<div><h4>Intravascular imaging guided versus coronary angiography guided percutaneous coronary intervention: systematic review and meta-analysis.</h4><i>Khan SU, Agarwal S, Arshad HB, Akbar UA, ... Kleiman NS, Shah AR</i><br /><b>Objective</b><br />To assess the absolute treatment effects of intravascular imaging guided versus angiography guided percutaneous coronary intervention in patients with coronary artery disease, considering their baseline risk.<br /><b>Design</b><br />Systematic review and meta-analysis.<br /><b>Data sources</b><br />PubMed/Medline, Embase, and Cochrane Library databases up to 31 August 2023.<br /><b>Study selection</b><br />Randomized controlled trials comparing intravascular imaging (intravascular ultrasonography or optical coherence tomography) guided versus coronary angiography guided percutaneous coronary intervention in adults with coronary artery disease.<br /><b>Main outcome measures</b><br />Random effect meta-analysis and GRADE (grading of recommendations, assessment, development, and evaluation) were used to assess certainty of evidence. Data included rate ratios and absolute risks per 1000 people for cardiac death, myocardial infarction, stent thrombosis, target vessel revascularization, and target lesion revascularization. Absolute risk differences were estimated using SYNTAX risk categories for baseline risks at five years, assuming constant rate ratios across different cardiovascular risk thresholds.<br /><b>Results</b><br />In 20 randomized controlled trials (n=11 698), intravascular imaging guided percutaneous coronary intervention was associated with a reduced risk of cardiac death (rate ratio 0.53, 95% confidence interval 0.39 to 0.72), myocardial infarction (0.81, 0.68 to 0.97), stent thrombosis (0.44, 0.27 to 0.72), target vessel revascularization (0.74, 0.61 to 0.89), and target lesion revascularization (0.71, 0.59 to 0.86) but not all cause death (0.81, 0.64 to 1.02). Using SYNTAX risk categories, high certainty evidence showed that from low risk to high risk, intravascular imaging was likely associated with 23 to 64 fewer cardiac deaths, 15 to 19 fewer myocardial infarctions, 9 to 13 fewer stent thrombosis events, 28 to 38 fewer target vessel revascularization events, and 35 to 48 fewer target lesion revascularization events per 1000 people.<br /><b>Conclusions</b><br />Compared with coronary angiography guided percutaneous coronary intervention, intravascular imaging guided percutaneous coronary intervention was associated with significantly reduced cardiac death and cardiovascular outcomes in patients with coronary artery disease. The estimated absolute effects of intravascular imaging guided percutaneous coronary intervention showed a proportional relation with baseline risk, driven by the severity and complexity of coronary artery disease.<br /><b>Systematic review registration</b><br />PROSPERO CRD42023433568.<br /><br />© 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.<br /><br /><small>BMJ: 15 Nov 2023; 383:e077848</small></div>

<div><h4>Treatment of lower urinary tract symptoms in men in primary care using a conservative intervention: cluster randomised controlled trial.</h4><i>Drake MJ, Worthington J, Frost J, Sanderson E, ... Noble S, Lane JA</i><br /><b>Objective</b><br />To determine whether a standardised and manualised care intervention in men in primary care could achieve superior improvement of lower urinary tract symptoms (LUTS) compared with usual care.<br /><b>Design</b><br />Cluster randomised controlled trial.<br /><b>Setting</b><br />30 National Health Service general practice sites in England.<br /><b>Participants</b><br />Sites were randomised 1:1 to the intervention and control arms. 1077 men (≥18 years) with bothersome LUTS recruited between June 2018 and August 2019: 524 were assigned to the intervention arm (n=17 sites) and 553 were assigned to the usual care arm (n=13 sites).<br /><b>Intervention</b><br />Standardised information booklet developed with patient and expert input, providing guidance on conservative and lifestyle interventions for LUTS in men. After assessment of urinary symptoms (manualised element), general practice nurses and healthcare assistants or research nurses directed participants to relevant sections of the manual and provided contact over 12 weeks to assist with adherence.<br /><b>Main outcome measures</b><br />The primary outcome was patient reported International Prostate Symptom Score (IPSS) measured 12 months after participants had consented to take part in the study. The target reduction of 2.0 points on which the study was powered reflects the minimal clinically important difference where baseline IPSS is <20. Secondary outcomes were patient reported quality of life, urinary symptoms and perception of LUTS, hospital referrals, and adverse events. The primary intention-to-treat analysis included 887 participants (82% of those recruited) and used a mixed effects multilevel linear regression model adjusted for site level variables used in the randomisation and baseline scores.<br /><b>Results</b><br />Participants in the intervention arm had a lower mean IPSS at 12 months (adjusted mean difference -1.81 points, 95% confidence interval -2.66 to -0.95) indicating less severe urinary symptoms than those in the usual care arm. LUTS specific quality of life, incontinence, and perception of LUTS also improved more in the intervention arm than usual care arm at 12 months. The proportion of urology referrals (intervention 7.3%, usual care 7.9%) and adverse events (intervention seven events, usual care eight events) were comparable between the arms.<br /><b>Conclusions</b><br />A standardised and manualised intervention in primary care showed a sustained reduction in LUTS in men at 12 months. The mean difference of -1.81 points (95% confidence interval -0.95 to -2.66) on the IPSS was less than the predefined target reduction of 2.0 points.<br /><b>Trial registration</b><br />ISRCTN Registry ISRCTN11669964.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 14 Nov 2023; 383:e075219</small></div>

<div><h4>Early, intense therapy for language problems after a stroke is linked to the greatest benefits.</h4><i>Saul H, Cassidy S, Deeney B, Imison C, Brady M</i><br /><AbstractText>The studyBrady MC, Ali M, VandenBerg K, et al. Complex speech-language therapy interventions for stroke-related aphasia: the RELEASE study incorporating a systematic review and individual participant data network meta-analysis. <i>Health Social Care Delivery Res</i> 2022;10.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/therapy-for-language-problems-after-a-stroke-is-most-effective-when-given-early-and-intensively/.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 13 Nov 2023; 383:2560</small></div>

<div><h4>Autism intervention meta-analysis of early childhood studies (Project AIM): updated systematic review and secondary analysis.</h4><i>Sandbank M, Bottema-Beutel K, Crowley LaPoint S, Feldman JI, ... Albarran S, Woynaroski T</i><br /><b>Objective</b><br />To summarize the breadth and quality of evidence supporting commonly recommended early childhood autism interventions and their estimated effects on developmental outcomes.<br /><b>Design</b><br />Updated systematic review and meta-analysis (autism intervention meta-analysis; Project AIM).<br /><b>Data sources</b><br />A search was conducted in November 2021 (updating a search done in November 2017) of the following databases and registers: Academic Search Complete, CINAHL Plus with full text, Education Source, Educational Administration Abstracts, ERIC, Medline, ProQuest Dissertations and Theses, PsycINFO, Psychology and Behavioral Sciences Collection, and SocINDEX with full text, <i>Trials</i>, and ClinicalTrials.gov.<br /><b>Eligibility criteria for selecting studies</b><br />Any controlled group study testing the effects of any non-pharmacological intervention on any outcome in young autistic children younger than 8 years.<br /><b>Review methods</b><br />Newly identified studies were integrated into the previous dataset and were coded for participant, intervention, and outcome characteristics. Interventions were categorized by type of approach (such as behavioral, developmental, naturalistic developmental behavioral intervention, and technology based), and outcomes were categorized by domain (such as social communication, adaptive behavior, play, and language). Risks of bias were evaluated following guidance from Cochrane. Effects were estimated for all intervention and outcome types with sufficient contributing data, stratified by risk of bias, using robust variance estimation to account for intercorrelation of effects within studies and subgroups.<br /><b>Results</b><br />The search yielded 289 reports of 252 studies, representing 13 304 participants and effects for 3291 outcomes. When contributing effects were restricted to those from randomized controlled trials, significant summary effects were estimated for behavioral interventions on social emotional or challenging behavior outcomes (Hedges\' g=0.58, 95% confidence interval 0.11 to 1.06; P=0.02), developmental interventions on social communication (0.28, 0.12 to 0.44; P=0.003); naturalistic developmental behavioral interventions on adaptive behavior (0.23, 0.02 to 0.43; P=0.03), language (0.16, 0.01 to 0.31; P=0.04), play (0.19, 0.02 to 0.36; P=0.03), social communication (0.35, 0.23 to 0.47; P<0.001), and measures of diagnostic characteristics of autism (0.38, 0.17 to 0.59; P=0.002); and technology based interventions on social communication (0.33, 0.02 to 0.64; P=0.04) and social emotional or challenging behavior outcomes (0.57, 0.04 to 1.09; P=0.04). When effects were further restricted to exclude caregiver or teacher report outcomes, significant effects were estimated only for developmental interventions on social communication (0.31, 0.13 to 0.49; P=0.003) and naturalistic developmental behavioral interventions on social communication (0.36, 0.23 to 0.49; P<0.001) and measures of diagnostic characteristics of autism (0.44, 0.20 to 0.68; P=0.002). When effects were then restricted to exclude those at high risk of detection bias, only one significant summary effect was estimated-naturalistic developmental behavioral interventions on measures of diagnostic characteristics of autism (0.30, 0.03 to 0.57; P=0.03). Adverse events were poorly monitored, but possibly common.<br /><b>Conclusion</b><br />The available evidence on interventions to support young autistic children has approximately doubled in four years. Some evidence from randomized controlled trials shows that behavioral interventions improve caregiver perception of challenging behavior and child social emotional functioning, and that technology based interventions support proximal improvements in specific social communication and social emotional skills. Evidence also shows that developmental interventions improve social communication in interactions with caregivers, and naturalistic developmental behavioral interventions improve core challenges associated with autism, particularly difficulties with social communication. However, potential benefits of these interventions cannot be weighed against the potential for adverse effects owing to inadequate monitoring and reporting.<br /><br />© 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.<br /><br /><small>BMJ: 13 Nov 2023; 383:e076733</small></div>

