Journal: BMJ

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Abstract

Trajectory of long covid symptoms after covid-19 vaccination: community based cohort study.

Ayoubkhani D, Bermingham C, Pouwels KB, Glickman M, ... Alwan NA, Walker AS
Objective
To estimate associations between covid-19 vaccination and long covid symptoms in adults with SARS-CoV-2 infection before vaccination.
Design
Observational cohort study.
Setting
Community dwelling population, UK.
Participants
28 356 participants in the Office for National Statistics COVID-19 Infection Survey aged 18-69 years who received at least one dose of an adenovirus vector or mRNA covid-19 vaccine after testing positive for SARS-CoV-2 infection.
Main outcome measure
Presence of long covid symptoms at least 12 weeks after infection over the follow-up period 3 February to 5 September 2021.
Results
Mean age of participants was 46 years, 55.6% (n=15 760) were women, and 88.7% (n=25 141) were of white ethnicity. Median follow-up was 141 days from first vaccination (among all participants) and 67 days from second vaccination (83.8% of participants). 6729 participants (23.7%) reported long covid symptoms of any severity at least once during follow-up. A first vaccine dose was associated with an initial 12.8% decrease (95% confidence interval -18.6% to -6.6%, P<0.001) in the odds of long covid, with subsequent data compatible with both increases and decreases in the trajectory (0.3% per week, 95% confidence interval -0.6% to 1.2% per week, P=0.51). A second dose was associated with an initial 8.8% decrease (95% confidence interval -14.1% to -3.1%, P=0.003) in the odds of long covid, with a subsequent decrease by 0.8% per week (-1.2% to -0.4% per week, P<0.001). Heterogeneity was not found in associations between vaccination and long covid by sociodemographic characteristics, health status, hospital admission with acute covid-19, vaccine type (adenovirus vector or mRNA), or duration from SARS-CoV-2 infection to vaccination.
Conclusions
The likelihood of long covid symptoms was observed to decrease after covid-19 vaccination and evidence suggested sustained improvement after a second dose, at least over the median follow-up of 67 days. Vaccination may contribute to a reduction in the population health burden of long covid, although longer follow-up is needed.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 18 May 2022; 377:e069676
Ayoubkhani D, Bermingham C, Pouwels KB, Glickman M, ... Alwan NA, Walker AS
BMJ: 18 May 2022; 377:e069676 | PMID: 35584816
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Abstract

Long term impact of prophylactic antibiotic use before incision versus after cord clamping on children born by caesarean section: longitudinal study of UK electronic health records.

Šumilo D, Nirantharakumar K, Willis BH, Rudge GM, ... Deeks JJ, Brocklehurst P
Objective
To investigate the impact on child health up to age 5 years of a policy to use antibiotic prophylaxis for caesarean section before incision compared with after cord clamping.
Design
Observational controlled interrupted time series study.
Setting
UK primary and secondary care.
Participants
515 945 children born in 2006-18 with linked maternal records and registered with general practices contributing to two UK primary care databases (The Health Improvement Network and Clinical Practice Research Datalink), and 7 147 884 children with linked maternal records in the Hospital Episode Statistics database covering England, of which 3 945 351 were linked to hospitals that reported the year of policy change to administer prophylactic antibiotics for caesarean section before incision rather than after cord clamping.
Intervention
Fetal exposure to antibiotics shortly before birth (using pre-incision antibiotic policy as proxy) compared with no exposure.
Main outcome measures
The primary outcomes were incidence rate ratios of asthma and eczema in children born by caesarean section when pre-incision prophylactic antibiotics were recommended compared with those born when antibiotics were administered post-cord clamping, adjusted for temporal changes in the incidence rates in children born vaginally.
Results
Prophylactic antibiotics administered before incision for caesarean section compared with after cord clamping were not associated with a significantly higher risk of asthma (incidence rate ratio 0.91, 95% confidence interval 0.78 to 1.05) or eczema (0.98, 0.94 to 1.03), including asthma and eczema resulting in hospital admission (1.05, 0.99 to 1.11 and 0.96, 0.71 to 1.29, respectively), up to age 5 years.
Conclusions
This study found no evidence of an association between pre-incision prophylactic antibiotic use and risk of asthma and eczema in early childhood in children born by caesarean section.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 17 May 2022; 377:e069704
Šumilo D, Nirantharakumar K, Willis BH, Rudge GM, ... Deeks JJ, Brocklehurst P
BMJ: 17 May 2022; 377:e069704 | PMID: 35580876
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Abstract

Visualising harms in publications of randomised controlled trials: consensus and recommendations.

Phillips R, Cro S, Wheeler G, Bond S, ... Collett L, Cornelius V
Objective
To improve communication of harm in publications of randomised controlled trials via the development of recommendations for visually presenting harm outcomes.
Design
Consensus study.
Setting
15 clinical trials units registered with the UK Clinical Research Collaboration, an academic population health department, Roche Products, and The BMJ.
Participants
Experts in clinical trials: 20 academic statisticians, one industry statistician, one academic health economist, one data graphics designer, and two clinicians.
Main outcome
measures A methodological review of statistical methods identified visualisations along with those recommended by consensus group members. Consensus on visual recommendations was achieved (at least 60% of the available votes) over a series of three meetings with participants. The participants reviewed and critically appraised candidate visualisations against an agreed framework and voted on whether to endorse each visualisation. Scores marginally below this threshold (50-60%) were revisited for further discussions and votes retaken until consensus was reached.
Results
28 visualisations were considered, of which 10 are recommended for researchers to consider in publications of main research findings. The choice of visualisations to present will depend on outcome type (eg, binary, count, time-to-event, or continuous), and the scenario (eg, summarising multiple emerging events or one event of interest). A decision tree is presented to assist trialists in deciding which visualisations to use. Examples are provided of each endorsed visualisation, along with an example interpretation, potential limitations, and signposting to code for implementation across a range of standard statistical software. Clinician feedback was incorporated into the explanatory information provided in the recommendations to aid understanding and interpretation.
Conclusions
Visualisations provide a powerful tool to communicate harms in clinical trials, offering an alternative perspective to the traditional frequency tables. Increasing the use of visualisations for harm outcomes in clinical trial manuscripts and reports will provide clearer presentation of information and enable more informative interpretations. The limitations of each visualisation are discussed and examples of where their use would be inappropriate are given. Although the decision tree aids the choice of visualisation, the statistician and clinical trial team must ultimately decide the most appropriate visualisations for their data and objectives. Trialists should continue to examine crude numbers alongside visualisations to fully understand harm profiles.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 16 May 2022; 377:e068983
Phillips R, Cro S, Wheeler G, Bond S, ... Collett L, Cornelius V
BMJ: 16 May 2022; 377:e068983 | PMID: 35577357
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Abstract

Multicomponent intervention to prevent mobility disability in frail older adults: randomised controlled trial (SPRINTT project).

