Showing papers in "BMJ Medicine in 2022"
TL;DR: During the periods when the alpha and delta variants of SARS-CoV-2 were dominant, covid-19 was associated with more severe maternal infection and worse pregnancy outcomes than during the wildtype dominance period.
Abstract: Objective To compare the severity of maternal infection and perinatal outcomes during periods in which wildtype, alpha variant, and delta variant of SARS-CoV-2 were dominant in the UK. Design Prospective cohort study. Setting 194 obstetric units across the UK, during the following periods: between 1 March and 30 November 2020 (wildtype dominance), between 1 December 2020 and 15 May 2021 (alpha variant dominance), and between 16 May and 31 October 2021 (delta variant dominance). Participants 4436 pregnant women admitted to hospital with covid-19 related symptoms. Main outcome measures Moderate to severe maternal SARS-CoV-2 infection (indicated by any of the following: oxygen saturation <95% on admission, need for oxygen treatment, evidence of pneumonia on imaging, admission to intensive care, or maternal death), and pregnancy and perinatal outcomes (including mode and gestation of birth, stillbirth, live birth, admission to neonatal intensive care, and neonatal death). Results 1387, 1613, and 1436 pregnant women were admitted to hospital with covid-19 related symptoms during the wildtype, alpha, and delta dominance periods, respectively; of these women, 340, 585, and 614 had moderate to severe infection, respectively. The proportion of pregnant women admitted with moderate to severe infection increased during the subsequent alpha and delta dominance periods, compared with the wildtype dominance period (wildtype 24.5% v alpha 36.2% (adjusted odds ratio 1.98, 95% confidence interval 1.66% to 2.37%); wildtype 24.5% v delta 42.8% (2.66, 2.21 to 3.20)). Compared with the wildtype dominance period, women admitted during the alpha dominance period were significantly more likely to have pneumonia, require respiratory support, and be admitted to intensive care; these three risks were even greater during the delta dominance period (wildtype v delta: pneumonia, adjusted odds ratio 2.52, 95% confidence interval 2.06 to 3.09; respiratory support, 1.90, 1.52 to 2.37; and intensive care, 2.71, 2.06 to 3.56). Of 1761 women whose vaccination status was known, 38 (2.2%) had one dose and 16 (1%) had two doses before their diagnosis (of whom 14 (88%) had mild infection). The proportion of women receiving drug treatment for SARS-CoV-2 management was low, but did increase between the wildtype dominance period and the alpha and delta dominance periods (10.4% wildtype v 14.9% alpha (2.74, 2.08 to 3.60); 10.4% wildtype v 13.6% delta (2.54, 1.90 to 3.38)). Conclusions While limited by the absence of variant sequencing data, these findings suggest that during the periods when the alpha and delta variants of SARS-CoV-2 were dominant, covid-19 was associated with more severe maternal infection and worse pregnancy outcomes than during the wildtype dominance period. Most women admitted with SARS-CoV-2 related symptoms were unvaccinated. Urgent action to prioritise vaccine uptake in pregnancy is essential. Study registration ISRCTN40092247.
48 citations
TL;DR: Covid-19 vaccination is associated with a small and likely to be temporary change in menstrual cycle length but no change in menses length.
Abstract: Objectives To identify whether covid-19 vaccines are associated with menstrual changes in order to address concerns about menstrual cycle disruptions after covid-19 vaccination. Design Global, retrospective cohort study of prospectively collected data. Setting International users of the menstrual cycle tracking application, Natural Cycles. Participants 19 622 individuals aged 18-45 years with cycle lengths of 24-38 days and consecutive data for at least three cycles before and one cycle after covid (vaccinated group; n=14 936), and those with at least four consecutive cycles over a similar time period (unvaccinated group; n=4686). Main outcome measures The mean change within individuals was assessed by vaccination group for cycle and menses length (mean of three cycles before vaccination to the cycles after first and second dose of vaccine and the subsequent cycle). Mixed effects models were used to estimate the adjusted difference in change in cycle and menses length between the vaccinated and unvaccinated. Results Most people (n=15 713; 80.08%) were younger than 35 years, from the UK (n=6222; 31.71%), US and Canada (28.59%), or Europe (33.55%). Two thirds (9929 (66.48%) of 14 936) of the vaccinated cohort received the Pfizer-BioNTech (BNT162b2) covid-19 vaccine, 17.46% (n=2608) received Moderna (mRNA-1273), 9.06% (n=1353) received Oxford-AstraZeneca (ChAdOx1 nCoV-19), and 1.89% (n=283) received Johnson & Johnson (Ad26.COV2.S). Individuals who were vaccinated had a less than one day adjusted increase in the length of their first and second vaccine cycles, compared with individuals who were not vaccinated (0.71 day increase (99.3% confidence interval 0.47 to 0.96) for first dose; 0.56 day increase (0.28 to 0.84) for second dose). The adjusted difference was larger in people who received two doses in a cycle (3.70 days increase (2.98 to 4.42)). One cycle after vaccination, cycle length was similar to before the vaccine in individuals who received one dose per cycle (0.02 day change (99.3% confidence interval −0.10 to 0.14), but not yet for individuals who received two doses per cycle (0.85 day change (99.3% confidence interval 0.24 to 1.46)) compared with unvaccinated individuals. Changes in cycle length did not differ by the vaccine’s mechanism of action (mRNA, adenovirus vector, or inactivated virus). Menses length was unaffected by vaccination. Conclusions Covid-19 vaccination is associated with a small and likely to be temporary change in menstrual cycle length but no change in menses length.
22 citations
TL;DR: This Delphi study identifies professional and public panel consensus guidance to facilitate consistency of definition and measurement, and to improve study comparability and reproducibility.
