Efficacy and safety of basal insulins in people with type 2 diabetes mellitus: a systematic review and network meta-analysis of randomized clinical trials.

Aim: The comparative effectiveness of basal insulins has been examined in several studies. However, current treatment algorithms provide a list of options with no clear differentiation between different basal insulins as the optimal choice for initiation. Methods: A comprehensive search of MEDLINE, Embase, Cochrane Library, ISI, and Scopus, and a reference list of retrieved studies and reviews were performed up to November 2023. We identified phase III randomized controlled trials (RCTs) comparing the efficacy and safety of basal insulin regimens. The primary outcomes evaluated were HbA1c reduction, weight change, and hypoglycemic events. The revised Cochrane ROB-2 tool was used to assess the methodological quality of the included studies. A random-effects frequentist network meta-analysis was used to estimate the pooled weighted mean difference (WMD) and odds ratio (OR) with 95% confidence intervals considering the critical assumptions in the networks. The certainty of the evidence and confidence in the rankings was assessed using the GRADE minimally contextualized approach. Results: Of 20,817 retrieved studies, 44 RCTs (23,699 participants) were eligible for inclusion in our network meta-analysis. We found no significant difference among various basal insulins (including Neutral Protamine Hagedorn (NPH), ILPS, insulin glargine, detemir, and degludec) in reducing HbA1c. Insulin glargine, 300 U/mL (IGlar-300) was significantly associated with less weight gain (mean difference ranged from 2.9 kg to 4.1 kg) compared to other basal insulins, namely thrice-weekly insulin degludec (IDeg-3TW), insulin degludec, 100 U/mL (IDeg-100), insulin degludec, 200 U/mL (IDeg-200), NPH, and insulin detemir (IDet), but with low to very low certainty regarding most comparisons. IDeg-100, IDeg-200, IDet, and IGlar-300 were associated with significantly lower odds of overall, nocturnal, and severe hypoglycemic events than NPH and insulin lispro protamine (ILPS) (moderate to high certainty evidence). NPH was associated with the highest odds of overall and nocturnal hypoglycemia compared to others. Network meta-analysis models were robust, and findings were consistent in sensitivity analyses. Conclusion: The efficacy of various basal insulin regimens is comparable. However, they have different safety profiles. IGlar-300 may be the best choice when weight gain is a concern. In contrast, IDeg-100, IDeg-200, IDet, and IGlar-300 may be preferred when hypoglycemia is the primary concern.

Influence of lack of blinding on the estimation of medication-related harms: a retrospective cohort study of randomized controlled trials.

BACKGROUND: Empirical evidence suggests that lack of blinding may be associated with biased estimates of treatment benefit in randomized controlled trials, but the influence on medication-related harms is not well-recognized. We aimed to investigate the association between blinding and clinical trial estimates of medication-related harms. METHODS: We searched PubMed from January 1, 2015, till January 1, 2020, for systematic reviews with meta-analyses of medication-related harms. Eligible meta-analyses must have contained trials both with and without blinding. Potential covariates that may confound effect estimates were addressed by restricting trials within the comparison or by hierarchical analysis of harmonized groups of meta-analyses (therefore harmonizing drug type, control, dosage, and registration status) across eligible meta-analyses. The weighted hierarchical linear regression was then used to estimate the differences in harm estimates (odds ratio, OR) between trials that lacked blinding and those that were blinded. The results were reported as the ratio of OR (ROR) with its 95% confidence interval (CI). RESULTS: We identified 629 meta-analyses of harms with 10,069 trials. We estimated a weighted average ROR of 0.68 (95% CI: 0.53 to 0.88, P < 0.01) among 82 trials in 20 meta-analyses where blinding of participants was lacking. With regard to lack of blinding of healthcare providers or outcomes assessors, the RORs were 0.68 (95% CI: 0.53 to 0.87, P < 0.01 from 81 trials in 22 meta-analyses) and 1.00 (95% CI: 0.94 to 1.07, P = 0.94 from 858 trials among 155 meta-analyses) respectively. Sensitivity analyses indicate that these findings are applicable to both objective and subjective outcomes. CONCLUSIONS: Lack of blinding of participants and health care providers in randomized controlled trials may underestimate medication-related harms. Adequate blinding in randomized trials, when feasible, may help safeguard against potential bias in estimating the effects of harms.

What really is nontokenistic fully inclusive patient and public involvement/engagement in research?