Bernabei R, Landi F, Calvani R, Cesari M, ... Marzetti E, SPRINTT consortium
Objective
To determine whether a multicomponent intervention based on physical activity with technological support and nutritional counselling prevents mobility disability in older adults with physical frailty and sarcopenia.
Design
Evaluator blinded, randomised controlled trial.
Setting
16 clinical sites across 11 European countries, January 2016 to 31 October 2019.
Participants
1519 community dwelling men and women aged 70 years or older with physical frailty and sarcopenia, operationalised as the co-occurrence of low functional status, defined as a short physical performance battery (SPPB) score of 3 to 9, low appendicular lean mass, and ability to independently walk 400 m. 760 participants were randomised to a multicomponent intervention and 759 received education on healthy ageing (controls).
Interventions
The multicomponent intervention comprised moderate intensity physical activity twice weekly at a centre and up to four times weekly at home. Actimetry data were used to tailor the intervention. Participants also received personalised nutritional counselling. Control participants received education on healthy ageing once a month. Interventions and follow-up lasted for up to 36 months.
Main outcome measures
The primary outcome was mobility disability (inability to independently walk 400 m in <15 minutes). Persistent mobility disability (inability to walk 400 m on two consecutive occasions) and changes from baseline to 24 and 36 months in physical performance, muscle strength, and appendicular lean mass were analysed as pre-planned secondary outcomes. Primary comparisons were conducted in participants with baseline SPPB scores of 3-7 (n=1205). Those with SPPB scores of 8 or 9 (n=314) were analysed separately for exploratory purposes.
Results
Mean age of the 1519 participants (1088 women) was 78.9 (standard deviation 5.8) years. The average follow-up was 26.4 (SD 9.5) months. Among participants with SPPB scores of 3-7, mobility disability occurred in 283/605 (46.8%) assigned to the multicomponent intervention and 316/600 (52.7%) controls (hazard ratio 0.78, 95% confidence interval 0.67 to 0.92; P=0.005). Persistent mobility disability occurred in 127/605 (21.0%) participants assigned to the multicomponent intervention and 150/600 (25.0%) controls (0.79, 0.62 to 1.01; P=0.06). The between group difference in SPPB score was 0.8 points (95% confidence interval 0.5 to 1.1 points; P<0.001) and 1.0 point (95% confidence interval 0.5 to 1.6 points; P<0.001) in favour of the multicomponent intervention at 24 and 36 months, respectively. The decline in handgrip strength at 24 months was smaller in women assigned to the multicomponent intervention than to control (0.9 kg, 95% confidence interval 0.1 to 1.6 kg; P=0.028). Women in the multicomponent intervention arm lost 0.24 kg and 0.49 kg less appendicular lean mass than controls at 24 months (95% confidence interval 0.10 to 0.39 kg; P<0.001) and 36 months (0.26 to 0.73 kg; P<0.001), respectively. Serious adverse events occurred in 237/605 (39.2%) participants assigned to the multicomponent intervention and 216/600 (36.0%) controls (risk ratio 1.09, 95% confidence interval 0.94 to 1.26). In participants with SPPB scores of 8 or 9, mobility disability occurred in 46/155 (29.7%) in the multicomponent intervention and 38/159 (23.9%) controls (hazard ratio 1.25, 95% confidence interval 0.79 to 1.95; P=0.34).
Conclusions
A multicomponent intervention was associated with a reduction in the incidence of mobility disability in older adults with physical frailty and sarcopenia and SPPB scores of 3-7. Physical frailty and sarcopenia may be targeted to preserve mobility in vulnerable older people.
Trial registration
ClinicalTrials.gov NCT02582138.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 11 May 2022; 377:e068788
Bernabei R, Landi F, Calvani R, Cesari M, ... Marzetti E, SPRINTT consortium
BMJ: 11 May 2022; 377:e068788 | PMID: 35545258
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Abstract

Agreement of treatment effects from observational studies and randomized controlled trials evaluating hydroxychloroquine, lopinavir-ritonavir, or dexamethasone for covid-19: meta-epidemiological study.

Moneer O, Daly G, Skydel JJ, Nyhan K, ... Ross JS, Wallach JD
Objective
To systematically identify, match, and compare treatment effects and study demographics from individual or meta-analysed observational studies and randomized controlled trials (RCTs) evaluating the same covid-19 treatments, comparators, and outcomes.
Design
Meta-epidemiological study.
Data sources
National Institutes of Health Covid-19 Treatment Guidelines, a living review and network meta-analysis published in The BMJ, a living systematic review with meta-analysis and trial sequential analysis in PLOS Medicine (The LIVING Project), and the Epistemonikos \"Living OVerview of Evidence\" (L·OVE) evidence database.
Eligibility criteria for selection of studies
RCTs in The BMJ\'s living review that directly compared any of the three most frequently studied therapeutic interventions for covid-19 across all data sources (that is, hydroxychloroquine, lopinavir-ritonavir, or dexamethasone) for any safety and efficacy outcomes. Observational studies that evaluated the same interventions, comparisons, and outcomes that were reported in The BMJ\'s living review.
Data extraction and synthesis
Safety and efficacy outcomes from observational studies were identified and treatment effects for dichotomous (odds ratios) or continuous (mean differences or ratios of means) outcomes were calculated and, when possible, meta-analyzed to match the treatment effects from individual RCTs or meta-analyses of RCTs reported in The BMJ\'s living review with the same interventions, comparisons, and outcomes (that is, matched pairs). The analysis compared the distribution of study demographics and the agreement between treatment effects from matched pairs. Matched pairs were in agreement if both observational and RCT treatment effects were significantly increasing or decreasing (P<0.05) or if both treatment effects were not significant (P≥0.05).
Results
17 new, independent meta-analyses of observational studies were conducted that compared hydroxychloroquine, lopinavir-ritonavir, or dexamethasone with an active or placebo comparator for any safety or efficacy outcomes in covid-19 treatment. These studies were matched and compared with 17 meta-analyses of RCTs reported in The BMJ\'s living review. 10 additional matched pairs with only one observational study and/or one RCT were identified. Across all 27 matched pairs, 22 had adequate reporting of demographical and clinical data for all individual studies. All 22 matched pairs had studies with overlapping distributions of sex, age, and disease severity. Overall, 21 (78%) of the 27 matched pairs had treatment effects that were in agreement. Among the 17 matched pairs consisting of meta-analyses of observational studies and meta-analyses of RCTs, 14 (82%) were in agreement; seven (70%) of the 10 matched pairs consisting of at least one observational study or one RCT were in agreement. The 18 matched pairs with treatment effects for dichotomous outcomes had a higher proportion of agreement (n=16, 89%) than did the nine matched pairs with treatment effects for continuous outcomes (n=5, 56%).
Conclusions
Meta-analyses of observational studies and RCTs evaluating treatments for covid-19 have summary treatment effects that are generally in agreement. Although our evaluation is limited to three covid-19 treatments, these findings suggest that meta-analyzed evidence from observational studies might complement, but should not replace, evidence collected from RCTs.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 10 May 2022; 377:e069400
Moneer O, Daly G, Skydel JJ, Nyhan K, ... Ross JS, Wallach JD
BMJ: 10 May 2022; 377:e069400 | PMID: 35537738
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Abstract

Validity of data extraction in evidence synthesis practice of adverse events: reproducibility study.

Xu C, Yu T, Furuya-Kanamori L, Lin L, ... Loke Y, Vohra S
Objectives
To investigate the validity of data extraction in systematic reviews of adverse events, the effect of data extraction errors on the results, and to develop a classification framework for data extraction errors to support further methodological research.
Design
Reproducibility study.
Data sources
PubMed was searched for eligible systematic reviews published between 1 January 2015 and 1 January 2020. Metadata from the randomised controlled trials were extracted from the systematic reviews by four authors. The original data sources (eg, full text and ClinicalTrials.gov) were then referred to by the same authors to reproduce the data used in these meta-analyses.
Eligibility criteria for selecting studies
Systematic reviews were included when based on randomised controlled trials for healthcare interventions that reported safety as the exclusive outcome, with at least one pair meta-analysis that included five or more randomised controlled trials and with a 2×2 table of data for event counts and sample sizes in intervention and control arms available for each trial in the meta-analysis.
Main outcome measures
The primary outcome was data extraction errors summarised at three levels: study level, meta-analysis level, and systematic review level. The potential effect of such errors on the results was further investigated.
Results
201 systematic reviews and 829 pairwise meta-analyses involving 10 386 randomised controlled trials were included. Data extraction could not be reproduced in 1762 (17.0%) of 10 386 trials. In 554 (66.8%) of 829 meta-analyses, at least one randomised controlled trial had data extraction errors; 171 (85.1%) of 201 systematic reviews had at least one meta-analysis with data extraction errors. The most common types of data extraction errors were numerical errors (49.2%, 867/1762) and ambiguous errors (29.9%, 526/1762), mainly caused by ambiguous definitions of the outcomes. These categories were followed by three others: zero assumption errors, misidentification, and mismatching errors. The impact of these errors were analysed on 288 meta-analyses. Data extraction errors led to 10 (3.5%) of 288 meta-analyses changing the direction of the effect and 19 (6.6%) of 288 meta-analyses changing the significance of the P value. Meta-analyses that had two or more different types of errors were more susceptible to these changes than those with only one type of error (for moderate changes, 11 (28.2%) of 39 v 26 (10.4%) 249, P=0.002; for large changes, 5 (12.8%) of 39 v 8 (3.2%) of 249, P=0.01).
Conclusion
Systematic reviews of adverse events potentially have serious issues in terms of the reproducibility of the data extraction, and these errors can mislead the conclusions. Implementation guidelines are urgently required to help authors of future systematic reviews improve the validity of data extraction.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 10 May 2022; 377:e069155
Xu C, Yu T, Furuya-Kanamori L, Lin L, ... Loke Y, Vohra S
BMJ: 10 May 2022; 377:e069155 | PMID: 35537752
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Abstract

Variation in revascularisation use and outcomes of patients in hospital with acute myocardial infarction across six high income countries: cross sectional cohort study.