Abstract: Objective To develop international consensus on the definition and measurement of multimorbidity in research. Design Delphi consensus study. Setting International consensus; data collected in three online rounds from participants between 30 November 2020 and 18 May 2021. Participants Professionals interested in multimorbidity and people with long term conditions were recruited to professional and public panels. Results 150 professional and 25 public participants completed the first survey round. Response rates for rounds 2/3 were 83%/92% for professionals and 88%/93% in the public panel, respectively. Across both panels, the consensus was that multimorbidity should be defined as two or more long term conditions. Complex multimorbidity was perceived to be a useful concept, but the panels were unable to agree on how to define it. Both panels agreed that conditions should be included in a multimorbidity measure if they were one or more of the following: currently active; permanent in their effects; requiring current treatment, care, or therapy; requiring surveillance; or relapsing-remitting conditions requiring ongoing care. Consensus was reached for 24 conditions to always include in multimorbidity measures, and 35 conditions to usually include unless a good reason not to existed. Simple counts were preferred for estimating prevalence and examining clustering or trajectories, and weighted measures were preferred for risk adjustment and outcome prediction. Conclusions Previous multimorbidity research is limited by inconsistent definitions and approaches to measuring multimorbidity. This Delphi study identifies professional and public panel consensus guidance to facilitate consistency of definition and measurement, and to improve study comparability and reproducibility.
19 citations
TL;DR: No compelling evidence indicates that preprints provide results that are inconsistent with published papers, and evidence users should be encouraged to consider data from preprints.
Abstract: Objective To assess the trustworthiness (ie, complete and consistent reporting of key methods and results between preprint and published trial reports) and impact (ie, effects of preprints on meta-analytic estimates and the certainty of evidence) of preprint trial reports during the covid-19 pandemic. Design Retrospective review. Data sources World Health Organization covid-19 database and the Living Overview of the Evidence (L-OVE) covid-19 platform by the Epistemonikos Foundation (up to 3 August 2021). Main outcome measures Comparison of characteristics of covid-19 trials with and without preprints, estimates of time to publication of covid-19 preprints, and description of differences in reporting of key methods and results between preprints and their later publications. For the effects of eight treatments on mortality and mechanical ventilation, the study comprised meta-analyses including preprints and excluding preprints at one, three, and six months after the first trial addressing the treatment became available either as a preprint or publication (120 meta-analyses in total, 60 of which included preprints and 60 of which excluded preprints) and assessed the certainty of evidence using the GRADE framework. Results Of 356 trials included in the study, 101 were only available as preprints, 181 as journal publications, and 74 as preprints first and subsequently published in journals. The median time to publication of preprints was about six months. Key methods and results showed few important differences between trial preprints and their subsequent published reports. Apart from two (3.3%) of 60 comparisons, point estimates were consistent between meta-analyses including preprints versus those excluding preprints as to whether they indicated benefit, no appreciable effect, or harm. For nine (15%) of 60 comparisons, the rating of the certainty of evidence was different when preprints were included versus being excluded—the certainty of evidence including preprints was higher in four comparisons and lower in five comparisons. Conclusion No compelling evidence indicates that preprints provide results that are inconsistent with published papers. Preprints remain the only source of findings of many trials for several months—an unsuitable length of time in a health emergency that is not conducive to treating patients with timely evidence. The inclusion of preprints could affect the results of meta-analyses and the certainty of evidence. Evidence users should be encouraged to consider data from preprints.
12 citations
TL;DR: It is suggested that in patients with severe or critical covid-19, tocilizumab, in combination with corticosteroids, probably reduces mortality, and that sarilumAB, in conjunction with cortiosteroid, might also reduce mortality.
Abstract: Objective To compare the effects of interleukin 6 receptor blockers, tocilizumab and sarilumab, with or without corticosteroids, on mortality in patients with covid-19. Design Systematic review and network meta-analysis. Data sources World Health Organization covid-19 database, a comprehensive multilingual source of global covid-19 literature, and two prospective meta-analyses (up to 9 June 2021). Review methods Trials in which people with suspected, probable, or confirmed covid-19 were randomised to interleukin 6 receptor blockers (with or without corticosteroids), corticosteroids, placebo, or standard care. The analysis used a bayesian framework and assessed the certainty of evidence using the GRADE approach. Results from the fixed effect meta-analysis were used for the primary analysis. Results Of 45 eligible trials (20 650 patients) identified, 36 (19 350 patients) could be included in the network meta-analysis. Of 36 trials, 27 were at high risk of bias, primarily due to lack of blinding. Tocilizumab, in combination with corticosteroids, suggested a reduction in the risk of death compared with corticosteroids alone (odds ratio 0.79, 95% credible interval 0.70 to 0.88; 35 fewer deaths per 1000 people, 95% credible interval 52 fewer to 18 fewer per 1000; moderate certainty of evidence), as did sarilumab in combination with corticosteroids, compared with corticosteroids alone (0.73, 0.58 to 0.92; 43 fewer per 1000, 73 fewer to 12 fewer; low certainty). Tocilizumab and sarilumab, each in combination with corticosteroids, appeared to have similar effects on mortality when compared with each other (1.07, 0.86 to 1.34; eight more per 1000, 20 fewer to 35 more; low certainty). The effects of tocilizumab (1.12, 0.91 to 1.38; 20 more per 1000, 16 fewer to 59 more; low certainty) and sarilumab (1.07, 0.81 to 1.40; 11 more per 1000, 38 fewer to 55 more; low certainty), when used alone, suggested an increase in the risk of death. Conclusion These findings suggest that in patients with severe or critical covid-19, tocilizumab, in combination with corticosteroids, probably reduces mortality, and that sarilumab, in combination with corticosteroids, might also reduce mortality. Tocilizumab and sarilumab, in combination with corticosteroids, could have similar effectiveness. Tocilizumab and sarilumab, when used alone, might not be beneficial.
11 citations
TL;DR: The genetics, structure, and transmission methods of SARS-CoV-2 and its variants are discussed, highlighting how mutations provide enhanced abilities to spread and inflict disease.
Abstract: As of 25 January 2022, over 349 million individuals have received a confirmed diagnosis of covid-19, with over 5.59 million confirmed deaths associated with the SARS-CoV-2 virus. The covid-19 pandemic has prompted an extensive global effort to study the molecular evolution of the virus and develop vaccines to prevent its spread. Although rigorous determination of SARS-CoV-2 infectivity remains elusive, owing to the continuous evolution of the virus, steps have been made to understand its genome, structure, and emerging genetic mutations. The SARS-CoV-2 genome is composed of several open reading frames and structural proteins, including the spike protein, which is essential for entry into host cells. As of 25 January 2022, the World Health Organization has reported five variants of concern, two variants of interest, and three variants under monitoring. Additional sublineages have since been identified, and are being monitored. The mutations harboured in these variants confer an increased transmissibility, severity of disease, and escape from neutralising antibodies compared with the primary strain. The current vaccine strategy, including booster doses, provides protection from severe disease. As of 24 January 2022, 33 vaccines have been approved for use in 197 countries. In this review, we discuss the genetics, structure, and transmission methods of SARS-CoV-2 and its variants, highlighting how mutations provide enhanced abilities to spread and inflict disease. This review also outlines the vaccines currently in use around the world, providing evidence for every vaccine's immunogenicity and effectiveness.