Patient and public involvement and engagement (PPIE) is critically important in healthcare research. A useful starting point for researchers to understand the scope of PPIE is to review the definition from the National Institute for Health and Care Research (NIHR) as, 'research being carried out "with" or "by" members of the public rather than "to", "about" or "for" them'. PPIE does not refer to participation in research, but to actively shaping its direction. The 'Effectiveness of a decision support tool to optimise community-based tailored management of sleep for people living with dementia or mild cognitive impairment (TIMES)' study is funded through the NIHR programme grant for applied research. TIMES has thoroughly embraced PPIE by ensuring the person's voice is heard, understood, and valued. This editorial showcases how the TIMES project maximised inclusivity, and we share our experiences and top tips for other researchers. We base our reflections on the six key UK standards for public involvement; Inclusive Opportunities, Working Together, Support and Learning, Communications, Impact and Governance. We present our work, which had been co-led by our PPIE leads, academics and partners including, together in dementia everyday, Innovations in Dementia, The UK Network of Dementia Voices (Dementia Engagement & Empowerment Project) and Liverpool Chinese Wellbeing. We have a Lived Experience Advisory Forum on Sleep, which includes people with dementia, family carers, representatives of the South Asian Community and the Chinese community.

Taxonomy development for term standardization in activity resulting from medication review processes: a Delphi study.

BACKGROUND: Medication review (MR) is the systematic assessment of a patient's medications for safety and effectiveness by a healthcare professional. The language used to describe MR activity, such as stopped medicine and increased dose, should be consistent across studies to assist researchers compare how different services operate and identify their mechanism of impact. AIM: To develop an international taxonomy of standardized terms and activity definitions related to medication reviews. METHOD: This was a three-stage Delphi-based consensus study with international medication review experts. A systematic review provided MR activity terms for the survey. Experts rated their consensus on each activity term and its definition on a Likert scale and provided written feedback. The consensus was 75% panel agreement. At each stage, consensus elements were retained, and feedback was used to revise definitions. RESULTS: Seven experts were recruited for the study (response rate 15.2%) from four countries: the United Kingdom (n = 4), New Zealand (n = 1), Australia (n = 1), and Malaysia (n = 1). The following terms achieved consensus: the term Medication as a descriptor for MR terms; discontinue medication, start medication, dose increase, dose decrease, dosage form change, and medication safety and efficacy monitor to describe MR activity; Educate to describe the delivery of healthcare professionals and patients/carers education. CONCLUSION: Standardized medication review activity terms and definitions have been selected for universal adoption in all future MR research to facilitate a meaningful comparison of process evaluations within different settings.

New Adverse Drug Reaction Signals from 2017 to 2021-Genuine Alerts or False Alarms?

Spontaneous adverse events reporting systems are used internationally to flag new or unexpected adverse drug reactions (ADRs). Disproportionality analysis is a recognised technique, but false alarms may arise. We aimed to determine whether these new ADR signals had subsequently been followed-up with detailed hypothesis-testing studies. We searched PubMed to identify published studies (years 2017-2021) where the authors reported findings of new ADR signals from disproportionality analyses. We used PubMed and forward citation tracking (Google Scholar) to identify any subsequent confirmatory studies of these ADR signals. We screened 414 titles and abstracts and checked the full-text articles of 57 studies. We found signals for 56 suspected new ADRs from 24 drugs. Google Scholar showed that the ADR studies had been cited a median of seven times (range 0-61). However, none of the suspected new ADRs had undergone detailed evaluation in the citing literature. Similarly, our PubMed search did not find any confirmation studies for the 56 suspected new ADRs. Although many suspected new ADR signals have been identified through disproportionality analysis, most signals have not been further verified as being either genuine ADRs or false alarms. Researchers must focus on follow-up studies for these new signals.

Bleeding risk in patients prescribed dual antiplatelet therapy and triple therapy after coronary interventions: the ADAPTT retrospective population-based cohort studies.

