Epidemiological drivers of transmissibility and severity of SARS-CoV-2 in England.

As the SARS-CoV-2 pandemic progressed, distinct variants emerged and dominated in England. These variants, Wildtype, Alpha, Delta, and Omicron were characterized by variations in transmissibility and severity. We used a robust mathematical model and Bayesian inference framework to analyse epidemiological surveillance data from England. We quantified the impact of non-pharmaceutical interventions (NPIs), therapeutics, and vaccination on virus transmission and severity. Each successive variant had a higher intrinsic transmissibility. Omicron (BA.1) had the highest basic reproduction number at 8.3 (95% credible interval (CrI) 7.7-8.8). Varying levels of NPIs were crucial in controlling virus transmission until population immunity accumulated. Immune escape properties of Omicron decreased effective levels of immunity in the population by a third. Furthermore, in contrast to previous studies, we found Alpha had the highest basic infection fatality ratio (2.9%, 95% CrI 2.7-3.2), followed by Delta (2.2%, 95% CrI 2.0-2.4), Wildtype (1.2%, 95% CrI 1.1-1.2), and Omicron (0.7%, 95% CrI 0.6-0.8). Our findings highlight the importance of continued surveillance. Long-term strategies for monitoring and maintaining effective immunity against SARS-CoV-2 are critical to inform the role of NPIs to effectively manage future variants with potentially higher intrinsic transmissibility and severe outcomes.

Quantifying the effect of delaying the second COVID-19 vaccine dose in England: a mathematical modelling study.

BACKGROUND: The UK was the first country to start national COVID-19 vaccination programmes, initially administering doses 3 weeks apart. However, early evidence of high vaccine effectiveness after the first dose and the emergence of the SARS-CoV-2 alpha variant prompted the UK to extend the interval between doses to 12 weeks. In this study, we aimed to quantify the effect of delaying the second vaccine dose in England. METHODS: We used a previously described model of SARS-CoV-2 transmission, calibrated to COVID-19 surveillance data from England, including hospital admissions, hospital occupancy, seroprevalence data, and population-level PCR testing data, using a Bayesian evidence-synthesis framework. We modelled and compared the epidemic trajectory in the counterfactual scenario in which vaccine doses were administered 3 weeks apart against the real reported vaccine roll-out schedule of 12 weeks. We estimated and compared the resulting numbers of daily infections, hospital admissions, and deaths. In sensitivity analyses, we investigated scenarios spanning a range of vaccine effectiveness and waning assumptions. FINDINGS: In the period from Dec 8, 2020, to Sept 13, 2021, the number of individuals who received a first vaccine dose was higher under the 12-week strategy than the 3-week strategy. For this period, we estimated that delaying the interval between the first and second COVID-19 vaccine doses from 3 to 12 weeks averted a median (calculated as the median of the posterior sample) of 58 000 COVID-19 hospital admissions (291 000 cumulative hospitalisations [95% credible interval 275 000-319 000] under the 3-week strategy vs 233 000 [229 000-238 000] under the 12-week strategy) and 10 100 deaths (64 800 deaths [60 200-68 900] vs 54 700 [52 800-55 600]). Similarly, we estimated that the 3-week strategy would have resulted in more infections compared with the 12-week strategy. Across all sensitivity analyses the 3-week strategy resulted in a greater number of hospital admissions. In results by age group, the 12-week strategy led to more hospitalisations and deaths in older people in spring 2021, but fewer following the emergence of the delta variant during summer 2021. INTERPRETATION: England's delayed-second-dose vaccination strategy was informed by early real-world data on vaccine effectiveness in the context of limited vaccine supplies in a growing epidemic. Our study shows that rapidly providing partial (single-dose) vaccine-induced protection to a larger proportion of the population was successful in reducing the burden of COVID-19 hospitalisations and deaths overall. FUNDING: UK National Institute for Health Research; UK Medical Research Council; Community Jameel; Wellcome Trust; UK Foreign, Commonwealth and Development Office; Australian National Health and Medical Research Council; and EU.

Avoiding C-hacking when evaluating survival distribution predictions with discrimination measures.

