Fluoroquinolones and the risk of severe hypoglycaemia among sulphonylurea users: Population-based cohort study.

AIM: Fluoroquinolone-related hypoglycaemia is rare but may become clinically relevant in individuals at high baseline hypoglycaemic risk, such as patients with diabetes using sulphonylureas. Our population-based cohort study assessed whether fluoroquinolones are associated with an increased risk of severe hypoglycaemia compared with amoxicillin among patients treated with sulphonylureas. MATERIALS AND METHODS: Using the UK's Clinical Practice Research Datalink Aurum linked to hospitalization and vital statistics data, we assembled a base cohort of patients who initiated second-generation sulphonylureas (1998-2020). The study cohort included patients initiating either fluoroquinolones or amoxicillin while on sulphonylureas. Using an intent-to-treat exposure definition, we assessed the 30-day risk of severe hypoglycaemia (hospitalization with or death because of hypoglycaemia) associated with fluoroquinolones compared with amoxicillin. Cox models estimated hazard ratios (HRs) with 95% confidence intervals (CIs) of severe hypoglycaemia after 1:5 matching on previous sulphonylurea use and propensity scores. Secondary analyses were stratified by demographics and glycated haemoglobin. RESULTS: Overall, 143 417 patients initiated fluoroquinolones (n = 13 123) or amoxicillin (n = 130 294) while on sulphonylureas. Compared with amoxicillin, fluoroquinolones were not associated with the risk of severe hypoglycaemia (HR, 1.17; 95% CI, 0.91-1.50). Fluoroquinolones were associated with an increased risk in patients <65 years (HR, 2.90; 95% CI, 1.41-5.97) but not in those ≥65 years (HR, 1.03; 95% CI, 0.79-1.35) in stratified analyses. There was no evidence of effect modification by sex or glycated haemoglobin. CONCLUSIONS: In patients using second-generation sulphonylureas, fluoroquinolones were not associated with an increased risk of severe hypoglycaemia compared with amoxicillin. An increased risk among younger adults is possible.

Time is money: general practitioners' reflections on the fee-for-service system.

BACKGROUND: Fee-for-service is a common payment model for remunerating general practitioners (GPs) in OECD countries. In Norway, GPs earn two-thirds of their income through fee-for-service, which is determined by the number of consultations and procedures they register as fees. In general, fee-for-service incentivises many and short consultations and is associated with high service provision. GPs act as gatekeepers for various treatments and interventions, such as addictive drugs, antibiotics, referrals, and sickness certification. This study aims to explore GPs' reflections on and perceptions of the fee-for-service system, with a specific focus on its potential impact on gatekeeping decisions. METHODS: We conducted six focus group interviews with 33 GPs in 2022 in Norway. We analysed the data using thematic analysis. RESULTS: We identified three main themes related to GPs' reflections and perceptions of the fee-for-service system. First, the participants were aware of the profitability of different fees and described potential strategies to increase their income, such as having shorter consultations or performing routine procedures on all patients. Second, the participants acknowledged that the fees might influence GP behaviour. Two perspectives on the fees were present in the discussions: fees as incentives and fees as compensation. The participants reported that financial incentives were not directly decisive in gatekeeping decisions, but that rejecting requests required substantially more time compared to granting them. Consequently, time constraints may contribute to GPs' decisions to grant patient requests even when the requests are deemed unreasonable. Last, the participants reported challenges with remembering and interpreting fees, especially complex fees. CONCLUSIONS: GPs are aware of the profitability within the fee-for-service system, believe that fee-for-service may influence their decision-making, and face challenges with remembering and interpreting certain fees. Furthermore, the fee-for-service system can potentially affect GPs' gatekeeping decisions by incentivising shorter consultations, which may result in increased consultations with inadequate time to reject unnecessary treatments.