<div><h4>Effectiveness of the live zoster vaccine during the 10 years following vaccination: real world cohort study using electronic health records.</h4><i>Klein NP, Bartlett J, Fireman B, Marks MA, ... Aukes L, Saddier P</i><br /><b>Objectives</b><br />To assess the effectiveness of live zoster vaccine during more than 10 years after vaccination; and to describe methods for ascertaining vaccine effectiveness in the context of waning.<br /><b>Design</b><br />Real world cohort study using electronic health records.<br /><b>Setting</b><br />Kaiser Permanente Northern California, an integrated healthcare delivery system in the US, 1 January 2007 to 31 December 2018.<br /><b>Population</b><br />More than 1.5 million people aged 50 years and older followed for almost 9.4 million person years.<br /><b>Main outcome measure</b><br />Vaccine effectiveness in preventing herpes zoster, postherpetic neuralgia, herpes zoster ophthalmicus, and admission to hospital for herpes zoster was assessed. Change in vaccine effectiveness by time since vaccination was examined using Cox regression with a calendar timeline. Time varying indicators were specified for each interval of time since vaccination (30 days to less than one year, one to less than two years, etc) and adjusted for covariates.<br /><b>Results</b><br />Of 1 505 647 people, 507 444 (34%) were vaccinated with live zoster vaccine. Among 75 135 incident herpes zoster cases, 4982 (7%) developed postherpetic neuralgia, 4439 (6%) had herpes zoster ophthalmicus, and 556 (0.7%) were admitted to hospital for herpes zoster. For each outcome, vaccine effectiveness was highest in the first year after vaccination and decreased substantially over time. Against herpes zoster, vaccine effectiveness waned from 67% (95% confidence interval 65% to 69%) in the first year to 15% (5% to 24%) after 10 years. Against postherpetic neuralgia, vaccine effectiveness waned from 83% (78% to 87%) to 41% (17% to 59%) after 10 years. Against herpes zoster ophthalmicus, vaccine effectiveness waned from 71% (63% to 76%) to 29% (18% to 39%) during five to less than eight years. Against admission to hospital for herpes zoster, vaccine effectiveness waned from 90% (67% to 97%) to 53% (25% to 70%) during five to less than eight years. Across all follow-up time, overall vaccine effectiveness was 46% (45% to 47%) against herpes zoster, 62% (59% to 65%) against postherpetic neuralgia, 45% (40% to 49%) against herpes zoster ophthalmicus, and 66% (55% to 74%) against admission to hospital for herpes zoster.<br /><b>Conclusions</b><br />Live zoster vaccine was effective initially. Vaccine effectiveness waned substantially yet some protection remained 10 years after vaccination. After 10 years, protection was low against herpes zoster but higher against postherpetic neuralgia.<br /><b>Trial registration</b><br />ClinicalTrials.gov number NCT01600079; EU PAS register number EUPAS17502.<br /><br />© 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.<br /><br /><small>BMJ: 07 Nov 2023; 383:e076321</small></div>

<div><h4>Weight regain does not eliminate the long term benefits of weight management programmes.</h4><i>Saul H, Deeney B, Kwint J, Aveyard P</i><br /><AbstractText>The studyHartmann-Boyce J, Theodoulou A, Oke JL, et al. Long term effect of weight regain following behavioral weight management programs on cardiometabolic disease incidence and risk: systematic review and meta-analysis. <i>Circ Cardiovasc Qual Outcomes</i> 2023;16:263-76.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/weight-regain-does-not-eliminate-the-long-term-benefits-of-weight-management-programmes/#:~:text=Study%20author&text=Many%20people%20believe%20that%20if,been%20the%20case%20without%20it.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 06 Nov 2023; 383:2403</small></div>

<div><h4>Effects of a multimodal intervention in primary care to reduce second line antibiotic prescriptions for urinary tract infections in women: parallel, cluster randomised, controlled trial.</h4><i>Schmiemann G, Greser A, Maun A, Bleidorn J, ... Heuschmann P, Gágyor I</i><br /><b>Objectives</b><br />To evaluate whether a multimodal intervention in general practice reduces the proportion of second line antibiotic prescriptions and the overall proportion of antibiotic prescriptions for uncomplicated urinary tract infections in women.<br /><b>Design</b><br />Parallel, cluster randomised, controlled trial.<br /><b>Setting</b><br />General practices in five regions in Germany. Data were collected between 1 April 2021 and 31 March 2022.<br /><b>Participants</b><br />General practitioners from 128 randomly assigned practices.<br /><b>Interventions</b><br />Multimodal intervention consisting of guideline recommendations for general practitioners and patients, provision of regional data for antibiotic resistance, and quarterly feedback, which included individual first line and second line proportions of antibiotic prescribing, benchmarking with regional or supra-regional practices, and telephone counselling. Participants in the control group received no information on the intervention.<br /><b>Main outcome measures</b><br />Primary outcome was the proportion of second line antibiotics prescribed by general practices, in relation to all antibiotics prescribed, for uncomplicated urinary tract infections after one year between the intervention and control group. General practices were randomly assigned in blocks (1:1), with a block size of four, into the intervention or control group using SAS version 9.4; randomisation was stratified by region. The secondary outcome was the prescription proportion of all antibiotics, relative within all cases (instances of UTI diagnosis), for the treatment of urinary tract infections after one year between the groups. Adverse events were assessed as exploratory outcomes.<br /><b>Results</b><br />110 practices with full datasets identified 10 323 cases during five quarters (ie, 15 months). The mean proportion of second line antibiotics prescribed was 0.19 (standard deviation 0.20) in the intervention group and 0.35 (0.25) in the control group after 12 months. After adjustment for preintervention proportions, the mean difference was -0.13 (95% confidence interval -0.21 to -0.06, P<0.001). The overall proportion of all antibiotic prescriptions for urinary tract infections over 12 months was 0.74 (standard deviation 0.22) in the intervention and 0.80 (0.15) in the control group with a mean difference of -0.08 (95% confidence interval -0.15 to -0.02, P<0.029). No differences were noted in the number of complications (ie, pyelonephritis, admission to hospital, or fever) between the groups.<br /><b>Conclusions</b><br />The multimodal intervention in general practice significantly reduced the proportion of second line antibiotics and all antibiotic prescriptions for uncomplicated urinary tract infections in women.<br /><b>Trial registration</b><br />German Clinical Trials Register (DRKS), DRKS00020389.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 02 Nov 2023; 383:e076305</small></div>

<div><h4>Pyrotinib versus placebo in combination with trastuzumab and docetaxel as first line treatment in patients with HER2 positive metastatic breast cancer (PHILA): randomised, double blind, multicentre, phase 3 trial.</h4><i>Ma F, Yan M, Li W, Ouyang Q, ... Xu B, PHILA Investigators</i><br /><b>Objective</b><br />To assess the efficacy and safety of pyrotinib (an irreversible pan-HER (human epidermal growth factor receptor) inhibitor), trastuzumab, and docetaxel compared with placebo, trastuzumab, and docetaxel for untreated HER2 positive metastatic breast cancer.<br /><b>Design</b><br />Randomised, double blind, placebo controlled, multicentre, phase 3 trial.<br /><b>Setting</b><br />40 centres in China between 6 May 2019 and 17 January 2022.<br /><b>Participants</b><br />590 female patients (median age 52 (interquartile range 46-58) years) with untreated HER2 positive metastatic breast cancer.<br /><b>Interventions</b><br />Eligible patients were randomised 1:1 to receive either oral pyrotinib (400 mg once daily) or placebo, both combined with intravenous trastuzumab (8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles) and docetaxel (75 mg/m<sup>2</sup>) on day 1 of each 21 day cycle. Randomisation was stratified by treatment history of trastuzumab in the (neo)adjuvant setting and hormone receptor status. Patients, investigators, and the sponsor\'s study team were masked to treatment assignment.<br /><b>Main outcome measures</b><br />The primary endpoint was progression-free survival as assessed by the investigator.<br /><b>Results</b><br />Of the 590 randomised patients, 297 received pyrotinib, trastuzumab, and docetaxel treatment (pyrotinib group), and 293 received placebo, trastuzumab, and docetaxel treatment (placebo group). At data cut-off on 25 May 2022, the median follow-up was 15.5 months. The median progression-free survival according to the investigator was significantly longer in the pyrotinib group than in the placebo group (24.3 (95% confidence interval 19.1 to 33.0) months versus 10.4 (9.3 to 12.3) months; hazard ratio 0.41 (95% confidence interval 0.32 to 0.53); one sided P<0.001). Treatment related adverse events of grade 3 or higher were reported in 267 (90%) of the 297 patients in the pyrotinib group and 224 (76%) of the 293 patients in the placebo group. No treatment related deaths occurred in the pyrotinib group, and one (<1%; diabetic hyperosmolar coma) treatment related death occurred in the placebo group. Survival and toxicities are still under assessment with longer follow-up.<br /><b>Conclusions</b><br />Pyrotinib, trastuzumab, and docetaxel showed superiority by significantly improving progression-free survival compared with placebo, trastuzumab, and docetaxel in patients with untreated HER2 positive metastatic breast cancer. The toxicity was manageable. The findings support this dual anti-HER2 regimen as an alternative first line treatment option in this patient population.<br /><b>Trial registration</b><br />ClinicalTrials.gov NCT03863223.<br /><br />© 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.<br /><br /><small>BMJ: 31 Oct 2023; 383:e076065</small></div>