11 citations
TL;DR: Most women with severe covid-19 disease were unvaccinated and vaccine coverage among pregnant women admitted to hospital with SARS-CoV-2 was low; a better understanding of the persistent low use of drug treatments is an urgent priority.
Abstract: Objectives To describe the severity of maternal infection when the omicron SARS-CoV-2 variant (B.1.1.529) was dominant (15 December 2021 to 14 March 2022) and describe outcomes by symptoms and vaccination status. Design Prospective, national cohort study using the UK Obstetric Surveillance System. Setting 94 hospitals in the UK with a consultant led maternity unit. Participants Pregnant women admitted to hospital for any cause with a positive SARS-CoV-2 test. Main outcome measures Symptomatic or asymptomatic infection, vaccination status by doses before admission, and severity of maternal infection (moderate or severe infection according to modified World Health Organization's criteria). Results Of 3699 women who were admitted to hospital, 986 (26.7%, 95% confidence interval 25.3% to 28.1%) had symptoms; of these, 144 (14.6%, 12.5% to 17.0%) had a moderate to severe infection, 99 (10.4%, 8.6% to 12.5%) of 953 received respiratory support, and 30 (3.0%, 2.1% to 4.3%) were admitted to an intensive care unit. Covid-19 specific drug treatment was given to 13 (43.3%) of the 30 women in intensive care. Four women with symptoms died (0.4%, 0.1% to 1.1%). Vaccination status was known for 845 (85.6%) women with symptoms; 489 (58.9%) were unvaccinated and only 55 (6.5%) had three doses. Moderate to severe infection was reported for 93 (19.0%) of 489 unvaccinated women with symptoms, decreasing to three (5.5%) of 55 after three doses. Among the 30 women with symptoms who were admitted to intensive care, 23 (76.7%) were unvaccinated and none had received three doses. Conclusion Most women with severe covid-19 disease were unvaccinated and vaccine coverage among pregnant women admitted to hospital with SARS-CoV-2 was low. Ongoing action to prioritise and advocate for vaccine uptake in pregnancy is essential. A better understanding of the persistent low use of drug treatments is an urgent priority. Trial registration ISRCTN 40092247.
10 citations
TL;DR: The importance of extrapolating beyond the end of trials to estimate the long term benefits associated with new treatments is explained, why this is done, and the limitations of various approaches are explained.
Abstract: This paper explains the importance of extrapolating beyond the end of trials to estimate the long term benefits associated with new treatments, why this is done, and the limitations of various approaches.
9 citations
TL;DR: In this paper , the association between individual participant characteristics and attrition from randomised controlled trials was estimated in logistic regression models and adjusted for age and sex, with minimal variation across drug classes and index conditions.
Abstract: Objectives To estimate the association between individual participant characteristics and attrition from randomised controlled trials. Design Meta-analysis of individual participant level data (IPD). Data sources Clinical trial repositories (Clinical Study Data Request and Yale University Open Data Access). Eligibility criteria for selecting studies Eligible phase 3 or 4 trials identified according to prespecified criteria (PROSPERO CRD42018048202). Main outcome measures Association between comorbidity count (identified using medical history or concomitant drug treatment data) and trial attrition (failure for any reason to complete the final trial visit), estimated in logistic regression models and adjusted for age and sex. Estimates were meta-analysed in bayesian linear models, with partial pooling across index conditions and drug classes. Results In 92 trials across 20 index conditions and 17 drug classes, the mean comorbidity count ranged from 0.3 to 2.7. Neither age nor sex was clearly associated with attrition (odds ratio 1.04, 95% credible interval 0.98 to 1.11; and 0.99, 0.93 to 1.05, respectively). However, comorbidity count was associated with trial attrition (odds ratio per additional comorbidity 1.11, 95% credible interval 1.07 to 1.14). No evidence of non-linearity (assessed via a second order polynomial) was seen in the association between comorbidity count and trial attrition, with minimal variation across drug classes and index conditions. At a trial level, an increase in participant comorbidity count has a minor impact on attrition: for a notional trial with high level of attrition in individuals without comorbidity, doubling the mean comorbidity count from 1 to 2 translates to an increase in trial attrition from 29% to 31%. Conclusions Increased comorbidity count, irrespective of age and sex, is associated with a modest increased odds of participant attrition. The benefit of increased generalisability of including participants with multimorbidity seems likely to outweigh the disadvantages of increased attrition.
9 citations
TL;DR: Although antimicrobial treatment might have a role in treating chronic pain states that involve active infectious inflammatory processes, their use in chronic pain conditions resulting from autoimmune mechanisms, central sensitization and irrevocable tissue are likely to cause more harm than benefit.
Abstract: Throughout human history, infection has been the leading cause of morbidity and mortality, with pain being one of the cardinal warning signs. However, in a substantial percentage of cases, pain can persist after resolution of acute illness, manifesting as neuropathic, nociplastic (eg, fibromyalgia, irritable bowel syndrome), or nociceptive pain. Mechanisms by which acute infectious pain becomes chronic are variable and can include immunological phenomena (eg, bystander activation, molecular mimicry), direct microbe invasion, central sensitization from physical or psychological triggers, and complications from treatment. Microbes resulting in a high incidence of chronic pain include bacteria such as the Borrelia species and Mycobacterium leprae, as well as viruses such as HIV, SARS-CoV-2 and herpeses. Emerging evidence also supports an infectious cause in a subset of patients with discogenic low back pain and inflammatory bowel disease. Although antimicrobial treatment might have a role in treating chronic pain states that involve active infectious inflammatory processes, their use in chronic pain conditions resulting from autoimmune mechanisms, central sensitization and irrevocable tissue (eg, arthropathy, vasculitis) or nerve injury, are likely to cause more harm than benefit. This review focuses on the relation between infection and chronic pain, with an emphasis on common viral and bacterial causes.