Cram P, Hatfield LA, Bakx P, Banerjee A, ... Yan L, Landon B
Objectives
To compare treatment and outcomes for patients admitted to hospital with a primary diagnosis of ST elevation or non-ST elevation myocardial infarction (STEMI or NSTEMI) in six high income countries with very different healthcare delivery systems.
Design
Retrospective cross sectional cohort study.
Setting
Patient level administrative data from the United States, Canada (Ontario and Manitoba), England, the Netherlands, Israel, and Taiwan.
Participants
Adults aged 66 years and older admitted to hospital with STEMI or NSTEMI between 1 January 2011 and 31 December 2017.
Outcomes measures
The three categories of outcomes were coronary revascularisation (percutaneous coronary intervention or coronary artery bypass graft surgery), mortality, and efficiency (hospital length of stay and 30 day readmission). Rates were standardised to the age and sex distribution of the US acute myocardial infarction population in 2017. Outcomes were assessed separately for STEMI and NSTEMI. Performance was evaluated longitudinally (over time) and cross sectionally (between countries).
Results
The total number of hospital admissions ranged from 19 043 in Israel to 1 064 099 in the US. Large differences were found between countries for all outcomes. For example, the proportion of patients admitted to hospital with STEMI who received percutaneous coronary intervention in hospital during 2017 ranged from 36.9% (England) to 78.6% (Canada; 71.8% in the US); use of percutaneous coronary intervention for STEMI increased in all countries between 2011 and 2017, with particularly large rises in Israel (48.4-65.9%) and Taiwan (49.4-70.2%). The proportion of patients with NSTEMI who underwent coronary artery bypass graft surgery within 90 days of admission during 2017 was lowest in the Netherlands (3.5%) and highest in the US (11.7%). Death within one year of admission for STEMI in 2017 ranged from 18.9% (Netherlands) to 27.8% (US) and 32.3% (Taiwan). Mean hospital length of stay in 2017 for STEMI was lowest in the Netherlands and the US (5.0 and 5.1 days) and highest in Taiwan (8.5 days); 30 day readmission for STEMI was lowest in Taiwan (11.7%) and the US (12.2%) and highest in England (23.1%).
Conclusions
In an analysis of myocardial infarction in six high income countries, all countries had areas of high performance, but no country excelled in all three domains. Our findings suggest that countries could learn from each other by using international comparisons of patient level nationally representative data.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 04 May 2022; 377:e069164
Cram P, Hatfield LA, Bakx P, Banerjee A, ... Yan L, Landon B
BMJ: 04 May 2022; 377:e069164 | PMID: 35508312
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Abstract

Venovenous extracorporeal membrane oxygenation in patients with acute covid-19 associated respiratory failure: comparative effectiveness study.

Urner M, Barnett AG, Bassi GL, Brodie D, ... Fan E, COVID-19 Critical Care Consortium Investigators
Objective
To estimate the effect of extracorporeal membrane oxygenation (ECMO) compared with conventional mechanical ventilation on outcomes of patients with covid-19 associated respiratory failure.
Design
Observational study.
Setting
30 countries across five continents, 3 January 2020 to 29 August 2021.
Participants
7345 adults admitted to the intensive care unit with clinically suspected or laboratory confirmed SARS-CoV-2 infection.
Interventions
ECMO in patients with a partial pressure of arterial oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio <80 mm Hg compared with conventional mechanical ventilation without ECMO.
Main outcome measure
The primary outcome was hospital mortality within 60 days of admission to the intensive care unit. Adherence adjusted estimates were calculated using marginal structural models with inverse probability weighting, accounting for competing events and for baseline and time varying confounding.
Results
844 of 7345 eligible patients (11.5%) received ECMO at any time point during follow-up. Adherence adjusted mortality was 26.0% (95% confidence interval 24.5% to 27.5%) for a treatment strategy that included ECMO if the PaO2/FiO2 ratio decreased <80 mm Hg compared with 33.2% (31.8% to 34.6%) had patients received conventional treatment without ECMO (risk difference -7.1%, 95% confidence interval -8.2% to -6.1%; risk ratio 0.78, 95% confidence interval 0.75 to 0.82). In secondary analyses, ECMO was most effective in patients aged <65 years and with a PaO2/FiO2 <80 mm Hg or with driving pressures >15 cmH2O during the first 10 days of mechanical ventilation.
Conclusions
ECMO was associated with a reduction in mortality in selected adults with covid-19 associated respiratory failure. Age, severity of hypoxaemia, and duration and intensity of mechanical ventilation were found to be modifiers of treatment effectiveness and should be considered when deciding to initiate ECMO in patients with covid-19.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 04 May 2022; 377:e068723
Urner M, Barnett AG, Bassi GL, Brodie D, ... Fan E, COVID-19 Critical Care Consortium Investigators
BMJ: 04 May 2022; 377:e068723 | PMID: 35508314
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Abstract

PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations.

Hao Q, Aertgeerts B, Guyatt G, Bekkering GE, ... Li S, Delvaux N
Clinical question
In adults with low density lipoprotein (LDL) cholesterol levels >1.8 mmol/L (>70 mg/dL) who are already taking the maximum dose of statins or are intolerant to statins, should another lipid-lowering drug be added, either a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor or ezetimibe, to reduce the risk of major cardiovascular events? If so, which drug is preferred? Having decided to use one, should we add the other lipid-lowering drug?
Current practice
Most guidelines emphasise LDL cholesterol targets in their recommendations for prescribing PCSK9 inhibitors and/or ezetimibe in adults at high risk of experiencing a major adverse cardiovascular event. However, to achieve these goals in very high risk patients with statins alone is almost impossible, so physicians are increasingly considering other lipid-lowering drugs solely for achieving LDL cholesterol treatment goals rather than for achieving important absolute cardiovascular risk reduction. Most guidelines do not systematically assess the cardiovascular benefits of adding PCSK9 inhibitors and/or ezetimibe for all risk groups across primary and secondary prevention, nor do they report, in accordance with explicit judgments of assumed patients\' values and preferences, absolute benefits and harms and potential treatment burdens.
Recommendations
The guideline panel provided mostly weak recommendations, which means we rely on shared decision making when applying these recommendations. For adults already using statins, the panel suggests adding a second lipid-lowering drug in people at very high and high cardiovascular risk but recommends against adding it in people at low cardiovascular risk. For adults who are intolerant to statins, the panel recommends using a lipid-lowering drug in people at very high and high cardiovascular risk but against adding it in those at low cardiovascular risk. When choosing to add another lipid-lowering drug, the panel suggests ezetimibe in preference to PCSK9 inhibitors. The panel suggests further adding a PCSK9 inhibitor to ezetimibe for adults already taking statins at very high risk and those at very high and high risk who are intolerant to statins.
How this guideline was created
An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified four risk groups of patients (low, moderate, high, and very high cardiovascular risk) and primarily applied an individual patient perspective in moving from evidence to recommendations, though societal issues were a secondary consideration. The panel considered the balance of benefits and harms and burdens of starting a PCSK9 inhibitor and/or ezetimibe, making assumptions of adults\' average values and preferences. Interactive evidence summaries and decision aids accompany multi-layered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that also allows re-use and adaptation.
The evidence
A linked systematic review and network meta-analysis (14 trials including 83 660 participants) of benefits found that PCSK9 inhibitors or ezetimibe probably reduce myocardial infarctions and stroke in patients with very high and high cardiovascular risk, with no impact on mortality (moderate to high certainty evidence), but not in those with moderate and low cardiovascular risk. PCSK9 inhibitors may have similar effects to ezetimibe on reducing non-fatal myocardial infarction or stroke (low certainty evidence). These relative benefits were consistent, but their absolute magnitude varied based on cardiovascular risk in individual patients (for example, for 1000 people treated with PCSK9 inhibitors in addition to statins over five years, benefits ranged from 2 fewer strokes in the lowest risk to 21 fewer in the highest risk). Two systematic reviews on harms found no important adverse events for these drugs (moderate to high certainty evidence). PCSK9 inhibitors require injections that sometimes result in injection site reactions (best estimate 15 more per 1000 in a 5 year timeframe), representing a burden and harm that may matter to patients. The MATCH-IT decision support tool allows you to interact with the evidence and your patients across the alternative options: https://magicevidence.org/match-it/220504dist-lipid-lowering-drugs/.
Understanding the recommendations
The stratification into four cardiovascular risk groups means that, to use the recommendations, physicians need to identify their patient\'s risk first. We therefore suggest, specific to various geographical regions, using some reliable risk calculators that estimate patients\' cardiovascular risk based on a mix of known risk factors. The largely weak recommendations concerning the addition of ezetimibe or PCSK9 inhibitors reflect what the panel considered to be a close balance between small reductions in stroke and myocardial infarctions weighed against the burdens and limited harms.Because of the anticipated large variability of patients\' values and preferences, well informed choices warrant shared decision making. Interactive evidence summaries and decision aids linked to the recommendations can facilitate such shared decisions. The strong recommendations against adding another drug in people at low cardiovascular risk reflect what the panel considered to be a burden without important benefits. The strong recommendation for adding either ezetimibe or PCSK9 inhibitors in people at high and very high cardiovascular risk reflect a clear benefit.The panel recognised the key uncertainty in the evidence concerning patient values and preferences, namely that what most people consider important reductions in cardiovascular risks, weighed against burdens and harms, remains unclear. Finally, availability and costs will influence decisions when healthcare systems, clinicians, or people consider adding ezetimibe or PCSK9 inhibitors.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 04 May 2022; 377:e069066
Hao Q, Aertgeerts B, Guyatt G, Bekkering GE, ... Li S, Delvaux N
BMJ: 04 May 2022; 377:e069066 | PMID: 35508320
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Impact:
Abstract

PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis.