<div><h4>Association of DCIS size and margin status with risk of developing breast cancer post-treatment: multinational, pooled cohort study.</h4><i>Schmitz RSJM, van den Belt-Dusebout AW, Clements K, Ren Y, ... Schmidt MK, Grand Challenge PRECISION consortium</i><br /><b>Objective</b><br />To examine the association between size and margin status of ductal carcinoma in situ (DCIS) and risk of developing ipsilateral invasive breast cancer and ipsilateral DCIS after treatment, and stage and subtype of ipsilateral invasive breast cancer.<br /><b>Design</b><br />Multinational, pooled cohort study.<br /><b>Setting</b><br />Four large international cohorts.<br /><b>Participants</b><br />Patient level data on 47 695 women with a diagnosis of pure, primary DCIS between 1999 and 2017 in the Netherlands, UK, and US who underwent surgery, either breast conserving or mastectomy, often followed by radiotherapy or endocrine treatment, or both.<br /><b>Main outcome measures</b><br />The main outcomes were 10 year cumulative incidence of ipsilateral invasive breast cancer and ipsilateral DCIS estimated in relation to DCIS size and margin status, and adjusted hazard ratios and 95% confidence intervals, estimated using multivariable Cox proportional hazards analyses with multiple imputed data <br /><b>Results:</b><br/>The 10 year cumulative incidence of ipsilateral invasive breast cancer was 3.2%. In women who underwent breast conserving surgery with or without radiotherapy, only adjusted risks for ipsilateral DCIS were significantly increased for larger DCIS (20-49 mm) compared with DCIS <20 mm (hazard ratio 1.38, 95% confidence interval 1.11 to 1.72). Risks for both ipsilateral invasive breast cancer and ipsilateral DCIS were significantly higher with involved compared with clear margins (invasive breast cancer 1.40, 1.07 to 1.83; DCIS 1.39, 1.04 to 1.87). Use of adjuvant endocrine treatment was not significantly associated with a lower risk of ipsilateral invasive breast cancer compared to treatment with breast conserving surgery only (0.86, 0.62 to 1.21). In women who received breast conserving treatment with or without radiotherapy, higher DCIS grade was not significantly associated with ipsilateral invasive breast cancer, only with a higher risk of ipsilateral DCIS (grade 1: 1.42, 1.08 to 1.87; grade 3: 2.17, 1.66 to 2.83). Higher age at diagnosis was associated with lower risk (per year) of ipsilateral DCIS (0.98, 0.97 to 0.99) but not ipsilateral invasive breast cancer (1.00, 0.99 to 1.00). Women with large DCIS (≥50 mm) more often developed stage III and IV ipsilateral invasive breast cancer compared to women with DCIS <20 mm. No such association was found between involved margins and higher stage of ipsilateral invasive breast cancer. Associations between larger DCIS and hormone receptor negative and human epidermal growth factor receptor 2 positive ipsilateral invasive breast cancer and involved margins and hormone receptor negative ipsilateral invasive breast cancer were found.<br /><b>Conclusions</b><br />The association of DCIS size and margin status with ipsilateral invasive breast cancer and ipsilateral DCIS was small. When these two factors were added to other known risk factors in multivariable models, clinicopathological risk factors alone were found to be limited in discriminating between low and high risk DCIS.<br /><br />© 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.<br /><br /><small>BMJ: 30 Oct 2023; 383:e076022</small></div>

<div><h4>Advances in molecular pathology, diagnosis, and treatment of amyotrophic lateral sclerosis.</h4><i>Ilieva H, Vullaganti M, Kwan J</i><br /><AbstractText>Although the past two decades have produced exciting discoveries in the genetics and pathology of amyotrophic lateral sclerosis (ALS), progress in developing an effective therapy remains slow. This review summarizes the critical discoveries and outlines the advances in disease characterization, diagnosis, imaging, and biomarkers, along with the current status of approaches to ALS care and treatment. Additional knowledge of the factors driving disease progression and heterogeneity will hopefully soon transform the care for patients with ALS into an individualized, multi-prong approach able to prevent disease progression sufficiently to allow for a dignified life with limited disability.</AbstractText><br /><br />© 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.<br /><br /><small>BMJ: 27 Oct 2023; 383:e075037</small></div>

<div><h4>Advances in the management of systemic lupus erythematosus.</h4><i>Morand EF, Fernandez-Ruiz R, Blazer A, Niewold TB</i><br /><AbstractText>Systemic lupus erythematosus (SLE) is a severe multisystem autoimmune disease that can cause injury in almost every body system. While considered a classic example of autoimmunity, it is still relatively poorly understood. Treatment with immunosuppressive agents is challenging, as many agents are relatively non-specific, and the underlying disease is characterized by unpredictable flares and remissions. This State of The Art Review provides a comprehensive current summary of systemic lupus erythematosus based on recent literature. In basic and translational science, this summary includes the current state of genetics, epigenetics, differences by ancestry, and updates about the molecular and immunological pathogenesis of systemic lupus erythematosus. In clinical science, the summary includes updates in diagnosis and classification, clinical features and subphenotypes, and current guidelines and strategies for treatment. The paper also provides a comprehensive review of the large number of recent clinical trials in systemic lupus erythematosus. Current knowns and unknowns are presented, and potential directions for the future are suggested. Improved knowledge of immunological pathogenesis and the molecular differences that exist between patients should help to personalize treatment, minimize side effects, and achieve better outcomes in this difficult disease.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 26 Oct 2023; 383:e073980</small></div>

<div><h4>Pharmaceutical industry payments and delivery of non-recommended and low value cancer drugs: population based cohort study.</h4><i>Mitchell AP, Dusetzina SB, Mishra Meza A, Trivedi NU, Bach PB, Winn AN</i><br /><b>Objective</b><br />To estimate the association between oncologists\' receipt of payments from the pharmaceutical industry and delivery of non-recommended or low value interventions among their patients.<br /><b>Design</b><br />Cohort study.<br /><b>Setting</b><br />Fee-for-service Medicare claims.<br /><b>Participants</b><br />Medicare beneficiaries with a diagnosis of incident cancer (new occurrence of a cancer diagnosis code in proximity to claims for cancer treatment, and no such diagnosis codes during a ≥1 year washout period) during 2014-19, who met additional requirements identifying them as at risk for one of four non-recommended or low value interventions: denosumab for castration sensitive prostate cancer, granulocyte colony stimulating factors (GCSF) for patients at low risk for neutropenic fever, nab-paclitaxel for cancers with no evidence of superiority over paclitaxel, and a branded drug in settings where a generic or biosimilar version was available.<br /><b>Main outcome measures</b><br />Receipt of the non-recommended or low value drug for which the patient was at risk. The primary association of interest was the assigned oncologist\'s receipt of any general payments from the manufacturer of the corresponding non-recommended or low value drug (measured in Open Payments) within 365 days before the patient\'s index cancer date. The two modeling approaches used were general linear model controlling for patients\' characteristics and calendar year, and general linear model with physician level indicator variables.<br /><b>Results</b><br />Oncologists were in receipt of industry payments for 2962 of 9799 patients (30.2%) at risk for non-recommended denosumab (median $63), 76 747 of 271 485 patients (28.3%) at risk for GCSF (median $60); 18 491 of 86 394 patients (21.4%) at risk for nab-paclitaxel (median $89), and 4170 of 13 386 patients (31.2%) at risk for branded drugs (median $156). The unadjusted proportion of patients who received non-recommended denosumab was 31.4% for those whose oncologist had not received payment and 49.5% for those whose oncologist had (prevalence difference 18.0%); the corresponding values for GCSF were 26.6% <i>v</i> 32.1% (5.5%), for nab-paclitaxel were 7.3% <i>v</i> 15.1% (7.8%), and for branded drugs were 88.3% <i>v</i> 83.5% (-4.8%). Controlling for patients\' characteristics and calendar year, payments from industry were associated with increased use of denosumab (17.5% (95% confidence interval 15.3% to 19.7%)), GCSF (5.8% (5.4% to 6.1%)), and nab-paclitaxel (7.6% (7.1% to 8.1%)), but lower use of branded drugs (-4.6% (-5.8% to -3.3%)). In physician level indicator models, payments from industry were associated with increased use of denosumab (7.4% (2.5% to 12.2%)) and nab-paclitaxel (1.7% (0.9% to 2.5%)), but not with GCSF (0.4% (-0.3% to 1.1%)) or branded drugs (1.2% (-6.0 to 8.5%)).<br /><b>Conclusions</b><br />Within some clinical scenarios, industry payments to physicians are associated with non-recommended and low value drugs. These findings raise quality of care concerns about the financial relationships between physicians and industry.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 25 Oct 2023; 383:e075512</small></div>

<div><h4>Racial differences in low value care among older adult Medicare patients in US health systems: retrospective cohort study.</h4><i>Ganguli I, Mackwood MB, Yang CW, Crawford M, ... Fisher ES, Morden NE</i><br /><b>Objective</b><br />To characterize racial differences in receipt of low value care (services that provide little to no benefit yet have potential for harm) among older Medicare beneficiaries overall and within health systems in the United States.<br /><b>Design</b><br />Retrospective cohort study <br /><b>Setting:</b><br/>100% Medicare fee-for-service administrative data (2016-18).<br /><b>Participants</b><br />Black and White Medicare patients aged 65 or older as of 2016 and attributed to 595 health systems in the United States.<br /><b>Main outcome measures</b><br />Receipt of 40 low value services among Black and White patients, with and without adjustment for patient age, sex, and previous healthcare use. Additional models included health system fixed effects to assess racial differences within health systems and separately, racial composition of the health system\'s population to assess the relative contributions of individual patient race and health system racial composition to low value care receipt.<br /><b>Results</b><br />The cohort included 9 833 304 patients (6.8% Black; 57.9% female). Of 40 low value services examined, Black patients had higher adjusted receipt of nine services and lower receipt of 20 services than White patients. Specifically, Black patients were more likely to receive low value acute diagnostic tests, including imaging for uncomplicated headache (6.9% <i>v</i> 3.2%) and head computed tomography scans for dizziness (3.1% <i>v</i> 1.9%). White patients had higher rates of low value screening tests and treatments, including preoperative laboratory tests (10.3% <i>v</i> 6.5%), prostate specific antigen tests (31.0% <i>v</i> 25.7%), and antibiotics for upper respiratory infections (36.6% <i>v</i> 32.7%; all P<0.001). Secondary analyses showed that these differences persisted within given health systems and were not explained by Black and White patients receiving care from different systems.<br /><b>Conclusions</b><br />Black patients were more likely to receive low value acute diagnostic tests and White patients were more likely to receive low value screening tests and treatments. Differences were generally small and were largely due to differential care within health systems. These patterns suggest potential individual, interpersonal, and structural factors that researchers, policy makers, and health system leaders might investigate and address to improve care quality and equity.<br /><br />© 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.<br /><br /><small>BMJ: 25 Oct 2023; 383:e074908</small></div>

<div><h4>Enhancing reporting quality and impact of early phase dose-finding clinical trials: CONSORT Dose-finding Extension (CONSORT-DEFINE) guidance.</h4><i>Yap C, Solovyeva O, de Bono J, Rekowski J, ... Dimairo M, Weir CJ</i><br /><AbstractText>The CONSORT (CONsolidated Standards Of Reporting Trials) 2010 statement is the standard guideline for reporting completed randomised trials. The CONSORT Dose-finding Extension (DEFINE) extends the guidance (with 21 new items and 19 modified items) to early phase dose-finding trials with interim dose escalation or de-escalation strategies. Such trials generally focus on safety, tolerability, activity, and recommending dosing and scheduling regimens for further clinical development. These trials are often inadequately reported, hampering their informativeness and making evidence informed decisions difficult. The CONSORT-DEFINE guidance aims to develop an international, consensus driven guideline for reporting early phase dose-finding trials to promote transparency, completeness, reproducibility, and facilitate the interpretation of the results. The CONSORT-DEFINE guidance provides recommendations for essential items that should be reported in early phase dose-finding trials to promote greater clarity, reproducibility, informativeness, and usefulness of results.</AbstractText><br /><br /><br /><br /><small>BMJ: 20 Oct 2023; 383:e076387</small></div>