8 citations
TL;DR: Ezetimibe results in little to no difference in adverse events or other undesirable effects compared with placebo, usual care or other lipid-lowering agents and no credible subgroup effects were identified for the harm outcomes, including shorter versus longer follow-up duration of trials.
Abstract: Objective To determine the harms of ezetimibe in people who need lipid-lowering treatment. Design Systematic review and meta-analysis. Data sources Randomised controlled trials and cohort studies. Eligibility criteria for selecting studies Studies comparing ezetimibe with placebo, standard care, or other lipid-lowering agents in people who need lipid-lowering treatment with a follow-up duration of at least six months (or 24 weeks). The relative effects for potential harms of ezetimibe were pooled by use of random effect pairwise meta-analyses for randomised controlled trials and the evidence from observational studies was narratively summarised. The certainty of evidence was assessed using the Grading of Recommendation Assessment, Development, and Evaluation. Results 48 randomised controlled trials with 28 444 participants (median follow-up 34 weeks, range 24-312 weeks) and four observational studies with 1667 participants (median follow-up 282 weeks, range 72-400 weeks) were included. The meta-analyses of randomised trials showed moderate to high certainty that ezetimibe was not associated with cancer (relative risk 1.01; 95% confidence interval 0.92 to 1.11), fractures (0.90; 0.74 to 1.10), discontinuation due to any adverse event (0.87; 0.74 to 1.03), gastrointestinal adverse events leading to discontinuation (1.34; 0.58 to 3.08), myalgia or muscular pain leading to discontinuation (0.82; 0.51 to 1.33), neurocognitive events (1.48; 0.58 to 3.81), or new-onset diabetes (0.88; 0.61 to 1.28). The narrative analysis of observational studies provided consistent findings. No credible subgroup effects were identified for the harm outcomes, including shorter versus longer follow-up duration of trials. Conclusions Ezetimibe results in little to no difference in adverse events or other undesirable effects compared with placebo, usual care or other lipid-lowering agents. Review registration PROSPERO CRD42020187437.
TL;DR: It is suggested that higher annual air pollution levels were associated with increased risk of first hospital admission related to diseases of the kidney and urinary system or CKD in the Medicare population.
Abstract: Objective To estimate the associations between long term exposure to air pollution and the first hospital admission related to kidney and total urinary system diseases. Design Nationwide longitudinal cohort study. Setting Data were collected from the Medicare fee-for-service for beneficiaries living in 34 849 zip codes across the continental United States from 2000 to 2016. Exposure variables were annual averages of traffic related pollutants (fine particles (PM2.5) and nitrogen dioxide (NO2)) that were assigned according to the zip code of residence of each beneficiary with the use of validated and published hybrid ensemble prediction models. Participants All beneficiaries aged 65 years or older who were enrolled in Medicare part A fee-for-service (n=61 097 767). Primary and secondary outcome measures First hospital admission with diagnosis codes for total kidney and urinary system disease or chronic kidney disease (CKD), analyzed separately. Results The average annual concentrations of air pollution were 9.8 µg/m3 for PM2.5 and 18.9 ppb for NO2. The total number of first admissions related to total kidney and urinary system disease and CKD were around 19.0 million and 5.9 million, respectively (2000-16). For total kidney and urinary system disease, hazard ratios were 1.076 (95% confidence interval 1.071 to 1.081) for a 5 µg/m3 increase in PM2.5 and 1.040 (1.036 to 1.043) for a 10 ppb increase in NO2. For CKD, hazard ratios were 1.106 (1.097 to 1.115) for a 5 µg/m3 increase in PM2.5 and 1.013 (1.008 to 1.019) for a 10 ppb increase in NO2. These positive associations between PM2.5 and kidney outcomes persisted at concentrations below national health based air quality standards. Conclusions The findings suggest that higher annual air pollution levels were associated with increased risk of first hospital admission related to diseases of the kidney and urinary system or CKD in the Medicare population.
TL;DR: In this paper , the adoption and discontinuation of four broadly used non-pharmaceutical interventions on shifts in the covid-19 burden among US states was evaluated by using generalised linear models accounting for weekly variability.
Abstract: Objective To evaluate the adoption and discontinuation of four broadly used non-pharmaceutical interventions on shifts in the covid-19 burden among US states. Design Retrospective, observational cohort study. Setting US state data on covid-19 between 19 January 2020 and 7 March 2021. Participants US population with a diagnosis of covid-19. Main outcome measures Empirically derived breakpoints in case and mortality velocities (ie, rate of change) were used to identify periods of stable, decreasing, or increasing covid-19 burden. Associations between adoption of non-pharmaceutical interventions and subsequent decreases in case or death rates were estimated by use of generalised linear models accounting for weekly variability across US states. State level case and mortality counts per day were obtained from the Covid-19 Tracking Project. State level policies on non-pharmaceutical interventions included stay-at-home orders, indoor public gathering bans (mild >10 or severe ≤10 people), indoor restaurant dining bans, and public mask mandates. National policies were not included in statistical models. Results 28 602 830 cases and 511 899 deaths were recorded during the study. Odds of a reduction in covid-19 case velocity increased for stay-at-home orders (odds ratio 2.02, 95% confidence interval 1.63 to 2.52), indoor dining bans (1.62, 1.25 to 2.10), public mask mandates (2.18, 1.47 to 3.23), and severe indoor public gathering bans (1.68, 1.31 to 2.16) in univariate analysis. In mutually adjusted models, odds remained elevated for orders to stay at home (adjusted odds ratio 1.47, 95% confidence interval 1.04 to 2.07) and public mask mandates (2.27, 1.51 to 3.41). Stay-at-home orders (odds ratio 2.00, 95% confidence interval 1.53 to 2.62; adjusted odds ratio 1.89, 95% confidence interval 1.25 to 2.87) was also associated with a greater likelihood of decrease in death velocity in unadjusted and adjusted models. Conclusions State level non-pharmaceutical interventions used in the US during the covid-19 pandemic, in particular stay-at-home orders, were associated with a decreased covid-19 burden.
TL;DR: A shifting landscape of covid-19 risk for pregnant women is presented in this paper , where pregnant women are infected with SARS-CoV-2, they are more likely than non-pregnant women to have severe covid19, with higher rates of hospital admission and admission to intensive care.