Long-Term Efficacy and Safety of Once-Weekly Semaglutide for Weight Loss in Patients Without Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Semaglutide, a glucagon-like peptide-1 receptor agonist, has demonstrated clinically important weight loss effects in patients with type 2 diabetes. However, its effects on sustained weight loss in patients without diabetes remains unclear. Our objective was to examine the long-term efficacy and safety of semaglutide use for weight loss in patients with overweight/obesity and without diabetes. MEDLINE, EMBASE, and the Cochrane Libraries were systematically searched to identify randomized controlled trials that randomized participants with overweight/obesity and without diabetes to once-weekly 2.4 mg subcutaneous semaglutide versus placebo, with a follow-up of at least 68 weeks. The primary outcome was a change in relative body weight from baseline to the longest follow-up. Random-effects models with inverse variance weighting were used to estimate the weighted mean differences (WMDs) and relative risks (RRs) with 95% confidence intervals (CIs). A total of 4 randomized controlled trials (n = 3,087) were included. Of the 3 trials that provided body mass index by category (n = 2,783), 94.0% of the participants had a baseline body mass index ≥30 kg/m2. Compared with placebo, the use of semaglutide was associated with substantial decreases in long-term relative (WMD -12.1%, 95% CI -13.5 to -10.7) and absolute body weight (WMD -12.3 kg, 95% CI -13.6 to -11.0). At the longest follow-up, 33.4% of participants randomized to semaglutide achieved ≥20% weight loss compared with 2.2% with placebo (RR 15.08, 95% CI 9.31 to 24.43). The risk of gastrointestinal adverse events was higher in participants who took semaglutide than placebo (RR 1:47, 95% CI 1.28 to 1.68); however, the majority of these events were transient and mild-to-moderate in severity and did not require treatment discontinuation. In conclusion, semaglutide is efficacious for sustained weight loss in patients with overweight/obesity and without diabetes.

Effectiveness and safety of direct oral anticoagulants among patients with non-valvular atrial fibrillation and liver disease: A multinational cohort study.

BACKGROUND AND AIMS: The effects of direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (NVAF) and liver disease remain poorly understood. Our multinational cohort study assessed the effectiveness and safety of DOACs in this high-risk population. METHODS: We assembled two population-based cohorts in United Kingdom and in Québec of NVAF patients with liver disease initiating DOACs or vitamin K antagonists (VKAs) between 2011 and 2020. Using an as-treated exposure definition, we compared DOACs to VKAs and apixaban to rivaroxaban. After inverse probability of treatment weighting, Cox proportional hazards models estimated site-specific hazard ratios (HRs) and 95 % confidence intervals (CIs) of ischemic stroke and major bleeding. Site-specific estimates were pooled using random-effects models. Analyses were repeated among NVAF patients with cirrhosis. RESULTS: There were 11,881 NVAF patients with liver disease (2683 with cirrhosis). Among those, 8815 initiated DOACs (4414 apixaban, 2497 rivaroxaban) and 3696 VKAs. The HRs (95 % CIs) for DOACs compared to VKAs were 1.01 (0.76-1.34) for ischemic stroke and 0.87 (0.77-0.99) for major bleeding. Results were consistent among patients with cirrhosis. The HRs (95 % CIs) for apixaban compared to rivaroxaban were 0.85 (0.60-1.20) for ischemic stroke and 0.80 (0.68-0.95) for major bleeding. This decreased bleeding risk was not observed among patients with cirrhosis (HR, 1.01; 95 % CI 0.72-1.43). CONCLUSIONS: Among NVAF patients with liver disease, DOACs were as effective and slightly safer than VKAs, and apixaban was as effective but safer than rivaroxaban. The safety benefit with apixaban was not present among patients with cirrhosis.

Prescribing trends of proton pump inhibitors and histamine blockers among children in the United Kingdom (1998-2019): A population-based assessment.