Khan SU, Yedlapati SH, Lone AN, Hao Q, ... Aertgeerts B, Rodondi N
Objective
To compare the impact of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on cardiovascular outcomes in adults taking maximally tolerated statin therapy or who are statin intolerant.
Design
Network meta-analysis.
Data sources
Medline, EMBASE, and Cochrane Library up to 31 December 2020.
Eligibility criteria for selecting studies
Randomised controlled trials of ezetimibe and PCSK9 inhibitors with ≥500 patients and follow-up of ≥6 months.
Main outcome measures
We performed frequentist fixed-effects network meta-analysis and GRADE (grading of recommendations, assessment, development, and evaluation) to assess certainty of evidence. Results included relative risks (RR) and absolute risks per 1000 patients treated for five years for non-fatal myocardial infarction (MI), non-fatal stroke, all-cause mortality, and cardiovascular mortality. We estimated absolute risk differences assuming constant RR (estimated from network meta-analysis) across different baseline therapies and cardiovascular risk thresholds; the PREDICT risk calculator estimated cardiovascular risk in primary and secondary prevention. Patients were categorised at low to very high cardiovascular risk. A guideline panel and systematic review authors established the minimal important differences (MID) of 12 per 1000 for MI and 10 per 1000 for stroke.
Results
We identified 14 trials assessing ezetimibe and PCSK9 inhibitors among 83 660 adults using statins. Adding ezetimibe to statins reduced MI (RR 0.87 (95% confidence interval 0.80 to 0.94)) and stroke (RR 0.82 (0.71 to 0.96)) but not all-cause mortality (RR 0.99 (0.92 to 1.06)) or cardiovascular mortality (RR 0.97 (0.87 to 1.09)). Similarly, adding PCSK9 inhibitor to statins reduced MI (0.81 (0.76 to 0.87)) and stroke (0.74 (0.64 to 0.85)) but not all-cause (0.95 (0.87 to 1.03)) or cardiovascular mortality (0.95 (0.87 to 1.03)). Among adults with very high cardiovascular risk, adding PCSK9 inhibitor was likely to reduce MI (16 per 1000) and stroke (21 per 1000) (moderate to high certainty); whereas adding ezetimibe was likely to reduce stroke (14 per 1000), but the reduction of MI (11 per 1000) (moderate certainty) did not reach MID. Adding ezetimibe to PCSK9 inhibitor and statin may reduce stroke (11 per 1000), but the reduction of MI (9 per 1000) (low certainty) did not reach MID. Adding PCSK9 inhibitors to statins and ezetimibe may reduce MI (14 per 1000) and stroke (17 per 1000) (low certainty). Among adults with high cardiovascular risk, adding PCSK9 inhibitor probably reduced MI (12 per 1000) and stroke (16 per 1000) (moderate certainty); adding ezetimibe probably reduced stroke (11 per 1000), but the reduction in MI did not achieve MID (8 per 1000) (moderate certainty). Adding ezetimibe to PCSK9 inhibitor and statins did not reduce outcomes beyond MID, while adding PCSK9 inhibitor to ezetimibe and statins may reduce stroke (13 per 1000). These effects were consistent in statin-intolerant patients. Among moderate and low cardiovascular risk groups, adding PCSK9 inhibitor or ezetimibe to statins yielded little or no benefit for MI and stroke.
Conclusions
Ezetimibe or PCSK9 inhibitors may reduce non-fatal MI and stroke in adults at very high or high cardiovascular risk who are receiving maximally tolerated statin therapy or are statin-intolerant, but not in those with moderate and low cardiovascular risk.

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BMJ: 04 May 2022; 377:e069116
Khan SU, Yedlapati SH, Lone AN, Hao Q, ... Aertgeerts B, Rodondi N
BMJ: 04 May 2022; 377:e069116 | PMID: 35508321
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Impact:
Abstract

Development and validation of the symptom burden questionnaire for long covid (SBQ-LC): Rasch analysis.

Hughes SE, Haroon S, Subramanian A, McMullan C, ... Walker A, Calvert MJ
Objective
To describe the development and validation of a novel patient reported outcome measure for symptom burden from long covid, the symptom burden questionnaire for long covid (SBQ-LC).
Design
Multiphase, prospective mixed methods study.
Setting
Remote data collection and social media channels in the United Kingdom, 14 April to 1 August 2021.
Participants
13 adults (aged ≥18 years) with self-reported long covid and 10 clinicians evaluated content validity. 274 adults with long covid field tested the draft questionnaire.
Main outcome measures
Published systematic reviews informed development of SBQ-LC\'s conceptual framework and initial item pool. Thematic analysis of transcripts from cognitive debriefing interviews and online clinician surveys established content validity. Consensus discussions with the patient and public involvement group of the Therapies for Long COVID in non-hospitalised individuals: From symptoms, patient reported outcomes and immunology to targeted therapies (TLC Study) confirmed face validity. Rasch analysis of field test data guided item and scale refinement and provided initial evidence of the SBQ-LC\'s measurement properties.
Results
SBQ-LC (version 1.0) is a modular instrument measuring patient reported outcomes and is composed of 17 independent scales with promising psychometric properties. Respondents rate their symptom burden during the past seven days using a dichotomous response or 4 point rating scale. Each scale provides coverage of a different symptom domain and returns a summed raw score that can be transformed to a linear (0-100) score. Higher scores represent higher symptom burden. After rating scale refinement and item reduction, all scales satisfied the Rasch model requirements for unidimensionality (principal component analysis of residuals: first residual contrast values <2.00 eigenvalue units) and item fit (outfit mean square values within 0.5 -1.5 logits). Rating scale categories were ordered with acceptable category fit statistics (outfit mean square values <2.0 logits). 14 item pairs had evidence of local dependency (residual correlation values >0.4). Across the 17 scales, person reliability ranged from 0.34 to 0.87, person separation ranged from 0.71 to 2.56, item separation ranged from 1.34 to 13.86, and internal consistency reliability (Cronbach\'s alpha) ranged from 0.56 to 0.91.
Conclusions
SBQ-LC (version 1.0) is a comprehensive patient reported outcome instrument developed using modern psychometric methods. It measures symptoms of long covid important to people with lived experience of the condition and may be used to evaluate the impact of interventions and inform best practice in clinical management.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 27 Apr 2022; 377:e070230
Hughes SE, Haroon S, Subramanian A, McMullan C, ... Walker A, Calvert MJ
BMJ: 27 Apr 2022; 377:e070230 | PMID: 35477524
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Impact:
Abstract

Public health impact of covid-19 vaccines in the US: observational study.

Suthar AB, Wang J, Seffren V, Wiegand RE, Griffing S, Zell E
Objective
To evaluate the impact of vaccine scale-up on population level covid-19 mortality and incidence in the United States.
Design
Observational study.
Setting
US county level case surveillance and vaccine administration data reported from 14 December 2020 to 18 December 2021.
Participants
Residents of 2558 counties from 48 US states.
Main outcome measures
The primary outcome was county covid-19 mortality rates (deaths/100 000 population/county week). The secondary outcome was incidence of covid-19 (cases/100 000 population/county week). Incidence rate ratios were used to compare rates across vaccination coverage levels. The impact of a 10% improvement in county vaccination coverage (defined as at least one dose of a covid-19 vaccine among adults ≥18 years of age) was estimated During the eras of alpha and delta variant predominance, the impact of very low (0-9%), low (10-39%), medium (40-69%), and high (≥70%) vaccination coverage levels was compared.
Results
In total, 30 643 878 cases of covid-19 and 439 682 deaths associated with covid-19 occurred over 132 791 county weeks. A 10% improvement in vaccination coverage was associated with an 8% (95% confidence interval 8% to 9%) reduction in mortality rates and a 7% (6% to 8%) reduction in incidence. Higher vaccination coverage levels were associated with reduced mortality and incidence rates during the eras of alpha and delta variant predominance.
Conclusions
Higher vaccination coverage was associated with lower rates of population level covid-19 mortality and incidence in the US.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 27 Apr 2022; 377:e069317
Suthar AB, Wang J, Seffren V, Wiegand RE, Griffing S, Zell E
BMJ: 27 Apr 2022; 377:e069317 | PMID: 35477670
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Impact:
Abstract

Diagnosis and management of covid-19 in pregnancy.