Background: Bleeding among populations undergoing percutaneous coronary intervention or coronary artery bypass grafting and among conservatively managed patients with acute coronary syndrome exposed to different dual antiplatelet therapy and triple therapy (i.e. dual antiplatelet therapy plus an anticoagulant) has not been previously quantified. Objectives: The objectives were to estimate hazard ratios for bleeding for different antiplatelet and triple therapy regimens, estimate resources and the associated costs of treating bleeding events, and to extend existing economic models of the cost-effectiveness of dual antiplatelet therapy. Design: The study was designed as three retrospective population-based cohort studies emulating target randomised controlled trials. Setting: The study was set in primary and secondary care in England from 2010 to 2017. Participants: Participants were patients aged ≥ 18 years undergoing coronary artery bypass grafting or emergency percutaneous coronary intervention (for acute coronary syndrome), or conservatively managed patients with acute coronary syndrome. Data sources: Data were sourced from linked Clinical Practice Research Datalink and Hospital Episode Statistics. Interventions: Coronary artery bypass grafting and conservatively managed acute coronary syndrome: aspirin (reference) compared with aspirin and clopidogrel. Percutaneous coronary intervention: aspirin and clopidogrel (reference) compared with aspirin and prasugrel (ST elevation myocardial infarction only) or aspirin and ticagrelor. Main outcome measures: Primary outcome: any bleeding events up to 12 months after the index event. Secondary outcomes: major or minor bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular events. Results: The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval -£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval -£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195). Conclusions: This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy. Limitations: The estimates for bleeding and major adverse cardiovascular events may be biased from unmeasured confounding and the exclusion of an eligible subgroup of patients who could not be assigned an intervention. Because of these limitations, a formal cost-effectiveness analysis could not be conducted. Future work: Future work should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions. Trial registration: This trial is registered as ISRCTN76607611. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 8. See the NIHR Journals Library website for further project information.

People who have a heart attack are treated with a stent to open up the blocked artery that caused the heart attack, with surgery to bypass the blocked artery or with medication only. Whatever the treatment, they are prescribed one or more antiplatelet drugs, either aspirin only or aspirin and an additional antiplatelet (clopidogrel, prasugrel or ticagrelor), for 12 months after the heart attack. Antiplatelets are given to prevent another heart attack, but increase the risk of bleeding. We used a large general practice database and a database describing patients' attendances and admissions to hospital to determine how many people bleed with different antiplatelet combinations. We found that, overall, up to 1 in 10 people taking antiplatelets (rising to 2 in 10 if also taking an anticoagulant such as warfarin or dabigatran) reported a bleed. Among patients treated with surgery or medication only, we compared aspirin only (which is a less potent therapy) with aspirin and clopidogrel (a more potent therapy). Among patients treated with stents, we compared aspirin and clopidogrel (less potent therapy) with aspirin and prasugrel or ticagrelor (more potent therapy). In all three populations, the more potent therapy increased the risk of bleeding by about one and a half times, but this was not offset by a reduced risk of having a subsequent heart attack. This may be explained by low adherence to the medication: between one-third and almost half of all patients did not adhere to their regimen, and non-adherence was generally higher among patients taking a more potent therapy. It may also be explained by bias inherent in the study, for example if the groups prescribed different antiplatelet regimens had different risks of having another heart attack. Nevertheless, the results show that doctors should be cautious about prescribing more potent antiplatelet therapy because it may increase serious bleeds without necessarily reducing the number of heart attacks.

Changes in exhaled volatile organic compounds following indirect bronchial challenge in suspected asthma.

BACKGROUND: Inhaled mannitol provokes bronchoconstriction via mediators released during osmotic degranulation of inflammatory cells, and, hence represents a useful diagnostic test for asthma and model for acute attacks. We hypothesised that the mannitol challenge would trigger changes in exhaled volatile organic compounds (VOCs), generating both candidate biomarkers and novel insights into their origin. METHODS: Participants with a clinical diagnosis of asthma, or undergoing investigation for suspected asthma, were recruited. Inhaled mannitol challenges were performed, followed by a sham challenge after 2 weeks in participants with bronchial hyper-responsiveness (BHR). VOCs were collected before and after challenges and analysed using gas chromatography-mass spectrometry. RESULTS: Forty-six patients (mean (SD) age 52 (16) years) completed a mannitol challenge, of which 16 (35%) were positive, and 15 of these completed a sham challenge. Quantities of 16 of 51 identified VOCs changed following mannitol challenge (p<0.05), of which 11 contributed to a multivariate sparse partial least square discriminative analysis model, with a classification error rate of 13.8%. Five of these 16 VOCs also changed (p<0.05) in quantity following the sham challenge, along with four further VOCs. In patients with BHR to mannitol distinct postchallenge VOC signatures were observed compared with post-sham challenge. CONCLUSION: Inhalation of mannitol was associated with changes in breath VOCs, and in people with BHR resulted in a distinct exhaled breath profile when compared with a sham challenge. These differentially expressed VOCs are likely associated with acute airway inflammation and/or bronchoconstriction and merit further investigation as potential biomarkers in asthma.

EVALUATION OF THE FIRST OLDER PEOPLE'S EMERGENCY DEPARTMENT IN ENGLAND - A RETROSPECTIVE COHORT STUDY.