Abstract: > A shifting landscape of covid-19 risk for pregnant women If pregnant women are infected with SARS-CoV-2, they are more likely than non-pregnant women to have severe covid-19, with higher rates of hospital admission, higher rates of admission to intensive care, and an increased need for
TL;DR: The most expensive new antibiotic was pretomanid at $36 399 (£29 618; €34 582) for a course of treatment, and the least expensive was rifamycin ($176) as mentioned in this paper .
Abstract: To review the clinical evidence, regulatory background, and cost of antibiotics approved by the US Food and Drug Administration (FDA), 2016-19.Cohort study of FDA approved drugs.FDA databases, ClinicalTrials.gov, and drug labelling. Launch prices were extracted from IBM Micromedex Red Book.Antibiotics approved by the FDA from October 2016 to December 2019 were identified, and key features of their clinical development were extracted from publicly available FDA databases, ClinicalTrials.gov, and drug labelling. Launch prices were extracted from IBM Micromedex Red Book to evaluate the cost of treatment against comparators.15 new antibiotics received at least one special regulatory designation and were supported by a median of two pivotal trials. More than half of the pivotal trials used an active control non-inferiority design. All drugs were approved based on surrogate outcome measures. 52 postmarketing requirements and commitments were included across the cohort (median 3 for each drug). From January 2021, 27 postmarketing requirements and commitments were listed as pending, seven as ongoing, three as delayed, one as submitted, eight as released, and four as fulfilled. The most expensive new antibiotic was pretomanid at $36 399 (£29 618; €34 582) for a course of treatment, and the least expensive was rifamycin ($176). Cost ratios between study drugs and comparators ranged from 0.48 to 134.New antibiotics have been approved by the FDA in recent years mostly based on fewer, smaller, and non-inferiority pivotal trials that often used surrogate outcome measures but were commonly more costly. Efforts to incentivise the development of antibiotics should balance growing the antibiotic development pipeline with ensuring that clinical trials provide clinically relevant evidence of effectiveness in showing added benefits for the patient.
TL;DR: In this article , Belbasis and colleagues explain the rationale for umbrella reviews and the key steps involved in conducting an umbrella review, using a working example, and present an example of how to conduct a review.
Abstract: In this article, Lazaros Belbasis and colleagues explain the rationale for umbrella reviews and the key steps involved in conducting an umbrella review, using a working example.
TL;DR: Kokosi and Harron as discussed by the authors describe synthetic data as "artificial data that can be used to support efficient medical and healthcare research, while minimising the need to access personal data".
Abstract: ⇒ Synthetic data are artificial data that can be used to support efficient medical and healthcare research, while minimising the need to access personal data ⇒ More research is needed to determine the extent to which synthetic data can be relied on for formal analysis, the cost effectiveness of generating synthetic data, and how to accurately assess disclosure risk Synthetic data have the potential to improve medical research while minimising the need to access personal data; Theodora Kokosi and Katie Harron explain what they are and how they are used.
TL;DR: It is indicated that gout is associated with an increased risk of cardiovascular events and the potential causal mechanisms of these associations require further exploration, including casual inference modelling in future studies.
Abstract: Objective To examine the association of gout with cardiovascular outcomes using linked administrative health data in Aotearoa New Zealand. Design Data linkage study. Setting National registries of pharmaceutical dispensing, hospital admission, and deaths linked to the Auckland/Northland regional repository of laboratory results to create a regional health contact population as of 31 December 2011. Participants 942 416 residents of the Auckland/Northland region, aged 20-79 years with no history of cardiovascular disease. Main outcome measures Time to first fatal or non-fatal cardiovascular event, identified from national datasets on hospital admissions and mortality, between 1 January 2012 and 31 December 2016. Cardiovascular disease was broadly defined as comprising ischaemic heart disease, ischaemic or haemorrhagic stroke, transient ischaemic attack, peripheral vascular disease, and heart failure. Interventions A history of gout identified from a discharge diagnosis of gout from a public hospital admission or previous dispensing of gout specific drug treatments. The cohort was then linked to national hospital admissions and deaths through to 31 December 2016 (ie, 5 years' follow-up). Multivariable Cox proportional hazard models were constructed to assess the associations between gout, other risk factors, and cardiovascular outcomes. Results Of 942 416 people included in the study, 31 907 (3.4%) had gout (6261 women and 25 646 men). After adjustment for multiple risk factors for cardiovascular disease, gout was associated with increased cardiovascular events (adjusted hazard ratio 1.34 (95% confidence interval 1.23 to 1.45) in women; 1.18 (1.12 to 1.24) in men). For men with gout, there was an increased risk of cardiovascular disease in those who were not dispensed regular allopurinol (1.15 (1.05 to 1.25)) and those with a serum urate above the treatment target of 0.36 mmol/L (1.16 (1.04 to 1.30)). Risk of cardiovascular events was lower for men with gout who were not dispensed colchicine compared with those who were (0.84 (0.77 to 0.92)). These findings were not observed in women. Conclusion These results indicate that gout is associated with an increased risk of cardiovascular events. In men with gout without history of cardiovascular disease, the cardiovascular risk was lower in those regularly dispensed allopurinol and those with serum urate levels at the recommended treatment target. By contrast, colchicine dispensing was associated with an increased risk of cardiovascular events in men with gout without a cardiovascular history. The potential causal mechanisms of these associations require further exploration, including casual inference modelling in future studies.
TL;DR: Key approaches for data linkage are outlined, and methods used to quantify, interpret, and account for errors in the linkage process are described.
Abstract: ⇒ Data linkage in medical research allows researchers to exploit and enhance existing data sources without the time and cost associated with primary data collection ⇒ Methods used to quantify, interpret, and account for errors in the linkage process are needed, alongside guidelines for transparent reporting Data linkage provides an opportunity to harness existing data for medical research. This article outlines key approaches for data linkage, and describes methods used to quantify, interpret, and account for errors.
TL;DR: Evidence is provided indicating that two doses of ChAdOx1-S is as effective as three doses of mRNA vaccines in France against the alpha and delta variants of SARS-CoV-2.
