Germline mismatch repair (MMR) gene analyses from English NHS regional molecular genomics laboratories 1996-2020: development of a national resource of patient-level genomics laboratory records.

Peer reviewed: TrueOBJECTIVE: To describe national patterns of National Health Service (NHS) analysis of mismatch repair (MMR) genes in England using individual-level data submitted to the National Disease Registration Service (NDRS) by the NHS regional molecular genetics laboratories. DESIGN: Laboratories submitted individual-level patient data to NDRS against a prescribed data model, including (1) patient identifiers, (2) test episode data, (3) per-gene results and (4) detected sequence variants. Individualised per-laboratory algorithms were designed and applied in NDRS to extract and map the data to the common data model. Laboratory-level MMR activity audit data from the Clinical Molecular Genetics Society/Association of Clinical Genomic Science were used to assess early years' missing data. RESULTS: Individual-level data from patients undergoing NHS MMR germline genetic testing were submitted from all 13 English laboratories performing MMR analyses, comprising in total 16 722 patients (9649 full-gene, 7073 targeted), with the earliest submission from 2000. The NDRS dataset is estimated to comprise >60% of NHS MMR analyses performed since inception of NHS MMR analysis, with complete national data for full-gene analyses for 2016 onwards. Out of 9649 full-gene tests, 2724 had an abnormal result, approximately 70% of which were (likely) pathogenic. Data linkage to the National Cancer Registry demonstrated colorectal cancer was the most frequent cancer type in which full-gene analysis was performed. CONCLUSION: The NDRS MMR dataset is a unique national pan-laboratory amalgamation of individual-level clinical and genomic patient data with pseudonymised identifiers enabling linkage to other national datasets. This growing resource will enable longitudinal research and can form the basis of a live national genomic disease registry

Estimating excess mortality due to the COVID-19 pandemic: a systematic analysis of COVID-19-related mortality, 2020???21

The full impact of the pandemic has been much greater than what is indicated by reported deaths due to COVID-19 alone. Strengthening death registration systems around the world, long understood to be crucial to global public health strategy, is necessary for improved monitoring of this pandemic and future pandemics. In addition, further research is warranted to help distinguish the proportion of excess mortality that was directly caused by SARS-CoV-2 infection and the changes in causes of death as an indirect consequence of the pandemic

Estimating global, regional, and national daily and cumulative infections with SARS-CoV-2 through Nov 14, 2021: a statistical analysis

Timely, accurate, and comprehensive estimates of SARS-CoV-2 daily infection rates, cumulative infections, the proportion of the population that has been infected at least once, and the effective reproductive number (Reffective) are essential for understanding the determinants of past infection, current transmission patterns, and a population’s susceptibility to future infection with the same variant. Although several studies have estimated cumulative SARS-CoV-2 infections in select locations at specific points in time, all of these analyses have relied on biased data inputs that were not adequately corrected for. In this study, we aimed to provide a novel approach to estimating past SARS-CoV-2 daily infections, cumulative infections, and the proportion of the population infected, for 190 countries and territories from the start of the pandemic to Nov 14, 2021. This approach combines data from reported cases, reported deaths, excess deaths attributable to COVID-19, hospitalisations, and seroprevalence surveys to produce more robust estimates that minimise constituent biases

Pandemic preparedness and COVID-19: an exploratory analysis of infection and fatality rates, and contextual factors associated with preparedness in 177 countries, from Jan 1, 2020, to Sept 30, 2021