<div><h4>Clinical effectiveness of septoplasty versus medical management for nasal airways obstruction: multicentre, open label, randomised controlled trial.</h4><i>Carrie S, O\'Hara J, Fouweather T, Homer T, ... Wilson JA, Teare MD</i><br /><b>Objective</b><br />To assess the clinical effectiveness of septoplasty.<br /><b>Design</b><br />Multicentre, randomised controlled trial.<br /><b>Setting</b><br />17 otolaryngology clinics in the UK\'s National Health Service.<br /><b>Participants</b><br />378 adults (≥18 years, 67% men) newly referred with symptoms of nasal obstruction associated with septal deviation and at least moderate symptoms of nasal obstruction (score >30 on the Nasal Obstruction and Symptom Evaluation (NOSE) scale).<br /><b>Interventions</b><br />Participants were randomised 1:1 to receive either septoplasty (n=188) or defined medical management (n=190, nasal steroid and saline spray for six months), stratified by baseline symptom severity and sex.<br /><b>Main outcome measures</b><br />The primary outcome measure was patient reported score on the Sino-Nasal Outcome Test-22 (SNOT-22) at six months, with 9 points defined as the minimal clinically important difference. Secondary outcomes included quality of life and objective nasal airflow measures.<br /><b>Results</b><br />Mean SNOT-22 scores at six months were 19.9 (95% confidence interval 17.0 to 22.7) in the septoplasty arm (n=152, intention-to-treat population) and 39.5 (36.1 to 42.9) in the medical management arm (n=155); an estimated 20.0 points lower (better) for participants randomised to receive septoplasty (95% confidence interval 16.4 to 23.6, P<0.001, adjusted for baseline continuous SNOT-22 score and the stratification variables sex and baseline NOSE severity categories). Greater improvement in SNOT-22 scores was predicted by higher baseline symptom severity scores. Quality of life outcomes and nasal airflow measures (including peak nasal inspiratory flow and absolute inhalational nasal partitioning ratio) improved more in participants in the septoplasty group. Readmission to hospital with bleeding after septoplasty occurred in seven participants (4% of 174 who had septoplasty), and a further 20 participants (12%) required antibiotics for infections.<br /><b>Conclusions</b><br />Septoplasty is a more effective intervention than a defined medical management regimen with a nasal steroid and saline spray in adults with nasal obstruction associated with a deviated nasal septum.<br /><b>Trial registration</b><br />ISRCTN Registry ISRCTN16168569.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 18 Oct 2023; 383:e075445</small></div>

<div><h4>Rosuvastatin versus atorvastatin treatment in adults with coronary artery disease: secondary analysis of the randomised LODESTAR trial.</h4><i>Lee YJ, Hong SJ, Kang WC, Hong BK, ... Hong MK, LODESTAR investigators</i><br /><b>Objective</b><br />To compare the long term efficacy and safety of rosuvastatin with atorvastatin treatment in adults with coronary artery disease.<br /><b>Design</b><br />Randomised, open label, multicentre trial.<br /><b>Setting</b><br />12 hospitals in South Korea, September 2016 to November 2019.<br /><b>Participants</b><br />4400 adults (age ≥19 years) with coronary artery disease.<br /><b>Interventions</b><br />Participants were assigned to receive either rosuvastatin (n=2204) or atorvastatin (n=2196) using 2×2 factorial randomisation.<br /><b>Main outcome measures</b><br />The primary outcome was a three year composite of all cause death, myocardial infarction, stroke, or any coronary revascularisation. Secondary outcomes were safety endpoints: new onset diabetes mellitus; hospital admissions due to heart failure; deep vein thrombosis or pulmonary thromboembolism; endovascular revascularisation for peripheral artery disease; aortic intervention or surgery; end stage kidney disease; discontinuation of study drugs owing to intolerance; cataract surgery; and a composite of laboratory detected abnormalities.<br /><b>Results</b><br />4341 of the 4400 participants (98.7%) completed the trial. Mean daily dose of study drugs was 17.1 mg (standard deviation (SD) 5.2 mg) in the rosuvastatin group and 36.0 (12.8) mg in the atorvastatin group at three years (P<0.001). The primary outcome occurred in 189 participants (8.7%) in the rosuvastatin group and 178 (8.2%) in the atorvastatin group (hazard ratio 1.06, 95% confidence interval 0.86 to 1.30; P=0.58). The mean low density lipoprotein (LDL) cholesterol level during treatment was 1.8 mmol/L (SD 0.5 mmol/L) in the rosuvastatin group and 1.9 (0.5) mmol/L in the atorvastatin group (P<0.001). The rosuvastatin group had a higher incidence of new onset diabetes mellitus requiring initiation of antidiabetics (7.2% <i>v</i> 5.3%; hazard ratio 1.39, 95% confidence interval 1.03 to 1.87; P=0.03) and cataract surgery (2.5% <i>v</i> 1.5%; 1.66, 1.07 to 2.58; P=0.02). Other safety endpoints did not differ between the two groups.<br /><b>Conclusions</b><br />In adults with coronary artery disease, rosuvastatin and atorvastatin showed comparable efficacy for the composite outcome of all cause death, myocardial infarction, stroke, or any coronary revascularisation at three years. Rosuvastatin was associated with lower LDL cholesterol levels but a higher risk of new onset diabetes mellitus requiring antidiabetics and cataract surgery compared with atorvastatin.<br /><b>Trial registration</b><br />ClinicalTrials.gov NCT02579499.<br /><br />© 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.<br /><br /><small>BMJ: 18 Oct 2023; 383:e075837</small></div>

<div><h4>What are the chances of having a second epileptic seizure?</h4><i>Saul H, Deeney B, Cassidy S, Neligan A</i><br /><AbstractText>The studyNeligan A, Adan G, Nevitt SJ, et al. Prognosis of adults and children following a first unprovoked seizure. <i>Cochrane Database Syst Rev</i> 2023;1:1-75.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/epilepsy-what-are-the-chances-of-having-a-second-seizure/.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 13 Oct 2023; 383:p2285</small></div>

<div><h4>Ultrasound guided lavage with corticosteroid injection versus sham lavage with and without corticosteroid injection for calcific tendinopathy of shoulder: randomised double blinded multi-arm study.</h4><i>Moosmayer S, Ekeberg OM, Hallgren HB, Heier I, ... Pripp AH, Brox JI</i><br /><b>Objective</b><br />To compare treatment effects between ultrasound guided lavage with corticosteroid injection and sham lavage with and without corticosteroid injection in patients with calcific tendinopathy of the shoulder.<br /><b>Design</b><br />Pragmatic, three arm, parallel group, double blinded, sham controlled, randomised, superiority trial with repeated measurements over 24 months.<br /><b>Setting</b><br />Six hospitals in Norway and Sweden.<br /><b>Participants</b><br />220 adults with calcific tendinopathy of the shoulder, persistent for at least three months.<br /><b>Interventions</b><br />Ultrasound guided deposit lavage plus subacromial injection of 20 mg triamcinolone acetonide and 9 mL 1% lidocaine hydrochloride (lavage+steroid); sham lavage plus subacromial injection of 20 mg triamcinolone acetonide and 9 mL 1% lidocaine hydrochloride (sham lavage+steroid); or sham lavage plus subacromial injection of 10 mL 1% lidocaine hydrochloride (sham). All patients received a physiotherapeutic treatment regimen consisting of four home exercises.<br /><b>Main outcome measures</b><br />The primary outcome was the result on the 48 point scale (0=worst; 48=best) of the Oxford Shoulder Score (OSS) at four month follow-up. Secondary outcomes included measurements on the short form of the Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH) and of pain intensity up to 24 months. The influence of the size of the deposit at baseline and of the persistence or disappearance of the deposit was investigated.<br /><b>Results</b><br />Data from 218 (99%) participants were included in the primary analysis. Differences between groups on the OSS at four months were not significant: lavage+steroid versus sham 0.2 (95% confidence interval -2.3 to 2.8; P=1.0); sham lavage+steroid versus sham 2.0 (-0.5 to 4.6; P=0.35); lavage+steroid versus sham lavage+steroid -1.8 (-4.3 to 0.7; P=0.47). After four months, 143 patients with insufficient treatment effect received supplementary treatment. At 24 months, none of the study procedures was superior to sham. No serious adverse events were reported.<br /><b>Conclusions</b><br />This study found no benefit for ultrasound guided lavage with a corticosteroid injection or for sham lavage with a corticosteroid injection compared with sham treatment in patients with calcific rotator cuff tendinopathy of the shoulder.<br /><b>Trial registration</b><br />NCT02419040EudraCT 2015-002343-34; Ethical committee Norway 2015-002343-34; Ethical committee Sweden 2015/79-31; Clinicaltrials.gov NCT02419040.<br /><br />© 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.<br /><br /><small>BMJ: 11 Oct 2023; 383:e076447</small></div>

<div><h4>Nutrition could prevent or promote non-alcoholic fatty liver disease: an opportunity for intervention.</h4><i>Romero-Gómez M, Zelber-Sagi S, Martín F, Bugianesi E, Soria B</i><br /><AbstractText><b>Manuel Romero-Gómez and colleagues</b> discuss how diet and modifiable factors can help prevent of non-alcoholic fatty liver disease and the importance of engaging all society through awareness, education, and policy change</AbstractText><br /><br /><br /><br /><small>BMJ: 09 Oct 2023; 383:e075179</small></div>