MOTIVATION: In this article, we consider how to evaluate survival distribution predictions with measures of discrimination. This is non-trivial as discrimination measures are the most commonly used in survival analysis and yet there is no clear method to derive a risk prediction from a distribution prediction. We survey methods proposed in literature and software and consider their respective advantages and disadvantages. RESULTS: Whilst distributions are frequently evaluated by discrimination measures, we find that the method for doing so is rarely described in the literature and often leads to unfair comparisons or 'C-hacking'. We demonstrate by example how simple it can be to manipulate results and use this to argue for better reporting guidelines and transparency in the literature. We recommend that machine learning survival analysis software implements clear transformations between distribution and risk predictions in order to allow more transparent and accessible model evaluation. AVAILABILITY AND IMPLEMENTATION: The code used in the final experiment is available at https://github.com/RaphaelS1/distribution_discrimination.

Spatial and temporal fluctuations in COVID-19 fatality rates in Brazilian hospitals.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Gamma variant of concern has spread rapidly across Brazil since late 2020, causing substantial infection and death waves. Here we used individual-level patient records after hospitalization with suspected or confirmed coronavirus disease 2019 (COVID-19) between 20 January 2020 and 26 July 2021 to document temporary, sweeping shocks in hospital fatality rates that followed the spread of Gamma across 14 state capitals, during which typically more than half of hospitalized patients aged 70 years and older died. We show that such extensive shocks in COVID-19 in-hospital fatality rates also existed before the detection of Gamma. Using a Bayesian fatality rate model, we found that the geographic and temporal fluctuations in Brazil's COVID-19 in-hospital fatality rates were primarily associated with geographic inequities and shortages in healthcare capacity. We estimate that approximately half of the COVID-19 deaths in hospitals in the 14 cities could have been avoided without pre-pandemic geographic inequities and without pandemic healthcare pressure. Our results suggest that investments in healthcare resources, healthcare optimization and pandemic preparedness are critical to minimize population-wide mortality and morbidity caused by highly transmissible and deadly pathogens such as SARS-CoV-2, especially in low- and middle-income countries.

The Wolfson Assessment Matrix: a potential tool to support clinicians in establishing access to specialized neuro rehabilitation by capturing important prognostic factors. Sharing more equitable and transparent criteria.

BACKGROUND: Specialized Rehabilitation Services (SRSs) are designed to offer intensive multidisciplinary rehabilitation to patients with complex needs, who are expected to make significant functional gains in their ADLs over a relatively limited period of time. Although national guidelines offer a guidance on how to band patients by complexity, there is no consensus on how to screen patients with regard to rehabilitation prognosis. AIM: The aim of this study was to improve the selection of patients admitted to an SRS, defining transparent and equitable prognostic criteria to guide clinicians' decision making. DESIGN: This is a retrospective observational study SETTING: an SRS in the UK. POPULATION: We included 121 patients affected by a neurological condition consecutively admitted for multidisciplinary rehabilitation. METHODS: Rehabilitation Complexity Scale Extended is used to describe rehabilitation complexity. A short list of potential barriers to rehabilitation was analysed to predict the functional outcome measured by the Functional Independent Measure and the Barthel Index. RESULTS: Older age, a heavier burden of co-morbidities, pre-morbid cognitive difficulties or dementia and a lower function level at admission were the most important variables to predict a lower functional gain. CONCLUSIONS: We have used this list of barriers to create the Wolfson Assessment Matrix as a potential support tool to guide clinicians navigating through the different rehabilitation service options when assessing complex patients for eligibility to an SRS. CLINICAL REHABILITATION IMPACT: SRSs are highly expensive services representing a possible step along the rehabilitation pathway for patients with complex needs. A tool such as the Wolfson Assessment Matrix would represent a step forward to help consistency in decision making regarding appropriateness for SRSs. It would also help to set realistic long-term goals with patients and families and support Health Services in the further development of alternative rehabilitation settings.

Non-pharmaceutical interventions, vaccination, and the SARS-CoV-2 delta variant in England: a mathematical modelling study.