Abstract: Objective To estimate the effectiveness of the three covid-19 vaccines by Pfizer-BioNTech (BNT162b2), Moderna (mRNA-1273), and Oxford-AstraZeneca (ChAdOx1-S) in people after receiving two doses. Design Cohort study. Setting Nationwide, population based data in France, from the French National Health Data System (Système National des Données de Santé), between 27 December 2020 and 30 April 2021. Participants Adults aged ≥50 years receiving a first dose of BNT162b2, mRNA-1273, or ChAdOx1-S were randomly selected (1:1) and matched on the date of vaccination with one unvaccinated control. Individuals were matched on year of birth, sex, region of residence, and residence in a nursing home (for individuals aged ≥75 years). All individuals were followed up until 20 August 2021. Main outcome measures Primary outcome measure was vaccine effectiveness estimated at least 14 days after the second dose against covid-19 related hospital admission using Cox proportional hazards models adjusted for baseline characteristics and comorbidities. Vaccine effectiveness against covid-19 related death in hospital was also investigated. Results 11 256 832 vaccinated individuals were included in the study (63.6% (n=7 161 658) with the BNT162b2 vaccine, 7.6% (n=856 599) with the mRNA-1273 vaccine, and 28.8% (n=3 238 575) with the ChAdOx1-S vaccine), along with 11 256 832 matched unvaccinated controls. During follow-up (up to 20 August 2021), 43 158 covid-19 related hospital admissions and 7957 covid-19 related deaths in hospital were registered. Compared with unvaccinated controls, vaccine effectiveness of two doses against covid-19 related hospital admission was 91% (95% confidence interval 91% to 92%), 95% (93% to 96%), and 91% (89% to 94%) for the BNT162b2, mRNA-1273, and ChAdOx1-S vaccines, respectively. Similar results were observed for vaccine effectiveness of two doses against covid-19 related deaths in hospital (BNT162b2, 91% (90% to 93%); mRNA-1273, 96% (92% to 98%); and ChAdOx1 nCoV-19, 88% (68% to 95%)). At 5-6 months after receiving the second dose of vaccine, effectiveness remained high at 94% (92% to 95%) for the BNT162b2 vaccine and 98% (93% to 100%) for the mRNA-1273 vaccine. Vaccine effectiveness of ChAdOx1-S estimated at 3-4 months was 90% (63% to 97%). All three vaccines remained effective at the time of circulation of the delta variant of SARS-CoV-2 between 1 July and 20 August 2021 (effectiveness between 89% and 95%). Conclusions These findings provide evidence indicating that two doses of ChAdOx1-S is as effective as two doses of mRNA vaccines in France against the alpha and delta variants of SARS-CoV-2. The effectiveness of ChAdOx1-S should be further examined with a longer follow-up and in the light of the circulation of new SARS-CoV-2 variants of concern.
TL;DR: In this article , an external validation cohort study was conducted to evaluate the QFracture risk prediction tool for predicting the risk of major osteoporotic fracture and hip fracture.
Abstract: Objective To externally evaluate the QFracture risk prediction tool for predicting the risk of major osteoporotic fracture and hip fracture. Design External validation cohort study. Setting UK primary care population. Linked general practice (Clinical Practice Research Datalink (CPRD) Gold), mortality registration (Office of National Statistics), and hospital inpatient (Hospital Episode Statistics) data, from 1 January 2004 to 31 March 2016. Participants 2 747 409 women and 2 684 730 men, aged 30-99 years, with up-to-standard linked data that had passed CPRD checks for at least one year. Main outcome measures Two outcomes were modelled based on the QFracture: major osteoporotic fracture and hip fracture. Major osteoporotic fracture was defined as any hip, distal forearm, proximal humerus, or vertebral crush fracture, from general practice, hospital discharge, and mortality data. The QFracture 10 year predicted risk of major osteoporotic fracture and hip fracture was calculated, and performance evaluated versus observed 10 year risk of fracture in the whole population, and in subgroups based on age and comorbidity. QFracture calibration was examined accounting for, and not accounting for, competing risk of mortality from causes other than the major osteoporotic fracture. Results 2 747 409 women with 95 598 major osteoporotic fractures and 36 400 hip fractures, and 2 684 730 men with 34 321 major osteoporotic fractures and 13 379 hip fractures were included in the analysis. The incidence of all fractures was higher than in the QFracture internal derivation. Competing risk of mortality was more common than fracture from middle age onwards. QFracture discrimination in the whole population was excellent or good for major osteoporotic fracture and hip fracture (Harrell’s C statistic in women 0.813 and 0.918, and 0.738 and 0.888 in men, respectively), but was poor to moderate in age subgroups (eg, Harrell’s C statistic in women and men aged 85-99 years was 0.576 and 0.624 for major osteoporotic fractures, and 0.601 and 0.637 for hip fractures, respectively). Without accounting for competing risks, QFracture systematically under-predicted the risk of fracture in all models, and more so for major osteoporotic fracture than for hip fracture, and more so in older people. Accounting for competing risks, QFracture still under-predicted the risk of fracture in the whole population, but over-prediction was considerable in older age groups and in people with high comorbidities at high risk of fracture. Conclusions The QFracture risk prediction tool systematically under-predicted the risk of fracture (because of incomplete determination of fracture rates) and over-predicted the risk in older people and in those with more comorbidities (because of competing mortality). The use of QFracture in its current form needs to be reviewed, particularly in people at high risk of death from other causes.
TL;DR: In this article , the effects of different nutritional intervention strategies in the school setting on anthropometric and quality of diet outcomes were examined by comparing and ranking outcomes in a network meta-analysis.