Nana M, Hodson K, Lucas N, Camporota L, Knight M, Nelson-Piercy C
Pregnant women with covid-19 are at greater risk of severe disease than their non-pregnant peers, and yet they are frequently denied investigations or treatments because of unfounded concerns about risk to the fetus. The basic principles of diagnosing and managing covid-19 are the same as for non-pregnant patients, and a multidisciplinary, expert team approach is essential to ensure optimal care. During pregnancy, treatment with corticosteroids should be modified to use non-fluorinated glucocorticoids. Il-6 inhibitors and monoclonal antibodies, together with specific antiviral therapies, may also be considered. Prophylaxis against venous thromboembolism is important. Women may require respiratory support with oxygen, non-invasive ventilation, ventilation in a prone position (either awake or during invasive ventilation), intubation and ventilation, and extracorporeal membrane oxygenation (ECMO). Pregnancy is not a contraindication for any of these supportive therapies, and the criteria for providing them are the same as in the general population. Decisions regarding timing, place, and mode of delivery should be taken with a multidisciplinary team including obstetricians, physicians, anesthetists, and intensivists experienced in the care of covid-19 in pregnancy. Ideally these decisions should take place in consultation with centers that have experience and expertise in all these specialties.

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BMJ: 26 Apr 2022; 377:e069739
Nana M, Hodson K, Lucas N, Camporota L, Knight M, Nelson-Piercy C
BMJ: 26 Apr 2022; 377:e069739 | PMID: 35473709
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Impact:
Abstract

One in two people admitted to hospital with covid-19 develop complications and may need support.

Saul H, Gursul D, Cassidy S, Harrison E
The studyDrake TM, Riad AM, Fairfield CJ, et al. Characterisation of in-hospital complications associated with covid-19 using the ISARIC WHO Clinical Characterisation Protocol UK: a prospective, multicentre cohort study. Lancet 2021;398:10296.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/one-in-two-people-hospitalised-with-covid-19-develop-complications-may-need-support/.

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BMJ: 22 Apr 2022; 377:o880
Saul H, Gursul D, Cassidy S, Harrison E
BMJ: 22 Apr 2022; 377:o880 | PMID: 35459717
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Impact:
Abstract

Sintilimab versus placebo in combination with chemotherapy as first line treatment for locally advanced or metastatic oesophageal squamous cell carcinoma (ORIENT-15): multicentre, randomised, double blind, phase 3 trial.

Lu Z, Wang J, Shu Y, Liu L, ... Shen L, ORIENT-15 study group
Objective
To evaluate sintilimab versus placebo in combination with chemotherapy (cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil) as first line treatment of unresectable locally advanced, recurrent, or metastatic oesophageal squamous cell carcinoma.
Design
Multicentre, randomised, double blind, phase 3 trial.
Setting
66 sites in China and 13 sites outside of China between 14 December 2018 and 9 April 2021.
Participants
659 adults (aged ≥18 years) with advanced or metastatic oesophageal squamous cell carcinoma who had not received systemic treatment.
Intervention
Participants were randomised 1:1 to receive sintilimab or placebo (3 mg/kg in patients weighing <60 kg or 200 mg in patients weighing ≥60 kg) in combination with cisplatin 75 mg/m2 plus paclitaxel 175 mg/m2 every three weeks. The trial was amended to allow investigators to choose the chemotherapy regimen: cisplatin plus paclitaxel or cisplatin plus 5-fluorouracil (800 mg/m2 continuous infusion on days 1-5).
Main outcome measures
Overall survival in all patients and in patients with combined positive scores of ≥10 for expression of programmed cell death ligand 1.
Results
659 patients were randomly assigned to sintilimab (n=327) or placebo (n=332) with chemotherapy. 616 of 659 patients (93%) received sintilimab or placebo in combination with cisplatin plus paclitaxel and 43 of 659 patients (7%) received sintilimab or placebo in combination with cisplatin plus 5-fluorouracil. At the interim analysis, sintilimab with chemotherapy showed better overall survival compared with placebo and chemotherapy in all patients (median 16.7 v 12.5 months, hazard ratio 0.63, 95% confidence interval 0.51 to 0.78, P<0.001) and in patients with combined positive scores of ≥10 (17.2 v 13.6 months, 0.64, 0.48 to 0.85, P=0.002). Sintilimab and chemotherapy significantly improved progression free survival compared with placebo and chemotherapy in all patients (7.2 v 5.7 months, 0.56, 0.46 to 0.68, P<0.001) and in patients with combined positive scores of ≥10 (8.3 v 6.4 months, 0.58, 0.45 to 0.75, P<0.001). Adverse events related to treatment occurred in 321 of 327 patients (98%) in the sintilimab-chemotherapy group versus 326 of 332 (98%) patients in the placebo-chemotherapy group. Rates of adverse events related to treatment, grade ≥3, were 60% (196/327) and 55% (181/332) in the sintilimab-chemotherapy and placebo-chemotherapy groups, respectively.
Conclusions
Compared with placebo, sintilimab in combination with cisplatin plus paclitaxel showed significant benefits in overall survival and progression free survival as first line treatment in patients with advanced or metastatic oesophageal squamous cell carcinoma. Similar benefits of sintilimab with cisplatin plus 5-fluorouracil seem promising.
Trial registration
ClinicalTrials.gov NCT03748134.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 19 Apr 2022; 377:e068714
Lu Z, Wang J, Shu Y, Liu L, ... Shen L, ORIENT-15 study group
BMJ: 19 Apr 2022; 377:e068714 | PMID: 35440464
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Impact:
Abstract

Healthy lifestyle and life expectancy with and without Alzheimer\'s dementia: population based cohort study.

Dhana K, Franco OH, Ritz EM, Ford CN, ... Evans DA, Rajan KB
Objective
To determine the impact of lifestyle factors on life expectancy lived with and without Alzheimer\'s dementia.
Design
Prospective cohort study.
Setting
The Chicago Health and Aging Project, a population based cohort study in the United States.
Participants
2449 men and women aged 65 years and older.
Main exposure
A healthy lifestyle score was developed based on five modifiable lifestyle factors: a diet for brain health (Mediterranean-DASH Diet Intervention for Neurodegenerative Delay-MIND diet score in upper 40% of cohort distribution), late life cognitive activities (composite score in upper 40%), moderate or vigorous physical activity (≥150 min/week), no smoking, and light to moderate alcohol consumption (women 1-15 g/day; men 1-30 g/day).
Main outcome
Life expectancy with and without Alzheimer\'s dementia in women and men.
Results
Women aged 65 with four or five healthy factors had a life expectancy of 24.2 years (95% confidence interval 22.8 to 25.5) and lived 3.1 years longer than women aged 65 with zero or one healthy factor (life expectancy 21.1 years, 19.5 to 22.4). Of the total life expectancy at age 65, women with four or five healthy factors spent 10.8% (2.6 years, 2.0 to 3.3) of their remaining years with Alzheimer\'s dementia, whereas women with zero or one healthy factor spent 19.3% (4.1 years, 3.2 to 5.1) with the disease. Life expectancy for women aged 65 without Alzheimer\'s dementia and four or five healthy factors was 21.5 years (20.0 to 22.7), and for those with zero or one healthy factor it was 17.0 years (15.5 to 18.3). Men aged 65 with four or five healthy factors had a total life expectancy of 23.1 years (21.4 to 25.6), which is 5.7 years longer than men aged 65 with zero or one healthy factor (life expectancy 17.4 years, 15.8 to 20.1). Of the total life expectancy at age 65, men with four or five healthy factors spent 6.1% (1.4 years, 0.3 to 2.0) of their remaining years with Alzheimer\'s dementia, and those with zero or one healthy factor spent 12.0% (2.1 years, 0.2 to 3.0) with the disease. Life expectancy for men aged 65 without Alzheimer\'s dementia and four or five healthy factors was 21.7 years (19.7 to 24.9), and for those with zero or one healthy factor life expectancy was 15.3 years (13.4 to 19.1).
Conclusion
A healthy lifestyle was associated with a longer life expectancy among men and women, and they lived a larger proportion of their remaining years without Alzheimer\'s dementia. The life expectancy estimates might help health professionals, policy makers, and stakeholders to plan future healthcare services, costs, and needs.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 13 Apr 2022; 377:e068390
Dhana K, Franco OH, Ritz EM, Ford CN, ... Evans DA, Rajan KB
BMJ: 13 Apr 2022; 377:e068390 | PMID: 35418416
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Impact:
Abstract

Multifaceted intervention to reduce haemodialysis catheter related bloodstream infections: REDUCCTION stepped wedge, cluster randomised trial.