BACKGROUND: England's COVID-19 roadmap out of lockdown policy set out the timeline and conditions for the stepwise lifting of non-pharmaceutical interventions (NPIs) as vaccination roll-out continued, with step one starting on March 8, 2021. In this study, we assess the roadmap, the impact of the delta (B.1.617.2) variant of SARS-CoV-2, and potential future epidemic trajectories. METHODS: This mathematical modelling study was done to assess the UK Government's four-step process to easing lockdown restrictions in England, UK. We extended a previously described model of SARS-CoV-2 transmission to incorporate vaccination and multi-strain dynamics to explicitly capture the emergence of the delta variant. We calibrated the model to English surveillance data, including hospital admissions, hospital occupancy, seroprevalence data, and population-level PCR testing data using a Bayesian evidence synthesis framework, then modelled the potential trajectory of the epidemic for a range of different schedules for relaxing NPIs. We estimated the resulting number of daily infections and hospital admissions, and daily and cumulative deaths. Three scenarios spanning a range of optimistic to pessimistic vaccine effectiveness, waning natural immunity, and cross-protection from previous infections were investigated. We also considered three levels of mixing after the lifting of restrictions. FINDINGS: The roadmap policy was successful in offsetting the increased transmission resulting from lifting NPIs starting on March 8, 2021, with increasing population immunity through vaccination. However, because of the emergence of the delta variant, with an estimated transmission advantage of 76% (95% credible interval [95% CrI] 69-83) over alpha, fully lifting NPIs on June 21, 2021, as originally planned might have led to 3900 (95% CrI 1500-5700) peak daily hospital admissions under our central parameter scenario. Delaying until July 19, 2021, reduced peak hospital admissions by three fold to 1400 (95% CrI 700-1700) per day. There was substantial uncertainty in the epidemic trajectory, with particular sensitivity to the transmissibility of delta, level of mixing, and estimates of vaccine effectiveness. INTERPRETATION: Our findings show that the risk of a large wave of COVID-19 hospital admissions resulting from lifting NPIs can be substantially mitigated if the timing of NPI relaxation is carefully balanced against vaccination coverage. However, with the delta variant, it might not be possible to fully lift NPIs without a third wave of hospital admissions and deaths, even if vaccination coverage is high. Variants of concern, their transmissibility, vaccine uptake, and vaccine effectiveness must be carefully monitored as countries relax pandemic control measures. FUNDING: National Institute for Health Research, UK Medical Research Council, Wellcome Trust, and UK Foreign, Commonwealth and Development Office.

mlr3proba: an R package for machine learning in survival analysis.

SUMMARY: As machine learning has become increasingly popular over the last few decades, so too has the number of machine-learning interfaces for implementing these models. Whilst many R libraries exist for machine learning, very few offer extended support for survival analysis. This is problematic considering its importance in fields like medicine, bioinformatics, economics, engineering and more. mlr3proba provides a comprehensive machine-learning interface for survival analysis and connects with mlr3's general model tuning and benchmarking facilities to provide a systematic infrastructure for survival modelling and evaluation. AVAILABILITY AND IMPLEMENTATION: mlr3proba is available under an LGPL-3 licence on CRAN and at https://github.com/mlr-org/mlr3proba, with further documentation at https://mlr3book.mlr-org.com/survival.html.

The role of impulsivity in neurorehabilitation: A prospective cohort study of a potential cognitive biomarker for fall risk?

BACKGROUND: Executive dysregulation and impulsivity can both predispose individuals to risk-prone actions. Although the risk of falls is well established in people with poor executive function, its association to impulsivity is less clear. PURPOSE: To describe and assess the prognostic capabilities of the relationship between impulsivity, executive function, functional capability, and falls in the in-patient neurorehabilitation population. MATERIALS AND METHODS: A prospective cohort study in a 26-bed neurorehabilitation unit in London, recruiting 121 patients, of whom 94 were deemed eligible for inclusion. Cognitive-behavioural assessment was undertaken using the short (16-item) version of the Urgency-Premeditation-Perseverance-Sensation Seeking-Positive Urgency (UPPS) impulsive behaviour scale, and the Trail Making Test (TMT). Patients also underwent a functional assessment at admission and discharge using the UK Functional Independence and Assessment Measure tool (FIM + FAM). The main outcome of interest was falling during an in-patient episode, which are routinely recorded in a computerized registry of adverse incidents. RESULTS: Measurements of impulsivity (based on the UPPS-Short form) and executive function (based on the Trail Making Test) were not found to be significantly associated with functional improvement, or risk of falling. Predictive modelling experiments demonstrated that neither of the aforementioned results were capable of identifying individuals at risk of falling more accurately than an informed guess. CONCLUSION: Where impulsivity is present, measurement using structured tools such as the UPPS may be informative to guide individualized rehabilitation programmes; however, its usefulness as the basis of risk prediction models for falls is less likely given the results of this study.