BACKGROUND: The complexity of older patients along with trends in poorer outcomes in the emergency department (ED) has prompted research into how EDs can adapt to meet the needs of an aging population. A separate Older People's Emergency Department (OPED) has been proposed to improve care at the front door. OBJECTIVE: Compare patient flow in a dedicated OPED at a University Hospital in Norfolk, United Kingdom, against that of the main ED. METHODS: We carried out a retrospective cohort study to compare older patients attending the ED in 2019 against those attending the newly formed OPED service in 2020. Multivariable logistic regression was performed to estimate adjusted odds ratios (emergency admissions, meeting England's 4-h national target, re-admissions, all-cause 30-day mortality, clinical frailty screening, and discharge to original place of residence). RESULTS: Clinical assessment in the OPED did not significantly lower the proportion of patients admitted to the hospital (adjusted odds ratio 0.84; 95% confidence interval 0.61-1.16).  There were significant reductions in overall time spent in the department, time to initial clinician review, and time to frailty screening. Patients seen in the OPED were more likely to meet the national 4-h target and more likely to be discharged to their original place of residence. CONCLUSIONS: Assessment in the OPED was not associated with a significantly reduced likelihood of hospitalization. However, patients had a shorter wait for clinical assessment, with concomitant reduction in department length of stay.

CONSORT Harms 2022 statement, explanation, and elaboration: updated guideline for the reporting of harms in randomized trials.

Randomized controlled trials remain the reference standard for healthcare research on effects of interventions, and the need to report both benefits and harms is essential. The Consolidated Standards of Reporting Trials (the main CONSORT) statement includes one item on reporting harms (i.e., all important harms or unintended effects in each group). In 2004, the CONSORT group developed the CONSORT Harms extension; however, it has not been consistently applied and needs to be updated. Here, we describe CONSORT Harms 2022, which replaces the CONSORT Harms 2004 checklist, and shows how CONSORT Harms 2022 items could be incorporated into the main CONSORT checklist. Thirteen items from the main CONSORT were modified to improve harms reporting. Three new items were added. In this article, we describe CONSORT Harms 2022 and how it was integrated into the main CONSORT checklist and elaborate on each item relevant to complete reporting of harms in randomized controlled trials. Until future work from the CONSORT group produces an updated checklist, authors, journal reviewers, and editors of randomized controlled trials should use the integrated checklist presented in this paper.

"I have travelled along on my own"-Experiences of seeking help for serious non-COVID health problems during the COVID-19 pandemic: A qualitative study.

OBJECTIVES: During COVID-19 the UK general population has been given strong messages to stay at home. Concurrently unprecedented changes occurred in healthcare access with moves to remote/triage systems. Data have shown that the number of people accessing healthcare services decreased and there are significant concerns that the pandemic has negatively affected help-seeking for serious conditions, with potentially increased morbidity and mortality. An understanding of help-seeking is urgently needed to inform public campaigns. We aimed to develop an in-depth, theory-based understanding of how, when and why people sought help for potentially serious symptoms (e.g., related to major cardiovascular events or cancer diagnoses) during the pandemic, and what influenced their decisions. DESIGN: Qualitative semi-structured interviews. METHODS: We interviewed 25 adults recruited through a targeted social media campaign. Interviews were conducted via telephone or online platform. Our topic guide was informed by the Model of Pathways to Treatment and the Capability-Opportunity-Motivation-Behaviour model. RESULTS: The analysis identified four main themes: Delay in recognition, Holding on to concerns, Weighing it up and Long-term impacts. Multiple societal and environmental factors influenced participants' help-seeking and motivation, capability and opportunity to seek help, with long-term impacts on well-being and future help-seeking. CONCLUSIONS: There is a need for clear guidance about pathways to raise concerns about symptoms and gain advice while usual healthcare contacts are paused or stopped. Recommendations for future interventions to support help-seeking during pandemics include clearer messaging, co-produced with end-users, on when, where and how to seek help.