Abstract: Objective To examine the effects of different nutritional intervention strategies in the school setting on anthropometric and quality of diet outcomes by comparing and ranking outcomes in a network meta-analysis. Design Systematic review and network meta-analysis. Data sources PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Education Resources Information Centre (ERIC), PsycInfo, CAB Abstracts, Campbell Library, Evidence for Policy and Practice Information and Co-ordinating Centre (EPPI-Centre) BiblioMap, Australian Education Index, Joanna Briggs Institute Evidence-Based Practice (JBI EBP) database, Practice-based Evidence in Nutrition (PEN) database, ClinicalTrials.gov, Current Controlled Trials, and World Health Organization International Clinical Trials Registry Platform. Eligibility criteria for selecting studies A systematic literature search was performed from inception to 2 May 2022. Cluster randomised controlled trials meeting these study criteria were included: generally healthy school students aged 4-18 years; intervention with ≥1 nutritional components in a school setting; and studies that assessed anthropometric measures (eg, body mass index, body fat) or measures related to the quality of diet (eg, intake of fruit and vegetables), or both. Random effects pairwise meta-analyses and network meta-analyses were performed with a frequentist approach. P scores, a frequentist analogue to surface under the cumulative ranking curve, ranging from 0 to 1 (indicating worst and best ranked interventions, respectively) were calculated. Risk of bias was assessed with Cochrane’s RoB 2 tool. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was used to rate the certainty of evidence. Results 51 cluster randomised controlled trials involving 75 954 participants and seven intervention nodes were included. Inconsistency could not be assessed (except for intake of fruit and vegetables) because the network meta-analyses were based mainly on star shaped networks with no direct evidence for specific pairs of nutritional interventions. Overall, little or no evidence was found to support a difference in body mass index, body weight, body fat, or waist circumference and moderate improvements in intake of fruit and vegetables with nutritional interventions in a school setting. Low to moderate certainty of evidence further suggested that multicomponent nutritional interventions likely reduced the prevalence (odds ratio 0.66, 95% confidence interval 0.55 to 0.80) and incidence (0.67, 0.47 to 0.96) of overweight compared with a control group. Based on low certainty of evidence, nutrition education and multicomponent interventions may be more effective than a control group (ie, usual practice) for increasing intake of fruit and vegetables. Multicomponent nutritional interventions were ranked the most effective for reducing body mass index (P score 0.76) and intake of fat (0.82). Nutrition education was ranked as best for body mass index z score (0.99), intake of fruit and vegetables (0.82), intake of fruit (0.92), and intake of vegetables (0.88). Conclusions The findings suggest that nutritional interventions in school settings may improve anthropometric and quality of diet measures, potentially contributing to the prevention of overweight and obesity in childhood and adolescence. The findings should be interpreted with caution because the certainty of evidence was often rated as low. The results of the network meta-analysis could be used by policy makers in developing and implementing effective, evidence based nutritional intervention strategies in the school setting. Systematic review registration PROSPERO CRD42020220451.
TL;DR: Few NICE recommendations of lifestyle interventions are supported by reliable evidence, and guidelines recommending clinicians to try to change people’s lifestyle need to be reconsidered given the substantial uncertainty about the effectiveness, harms, and opportunity costs of such interventions.
Abstract: Objectives To assess whether recommendations of individually oriented lifestyle interventions (IOLIs) in guidelines from the National Institute for Health and Care Excellence (NICE) were underpinned by evidence of benefit, and whether harms and opportunity costs were considered. Design Cross sectional survey. Setting UK. Data sources NICE guidelines and supporting evidence. Eligibility criteria All NICE pathways for IOLI recommendations (ie, non-drug interventions that healthcare professionals administer to adults to achieve a healthier lifestyle and improve health) were searched systematically on 26 August 2020. One author screened all retrieved pathways for candidate guidelines, while a second author verified these judgments. Two authors independently and in duplicate screened all retrieved guidelines and recommendations for eligibility, extracted data, and evaluated the evidence cited and the outcomes considered. Disagreements were noted and resolved by consensus. Results Within 57 guidelines, 379 NICE recommendations were found for IOLIs; almost all (n=374; 99%) recommended the lifestyle intervention and five (1%) recommended against the intervention. Of the 379 recommendations, 13 (3%) were supported by moderate or high certainty evidence of a beneficial effect on patient relevant outcomes (n=7; 2%) or surrogate outcomes (n=13; 3%). 19 (5%) interventions considered psychosocial harms, 32 (8%) considered physical harms, and one (<1%) considered the opportunity costs of implementation. No intervention considered the burden placed on individuals by these recommendations. Conclusion Few NICE recommendations of lifestyle interventions are supported by reliable evidence. While this finding does not contest the beneficial effects of healthy habits, guidelines recommending clinicians to try to change people’s lifestyle need to be reconsidered given the substantial uncertainty about the effectiveness, harms, and opportunity costs of such interventions.
TL;DR: The majority of deaths of women during pregnancy, or up to six weeks after the end of pregnancy, are due to medical and social factors as discussed by the authors , and better advice and support before and after pregnancy is needed from health and social care beyond maternity services.
Abstract: > Better advice and support before and after pregnancy is needed from health and social care beyond maternity services For almost two decades in the UK, it has been clear that the majority of deaths of women during pregnancy, or up to six weeks after the end of pregnancy, are due to medical and
TL;DR: This core outcome set caters for global burn research, and future trials are recommended to include measures of seven core outcomes: death, specified complications, ability to do daily tasks, wound healing, neuropathic pain and itch, psychological wellbeing and return to school or work.
Abstract: Objective To develop a core outcome set for international burn research. Design Development and international consensus, from April 2017 to November 2019. Methods Candidate outcomes were identified from systematic reviews and stakeholder interviews. Through a Delphi survey, international clinicians, researchers, and UK patients prioritised outcomes. Anonymised feedback aimed to achieve consensus. Pre-defined criteria for retaining outcomes were agreed. A consensus meeting with voting was held to finalise the core outcome set. Results Data source examination identified 1021 unique outcomes grouped into 88 candidate outcomes. Stakeholders in round 1 of the survey, included 668 health professionals from 77 countries (18% from low or low middle income countries) and 126 UK patients or carers. After round 1, one outcome was discarded, and 13 new outcomes added. After round 2, 69 items were discarded, leaving 31 outcomes for the consensus meeting. Outcome merging and voting, in two rounds, with prespecified thresholds agreed seven core outcomes: death, specified complications, ability to do daily tasks, wound healing, neuropathic pain and itch, psychological wellbeing, and return to school or work. Conclusions This core outcome set caters for global burn research, and future trials are recommended to include measures of these outcomes.
TL;DR: In this paper , the probability of exertion shortly before MI is compared to the probability 24hr before in the same individuals, but the authors do not specify when the MI occurred.
Abstract: 4) “The probability of exertion shortly before MI is compared to the probability 24hr before in the same individuals” – I think we need more clarity here. Is this at exactly 24 hours before? For example, if someone played football 25 before, but not 24 before, then does it count? I cannot understand from the text how the ‘probability of exertion’ is derived and what assumptions this calculation is making. We need more practical details. Also, if an individual died, then how do we know what they were doing 24 hours earlier? I know the window is considered in a later section, but some clarity early on, for this example, would help.