Type 2 Diabetes and COVID-19-Related Mortality in the Critical Care Setting: A National Cohort Study in England, March-July 2020.

OBJECTIVE: To describe the relationship between type 2 diabetes and all-cause mortality among adults with coronavirus disease 2019 (COVID-19) in the critical care setting. RESEARCH DESIGN AND METHODS: This was a nationwide retrospective cohort study in people admitted to hospital in England with COVID-19 requiring admission to a high dependency unit (HDU) or intensive care unit (ICU) between 1 March 2020 and 27 July 2020. Cox proportional hazards models were used to estimate 30-day in-hospital all-cause mortality associated with type 2 diabetes, with adjustment for age, sex, ethnicity, obesity, and other major comorbidities (chronic respiratory disease, asthma, chronic heart disease, hypertension, immunosuppression, chronic neurological disease, chronic renal disease, and chronic liver disease). RESULTS: A total of 19,256 COVID-19-related HDU and ICU admissions were included in the primary analysis, including 13,809 HDU (mean age 70 years) and 5,447 ICU (mean age 58 years) admissions. Of those admitted, 3,524 (18.3%) had type 2 diabetes and 5,077 (26.4%) died during the study period. Patients with type 2 diabetes were at increased risk of death (adjusted hazard ratio [aHR] 1.23 [95% CI 1.14, 1.32]), and this result was consistent in HDU and ICU subsets. The relative mortality risk associated with type 2 diabetes decreased with higher age (age 18-49 years aHR 1.50 [95% CI 1.05, 2.15], age 50-64 years 1.29 [1.10, 1.51], and age ≥65 years 1.18 [1.09, 1.29]; P value for age-type 2 diabetes interaction = 0.002). CONCLUSIONS: Type 2 diabetes may be an independent prognostic factor for survival in people with severe COVID-19 requiring critical care treatment, and in this setting the risk increase associated with type 2 diabetes is greatest in younger people.

Genomics and epidemiology of the P 1 SARS-CoV-2 lineage in Manaus, Brazil

Cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Manaus, Brazil, resurged in late 2020 despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1 acquired 17 mutations, including a trio in the spike protein (K417T, E484K, and N501Y) associated with increased binding to the human ACE2 (angiotensin-converting enzyme 2) receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7- to 2.4-fold more transmissible and that previous (non-P.1) infection provides 54 to 79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.

Assessing the influence of culture on craft skills: A quantitative study with expert Nepalese potters.

Studies have documented that traditional motor skills (i.e. motor habits) are part of the cultural way of life that characterises each society. Yet, it is still unclear to what extent motor skills are inherited through culture. Drawing on ethnology and motor behaviour, we addressed this issue through a detailed description of traditional pottery skills. Our goal was to quantify the influence of three kinds of constraints: the transcultural constraints of wheel-throwing, the cultural constraints induced via cultural transmission, and the potters' individual constraints. Five expert Nepalese potters were invited to produce three familiar pottery types, each in five specimens. A total of 31 different fashioning hand positions were identified. Most of them (14) were cross-cultural, ten positions were cultural, five positions were individual, and two positions were unique. Statistical tests indicated that the subset of positions used by the participants in this study were distinct from those of other cultural groups. Behaviours described in terms of fashioning duration, number of gestures, and hand position repertoires size highlighted both individual and cross-cultural traits. We also analysed the time series of the successive hand positions used throughout the fashioning of each vessel. Results showed, for each pottery type, strong reproducible sequences at the individual level and a clearly higher level of variability between potters. Overall, our findings confirm the existence of a cultural transmission in craft skills but also demonstrated that the skill is not fully determined by a cultural marking. We conclude that the influence of culture on craft skills should not be overstated, even if its role is significant given the fact that it reflects the socially transmitted part of the skill. Such research offers insights into archaeological problems in providing a representative view of how cultural constraints influence the motor skills implied in artefact manufacturing.