Urinary Leukotriene E4 as a Biomarker in NSAID-Exacerbated Respiratory Disease (N-ERD): a Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: Non-steroidal exacerbated respiratory disease (N-ERD) currently requires aspirin challenge testing for diagnosis. Urinary leukotriene E4 (uLTE4) has been extensively investigated as potential biomarker in N-ERD. We aimed to assess the usefulness of uLTE4 as a biomarker in the diagnosis of N-ERD. RECENT FINDINGS: N-ERD, formerly known as aspirin-intolerant asthma (AIA), is characterised by increased leukotriene production. uLTE4 indicates cysteinyl leukotriene production, and a potential biomarker in N-ERD. Although several studies and have examined the relationship between uLTE4 and N-ERD, the usefulness of uLTE4 as a biomarker in a clinical setting remains unclear. FINDINGS: Our literature search identified 38 unique eligible studies, 35 were included in the meta-analysis. Meta-analysis was performed (i.e. pooled standardised mean difference (SMD) with 95% confidence intervals (95% CI)) and risk of bias assessed (implementing Cochrane Handbook for Systematic Reviews of Diagnostic Test Accuracy (Cochrane DTA)). Data from 3376 subjects was analysed (1354 N-ERD, 1420 ATA, and 602 HC). uLTE4 was higher in N-ERD vs ATA (n = 35, SMD 0.80; 95% CI 0.72-0.89). uLTE4 increased following aspirin challenge in N-ERD (n = 12, SMD 0.56; 95% CI 0.26-0.85) but not ATA (n = 8, SMD 0.12; CI - 0.08-0.33). This systematic review and meta-analysis showed that uLTE4 is higher in N-ERD than ATA or HC. Likewise, people with N-ERD have greater increases in uLTE4 following aspirin challenge. However, due to the varied uLTE4 measurement and result reporting practice, clinical utility of these findings is limited. Future studies should be standardised to increase clinical significance and interpretability of the results.

Real-world bleeding in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) and prescribed different combinations of dual antiplatelet therapy (DAPT) in England: a population-based cohort study emulating a 'target trial'.

OBJECTIVE: To estimate the incidence and HRs for bleeding for different dual antiplatelet therapies (DAPT) in a real-world population with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI) in England. DESIGN: A retrospective, population-based cohort study emulating a target randomised controlled trial (tRCT). DATA SOURCES: Linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES). SETTING: Primary and secondary care. PARTICIPANTS: Patients ≥18 years old with ACS undergoing emergency PCI. INTERVENTIONS: Aspirin and clopidogrel (AC, reference) versus aspirin and prasugrel (AP) or aspirin and ticagrelor (AT); AP evaluated only in patients with ST-elevation myocardial infarction (STEMI). MAIN OUTCOME MEASURES: Primary: any bleeding up to 12 months after the index event (HES- or CPRD- recorded). Secondary: HES-recorded bleeding, CPRD-recorded bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular and cerebrovascular events (MACCE). RESULTS: In ACS, the rates of any bleeding for AC and AT were 89 per 1000 person years and 134 per 1000 person years, respectively. In STEMI, rates for AC, AP and AT were 93 per 1000 person years, 138 per 1000 person years and 143 per 100 person years, respectively. In ACS, compared with AC, AT increased the hazard of any bleeding (HR: 1.47, 95% CI 1.19 to 1.82) but did not reduce MACCE (HR: 1.06, 95% CI 0.89 to 1.27). In STEMI, compared with AC, AP and AT increased the hazard of any bleeding (HR: 1.77, 95% CI 1.21 to 2.59 and HR: 1.50, 95% CI 1.10 to 2.05, respectively) but did not reduce MACCE (HR: 1.10, 95% CI 0.80 to 1.51 and HR: 1.21, 95% CI 0.94 to 1.51, respectively). Non-adherence to the prescribed DAPT regimen was 28% in AC (29% in STEMI only), 31% in AP (STEMI only) and 33% in AT (32% in STEMI only). CONCLUSIONS: In a real-world population with ACS, DAPT with ticagrelor or prasugrel are associated with increased bleeding compared with DAPT with clopidogrel. TRIAL REGISTRATION NUMBER: ISRCTN76607611.

Comparison of the prognostic performance of the CURB-65 and a modified version of the pneumonia severity index designed to identify high-risk patients using the International Community-Acquired Pneumonia Collaboration Cohort.

BACKGROUND: Although the PSI and CURB-65 represent well-validated prediction rules for pneumonia prognosis, PSI was designed to identify patients at low risk and CURB- 65 patients at high risk of mortality. We compared the prognostic performance of a modified version of the PSI designed to identify high-risk patients (i.e., PSI-HR) to CURB-65 in predicting short-term mortality. METHODS: Using data from 6 pneumonia cohorts, we designed PSI-HR as a 6-class prediction rule using the original prognostic weights of all PSI variables and modifying the risk score thresholds to define risk classes. We calculated the proportion of low-risk and high-risk patients using CURB-65 and PSI-HR and 30-day mortality in these subgroups. We compared the rules' sensitivity, specificity, positive and negative predictive values for mortality at all risk class thresholds and assessed discriminatory power using areas under their receiver operating characteristic curves (AUROCs). RESULTS: Among 13,874 patients with pneumonia, 1,036 (7.5%) died. For PSI-HR versus CURB-65, aggregate mortality was lower in low-risk patients (1.6% vs. 2.2%, p = 0.005) and higher in high-risk patients (36.5% vs. 32.2%, p = 0.27). PSI-HR had higher sensitivities than CURB-65 at all thresholds; PSI-HR also had higher specificities at the 3 lowest thresholds and specificities within 0.5% points of CURB-65 at the 2 highest thresholds. The AUROC was larger for PSI-HR than CURB- 65 (0.82 vs. 0.77, p < 0.0001). CONCLUSIONS: PSI-HR demonstrated superior prognostic accuracy to CURB-65 at the lower end of the severity spectrum and identified high-risk patients with nonsignificant higher short-term mortality at the higher end.