TL;DR: Industry payments to physicians, particularly those involving physical interactions such as meals and travel, substantially decreased during the pandemic, and how such changes affect prescription practices and the quality of clinical practice in the long term should be investigated.
Abstract: Objective To determine changes in industry marketing payments to physicians due to the covid-19 pandemic. Design Quasi experimental, difference-in-difference study. Data source US nationwide database of licensed physicians, the National Plan and Provider Enumeration System, which was linked to a database of industry marketing payments made to physicians, Open Payments. Population All licensed US physicians from 2018 to 2020 and those who received payments from industry. Main outcome measures Changes in the value and the number of monthly industry payments physician received before (January-February 2020) and during the pandemic (April-December 2020) were assessed, adjusting for physicians’ characteristics (gender and specialty). As the control, data for the same months in 2019 were used. Industry payments by type of payments (eg, meals, travel, consulting fees, speaker compensation, honorariums), were also examined. Results Among 880 589 US physicians included in this study, 267 463 (30.4%) physicians received a total of 4 117 482 non-research payments with $626 million ($710 per physician; £610; €708) in 2020 (40-44% decrease from $1047m in 2018 and $1115m in 2019). Industry payments decreased significantly in the months of the covid-19 pandemic (adjusted change in the value of −48.4%; 95% confidence interval −50.6 to −46.2; P<0.001; and adjusted change in the number of −47.4%, 95% confidence interval −47.7 to −47.1; P<0.001), particularly for meals and travel fees. No evidence was seen of a decrease in the number of industry payments for consulting and honorariums. A similar pattern was observed across physicians’ gender and specialty. Conclusions Industry payments to physicians, particularly those involving physical interactions such as meals and travel, substantially decreased during the pandemic. How such changes affect prescription practices and the quality of clinical practice in the long term should be investigated.
TL;DR: An overview of the current literature emphasising the pathophysiology and risk factors of exertional heat stroke is provided, highlighting gaps in knowledge with the objective to stimulate future research.
Abstract: Exertional heat stroke, the third leading cause of mortality in athletes during physical activity, is the most severe manifestation of exertional heat illnesses. Exertional heat stroke is characterised by central nervous system dysfunction in people with hyperthermia during physical activity and can be influenced by environmental factors such as heatwaves, which extend the incidence of exertional heat stroke beyond athletics only. Epidemiological data indicate mortality rates of about 27%, and survivors display long term negative health consequences ranging from neurological to cardiovascular dysfunction. The pathophysiology of exertional heat stroke involves thermoregulatory and cardiovascular overload, resulting in severe hyperthermia and subsequent multiorgan injury due to a systemic inflammatory response syndrome and coagulopathy. Research about risk factors for exertional heat stroke remains limited, but dehydration, sex differences, ageing, body composition, and previous illness are thought to increase risk. Immediate cooling remains the most effective treatment strategy. In this review, we provide an overview of the current literature emphasising the pathophysiology and risk factors of exertional heat stroke, highlighting gaps in knowledge with the objective to stimulate future research.
TL;DR: A review of advances in the diagnosis and early management of gestational trophoblastic disease and highlights updates to disease classification and clinical guidelines can be found in this article , where molecular genotyping for improved diagnostic accuracy and risk stratification is reviewed and future biomarkers for the earlier detection of malignancy are considered.
Abstract: Gestational trophoblastic disease describes a group of rare pregnancy related disorders that span a spectrum of premalignant and malignant conditions. Hydatidiform mole (also termed molar pregnancy) is the most common form of this disease. Hydatidiform mole describes an abnormal conceptus containing two copies of the paternal genome, which is classified as partial when the maternal genome is present or complete when the maternal genome is absent. Hydatidiform mole typically presents in the first trimester with irregular vaginal bleeding and can be suspected on ultrasound but confirmation requires histopathological evaluation of the products of conception. Most molar pregnancies resolve without treatment after uterine evacuation, but occasionally the disease persists and develops into gestational trophoblastic neoplasia. Close monitoring of women after molar pregnancy, with regular measurement of human chorionic gonadotrophin concentrations, allows for early detection of malignancy. Given the rarity of the disease, clinical management and treatment is best provided in specialist centres where very high cure rates are achievable. This review looks at advances in the diagnosis and early management of gestational trophoblastic disease and highlights updates to disease classification and clinical guidelines. Use of molecular genotyping for improved diagnostic accuracy and risk stratification is reviewed and future biomarkers for the earlier detection of malignancy are considered.
TL;DR: Results suggest that schools were not an important setting for transmission of the virus in Norway during the covid-19 pandemic in the academic year 2020-21, and the number of people infected with SARS-CoV-2 among students and staff is low.
Abstract: Objective To assess the risk of transmission of SARS-CoV-2 in schools in Norway mainly kept open during the covid-19 pandemic in the academic year 2020-21. Design Population wide, register based cohort study. Setting Primary and lower secondary schools in Norway open during the academic year 2020-21, with strict infection prevention and control measures in place, such as organisation of students into smaller cohorts. Contact tracing, quarantine, and isolation were also implemented, and testing of students and staff identified as close contacts. Participants All students and educational staff in primary and lower secondary schools in Norway, from August 2020 to June 2021. Main outcome measures Overall attack rate of SARS-CoV-2 transmission (AR14) was defined as the number of individuals (among students, staff, or both) in the school with covid-19, detected within 14 days of the index case, divided by the number of students and staff members in the school. AR14 to students (attack rates from all index cases to students only) and AR14 to school staff (attack rates from all index cases to staff members only) were also calculated. These measures for student and school staff index cases were also calculated separately to explore variation in AR14 based on the characteristics of the index case. Results From August 2020 to June 2021, 4078 index cases were identified; 3220 (79%) students and 858 (21%) school staff. In most (2230 (55%)) schools with an index case, no subsequent individuals with covid-19 were found within 14 days; in 631 (16%) schools, only one more individual with covid-19 within 14 days was found. Overall, AR14 was 0.33% (95% confidence interval 0.32% to 0.33%). When restricting index cases and subsequent individuals with covid-19 to students born in the same year, AR14 to students (0.56-0.78%) was slightly higher. Conclusions Regarding the number of people infected with SARS-CoV-2 among students and staff, these results suggest that schools were not an important setting for transmission of the virus in Norway during the covid-19 pandemic in the academic year 2020-21.