<div><h4>Early versus delayed antihypertensive treatment in patients with acute ischaemic stroke: multicentre, open label, randomised, controlled trial.</h4><i>Liu L, Xie X, Pan Y, Wang A, ... He J, CATIS-2 Investigators</i><br /><b>Objectives</b><br />To compared the effect of early antihypertensive treatment started within 24-48 h of stroke onset versus delaying treatment until day eight on reducing dependency or death.<br /><b>Design</b><br />Multicentre, randomised, open label trial.<br /><b>Setting</b><br />106 hospitals in China between 13 June 2018 and 10 July 2022.<br /><b>Participants</b><br />4810 patients (≥40 years) were enrolled with acute ischaemic stroke within 24-48 h of symptom onset and elevated systolic blood pressure between 140 mm Hg and <220 mm Hg.<br /><b>Interventions</b><br />Patients were randomly assigned to receive antihypertensive treatment immediately after randomisation (aimed at reducing systolic blood pressure by 10%-20% within the first 24 h and a mean blood pressure <140/90 mm Hg within seven days) or to discontinue antihypertensive medications for seven days if they were taking them, and then receive treatment on day 8 (aimed at achieving mean blood pressure <140/90 mm Hg).<br /><b>Main outcome measures</b><br />The primary outcome was the combination of functional dependency or death (modified Rankin scale score ≥3) at 90 days. Intention to treat analyses were conducted.<br /><b>Results</b><br />2413 patients were assigned to the early treatment group and 2397 were assigned to the delayed treatment group. Mean systolic blood pressure was reduced by 9.7% (from 162.9 mm Hg to 146.4 mm Hg) in the early treatment group and by 4.9% (from 162.8 mm Hg to 154.3 mm Hg) in the delayed treatment group within 24 h after randomisation (P for group difference <0.001). Mean systolic blood pressure was 139.1 mm Hg in the early treatment group and 150.9 mm Hg in the delayed treatment group on day seven (P for group difference <0.001). Additionally, 54.6% of patients in the early treatment group and 22.4% in the delayed treatment group had blood pressure of less than 140/90 mm Hg (P<0.001 for group difference) on day seven. At day 90, 289 trial participants (12.0%) in the early treatment group, compared with 250 (10.5%) in the delayed treatment group, had died or experienced a dependency (odds ratio 1.18 (95% confidence interval 0.98 to 1.41), P=0.08). No significant differences in recurrent stroke or adverse events were reported between the two groups.<br /><b>Conclusions</b><br />Among patients with mild-to-moderate acute ischaemic stroke and systolic blood pressure between 140 mm Hg and <220 mm Hg who did not receive intravenous thrombolytic treatment, early antihypertensive treatment did not reduce the odds of dependency or death at 90 days.<br /><b>Trial registration</b><br />ClinicalTrials.gov Identifier NCT03479554.<br /><br />© 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.<br /><br /><small>BMJ: 09 Oct 2023; 383:e076448</small></div>

<div><h4>Interwoven challenges of covid-19, poor diet, and cardiometabolic health.</h4><i>Piernas C, Merino J</i><br /><AbstractText><b>Carmen Piernas</b> and <b>Jordi Merino</b> argue that suboptimal diet and poor metabolic health aggravated the covid-19 pandemic and require greater attention to increase population resilience and reduce health inequalities</AbstractText><br /><br /><br /><br /><small>BMJ: 09 Oct 2023; 383:e076810</small></div>

<div><h4>Ultra-processed foods and cardiometabolic health: public health policies to reduce consumption cannot wait.</h4><i>Touvier M, da Costa Louzada ML, Mozaffarian D, Baker P, Juul F, Srour B</i><br /><AbstractText>Incomplete understanding of the multiple mechanisms underlying the link between ultra-processed foods and cardiometabolic health should not be an excuse for inaction argue <b>Mathilde Touvier and colleagues</b></AbstractText><br /><br /><br /><br /><small>BMJ: 09 Oct 2023; 383:e075294</small></div>

<div><h4>Mortality risks associated with floods in 761 communities worldwide: time series study.</h4><i>Yang Z, Huang W, McKenzie JE, Xu R, ... Li S, MCC Collaborative Research Network</i><br /><b>Objective</b><br />To evaluate lag-response associations and effect modifications of exposure to floods with risks of all cause, cardiovascular, and respiratory mortality on a global scale.<br /><b>Design</b><br />Time series study.<br /><b>Setting</b><br />761 communities in 35 countries or territories with at least one flood event during the study period.<br /><b>Participants</b><br />Multi-Country Multi-City Collaborative Research Network database, Australian Cause of Death Unit Record File, New Zealand Integrated Data Infrastructure, and the International Network for the Demographic Evaluation of Populations and their Health Network database.<br /><b>Main outcome measures</b><br />The main outcome was daily counts of deaths. An estimation for the lag-response association between flood and daily mortality risk was modelled, and the relative risks over the lag period were cumulated to calculate overall effects. Attributable fractions of mortality due to floods were further calculated. A quasi-Poisson model with a distributed lag non-linear function was used to examine how daily death risk was associated with flooded days in each community, and then the community specific associations were pooled using random effects multivariate meta-analyses. Flooded days were defined as days from the start date to the end date of flood events.<br /><b>Results</b><br />A total of 47.6 million all cause deaths, 11.1 million cardiovascular deaths, and 4.9 million respiratory deaths were analysed. Over the 761 communities, mortality risks increased and persisted for up to 60 days (50 days for cardiovascular mortality) after a flooded day. The cumulative relative risks for all cause, cardiovascular, and respiratory mortality were 1.021 (95% confidence interval 1.006 to 1.036), 1.026 (1.005 to 1.047), and 1.049 (1.008 to 1.092), respectively. The associations varied across countries or territories and regions. The flood-mortality associations appeared to be modified by climate type and were stronger in low income countries and in populations with a low human development index or high proportion of older people. In communities impacted by flood, up to 0.10% of all cause deaths, 0.18% of cardiovascular deaths, and 0.41% of respiratory deaths were attributed to floods.<br /><b>Conclusions</b><br />This study found that the risks of all cause, cardiovascular, and respiratory mortality increased for up to 60 days after exposure to flood and the associations could vary by local climate type, socioeconomic status, and older age.<br /><br />© 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.<br /><br /><small>BMJ: 04 Oct 2023; 383:e075081</small></div>

<div><h4>Interactive effects of ambient fine particulate matter and ozone on daily mortality in 372 cities: two stage time series analysis.</h4><i>Liu C, Chen R, Sera F, Vicedo-Cabrera AM, ... Gasparrini A, Kan H</i><br /><b>Objective</b><br />To investigate potential interactive effects of fine particulate matter (PM<sub>2.5</sub>) and ozone (O<sub>3</sub>) on daily mortality at global level.<br /><b>Design</b><br />Two stage time series analysis.<br /><b>Setting</b><br />372 cities across 19 countries and regions.<br /><b>Population</b><br />Daily counts of deaths from all causes, cardiovascular disease, and respiratory disease.<br /><b>Main outcome measure</b><br />Daily mortality data during 1994-2020. Stratified analyses by co-pollutant exposures and synergy index (>1 denotes the combined effect of pollutants is greater than individual effects) were applied to explore the interaction between PM<sub>2.5</sub> and O<sub>3</sub> in association with mortality.<br /><b>Results</b><br />During the study period across the 372 cities, 19.3 million deaths were attributable to all causes, 5.3 million to cardiovascular disease, and 1.9 million to respiratory disease. The risk of total mortality for a 10 μg/m<sup>3</sup> increment in PM<sub>2.5</sub> (lag 0-1 days) ranged from 0.47% (95% confidence interval 0.26% to 0.67%) to 1.25% (1.02% to 1.48%) from the lowest to highest fourths of O<sub>3</sub> concentration; and for a 10 μg/m<sup>3</sup> increase in O<sub>3</sub> ranged from 0.04% (-0.09% to 0.16%) to 0.29% (0.18% to 0.39%) from the lowest to highest fourths of PM<sub>2.5</sub> concentration, with significant differences between strata (P for interaction <0.001). A significant synergistic interaction was also identified between PM<sub>2.5</sub> and O<sub>3</sub> for total mortality, with a synergy index of 1.93 (95% confidence interval 1.47 to 3.34). Subgroup analyses showed that interactions between PM<sub>2.5</sub> and O<sub>3</sub> on all three mortality endpoints were more prominent in high latitude regions and during cold seasons.<br /><b>Conclusion</b><br />The findings of this study suggest a synergistic effect of PM<sub>2.5</sub> and O<sub>3</sub> on total, cardiovascular, and respiratory mortality, indicating the benefit of coordinated control strategies for both pollutants.<br /><br />© 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.<br /><br /><small>BMJ: 04 Oct 2023; 383:e075203</small></div>

<div><h4>Association between changes in carbohydrate intake and long term weight changes: prospective cohort study.</h4><i>Wan Y, Tobias DK, Dennis KK, Guasch-Ferré M, ... Devinsky O, Willett WC</i><br /><b>Objective</b><br />To comprehensively examine the associations between changes in carbohydrate intake and weight change at four year intervals.<br /><b>Design</b><br />Prospective cohort study.<br /><b>Setting</b><br />Nurses\' Health Study (1986-2010), Nurses\' Health Study II (1991-2015), and Health Professionals Follow-Up Study (1986-2014).<br /><b>Participants</b><br />136 432 men and women aged 65 years or younger and free of diabetes, cancer, cardiovascular disease, respiratory disease, neurodegenerative disorders, gastric conditions, chronic kidney disease, and systemic lupus erythematosus before baseline.<br /><b>Main outcome measure</b><br />Weight change within a four year period.<br /><b>Results</b><br />The final analyses included 46 722 women in the Nurses\' Health Study, 67 186 women in the Nurses\' Health Study II, and 22 524 men in the Health Professionals Follow-up Study. On average, participants gained 1.5 kg (5th to 95th centile -6.8 to 10.0) every four years, amounting to 8.8 kg on average over 24 years. Among men and women, increases in glycemic index and glycemic load were positively associated with weight gain. For example, a 100 g/day increase in starch or added sugar was associated with 1.5 kg and 0.9 kg greater weight gain over four years, respectively, whereas a 10 g/day increase in fiber was associated with 0.8 kg less weight gain. Increased carbohydrate intake from whole grains (0.4 kg less weight gain per 100 g/day increase), fruit (1.6 kg less weight gain per 100 g/day increase), and non-starchy vegetables (3.0 kg less weight gain per 100 g/day increase) was inversely associated with weight gain, whereas increased intake from refined grains (0.8 kg more weight gain per 100 g/day increase) and starchy vegetables (peas, corn, and potatoes) (2.6 kg more weight gain per 100 g/day increase) was positively associated with weight gain. In substitution analyses, replacing refined grains, starchy vegetables, and sugar sweetened beverages with equal servings of whole grains, fruit, and non-starchy vegetables was associated with less weight gain. The magnitude of these associations was stronger among participants with overweight or obesity compared with those with normal weight (P<0.001 for interaction). Most of these associations were also stronger among women.<br /><b>Conclusions</b><br />The findings of this study highlight the potential importance of carbohydrate quality and source for long term weight management, especially for people with excessive body weight. Limiting added sugar, sugar sweetened beverages, refined grains, and starchy vegetables in favor of whole grains, fruit, and non-starchy vegetables may support efforts to control weight.<br /><br />© 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.<br /><br /><small>BMJ: 27 Sep 2023; 382:e073939</small></div>