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

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.

A review of trial and real-world data applying elements of a realist approach to identify behavioural mechanisms supporting practitioners to taper opioids.

This evidence synthesis applying realist concepts and behavioural science aimed to identify behavioural mechanisms and contexts that facilitate prescribers tapering opioids. We identified relevant opioid-tapering interventions and services from a 2018 international systematic review and a 2019 England-wide survey, respectively. Interventions and services were eligible if they provided information about contexts and/or behavioural mechanisms influencing opioid-tapering success. A stakeholder group (n = 23) generated draft programme theories based around the 14 domains of the Theoretical Domains Framework. We refined these using the trial and service data. From 71 articles and 21 survey responses, 56 and 16 respectively were included, representing primary care, hospital, specialist pain facilities and prison services. We identified 6 programme theories comprising 5 behavioural mechanisms: prescribers' knowledge about how to taper; build prescribers' beliefs about capabilities to initiate tapering discussions and manage psychological consequences of tapering; perceived professional role in tapering; the environmental context enabling referral to specialists; and facilitating positive social influence by aligning patient: prescriber expectations of tapering. No interventions are addressing all 6 mechanisms supportive of tapering. Work is required to operationalise programme theories according to organisational structures and resources. An example operationalisation is combining tapering guidelines with information about local excess opioid problems and endorsing these with organisational branding. Prescribers being given the skills and confidence to initiate tapering discussions by training them in cognitive-based interventions and incorporating access to psychological and physical support in the patient pathway. Patients being provided with leaflets about the tapering process and informed about the patient pathway.

Smoking cessation after acute coronary syndrome: A systematic review and meta-analysis.

BACKGROUND: Smoking cessation is an effective secondary prevention measure after acute coronary syndrome (ACS). We conducted a systematic review with the aim to better understand which patients have a greater propensity to quit smoking and the risk factors for continued smoking after ACS. METHODS: We searched MEDLINE and EMBASE for studies that evaluated smoking cessation after ACS. The pooled rate of smoking cessation across included studies was performed. Random effects meta-analysis for different variables and their association with smoking cessation was conducted. RESULTS: A total of 39 studies with 11 228 patients were included in this review. The pooled rate of smoking cessation following ACS across 38 studies was 45.0%. Factors associated with greater likelihood of smoking cessation were attendance at cardiac rehabilitation (OR 1.90 95% CI 1.44-2.51), married/not alone (OR 1.68 95% CI 1.32-2.13), intention/attempt to quit smoking (OR 1.27 95% CI 1.11-1.46), diabetes mellitus (OR 1.24 95% CI 1.03-1.51) and hospitalised duration (OR 1.09 95% CI 1.02-1.15). Variables associated with a lower likelihood of smoking cessation were depression (OR 0.57 95% CI 0.43-0.75), chronic obstructive pulmonary disease/lung disease (OR 0.73 95% CI 0.57-0.93), previous admission with acute myocardial infarction/cardiac admission (OR 0.61 95% CI 0.47-0.80), cerebrovascular disease/transient ischaemic attack (OR 0.42 95% CI 0.30-0.58) and unemployment (OR 0.37 95% CI 0.17-0.80). CONCLUSIONS: The majority of smokers with an ACS continue to smoke after admission. Patients attending cardiac rehabilitation show increased odds of quitting while people who are depressed and those with chronic lung disease were less likely to quit smoking and should be targeted for intensive smoking cessation interventions.

Anticholinergic burden measures and older people's falls risk: a systematic prognostic review.