PURPOSE: To describe the prescribing trends of proton pump inhibitors (PPIs) and H2 receptor antagonists (H2 RAs) among children with gastroesophageal reflux in the United Kingdom between 1998 and 2019. METHODS: We conducted a population-based retrospective cohort study using data from the Clinical Practice Research Datalink that included all children aged ≤18 years with a first ever diagnosis of gastroesophageal reflux between 1998 and 2019. Using negative binomial regression, we estimated crude and adjusted annual prescription rates per 1000 person-years and corresponding 95% confidence intervals (CIs) for PPIs and H2 RAs. We also assessed rate ratios of PPIs and H2 RAs prescription rates to examine changes in prescribing over time. RESULTS: Our cohort included 177 477 children with a first ever diagnosis of gastroesophageal reflux during the study period. The median age was 13 years (IQR: 1, 17) among children prescribed PPIs and 0.2 years (IQR: 0.1, 0.6) among those prescribed H2 RAs. The total prescription rate of all GERD drugs was 1468 prescriptions per 1000 person-years (PYs) (95% CI 1463-1472). Overall, PPIs had a higher prescription rate (815 per 1000 PYs, 95% CI 812-818) than H2 RAs (653 per 1000 PYs 95% CI 650-655). Sex- and age-adjusted rate ratios of 2019 versus 1998 demonstrated a 10% increase and a 76% decrease in the prescription rates of PPIs and H2 RAs, respectively. CONCLUSIONS: Prescription rates for PPIs increased, especially during the first half of the study period, while prescription rates for H2 RA decreased over time.

Efficacy of interventions targeted at physician prescribers of opioids for chronic non-cancer pain: an overview of systematic reviews.

BACKGROUND: To combat the opioid crisis, interventions targeting the opioid prescribing behaviour of physicians involved in the management of patients with chronic non-cancer pain (CNCP) have been introduced in clinical settings. An integrative synthesis of systematic review evidence is required to better understand the effects of these interventions. Our objective was to synthesize the systematic review evidence on the effect of interventions targeting the behaviours of physician opioid prescribers for CNCP among adults on patient and population health and prescriber behaviour. METHODS: We searched MEDLINE, Embase, and PsycInfo via Ovid; the Cochrane Database of Systematic Reviews; and Epistemonikos. We included systematic reviews that evaluate any type of intervention aimed at impacting opioid prescriber behaviour for adult CNCP in an outpatient setting. RESULTS: We identified three full texts for our review that contained 68 unique primary studies. The main interventions we evaluated were structured prescriber education (one review) and prescription drug monitoring programmes (PDMPs) (two reviews). Due to the paucity of data available, we could not determine with certainty that education interventions improved outcomes in deprescribing. There is some evidence that PDMPs decrease the number of adverse opioid-related events, increase communication among healthcare workers and patients, modify healthcare practitioners' approach towards their opioid prescribed patients, and offer more chances for education and counselling. CONCLUSIONS: Our overview explores the possibility of PDMPs as an opioid deprescribing intervention and highlights the need for more high-quality primary research on this topic.

The cost of saying no: general practitioners' gatekeeping role in sickness absence certification.

BACKGROUND: General practitioners (GPs) have an important gatekeeping role in the Norwegian sickness insurance system. This role includes limiting access to paid sick leave when this is not justified according to sick leave criteria. 85% of GPs in Norway operate within a fee-for-service system that incentivises short consultations and high service provision. In this qualitative study, we explore how GPs practise the gatekeeping role in sickness absence certification. METHODS: Qualitative data was collected through six focus group interviews with 33 GPs, working in practices with a minimum of four practising GPs, in different geographical regions across Norway, including both urban and rural areas. Data was analysed using Braune and Clarke's thematic analysis approach. RESULTS: Our results indicate that GPs' sick-listing decisions are largely driven by patient demand and preferences for sick leave. GPs reported that they rarely overrule patient requests for sickness absence, including in cases where such requests conflict with the GPs' opinion of whether sick leave is justified or benefits the patient. The degree of effort made to limit unjustified or non-beneficial sick leave seems to depend on the GPs' available time and perceived risk of conflict with the patient. GPs generally expressed dissatisfaction with their role as certifiers of sickness absence. CONCLUSION: Our study suggests that GPs' decisions about sickness certification is largely driven by patient preferences. The GPs' gatekeeping function is limited to negotiations about grade and duration of absence spells.

Standardizing to specific target populations in distributed networks and multisite pharmacoepidemiologic studies.