National rates of COVID-19 infection and fatality have varied dramatically since the onset of the pandemic. Understanding the conditions associated with this cross-country variation is essential to guiding investment in more effective preparedness and response for future pandemics. Daily SARS-CoV-2 infections and COVID-19 deaths for 177 countries and territories and 181 subnational locations were extracted from the Institute for Health Metrics and Evaluation's modelling database. Cumulative infection rate and infection-fatality ratio (IFR) were estimated and standardised for environmental, demographic, biological, and economic factors. For infections, we included factors associated with environmental seasonality (measured as the relative risk of pneumonia), population density, gross domestic product (GDP) per capita, proportion of the population living below 100 m, and a proxy for previous exposure to other betacoronaviruses. For IFR, factors were age distribution of the population, mean body-mass index (BMI), exposure to air pollution, smoking rates, the proxy for previous exposure to other betacoronaviruses, population density, age-standardised prevalence of chronic obstructive pulmonary disease and cancer, and GDP per capita. These were standardised using indirect age standardisation and multivariate linear models. Standardised national cumulative infection rates and IFRs were tested for associations with 12 pandemic preparedness indices, seven health-care capacity indicators, and ten other demographic, social, and political conditions using linear regression. To investigate pathways by which important factors might affect infections with SARS-CoV-2, we also assessed the relationship between interpersonal and governmental trust and corruption and changes in mobility patterns and COVID-19 vaccination rates. The factors that explained the most variation in cumulative rates of SARS-CoV-2 infection between Jan 1, 2020, and Sept 30, 2021, included the proportion of the population living below 100 m (5·4% [4·0–7·9] of variation), GDP per capita (4·2% [1·8–6·6] of variation), and the proportion of infections attributable to seasonality (2·1% [95% uncertainty interval 1·7–2·7] of variation). Most cross-country variation in cumulative infection rates could not be explained. The factors that explained the most variation in COVID-19 IFR over the same period were the age profile of the country (46·7% [18·4–67·6] of variation), GDP per capita (3·1% [0·3–8·6] of variation), and national mean BMI (1·1% [0·2–2·6] of variation). 44·4% (29·2–61·7) of cross-national variation in IFR could not be explained. Pandemic-preparedness indices, which aim to measure health security capacity, were not meaningfully associated with standardised infection rates or IFRs. Measures of trust in the government and interpersonal trust, as well as less government corruption, had larger, statistically significant associations with lower standardised infection rates. High levels of government and interpersonal trust, as well as less government corruption, were also associated with higher COVID-19 vaccine coverage among middle-income and high-income countries where vaccine availability was more widespread, and lower corruption was associated with greater reductions in mobility. If these modelled associations were to be causal, an increase in trust of governments such that all countries had societies that attained at least the amount of trust in government or interpersonal trust measured in Denmark, which is in the 75th percentile across these spectrums, might have reduced global infections by 12·9% (5·7–17·8) for government trust and 40·3% (24·3–51·4) for interpersonal trust. Similarly, if all countries had a national BMI equal to or less than that of the 25th percentile, our analysis suggests global standardised IFR would be reduced by 11·1%. Efforts to improve pandemic preparedness and response for the next pandemic might benefit from greater investment in risk communication and community engagement strategies to boost the confidence that individuals have in public health guidance. Our results suggest that increasing health promotion for key modifiable risks is associated with a reduction of fatalities in such a scenario

International Consensus Statement on Obstructive Sleep Apnea

BackgroundEvaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA).MethodsUsing previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus.ResultsThe ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated.ConclusionThis review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy

International consensus statement on obstructive sleep apnea

BACKGROUND: Evaluation and interpretation of the literature on obstructive sleep apnea is needed to consolidate and summarize key factors important for clinical management of the OSA adult patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). METHODS: Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. RESULTS: The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA and treatment on the multiple comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. CONCLUSION: This review of the literature in OSA consolidates the available knowledge and identifies the limitations of the current evidence. This effort aims to highlight the basis of OSA evidence-based practice and identify future research needs. Knowledge gaps and opportunities for improvement include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy

International Consensus Statement on Obstructive Sleep Apnea

Evaluation and interpretation of the literature on obstructive sleep apnea (OSA) allows for consolidation and determination of the key factors important for clinical management of the adult OSA patient. Toward this goal, an international collaborative of multidisciplinary experts in sleep apnea evaluation and treatment have produced the International Consensus statement on Obstructive Sleep Apnea (ICS:OSA). Using previously defined methodology, focal topics in OSA were assigned as literature review (LR), evidence-based review (EBR), or evidence-based review with recommendations (EBR-R) formats. Each topic incorporated the available and relevant evidence which was summarized and graded on study quality. Each topic and section underwent iterative review and the ICS:OSA was created and reviewed by all authors for consensus. The ICS:OSA addresses OSA syndrome definitions, pathophysiology, epidemiology, risk factors for disease, screening methods, diagnostic testing types, multiple treatment modalities, and effects of OSA treatment on multiple OSA-associated comorbidities. Specific focus on outcomes with positive airway pressure (PAP) and surgical treatments were evaluated. This review of the literature consolidates the available knowledge and identifies the limitations of the current evidence on OSA. This effort aims to create a resource for OSA evidence-based practice and identify future research needs. Knowledge gaps and research opportunities include improving the metrics of OSA disease, determining the optimal OSA screening paradigms, developing strategies for PAP adherence and longitudinal care, enhancing selection of PAP alternatives and surgery, understanding health risk outcomes, and translating evidence into individualized approaches to therapy