INTRODUCTION: Several adverse outcomes have been associated with anticholinergic burden (ACB), and these risks increase with age. Several approaches to measuring this burden are available but, to date, no comparison of their prognostic abilities has been conducted. This PROSPERO-registered systematic review (CRD42019115918) compared the evidence behind ACB measures in relation to their ability to predict risk of falling in older people. METHODS: Medline (OVID), EMBASE (OVID), CINAHL (EMBSCO) and PsycINFO (OVID) were searched using comprehensive search terms and a validated search filter for prognostic studies. Inclusion criteria included: participants aged 65 years and older, use of one or more ACB measure(s) as a prognostic factor, cohort or case-control in design, and reporting falls as an outcome. Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool. RESULTS: Eight studies reporting temporal associations between ACB and falls were included. All studies were rated high risk of bias in ⩾1 QUIPS tool categories, with five rated high risk ⩾3 categories. All studies (274,647 participants) showed some degree of association between anticholinergic score and increased risk of falls. Findings were most significant with moderate to high levels of ACB. Most studies (6/8) utilised the anticholinergic cognitive burden scale. No studies directly compared two or more ACB measures and there was variation in how falls were measured for analysis. CONCLUSION: The evidence supports an association between moderate to high ACB and risk of falling in older people, but no conclusion can be made regarding which ACB scale offers best prognostic value in older people. PLAIN LANGUAGE SUMMARY: A review of published studies to explore which anticholinergic burden scale is best at predicting the risk of falls in older people Introduction: One third of older people will experience a fall. Falls have many consequences including fractures, a loss of independence and being unable to enjoy life. Many things can increase the chances of having a fall. This includes some medications. One type of medication, known as anticholinergic medication, may increase the risk of falls. These medications are used to treat common health issues including depression and bladder problems. Anticholinergic burden is the term used to describe the total effects from taking these medications. Some people may use more than one of these medications. This would increase their anticholinergic burden. It is possible that reducing the use of these medications could reduce the risk of falls. We need to carry out studies to see if this is possible. To do this, we need to be able to measure anticholinergic burden. There are several scales available, but we do not know which is best.Methods: We wanted to answer: 'Which anticholinergic scale is best at predicting the risk of falling in older people?'. We reviewed studies that could answer this. We did this in a systematic way to capture all published studies. We restricted the search in several ways. We only included studies relevant to our question.Results: We found eight studies. We learned that people who are moderate to high users of these medications (often people who will use more than one of these medications) had a higher risk of falling. It was less clear if people who have a lower burden (often people who only use one of these medications) had an increased risk of falling. The low number of studies prevented us from determining if one scale was better than another.Conclusion: These findings suggest that we should reduce use of these medications. This could reduce the number falls and improve the well-being of older people.

Anticholinergic burden (prognostic factor) for prediction of dementia or cognitive decline in older adults with no known cognitive syndrome.

BACKGROUND: Medications with anticholinergic properties are commonly prescribed to older adults. The cumulative anticholinergic effect of all the medications a person takes is referred to as the 'anticholinergic burden' because of its potential to cause adverse effects. It is possible that high anticholinergic burden may be a risk factor for development of cognitive decline or dementia. There are various scales available to measure anticholinergic burden but agreement between them is often poor. OBJECTIVES: To assess whether anticholinergic burden, as defined at the level of each individual scale, is a prognostic factor for future cognitive decline or dementia in cognitively unimpaired older adults. SEARCH METHODS: We searched the following databases from inception to 24 March 2021: MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost), and ISI Web of Science Core Collection (ISI Web of Science). SELECTION CRITERIA: We included prospective and retrospective longitudinal cohort and case-control observational studies with a minimum of one year' follow-up that examined the association between an anticholinergic burden measurement scale and future cognitive decline or dementia in cognitively unimpaired older adults. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion, and undertook data extraction, assessment of risk of bias, and GRADE assessment. We extracted odds ratios (OR) and hazard ratios, with 95% confidence intervals (CI), and linear data on the association between anticholinergic burden and cognitive decline or dementia. We intended to pool each metric separately; however, only OR-based data were suitable for pooling via a random-effects meta-analysis. We initially established adjusted and unadjusted pooled rates for each available anticholinergic scale; then, as an exploratory analysis, established pooled rates on the prespecified association across scales. We examined variability based on severity of anticholinergic burden. MAIN RESULTS: We identified 25 studies that met our inclusion criteria (968,428 older adults). Twenty studies were conducted in the community care setting, two in primary care clinics, and three in secondary care settings. Eight studies (320,906 participants) provided suitable data for meta-analysis. The Anticholinergic Cognitive Burden scale (ACB scale) was the only scale with sufficient data for 'scale-based' meta-analysis. Unadjusted ORs suggested an increased risk for cognitive decline or dementia in older adults with an anticholinergic burden (OR 1.47, 95% CI 1.09 to 1.96) and adjusted ORs similarly suggested an increased risk for anticholinergic burden, defined according to the ACB scale (OR 2.63, 95% CI 1.09 to 6.29). Exploratory analysis combining adjusted ORs across available scales supported these results (OR 2.16, 95% CI 1.38 to 3.38), and there was evidence of variability in risk based on severity of anticholinergic burden (ACB scale 1: OR 2.18, 95% CI 1.11 to 4.29; ACB scale 2: OR 2.71, 95% CI 2.01 to 3.56; ACB scale 3: OR 3.27, 95% CI 1.41 to 7.61); however, overall GRADE evaluation of certainty of the evidence was low. AUTHORS' CONCLUSIONS: There is low-certainty evidence that older adults without cognitive impairment who take medications with anticholinergic effects may be at increased risk of cognitive decline or dementia.