Kotwal S, Cass A, Coggan S, Gray NA, ... Gallagher M, REDUCCTION Investigators
Objective
To identify whether multifaceted interventions, or care bundles, reduce catheter related bloodstream infections (CRBSIs) from central venous catheters used for haemodialysis.
Design
Stepped wedge, cluster randomised design.
Setting
37 renal services across Australia.
Participants
All adults (age ≥18 years) under the care of a renal service who required insertion of a new haemodialysis catheter.
Interventions
After a baseline observational phase, a service-wide, multifaceted intervention bundle that included elements of catheter care (insertion, maintenance, and removal) was implemented at one of three randomly assigned time points (12 at the first time point, 12 at the second, and 13 at the third) between 20 December 2016 and 31 March 2020.
Main outcomes measure
The primary endpoint was the rate of CRBSI in the baseline phase compared with intervention phase at the renal service level using the intention-to-treat principle.
Results
1.14 million haemodialysis catheter days of use were monitored across 6364 patients. Patient characteristics were similar across baseline and intervention phases. 315 CRBSIs occurred (158 in the baseline phase and 157 in the intervention phase), with a rate of 0.21 per 1000 days of catheter use in the baseline phase and 0.29 per 1000 days in the intervention phase, giving an incidence rate ratio of 1.37 (95% confidence interval 0.85 to 2.21; P=0.20). This translates to one in 10 patients who undergo dialysis for a year with a catheter experiencing an episode of CRBSI.
Conclusions
Among patients who require a haemodialysis catheter, the implementation of a multifaceted intervention did not reduce the rate of CRBSI. Multifaceted interventions to prevent CRBSI might not be effective in clinical practice settings.
Trial registration
Australia New Zealand Clinical Trials Registry ACTRN12616000830493.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 12 Apr 2022; 377:e069634
Kotwal S, Cass A, Coggan S, Gray NA, ... Gallagher M, REDUCCTION Investigators
BMJ: 12 Apr 2022; 377:e069634 | PMID: 35414532
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Impact:
Abstract

Risk of adverse events after covid-19 in Danish children and adolescents and effectiveness of BNT162b2 in adolescents: cohort study.

Kildegaard H, Lund LC, Højlund M, Stensballe LG, Pottegård A
Objectives
To assess the risk of acute and post-acute adverse events after SARS-CoV-2 infection in children and adolescents in Denmark and to evaluate the real world effectiveness of the BNT162b2 mRNA vaccine (Pfizer-BioNTech) among adolescents.
Design
Cohort study.
Setting
Nationwide Danish healthcare registers.
Participants
All Danish people younger than 18 years who were either tested for SARS-CoV-2 using reverse transcriptase polymerase chain reaction (RT-PCR) or vaccinated with BNT162b2 to 1 October 2021.
Main outcome measures
Risk of hospital admissions (any hospital contact of ≥12 hours); intensive care unit (ICU) admissions; serious complications, including multisystem inflammatory syndrome in children (MIS-C), myocarditis, and neuroimmune disorders; and initiating drug treatment and health service use up to six months after being tested. Vaccine effectiveness in vaccine recipients compared with unvaccinated peers was evaluated as one minus the risk ratio at 20 days after the first dose and 60 days after the second dose.
Results
Of 991 682 children and adolescents tested for SARS-CoV-2 using RT-PCR in Denmark, 74 611 (7.5%) were positive. The risk of hospital admission with any variant for ≥12 hours was 0.49% (95% confidence interval 0.44% to 0.54%; 361/74 350), and 0.01% (0.01% to 0.03%; 10/73 187) of participants were admitted to an ICU within 30 days of testing positive. The risk of MIS-C within two months of SARS-CoV-2 infection was 0.05% (0.03% to 0.06%; 32/70 666), whereas no participants had myocarditis outside of MIS-C or encephalitis and fewer than five had Guillain-Barré syndrome. In the post-acute phase (1-6 months after infection), participants who tested positive for SARS-CoV-2 showed a 1.08-fold (95% confidence interval 1.06-fold to 1.10-fold) increase in rate of contacts with general practitioners compared with a reference cohort sampled among all children tested for SARS-CoV-2 during the study period. Overall, 278 649 adolescents received BNT162b2. Compared with unvaccinated adolescents, the estimated vaccine effectiveness among 229 799 adolescents vaccinated with one dose was 62% (95% confidence interval 59% to 65%) after 20 days, and among 175 176 vaccinated with two doses was 93% (92% to 94%) after 60 days during a period when delta was the dominant variant.
Conclusions
The absolute risks of adverse events after SARS-CoV-2 infection were generally low in Danish children and adolescents, although MIS-C occurred in 0.05% (32/70 666) of participants with RT-PCR confirmed SARS-CoV-2 infection. In adjusted analyses, rates of general practitioner visits were slightly increased in SARS-CoV-2 positive children and adolescents, which could indicate persisting symptoms. BNT162b2 appeared to be effective in reducing the risk of SARS-CoV-2 infection with the delta variant in adolescents.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 11 Apr 2022; 377:e068898
Kildegaard H, Lund LC, Højlund M, Stensballe LG, Pottegård A
BMJ: 11 Apr 2022; 377:e068898 | PMID: 35410884
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Impact:
Abstract

Risks of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19: nationwide self-controlled cases series and matched cohort study.

Katsoularis I, Fonseca-Rodríguez O, Farrington P, Jerndal H, ... Lindmark K, Fors Connolly AM
Objective
To quantify the risk of deep vein thrombosis, pulmonary embolism, and bleeding after covid-19.
Design
Self-controlled case series and matched cohort study.
Setting
National registries in Sweden.
Participants
1 057 174 people who tested positive for SARS-CoV-2 between 1 February 2020 and 25 May 2021 in Sweden, matched on age, sex, and county of residence to 4 076 342 control participants.
Main outcomes measures
Self-controlled case series and conditional Poisson regression were used to determine the incidence rate ratio and risk ratio with corresponding 95% confidence intervals for a first deep vein thrombosis, pulmonary embolism, or bleeding event. In the self-controlled case series, the incidence rate ratios for first time outcomes after covid-19 were determined using set time intervals and the spline model. The risk ratios for first time and all events were determined during days 1-30 after covid-19 or index date using the matched cohort study, and adjusting for potential confounders (comorbidities, cancer, surgery, long term anticoagulation treatment, previous venous thromboembolism, or previous bleeding event).
Results
Compared with the control period, incidence rate ratios were significantly increased 70 days after covid-19 for deep vein thrombosis, 110 days for pulmonary embolism, and 60 days for bleeding. In particular, incidence rate ratios for a first pulmonary embolism were 36.17 (95% confidence interval 31.55 to 41.47) during the first week after covid-19 and 46.40 (40.61 to 53.02) during the second week. Incidence rate ratios during days 1-30 after covid-19 were 5.90 (5.12 to 6.80) for deep vein thrombosis, 31.59 (27.99 to 35.63) for pulmonary embolism, and 2.48 (2.30 to 2.68) for bleeding. Similarly, the risk ratios during days 1-30 after covid-19 were 4.98 (4.96 to 5.01) for deep vein thrombosis, 33.05 (32.8 to 33.3) for pulmonary embolism, and 1.88 (1.71 to 2.07) for bleeding, after adjusting for the effect of potential confounders. The rate ratios were highest in patients with critical covid-19 and highest during the first pandemic wave in Sweden compared with the second and third waves. In the same period, the absolute risk among patients with covid-19 was 0.039% (401 events) for deep vein thrombosis, 0.17% (1761 events) for pulmonary embolism, and 0.101% (1002 events) for bleeding.
Conclusions
The findings of this study suggest that covid-19 is a risk factor for deep vein thrombosis, pulmonary embolism, and bleeding. These results could impact recommendations on diagnostic and prophylactic strategies against venous thromboembolism after covid-19.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 06 Apr 2022; 377:e069590
Katsoularis I, Fonseca-Rodríguez O, Farrington P, Jerndal H, ... Lindmark K, Fors Connolly AM
BMJ: 06 Apr 2022; 377:e069590 | PMID: 35387772
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Impact:
Abstract

Clinical effectiveness of one ultrasound guided intra-articular corticosteroid and local anaesthetic injection in addition to advice and education for hip osteoarthritis (HIT trial): single blind, parallel group, three arm, randomised controlled trial.

