI, 30.9%-33.5%) to 25.7% (95% CI, 24.5%-26.9%). This estimate is qualitatively identical to the WHO meta-analysis odds ratio of 0.66 (95% CI, 0.53-0.82). Hazard ratios using methods comparable with current corticosteroid research range in size and direction, from 0.50 (95% CI, 0.41-0.62) to 1.08 (95% CI, 0.80-1.47).Conclusions and RelevanceThese findings suggest that clinical research based on observational data can be used to estimate findings similar to those from randomized clinical trials; however, the correctness of these estimates requires designing the study and analyzing the data based on principles that are different from the current standard in clinical research.

Background Effective analgesia after bariatric procedures is vital as it can reduce post-operative opioid use. This leads to less nausea which may be associated with shorter post-operative length of stay (LOS). Understanding analgesic requirements in patients with obesity is important due to the varied physiology and increased number of comorbidities. Objectives The aim of this study was to evaluate the efficacy of intraperitoneal instillation of local anesthetic (IPILA) to reduce opioid requirements in patients undergoing laparoscopic bariatric surgery. Methods A double-blinded randomized control trial was conducted to compare intraperitoneal instillation of ropivacaine to normal saline in 104 patients undergoing bariatric surgery. The primary endpoint was pain in recovery with secondary endpoints at 1, 2, 4, 6, 24, and 48 h post-operatively. Further endpoints were post-operative analgesic use and LOS. Safety endpoints included unexpected reoperation or readmission, complications, and mortality. Results There were 54 patients in the placebo arm and 50 in the IPILA. Pain scores were significantly lower in the IPILA group both at rest (p = 0.04) and on movement (p = 0.02) in recovery with no difference seen at subsequent time points. Equally, IPILA was independently associated with reducing severe post-operative pain at rest and movement (adjusted odds ratio [aOR] 0.28, 95% CI 0.11–0.69, p = 0.007 and aOR 0.25, 95% CI 0.09–0.62, p = 0.004, respectively). There was no significant difference in LOS, opioid use, antiemetic use, morbidity, or mortality between the intervention and placebo groups. Conclusion The administration of ropivacaine intraperitoneally during laparoscopic bariatric surgery reduces post-operative pain in the recovery room but does not reduce opioid use nor LOS.

OBJECTIVE: To explore public attitudes to COVID-19 vaccines in the UK, focused on intentions and decisions around taking vaccines, views on ‘vaccine passports’, and experiences and perspectives on post-vaccination behaviour.DESIGN: Qualitative study consisting of 6 online focus groups conducted between 15th March – 22nd April 2021. SETTING: Online video conferencingPARTICIPANTS: 29 adult UK-based participantsRESULTS: Three main groups regarding participants’ decision or intention to receive a COVID-19 vaccine were identified: (1) Accepters, (2) Delayers and (3) Refusers. Two reasons for vaccine delay were identified: delay due to a perceived need more information and delay until vaccine was “required” in the future. Three main facilitators (Vaccination as a social norm; Vaccination as a necessity; Trust in science) and six barriers (Preference for “natural immunity”; Concerns over possible side effects; Distrust in government; Perceived lack of information; Conspiracy theories; “Covid echo chambers”) to vaccine uptake were identified. For some delayers, 'vaccine passports' were perceived to be a reason why they would get vaccinated in the future. However, vaccine passports were controversial, and were framed in four main ways: as “a necessary evil”; as “Orwellian”; as a “human rights problem”; and as a source of confidence”. Participants generally felt that receiving a vaccine was not changing the extent to which people were adhering to COVID-19 measures. CONCLUSIONS: Overall positive sentiment around vaccines is high. However, there remains a number of potential barriers which might be leading to vaccine delay in some. ‘Vaccine delay’ might be a more useful and precise construct than vaccine hesitancy in explaining why some may initially ignore or be uncertain about vaccination invitations. Vaccine passports may increase or ‘nudge’ uptake in some delayers but may be unpopular in others. Earlier concerns that vaccination might reduce adherence to social distancing measures are not borne out in our data, with most people reporting adherence and caution.

A new class of heart-rate sensing, closed-loop vagal nerve stimulator (VNS) devices for refractory epilepsy may improve seizure control by using pre-ictal autonomic changes as an indicator for stimulation. We compared our experience with closed- versus open-loop stimulator implantation at a single institution.We conducted a retrospective chart review of consecutive VNS implantations performed from 2004 to 2018. Bivariate and multivariable analyses were performed to compare changes in seizure frequency and clinical outcomes (Engel score) with closed- versus open-loop devices. Covariates included age, duration of seizure history, prior epilepsy surgery, depression, Lennox Gastaut Syndrome (LGS), tonic seizures, multiple seizure types, genetic etiology, and VNS settings. We examined early (9-month) and late (24-month) outcomes.Seventy subjects received open-loop devices, and thirty-one received closed-loop devices. At a median of 8.5 months, there was a greater reduction of seizure frequency after use of closed-loop devices (median 75% [IQR 10-89%]) versus open-loop (50% [0-78%], p0.05), confirmed in multivariable analysis (odds ratio 2.72 [95% CI 1.02 - 7.4]). Similarly, Engel outcomes were better after closed-loop compared to open-loop confirmed in the multivariable analysis at the early timepoint (OR 0.26 [95% CI 0.09 - 0.69]). These differences did not persist at a median of 24.5 months.This retrospective single-center study suggests the use of closed-loop VNS devices is associated with greater seizure reduction and more favorable clinical outcomes than open-loop devices at 9-months though not at 24-months. Expansion of this study to other centers is warranted to increase the generalizability of our study.