<div><h4>Association between recently raised anticholinergic burden and risk of acute cardiovascular events: nationwide case-case-time-control study.</h4><i>Huang WC, Yang AS, Tsai DH, Shao SC, Lin SJ, Lai EC</i><br /><b>Objective</b><br />To evaluate the association between recently raised anticholinergic burden and risk of acute cardiovascular events in older adults.<br /><b>Design</b><br />Case-case-time-control study (ie, incorporating a case crossover design and a control crossover design consisting of future cases).<br /><b>Setting</b><br />Taiwan\'s National Health Insurance Research Database.<br /><b>Participants</b><br />317 446 adults aged ≥65 who were admitted to hospital because of an incident acute cardiovascular event between 2011 and 2018. Acute cardiovascular events included myocardial infarction, strokes, arrhythmias, conduction disorders, and cardiovascular death.<br /><b>Main outcome measures</b><br />The anticholinergic burden was measured for each participant by adding up the anticholinergic scores for individual drugs using the Anticholinergic Cognitive Burden Scale. Scores were classified into three levels (0 points, 1-2 points, and ≥3 points). For each participant, anticholinergic burden levels during hazard periods (day -1 to -30 before the cardiovascular event) were compared with randomly selected 30 day reference periods (ie, periods between days -61 and -180). Conditional logistic regression determined odds ratios with 95% confidence intervals to evaluate the association between acute cardiovascular events and recently raised anticholinergic burden.<br /><b>Results</b><br />The crossover analyses included 248 579 current cases. Participants\' average age on the index date was 78.4 years (standard deviation 0.01), and 53.4% were men. The most frequently prescribed drugs with anticholinergic activity were antihistamines (68.9%), gastrointestinal antispasmodics (40.9%), and diuretics (33.8%). Among patients with varying levels of anticholinergic burden in different periods, more patients carried higher levels of anticholinergic burden during hazard periods than during reference periods. For example, 17 603 current cases had 1-2 points of anticholinergic burden in the hazard period with 0 points in the reference period, while 8507 current cases had 0 points in the hazard period and 1-2 points in the reference period. In the comparison of 1-2 points versus 0 points of anticholinergic burden, the odds ratio was 1.86 (95% confidence interval 1.83 to 1.90) in the case crossover analysis and 1.35 (1.33 to 1.38) in the control crossover analysis, which yielded a case-case-time-control odds ratio of 1.38 (1.34 to 1.42). Similar results were found in the comparison of ≥3 versus 0 points (2.03, 1.98 to 2.09) and ≥3 versus 1-2 points (1.48, 1.44 to 1.52). The findings remained consistent throughout a series of sensitivity analyses (eg, cut-off points for anticholinergic burden categories were redefined and different scales were used to measure anticholinergic burden).<br /><b>Conclusions</b><br />An association was found between recently raised anticholinergic burden and increased risk of acute cardiovascular events. Furthermore, a greater increase in anticholinergic burden was associated with a higher risk of acute cardiovascular events.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 27 Sep 2023; 382:e076045</small></div>

<div><h4>Efficacy and safety of an inactivated virus-particle vaccine for SARS-CoV-2, BIV1-CovIran: randomised, placebo controlled, double blind, multicentre, phase 3 clinical trial.</h4><i>Mohraz M, Vahdat K, Ghamari SH, Abbasi-Kangevari M, ... Salehi M, Hosseini H</i><br /><b>Objective</b><br />To report the efficacy, safety, and exploratory immunogenicity findings of two 5 µg doses of the BIV1-CovIran vaccine.<br /><b>Design</b><br />Randomised, placebo controlled, double blind, multicentre, phase 3 clinical trial.<br /><b>Setting</b><br />In six cities of Iran, including Bushehr, Isfahan, Karaj, Mashhad, Shiraz, and Tehran. The first vaccine or placebo injection of the first participant was on 16 May 2021 in Tehran. The last vaccine or placebo injection of the last participant occurred on 15 July 2021 in Isfahan.<br /><b>Participants</b><br />20 000 participants aged 18-75 years were randomly assigned to the intervention or placebo groups with a ratio of 2:1.<br /><b>Intervention</b><br />5 µg vaccine or placebo with the interval of 28 days.<br /><b>Main outcome measures</b><br />Vaccine efficacy for a 90 day follow-up period, safety and explanatory immunogenicity assessment, and variant detection during the trial.<br /><b>Results</b><br />20 000 participants were recruited and randomly assigned to receive BIV1-CovIran (n=13 335 (66.7%)) or placebo (n=6665 (33.3%)). Participants\' mean age was 38.3 (standard deviation 11.2) years, and 6913 (34.6%) were female. Among vaccinated participants that had covid-19 reported during the follow-up (median 83 days), 758 (5.9%) had symptoms, 144 (1.1%) had severe infection, and seven (0.1%) were critical. Among participants who received placebo during the follow-up, 688 (10.7%) had symptoms, 221 (3.4%) had severe infection, and 19 (0.3%) were critical. Overall efficacy was 50.2% (95% confidence interval 44.7% to 55.0%) against symptomatic covid-19, 70.5% (63.7% to 76.1%) against severe disease, and 83.1% (61.2% to 93.5%) against critical cases. Two deaths were reported in the efficacy population in the placebo group, no deaths were from the intervention group. During follow-up, 41 922 adverse events were reported: 28 782 (68.7%) were adverse reactions, of which 19 363 (67.3%) were in the intervention group. Most adverse reactions were mild or moderate in severity (grade 1 or 2) and self-limiting. No serious adverse events were related to the injections. For variant investigation, of 119 participants positive for the SARS-CoV-2 variant, 106 (89.1%) were positive for the delta variant.<br /><b>Conclusions</b><br />A two dose regimen of the BIV1-CovIran vaccine conferred efficacy of 50.2% against symptomatic covid-19, 70.5% against severe disease, and 83.1% against critical disease. Vaccination was well tolerated, with no safety concerns raised.<br /><b>Trial registration</b><br />Iranian Registry of Clinical Trials, IRCT20201202049567N3.<br /><b>Funding</b><br />Shifa-Pharmed Industrial Group.<br /><br />© 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.<br /><br /><small>BMJ: 21 Sep 2023; 382:e070464</small></div>

<div><h4>Suboptimal gestational weight gain and neonatal outcomes in low and middle income countries: individual participant data meta-analysis.</h4><i>Perumal N, Wang D, Darling AM, Liu E, ... Fawzi WW, GWG Pooling Project Consortium</i><br /><b>Objective</b><br />To estimate the associations between gestational weight gain (GWG) during pregnancy and neonatal outcomes in low and middle income countries.<br /><b>Design</b><br />Individual participant data meta-analysis.<br /><b>Setting</b><br />Prospective pregnancy studies from 24 low and middle income countries.<br /><b>Main outcome measures</b><br />Nine neonatal outcomes related to timing (preterm birth) and anthropometry (weight, length, and head circumference) at birth, stillbirths, and neonatal death.<br /><b>Analysis methods</b><br />A systematic search was conducted in PubMed, Embase, and Web of Science which identified 53 prospective pregnancy studies published after the year 2000 with data on GWG, timing and anthropometry at birth, and neonatal mortality. GWG adequacy was defined as the ratio of the observed maternal weight gain over the recommended weight gain based on the Institute of Medicine body mass index specific guidelines, which are derived from data in high income settings, and the INTERGROWTH-21st GWG standards. Study specific estimates, adjusted for confounders, were generated and then pooled using random effects meta-analysis models. Maternal age and body mass index before pregnancy were examined as potential modifiers of the associations between GWG adequacy and neonatal outcomes.<br /><b>Results</b><br />Overall, 55% of participants had severely inadequate (<70%) or moderately inadequate (70% to <90%) GWG, 22% had adequate GWG (90-125%), and 23% had excessive GWG (≥125%). Severely inadequate GWG was associated with a higher risk of low birthweight (adjusted relative risk 1.62, 95% confidence interval 1.51 to 1.72; 48 studies, 93 337 participants; τ<sup>2</sup>=0.006), small for gestational age (1.44, 1.36 to 1.54; 51 studies, 93 191 participants; τ<sup>2</sup>=0.016), short for gestational age (1.47, 1.29 to 1.69; 40 studies, 83 827 participants; τ<sup>2</sup>=0.074), and microcephaly (1.57, 1.31 to 1.88; 31 studies, 80 046 participants; τ<sup>2</sup>=0.145) compared with adequate GWG. Excessive GWG was associated with a higher risk of preterm birth (1.22, 1.13 to 1.31; 48 studies, 103 762 participants; τ<sup>2</sup>=0.008), large for gestational age (1.44, 1.33 to 1.57; 47 studies, 90 044 participants; τ<sup>2</sup>=0.009), and macrosomia (1.52, 1.33 to 1.73; 29 studies, 68 138 participants; τ<sup>2</sup>=0) compared with adequate GWG. The direction and magnitude of the associations between GWG adequacy and several neonatal outcomes were modified by maternal age and body mass index before pregnancy.<br /><b>Conclusions</b><br />Inadequate and excessive GWG are associated with a higher risk of adverse neonatal outcomes across settings. Interventions to promote optimal GWG during pregnancy are likely to reduce the burden of adverse neonatal outcomes, however further research is needed to assess optimal ranges of GWG based on data from low and middle income countries.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 21 Sep 2023; 382:e072249</small></div>

<div><h4>Effect of invitation letter in language of origin on screening attendance: randomised controlled trial in BreastScreen Norway.</h4><i>Hofvind S, Iqbal N, Thy JE, Mangerud G, ... Zackrisson S, Berstad P</i><br /><b>Objective</b><br />To explore attendance at organised mammographic screening among immigrant groups that received an invitation letter and information leaflet (invitation) in their language of origin and Norwegian compared with Norwegian only.<br /><b>Design</b><br />Randomised controlled trial.<br /><b>Setting</b><br />Population based screening programme for breast cancer in Norway (BreastScreen Norway), which invites women aged 50-69 to two-view mammographic screening biennially.<br /><b>Participants</b><br />All women invited to BreastScreen Norway in the study period April 2021 to June 2022 whose language of origin was Arabic (women born in Algeria, Egypt, Lebanon, Iraq, Palestine, Sudan, Syria, Tunisia, or Morocco), English (women born in the Philippines), Polish (women born in Poland), Somali (women born in Somalia), or Urdu (women born in Pakistan) (n=11 347).<br /><b>Intervention</b><br />The study group received an invitation to screening in their language of origin and in Norwegian, whereas the control group received an invitation in Norwegian only during the study period.<br /><b>Main outcome measure</b><br />Attendance at BreastScreen Norway during the study period.<br /><b>Results</b><br />Overall attendance was 46.5% (2642/5683) in the study group and 47.4% (2682/5664) in the control group. No statistical differences in attendance were observed after stratification by language of invitation, age at invitation, or years since immigration.<br /><b>Conclusions</b><br />No difference in attendance was observed between immigrant women invited to BreastScreen Norway in their language of origin and in Norwegian compared with Norwegian only. Several barriers to cancer screening may exist among immigrants, and translating the invitation is probably only a part of a complex explanation.<br /><b>Trial registration</b><br />NCT04672265.<br /><b>Clinicaltrials</b><br />gov NCT04672265.<br /><br />© 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.<br /><br /><small>BMJ: 19 Sep 2023; 382:e075465</small></div>