Paskins Z, Bromley K, Lewis M, Hughes G, ... Mallen CD, Roddy E
Objective
To compare the clinical effectiveness of adding a single ultrasound guided intra-articular hip injection of corticosteroid and local anaesthetic to advice and education in adults with hip osteoarthritis.
Design
Pragmatic, three arm, parallel group, single blind, randomised controlled trial.
Setting
Two community musculoskeletal services in England.
Participants
199 adults aged ≥40 years with hip osteoarthritis and at least moderate pain: 67 were randomly assigned to receive advice and education (best current treatment (BCT)), 66 to BCT plus ultrasound guided injection of triamcinolone and lidocaine, and 66 to BCT plus ultrasound guided injection of lidocaine.
Interventions
BCT alone, BCT plus ultrasound guided intra-articular hip injection of 40 mg triamcinolone acetonide and 4 mL 1% lidocaine hydrochloride, or BCT plus ultrasound guided intra-articular hip injection of 5 mL 1% lidocaine. Participants in the ultrasound guided arms were masked to the injection they received.
Main outcome measures
The primary outcome was self-reported current intensity of hip pain (0-10 Numerical Rating Scale) over six months. Outcomes were self-reported at two weeks and at two, four, and six months.
Results
Mean age of the study sample was 62.8 years (standard deviation 10.0) and 113 (57%) were women. Average weighted follow-up rate across time points was 93%. Greater mean improvement in hip pain intensity over six months was reported with BCT plus ultrasound-triamcinolone-lidocaine compared with BCT: mean difference -1.43 (95% confidence interval -2.15 to -0.72), P<0.001; standardised mean difference -0.55 (-0.82 to -0.27). No difference in hip pain intensity over six months was reported between BCT plus ultrasound-triamcinolone-lidocaine compared with BCT plus ultrasound-lidocaine (-0.52 (-1.21 to 0.18)). The presence of ultrasound confirmed synovitis or effusion was associated with a significant interaction effect favouring BCT plus ultrasound-triamcinolone-lidocaine (-1.70 (-3.10 to -0.30)). One participant in the BCT plus ultrasound-triamcinolone-lidocaine group with a bioprosthetic aortic valve died from subacute bacterial endocarditis four months after the intervention, deemed possibly related to the trial treatment.
Conclusions
Ultrasound guided intra-articular hip injection of triamcinolone is a treatment option to add to BCT for people with hip osteoarthritis.
Trial registration
EudraCT 2014-003412-37; ISRCTN50550256.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 06 Apr 2022; 377:e068446
Paskins Z, Bromley K, Lewis M, Hughes G, ... Mallen CD, Roddy E
BMJ: 06 Apr 2022; 377:e068446 | PMID: 35387783
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Impact:
Abstract

Efficacy of interventions to reduce long term opioid treatment for chronic non-cancer pain: systematic review and meta-analysis.

Avery N, McNeilage AG, Stanaway F, Ashton-James CE, ... Gholamrezaei A, Glare P
Objective
To review interventions to reduce long term opioid treatment in people with chronic non-cancer pain, considering efficacy on dose reduction and discontinuation, pain, function, quality of life, withdrawal symptoms, substance use, and adverse events.
Design
Systematic review and meta-analysis of randomised controlled trials and non-randomised studies of interventions.
Data sources
Medline, Embase, PsycINFO, CINAHL, and the Cochrane Library searched from inception to July 2021. Reference lists and previous reviews were also searched and experts were contacted.
Eligibility criteria for study selection
Original research in English. Case reports and cross sectional studies were excluded.
Data extraction and synthesis
Two authors independently selected studies, extracted data, and used the Cochrane risk-of-bias tools for randomised and non-randomised studies (RoB 2 and ROBINS-I). Authors grouped interventions into five categories (pain self-management, complementary and alternative medicine, pharmacological and biomedical devices and interventions, opioid replacement treatment, and deprescription methods), estimated pooled effects using random effects meta-analytical models, and appraised the certainty of evidence using GRADE (grading of recommendations, assessment, development, and evaluation).
Results
Of 166 studies meeting inclusion criteria, 130 (78%) were considered at critical risk of bias and were excluded from the evidence synthesis. Of the 36 included studies, few had comparable treatment arms and sample sizes were generally small. Consequently, the certainty of the evidence was low or very low for more than 90% (41/44) of GRADE outcomes, including for all non-opioid patient outcomes. Despite these limitations, evidence of moderate certainty indicated that interventions to support prescribers\' adherence to guidelines increased the likelihood of patients discontinuing opioid treatment (adjusted odds ratio 1.5, 95% confidence interval 1.0 to 2.1), and that these prescriber interventions as well as pain self-management programmes reduced opioid dose more than controls (intervention v control, mean difference -6.8 mg (standard error 1.6) daily oral morphine equivalent, P<0.001; pain programme v control, -14.31 mg daily oral morphine equivalent, 95% confidence interval -21.57 to -7.05).
Conclusions
Evidence on the reduction of long term opioid treatment for chronic pain continues to be constrained by poor study methodology. Of particular concern is the lack of evidence relating to possible harms. Agreed standards for designing and reporting studies on the reduction of opioid treatment are urgently needed.
Review registration
PROSPERO CRD42020140943.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 04 Apr 2022; 377:e066375
Avery N, McNeilage AG, Stanaway F, Ashton-James CE, ... Gholamrezaei A, Glare P
BMJ: 04 Apr 2022; 377:e066375 | PMID: 35379650
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Abstract

Why don\'t children and young people engage with diabetes services?

Saul H, Gursul D, Cassidy S, Sharpe D
The studySharpe D, Rajabi M, Harden A, et al. Supporting disengaged children and young people living with diabetes to self-care: a qualitative study in a socially disadvantaged and ethnically diverse urban area. BMJ Open 2021;11:e046989.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/why-dont-young-people-engage-with-diabetes-services/.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 04 Apr 2022; 377:o750
Saul H, Gursul D, Cassidy S, Sharpe D
BMJ: 04 Apr 2022; 377:o750 | PMID: 35379673
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Abstract

Association of computed tomography screening with lung cancer stage shift and survival in the United States: quasi-experimental study.

Potter AL, Rosenstein AL, Kiang MV, Shah SA, ... Fintelmann FJ, Yang CJ
Objective
To determine the effect of the introduction of low dose computed tomography screening in 2013 on lung cancer stage shift, survival, and disparities in the stage of lung cancer diagnosed in the United States.
Design
Quasi-experimental study using Joinpoint modeling, multivariable ordinal logistic regression, and multivariable Cox proportional hazards modeling.
Setting
US National Cancer Database and Surveillance Epidemiology End Results program database.
Participants
Patients aged 45-80 years diagnosed as having non-small cell lung cancer (NSCLC) between 1 January 2010 and 31 December 2018.
Main outcome measures
Annual per cent change in percentage of stage I NSCLC diagnosed among patients aged 45-54 (ineligible for screening) and 55-80 (potentially eligible for screening), median all cause survival, and incidence of NSCLC; multivariable adjusted odds ratios for year-to-year changes in likelihood of having earlier stages of disease at diagnosis and multivariable adjusted hazard ratios for changes in hazard of death before versus after introduction of screening.
Results
The percentage of stage I NSCLC diagnosed among patients aged 55-80 did not significantly increase from 2010 to 2013 (from 27.8% to 29.4%) and then increased at 3.9% (95% confidence interval 3.0% to 4.8%) per year from 2014 to 2018 (from 30.2% to 35.5%). In multivariable adjusted analysis, the increase in the odds per year of a patient having one lung cancer stage lower at diagnosis during the time period from 2014 to 2018 was 6.2% (multivariable adjusted odds ratio 1.062, 95% confidence interval 1.048 to 1.077; P<0.001) higher than the increase in the odds per year from 2010 to 2013. Similarly, the median all cause survival of patients aged 55-80 did not significantly increase from 2010 to 2013 (from 15.8 to 18.1 months), and then increased at 11.9% (8.9% to 15.0%) per year from 2014 to 2018 (from 19.7 to 28.2 months). In multivariable adjusted analysis, the hazard of death decreased significantly faster after 2014 compared with before 2014 (P<0.001). By 2018, stage I NSCLC was the predominant diagnosis among non-Hispanic white people and people living in the highest income or best educated regions. Non-white people and those living in lower income or less educated regions remained more likely to have stage IV disease at diagnosis. Increases in the detection of early stage disease in the US from 2014 to 2018 led to an estimated 10 100 averted deaths.
Conclusions
A recent stage shift toward stage I NSCLC coincides with improved survival and the introduction of lung cancer screening. Non-white patients and those living in areas of greater deprivation had lower rates of stage I disease identified, highlighting the need for efforts to increase access to screening in the US.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 30 Mar 2022; 376:e069008
Potter AL, Rosenstein AL, Kiang MV, Shah SA, ... Fintelmann FJ, Yang CJ
BMJ: 30 Mar 2022; 376:e069008 | PMID: 35354556
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Abstract

Psychological interventions for chronic, non-specific low back pain: systematic review with network meta-analysis.