ANTECEDENTES: A los adultos mayores se les prescriben con frecuencia fármacos con propiedades anticolinérgicas. El efecto anticolinérgico acumulado de todos los fármacos que toma una persona se denomina "carga anticolinérgica" por su potencial para causar efectos adversos. Es posible que una alta carga anticolinérgica sea un factor de riesgo para la aparición de un deterioro cognitivo o la demencia. Existen varias escalas para medir la carga anticolinérgica, pero la concordancia entre ellas suele ser mala. OBJETIVOS: Evaluar si la carga anticolinérgica, definida a nivel de cada escala individual, es un factor pronóstico de un futuro deterioro cognitivo o demencia en adultos mayores sin deterioro cognitivo. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en las siguientes bases de datos desde su creación hasta el 24 de marzo de 2021: MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP), CINAHL (EBSCOhost) e ISI Web of Science Core Collection (ISI Web of Science). CRITERIOS DE SELECCIÓN: Se incluyeron los estudios observacionales de cohortes y de casos y controles longitudinales prospectivos y retrospectivos con un seguimiento mínimo de un año, que examinaron la asociación entre una escala de medición de la carga anticolinérgica y el futuro deterioro cognitivo o demencia en adultos mayores sin deterioro cognitivo. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión, de forma independiente, evaluaron los estudios para su inclusión y realizaron la extracción de los datos, la evaluación del riesgo de sesgo y la evaluación GRADE. Se extrajeron los odds ratios (OR) y los cociente de riesgos instantáneos, con intervalos de confianza (IC) del 95%, y los datos lineales sobre la asociación entre la carga anticolinérgica y el deterioro cognitivo o la demencia. La intención fue agrupar cada métrica por separado; sin embargo, sólo los datos basados en el OR fueron aptos para agruparlos mediante un metanálisis de efectos aleatorios. Inicialmente se establecieron las tasas agrupadas ajustadas y no ajustadas para cada escala anticolinérgica disponible; luego, como un análisis exploratorio, se establecieron las tasas agrupadas sobre la asociación predeterminada entre las escalas. Se examinó la variabilidad según la intensidad de la carga anticolinérgica. RESULTADOS PRINCIPALES: Se identificaron 25 estudios que cumplían los criterios de inclusión (968 428 adultos mayores). Veinte estudios se realizaron en ámbitos de atención comunitaria, dos en centros de atención primaria y tres en ámbitos de atención secundaria. Ocho estudios (320 906 participantes) proporcionaron datos adecuados para el metanálisis. La escala Anticholinergic Cognitive Burden (escala ACB) fue la única escala con datos suficientes para un metanálisis "basado en la escala". Los OR no ajustados indicaron un aumento en el riesgo de deterioro cognitivo o demencia en los adultos mayores con sobrecarga anticolinérgica (OR 1,47; IC del 95%: 1,09 a 1,96) y los OR ajustados indicaron igualmente un aumento en el riesgo de sobrecarga anticolinérgica, definida según la escala ACB (OR 2,63; IC del 95%: 1,09 a 6,29). El análisis exploratorio que combina los OR ajustados entre las escalas disponibles apoyó estos resultados (OR 2,16; IC del 95%: 1,38 a 3,38) y hubo evidencia de variabilidad en el riesgo según la intensidad de la carga anticolinérgica (1 en escala ACB): OR 2,18; IC del 95%: 1,11 a 4,29; 2 en escala ACB: OR 2,71; IC del 95%: 2,01 a 3,56; 3 en escala ACB: OR 3,27; IC del 95%: 1,41 a 7,61); sin embargo, la evaluación global de la certeza de la evidencia con el método GRADE fue baja. CONCLUSIONES DE LOS AUTORES: Existe evidencia de certeza baja de que los adultos mayores sin deterioro cognitivo que toman fármacos con efectos anticolinérgicos podrían tener un mayor riesgo de deterioro cognitivo o demencia.