<div><h4>Advances in the care of breast cancer survivors.</h4><i>Cathcart-Rake EJ, Tevaarwerk AJ, Haddad TC, D\'Andre SD, Ruddy KJ</i><br /><AbstractText>Breast cancer survivors may experience significant after effects from diagnoses of breast cancer and cancer directed therapies. This review synthesizes the evidence about optimal management of the sequelae of a diagnosis of breast cancer. It describes the side effects of chemotherapy and endocrine therapy and evidence based strategies for management of such effects, with particular attention to effects of therapies with curative intent. It includes strategies to promote health and wellness among breast cancer survivors, along with data to support the use of integrative oncology strategies. In addition, this review examines models of survivorship care and ways in which digital tools may facilitate communication between clinicians and patients. The strategies outlined in this review are paramount to supporting breast cancer survivors\' quality of life.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 18 Sep 2023; 382:e071565</small></div>

<div><h4>Provision of evaluation and management visits by nurse practitioners and physician assistants in the USA from 2013 to 2019: cross-sectional time series study.</h4><i>Patel SY, Auerbach D, Huskamp HA, Frakt A, ... Smith LB, Mehrotra A</i><br /><b>Objective</b><br />To examine the proportion of healthcare visits are delivered by nurse practitioners and physician assistants versus physicians and how this has changed over time and by clinical setting, diagnosis, and patient demographics.<br /><b>Design</b><br />Cross-sectional time series study.<br /><b>Setting</b><br />National data from the traditional Medicare insurance program in the USA.<br /><b>Participants</b><br />Of people using Medicare (ie, those older than 65 years, permanently disabled, and people with end stage renal disease), a 20% random sample was taken.<br /><b>Main outcome measures</b><br />The proportion of physician, nurse practitioner, and physician assistant visits in the outpatient and skilled nursing facility settings delivered by physicians, nurse practitioners, and physician assistants, and how this proportion varies by type of visit and diagnosis.<br /><b>Results</b><br />From 1 January 2013 to 31 December 2019, 276 million visits were included in the sample. The proportion of all visits delivered by nurse practitioners and physician assistants in a year increased from 14.0% (95% confidence interval 14.0% to 14.0%) to 25.6% (25.6% to 25.6%). In 2019, the proportion of visits delivered by a nurse practitioner or physician assistant varied across conditions, ranging from 13.2% for eye disorders and 20.4% for hypertension to 36.7% for anxiety disorders and 41.5% for respiratory infections. Among all patients with at least one visit in 2019, 41.9% had one or more nurse practitioner or physician assistant visits. Compared with patients who had no visits from a nurse practitioner or physician assistant, the likelihood of receiving any care was greatest among patients who were lower income (2.9% greater), rural residents (19.7%), and disabled (5.6%).<br /><b>Conclusion</b><br />The proportion of visits delivered by nurse practitioners and physician assistants in the USA is increasing rapidly and now accounts for a quarter of all healthcare visits.<br /><br />© 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.<br /><br /><small>BMJ: 14 Sep 2023; 382:e073933</small></div>

<div><h4>Non-erosive gastro-oesophageal reflux disease and incidence of oesophageal adenocarcinoma in three Nordic countries: population based cohort study.</h4><i>Holmberg D, Santoni G, von Euler-Chelpin M, Färkkilä M, ... Ness-Jensen E, Lagergren J</i><br /><b>Objective</b><br />To assess the incidence rate of oesophageal adenocarcinoma among patients with non-erosive gastro-oesophageal reflux disease compared with the general population.<br /><b>Design</b><br />Population based cohort study.<br /><b>Setting</b><br />All patients in hospital and specialised outpatient healthcare in Denmark, Finland, and Sweden from 1 January 1987 to 31 December 2019.<br /><b>Participants</b><br />486 556 adults (>18 years) who underwent endoscopy were eligible for inclusion: 285 811 patients were included in the non-erosive gastro-oesophageal reflux disease cohort and 200 745 patients in the validation cohort with erosive gastro-oesophageal reflux disease.<br /><b>Exposures</b><br />Non-erosive gastro-oesophageal reflux disease was defined by an absence of oesophagitis and any other oesophageal diagnosis at endoscopy. Erosive gastro-oesophageal reflux disease was examined for comparison reasons and was defined by the presence of oesophagitis at endoscopy.<br /><b>Main outcome measures</b><br />The incidence rate of oesophageal adenocarcinoma was assessed for up to 31 years of follow-up. Standardised incidence ratios with 95% confidence intervals were calculated by dividing the observed number of oesophageal adenocarcinomas in each of the gastro-oesophageal reflux disease cohorts by the expected number, derived from the general populations in Denmark, Finland, and Sweden of the corresponding age, sex, and calendar period.<br /><b>Results</b><br />Among 285 811 patients with non-erosive gastro-oesophageal reflux disease, 228 developed oesophageal adenocarcinomas during 2 081 051 person-years of follow-up. The incidence rate of oesophageal adenocarcinoma in patients with non-erosive gastro-oesophageal reflux disease was 11.0/100 000 person-years. The incidence was similar to that of the general population (standardised incidence ratio 1.04 (95% confidence interval 0.91 to 1.18)), and did not increase with longer follow-up (1.07 (0.65 to 1.65) for 15-31 years of follow-up). For validity reasons, we also analysed people with erosive oesophagitis at endoscopy (200 745 patients, 1 750 249 person-years, and 542 oesophageal adenocarcinomas, corresponding to an incidence rate of 31.0/100 000 person-years) showing an increased overall standardised incidence ratio of oesophageal adenocarcinoma (2.36 (2.17 to 2.57)), which became more pronounced with longer follow-up.<br /><b>Conclusions</b><br />Patients with non-erosive gastro-oesophageal reflux disease seem to have a similar incidence of oesophageal adenocarcinoma as the general population. This finding suggests that endoscopically confirmed non-erosive gastro-oesophageal reflux disease does not require additional endoscopic monitoring for oesophageal adenocarcinoma.<br /><br />© 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.<br /><br /><small>BMJ: 13 Sep 2023; 382:e076017</small></div>

<div><h4>Management of epilepsy during pregnancy and lactation.</h4><i>Hope OA, Harris KM</i><br /><AbstractText>Epilepsy is a group of neurological diseases characterized by susceptibility to recurrent seizures. Antiseizure medications (ASMs) are the mainstay of treatment, but many antiseizure medications with variable safety profiles have been approved for use. For women with epilepsy in their childbearing years, the safety profile is important for them and their unborn children, because treatment is often required to protect them from seizures during pregnancy and lactation. Since no large randomized controlled trials have investigated safety in this subgroup of people with epilepsy, pregnancy registries, cohort and case-control studies from population registries, and a few large prospective cohort studies have played an important role. Valproate, in monotherapy and polytherapy, has been associated with elevated risk of major congenital malformations and neurodevelopmental disorders in children born to mothers who took it. Topiramate and phenobarbital are also associated with elevated risks of congenital malformations and neurodevelopmental disorders, though the risks are lower than those of valproate. Lamotrigine and levetiracetam are relatively safe. Insufficient data exist to reach strong conclusions about the newest antiseizure medications such as eslicarbazepine, perampanel, brivaracetam, cannabidiol, and cenobamate. Besides antiseizure medications, other treatments such as vagal nerve stimulation, responsive neurostimulation, and deep brain stimulation are likely safe. In general, breastfeeding does not appear to add any additional long term risks to the child. Creative ways of optimizing registry enrollment and data collection are needed to enhance patient safety.</AbstractText><br /><br />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.<br /><br /><small>BMJ: 08 Sep 2023; 382:e074630</small></div>

<div><h4>Food additive emulsifiers and risk of cardiovascular disease in the NutriNet-Santé cohort: prospective cohort study.</h4><i>Sellem L, Srour B, Javaux G, Chazelas E, ... Deschasaux-Tanguy M, Touvier M</i><br /><b>Objective</b><br />To assess the associations between exposure to food additive emulsifiers and risk of cardiovascular disease (CVD).<br /><b>Design</b><br />Prospective cohort study.<br /><b>Setting</b><br />French NutriNet-Santé study, 2009-21.<br /><b>Participants</b><br />95 442 adults (>18 years) without prevalent CVD who completed at least three 24 hour dietary records during the first two years of follow-up.<br /><b>Main outcome measures</b><br />Associations between intake of food additive emulsifiers (continuous (mg/day)) and risk of CVD, coronary heart disease, and cerebrovascular disease characterised using multivariable proportional hazard Cox models to compute hazard ratios for each additional standard deviation (SD) of emulsifier intake, along with 95% confidence intervals.<br /><b>Results</b><br />Mean age was 43.1 (SD 14.5) years, and 79.0% (n=75 390) of participants were women. During follow-up (median 7.4 years), 1995 incident CVD, 1044 coronary heart disease, and 974 cerebrovascular disease events were diagnosed. Higher intake of celluloses (E460-E468) was found to be positively associated with higher risks of CVD (hazard ratio for an increase of 1 standard deviation 1.05, 95% confidence interval 1.02 to 1.09, P=0.003) and coronary heart disease (1.07, 1.02 to 1.12, P=0.004). Specifically, higher cellulose E460 intake was linked to higher risks of CVD (1.05, 1.01 to 1.09, P=0.007) and coronary heart disease (1.07, 1.02 to 1.12, P=0.005), and higher intake of carboxymethylcellulose (E466) was associated with higher risks of CVD (1.03, 1.01 to 1.05, P=0.004) and coronary heart disease (1.04, 1.02 to 1.06, P=0.001). Additionally, higher intakes of monoglycerides and diglycerides of fatty acids (E471 and E472) were associated with higher risks of all outcomes. Among these emulsifiers, lactic ester of monoglycerides and diglycerides of fatty acids (E472b) was associated with higher risks of CVD (1.06, 1.02 to 1.10, P=0.002) and cerebrovascular disease (1.11, 1.06 to 1.16, P<0.001), and citric acid ester of monoglycerides and diglycerides of fatty acids (E472c) was associated with higher risks of CVD (1.04, 1.02 to 1.07, P=0.004) and coronary heart disease (1.06, 1.03 to 1.09, P<0.001). High intake of trisodium phosphate (E339) was associated with an increased risk of coronary heart disease (1.06, 1.00 to 1.12, P=0.03). Sensitivity analyses showed consistent associations.<br /><b>Conclusion</b><br />This study found positive associations between risk of CVD and intake of five individual and two groups of food additive emulsifiers widely used in industrial foods.<br /><b>Trial registration</b><br />ClinicalTrials.gov NCT03335644.<br /><br />© 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.<br /><br /><small>BMJ: 06 Sep 2023; 382:e076058</small></div>