Ho EK, Chen L, Simic M, Ashton-James CE, ... Ferreira ML, Ferreira PH
Objective
To determine the comparative effectiveness and safety of psychological interventions for chronic low back pain.
Design
Systematic review with network meta-analysis.
Data sources
Medline, Embase, PsycINFO, Cochrane Central Register of Controlled Trials, Web of Science, SCOPUS, and CINAHL from database inception to 31 January 2021.
Eligibility criteria for study selection
Randomised controlled trials comparing psychological interventions with any comparison intervention in adults with chronic, non-specific low back pain. Two reviewers independently screened studies, extracted data, and assessed risk of bias and confidence in the evidence. Primary outcomes were physical function and pain intensity. A random effects network meta-analysis using a frequentist approach was performed at post-intervention (from the end of treatment to <2 months post-intervention); and at short term (≥2 to <6 months post-intervention), mid-term (≥6 to <12 months post-intervention), and long term follow-up (≥12 months post-intervention). Physiotherapy care was the reference comparison intervention. The design-by-treatment interaction model was used to assess global inconsistency and the Bucher method was used to assess local inconsistency.
Results
97 randomised controlled trials involving 13 136 participants and 17 treatment nodes were included. Inconsistency was detected at short term and mid-term follow-up for physical function, and short term follow-up for pain intensity, and were resolved through sensitivity analyses. For physical function, cognitive behavioural therapy (standardised mean difference 1.01, 95% confidence interval 0.58 to 1.44), and pain education (0.62, 0.08 to 1.17), delivered with physiotherapy care, resulted in clinically important improvements at post-intervention (moderate quality evidence). The most sustainable effects of treatment for improving physical function were reported with pain education delivered with physiotherapy care, at least until mid-term follow-up (0.63, 0.25 to 1.00; low quality evidence). No studies investigated the long term effectiveness of pain education delivered with physiotherapy care. For pain intensity, behavioural therapy (1.08, 0.22 to 1.94), cognitive behavioural therapy (0.92, 0.43 to 1.42), and pain education (0.91, 0.37 to 1.45), delivered with physiotherapy care, resulted in clinically important effects at post-intervention (low to moderate quality evidence). Only behavioural therapy delivered with physiotherapy care maintained clinically important effects on reducing pain intensity until mid-term follow-up (1.01, 0.41 to 1.60; high quality evidence).
Conclusions
For people with chronic, non-specific low back pain, psychological interventions are most effective when delivered in conjunction with physiotherapy care (mainly structured exercise). Pain education programmes (low to moderate quality evidence) and behavioural therapy (low to high quality evidence) result in the most sustainable effects of treatment; however, uncertainty remains as to their long term effectiveness. Although inconsistency was detected, potential sources were identified and resolved.
Systematic review registration
PROSPERO CRD42019138074.

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BMJ: 30 Mar 2022; 376:e067718
Ho EK, Chen L, Simic M, Ashton-James CE, ... Ferreira ML, Ferreira PH
BMJ: 30 Mar 2022; 376:e067718 | PMID: 35354560
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Abstract

National experience in the first two years of primary human papillomavirus (HPV) cervical screening in an HPV vaccinated population in Australia: observational study.

Smith MA, Sherrah M, Sultana F, Castle PE, ... Saville M, Canfell K
Objective
To review the first two years of the primary human papillomavirus (HPV) cervical screening programme in an HPV vaccinated population.
Design
Observational study.
Setting
Australia.
Participants
3 745 318 women with a primary HPV test between 1 December 2017 and 31 December 2019; most women aged <40 years had previously been offered vaccination against HPV16 and HPV18.
Interventions
Primary HPV screening with referral if HPV16 or HPV18 (HPV16/18) positive and triage with liquid based cytology testing (threshold atypical squamous cells-cannot exclude high grade squamous intraepithelial lesion) for women who were positive for high risk HPV types other than 16/18. A 12 month follow-up HPV test was recommended in triaged women with a negative or low grade cytology result, with referral if they tested positive for any high risk HPV type at follow-up.
Main outcome measures
Proportion of women who had attended for their first HPV screening test, tested positive, and were referred for colposcopy; and short term risk of detecting cervical intraepithelial neoplasia (CIN) grade 2 or worse, CIN grade 3 or worse, or cancer.
Results
54.6% (n=3 507 281) of an estimated 6 428 677 eligible women aged 25-69 had undergone their first HPV test by the end of 2019. Among those attending for routine screening, positivity for HPV16/18 and for HPV types not 16/18 was, respectively, 2.0% and 6.6% in women aged 25-69 (n=3 045 844) and 2.2% and 13.3% in highly vaccinated cohorts of women aged 25-34 (n=768 362). Colposcopy referral (ages 25-69 years) was 3.5%, increasing to an estimated 6.2% after accounting for women who had not yet had a 12 month repeat test. Cervical cancer was detected in 0.98% (456/46 330) of women positive for HPV16/18 at baseline, including 0.32% (89/28 003) of women with HPV16/18 and negative cytology. Women with HPV types not 16/18 and negative or low grade cytology at both baseline and 12 months were at low risk of serious disease (3.4% CIN grade 3 or worse; 0.02% cancer; n=20 019) but estimated to account for 62.0% of referrals for this screening algorithm.
Conclusions
Colposcopy referral thresholds need to consider underlying cancer risk; on this basis, women with HPV16/18 in the first round of HPV screening were found to be at higher risk regardless of cytology result, even in a previously well screened population. Women with HPV types not 16/18 and negative or low grade cytology showed a low risk of serious abnormalities but constitute most referrals and could be managed safely with two rounds of repeat HPV testing rather than one. HPV16/18 driven referrals were low in HPV vaccinated cohorts.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 30 Mar 2022; 376:e068582
Smith MA, Sherrah M, Sultana F, Castle PE, ... Saville M, Canfell K
BMJ: 30 Mar 2022; 376:e068582 | PMID: 35354610
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Abstract

Global, regional, and national burden of diseases and injuries for adults 70 years and older: systematic analysis for the Global Burden of Disease 2019 Study.

GBD 2019 Ageing Collaborators
Objectives
To use data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) to estimate mortality and disability trends for the population aged ≥70 and evaluate patterns in causes of death, disability, and risk factors.
Design
Systematic analysis.
Setting
Participants were aged ≥70 from 204 countries and territories, 1990-2019.
Main outcomes measures
Years of life lost, years lived with disability, disability adjusted life years, life expectancy at age 70 (LE-70), healthy life expectancy at age 70 (HALE-70), proportion of years in ill health at age 70 (PYIH-70), risk factors, and data coverage index were estimated based on standardised GBD methods.
Results
Globally the population of older adults has increased since 1990 and all cause death rates have decreased for men and women. However, mortality rates due to falls increased between 1990 and 2019. The probability of death among people aged 70-90 decreased, mainly because of reductions in non-communicable diseases. Globally disability burden was largely driven by functional decline, vision and hearing loss, and symptoms of pain. LE-70 and HALE-70 showed continuous increases since 1990 globally, with certain regional disparities. Globally higher LE-70 resulted in higher HALE-70 and slightly increased PYIH-70. Sociodemographic and healthcare access and quality indices were positively correlated with HALE-70 and LE-70. For high exposure risk factors, data coverage was moderate, while limited data were available for various dietary, environmental or occupational, and metabolic risks.
Conclusions
Life expectancy at age 70 has continued to rise globally, mostly because of decreases in chronic diseases. Adults aged ≥70 living in high income countries and regions with better healthcare access and quality were found to experience the highest life expectancy and healthy life expectancy. Disability burden, however, remained constant, suggesting the need to enhance public health and intervention programmes to improve wellbeing among older adults.

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BMJ: 09 Mar 2022; 376:e068208
GBD 2019 Ageing Collaborators
BMJ: 09 Mar 2022; 376:e068208 | PMID: 35273014
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This program is still in alpha version.