<div><h4>Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study.</h4><i>Meaidi A, Mascolo A, Sessa M, Toft-Petersen AP, ... Lidegaard O, Torp-Pedersen C</i><br /><b>Objective</b><br />To study the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism.<br /><b>Design</b><br />Nationwide cohort study.<br /><b>Setting</b><br />Denmark through national registries.<br /><b>Participants</b><br />All 15-49 year old women living in Denmark between 1996 and 2017 with no medical history of any venous or arterial thrombotic event, cancer, thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility treatment (n=2 029 065).<br /><b>Main outcome measure</b><br />A first time discharge diagnosis of lower limb deep venous thrombosis or pulmonary embolism.<br /><b>Results</b><br />Among 2.0 million women followed for 21.0 million person years, 8710 venous thromboembolic events occurred. Compared with non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of venous thromboembolism of 7.2 (95% confidence interval 6.0 to 8.5) in women not using hormonal contraception, 11.0 (9.6 to 12.6) in women using high risk hormonal contraception, 7.9 (5.9 to 10.6) in those using medium risk hormonal contraception, and 4.5 (2.6 to 8.1) in users of low/no risk hormonal contraception. The corresponding numbers of extra venous thromboembolic events per 100 000 women over the first week of NSAID treatment compared with non-use of NSAIDs were 4 (3 to 5) in women not using hormonal contraception, 23 (19 to 27) in women using high risk hormonal contraception, 11 (7 to 15) in those using medium risk hormonal contraception, and 3 (0 to 5) in users of low/no risk hormonal contraception.<br /><b>Conclusions</b><br />NSAID use was positively associated with the development of venous thromboembolism in women of reproductive age. The number of extra venous thromboembolic events with NSAID use compared with non-use was significantly larger with concomitant use of high/medium risk hormonal contraception compared with concomitant use of low/no risk hormonal contraception. Women needing both hormonal contraception and regular use of NSAIDs should be advised accordingly.<br /><br />© 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.<br /><br /><small>BMJ: 06 Sep 2023; 382:e074450</small></div>

<div><h4>Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of randomised controlled trials and observational studies.</h4><i>Solmi M, De Toffol M, Kim JY, Choi MJ, ... Shin JI, Dragioti E</i><br /><b>Objective</b><br />To systematically assess credibility and certainty of associations between cannabis, cannabinoids, and cannabis based medicines and human health, from observational studies and randomised controlled trials (RCTs).<br /><b>Design</b><br />Umbrella review.<br /><b>Data sources</b><br />PubMed, PsychInfo, Embase, up to 9 February 2022.<br /><b>Eligibility criteria for selecting studies</b><br />Systematic reviews with meta-analyses of observational studies and RCTs that have reported on the efficacy and safety of cannabis, cannabinoids, or cannabis based medicines were included. Credibility was graded according to convincing, highly suggestive, suggestive, weak, or not significant (observational evidence), and by GRADE (Grading of Recommendations, Assessment, Development and Evaluations) (RCTs). Quality was assessed with AMSTAR 2 (A Measurement Tool to Assess Systematic Reviews 2). Sensitivity analyses were conducted.<br /><b>Results</b><br />101 meta-analyses were included (observational=50, RCTs=51) (AMSTAR 2 high 33, moderate 31, low 32, or critically low 5). From RCTs supported by high to moderate certainty, cannabis based medicines increased adverse events related to the central nervous system (equivalent odds ratio 2.84 (95% confidence interval 2.16 to 3.73)), psychological effects (3.07 (1.79 to 5.26)), and vision (3.00 (1.79 to 5.03)) in people with mixed conditions (GRADE=high), improved nausea/vomit, pain, spasticity, but increased psychiatric, gastrointestinal adverse events, and somnolence among others (GRADE=moderate). Cannabidiol improved 50% reduction of seizures (0.59 (0.38 to 0.92)) and seizure events (0.59 (0.36 to 0.96)) (GRADE=high), but increased pneumonia, gastrointestinal adverse events, and somnolence (GRADE=moderate). For chronic pain, cannabis based medicines or cannabinoids reduced pain by 30% (0.59 (0.37 to 0.93), GRADE=high), across different conditions (n=7), but increased psychological distress. For epilepsy, cannabidiol increased risk of diarrhoea (2.25 (1.33 to 3.81)), had no effect on sleep disruption (GRADE=high), reduced seizures across different populations and measures (n=7), improved global impression (n=2), quality of life, and increased risk of somnolence (GRADE=moderate). In the general population, cannabis worsened positive psychotic symptoms (5.21 (3.36 to 8.01)) and total psychiatric symptoms (7.49 (5.31 to 10.42)) (GRADE=high), negative psychotic symptoms, and cognition (n=11) (GRADE=moderate). In healthy people, cannabinoids improved pain threshold (0.74 (0.59 to 0.91)), unpleasantness (0.60 (0.41 to 0.88)) (GRADE=high). For inflammatory bowel disease, cannabinoids improved quality of life (0.34 (0.22 to 0.53) (GRADE=high). For multiple sclerosis, cannabinoids improved spasticity, pain, but increased risk of dizziness, dry mouth, nausea, somnolence (GRADE=moderate). For cancer, cannabinoids improved sleep disruption, but had gastrointestinal adverse events (n=2) (GRADE=moderate). Cannabis based medicines, cannabis, and cannabinoids resulted in poor tolerability across various conditions (GRADE=moderate). Evidence was convincing from observational studies (main and sensitivity analyses) in pregnant women, small for gestational age (1.61 (1.41 to 1.83)), low birth weight (1.43 (1.27 to 1.62)); in drivers, car crash (1.27 (1.21 to 1.34)); and in the general population, psychosis (1.71 (1.47 to 2.00)). Harmful effects were noted for additional neonatal outcomes, outcomes related to car crash, outcomes in the general population including psychotic symptoms, suicide attempt, depression, and mania, and impaired cognition in healthy cannabis users (all suggestive to highly suggestive).<br /><b>Conclusions</b><br />Convincing or converging evidence supports avoidance of cannabis during adolescence and early adulthood, in people prone to or with mental health disorders, in pregnancy and before and while driving. Cannabidiol is effective in people with epilepsy. Cannabis based medicines are effective in people with multiple sclerosis, chronic pain, inflammatory bowel disease, and in palliative medicine but not without adverse events.<br /><b>Study registration</b><br />PROSPERO CRD42018093045.<br /><b>Funding</b><br />None.<br /><br />© 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.<br /><br /><small>BMJ: 30 Aug 2023; 382:e072348</small></div>

<div><h4>Promoting Activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED): randomised controlled trial.</h4><i>Harwood RH, Goldberg SE, Brand A, van Der Wardt V, ... Orrell M, Masud T</i><br /><b>Objective</b><br />To determine the effectiveness of an exercise and functional activity therapy intervention in adults with early dementia or mild cognitive impairment compared with usual care.<br /><b>Design</b><br />Randomised controlled trial.<br /><b>Setting</b><br />Participants\' homes and communities at five sites in the United Kingdom.<br /><b>Participants</b><br />365 adults with early dementia or mild cognitive impairment who were living at home, and family members or carers.<br /><b>Intervention</b><br />The intervention, Promoting activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED), was a specially designed, dementia specific, rehabilitation programme focusing on strength, balance, physical activity, and performance of activities of daily living, which was tailored and progressive and addressed risk and the psychological needs of people with dementia. Up to 50 therapy sessions were provided over 12 months. The control group received usual care plus a falls risk assessment. Procedures were adapted during the covid-19 pandemic.<br /><b>Main outcome measures</b><br />The primary outcome was score on the carer (informant) reported disability assessment for dementia scale 12 months after randomisation. Secondary outcomes were self-reported activities of daily living, physical activity, quality of life, balance, functional mobility, fear of falling, frailty, cognition, mood, carer strain, service use at 12 months, and falls between months 4 and 15.<br /><b>Results</b><br />365 patient participants were randomised, 183 to intervention and 182 to control. The median age of participants was 80 years (range 65-95), median Montreal cognitive assessment score was 20 out of 30 (range 13-26), and 58% (n=210) were men. Intervention participants received a median of 31 therapy sessions (interquartile range 22-40) and reported completing a mean 121 minutes of PrAISED exercise each week. Primary outcome data were available for 149 intervention and 141 control participants. Scores on the disability assessment for dementia scale did not differ between groups: adjusted mean difference -1.3, 95% confidence interval -5.2 to 2.6; Cohen\'s d effect size -0.06, 95% confidence interval -0.26 to 0.15; P=0.51). Upper 95% confidence intervals excluded small to moderate effects on any of the range of outcome measures. Between months 4 and 15 the intervention group experienced 79 falls and the control group 200 falls (adjusted incidence rate ratio 0.78, 95% confidence interval 0.5 to 1.3; P=0.3).<br /><b>Conclusion</b><br />The intensive PrAISED programme of exercise and functional activity training did not improve activities of daily living, physical activity, or quality of life; reduce falls; or improve any other secondary health status outcomes, despite good uptake. Future research should consider alternative approaches to maintaining ability and wellbeing in people with dementia.<br /><b>Trial registration</b><br />ISRCTN Registry ISRCTN15320670.<br /><br />© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. No commercial re-use. See rights and permissions. Published by BMJ.<br /><br /><small>BMJ: 29 Aug 2023; 382:e074787</small></div>