Distributed network studies and multisite studies assess drug safety and effectiveness in diverse populations by pooling information. Targeting groups of clinical or policy interest (including specific sites or site combinations) and applying weights based on effect measure modifiers (EMMs) prior to pooling estimates within multisite studies may increase interpretability and improve precision. We simulated a 4-site study, standardized each site using inverse odds weights (IOWs) to resemble the 3 smallest sites or the smallest site, estimated IOW-weighted risk differences (RDs), and combined estimates with inverse variance weights (IVWs). We also created an artificial distributed network in the Clinical Practice Research Datalink (CPRD) Aurum consisting of 1 site for each geographic region. We compared metformin and sulfonylurea initiators with respect to mortality, targeting the smallest region. In the simulation, IOWs reduced differences between estimates and increased precision when targeting the 3 smallest sites or the smallest site. In the CPRD Aurum study, the IOW + IVW estimate was also more precise (smallest region: RD = 5.41% [95% CI, 1.03-9.79]; IOW + IVW estimate: RD = 3.25% [95% CI, 3.07-3.43]). When performing pharmacoepidemiologic research in distributed networks or multisite studies in the presence of EMMs, designation of target populations has the potential to improve estimate precision and interpretability. This article is part of a Special Collection on Pharmacoepidemiology.

Regulatory Strategies for Preventing and Reducing Nicotine Vaping Among Youth: A Systematic Review.

INTRODUCTION: Many jurisdictions have implemented different regulatory strategies to reduce vaping among youth. The objective of this systematic review is to synthesize the evidence of the effectiveness of different regulatory strategies for preventing and reducing nicotine vaping among youth. METHODS: Five electronic databases were searched from January 1, 2004 to July 17, 2022 for primary studies examining state/provincial or national regulations targeting vaping among youth (aged 12-21 years) in high-income countries. The primary outcome was vaping prevalence. Included studies were qualitatively synthesized through systematic review. RESULTS: The systematic review included 30 studies. There was insufficient evidence to recommend age restrictions (n=16), restrictions on location of use (n=1), and mixed/combined regulations (n=3). Flavor bans (n=4), sales licenses (n=2), and taxation (n=2) were generally shown to be associated with decreased rates of youth vaping. Warning labels (n=2) were associated with a decreased desire to initiate vaping. Included studies had moderate-to-serious risks of bias. DISCUSSION: Although several regulatory interventions have been shown to be effective at reducing vaping among youth, evidence is insufficient to recommend a specific type of regulation. Regulatory authorities could implement various regulations targeting the price, accessibility, and desirability (i.e., flavors and packaging) of E-cigarettes.

Serious Infections in Offspring Exposed in Utero to Vedolizumab.

Controlling IBD during pregnancy is important for maternal and fetal outcomes. We created a cohort of children born to mothers with IBD, comparing the risk of infections in those exposed to vedolizumab vs unexposed. We detected no increased risk.

Interventions for Preventing E-Cigarette Use Among Children and Youth: A Systematic Review.

INTRODUCTION: Many nonregulatory interventions targeting children and youth have been implemented at three levels: directed at the individual (e.g., interactive video games), delivered to students at school (e.g., campus bans), and launched in the community (e.g., mass media campaigns). This systematic review aims to synthesize the evidence on the effectiveness of interventions aimed at preventing e-cigarette initiation among children and youth. METHODS: MEDLINE, CINAHL, Embase, APA PsycINFO, and Web of Science Core Collection were searched for papers published between January 1, 2004 and September 1, 2022 that reported more than one outcome on vaping prevention among individuals aged less than 21-years-old: vaping prevalence/incidence, initiation intentions, knowledge/attitudes, and other tobacco product use prevalence/initiation intentions. Interventions were at the individual, school, or community level. The risk of bias was assessed using ROBINS-I and RoB 1. RESULTS: Thirty-nine publications met the eligibility criteria. Fourteen individually-based (4 parental monitoring, 3 video games, 2 text messages, 3 graphic message themes, 2 healthcare), 19 school-based (14 educational and skill interventions, 5 vape-free policies/bans), and 6 community-based (3 social media, 3 mass media campaigns) interventions were reported. E-cigarette initiation prevention was observed with high perceived parental monitoring; however, the cross-sectional study designs precluded causal claims. There was promising but limited evidence that social-emotional skills curricula and peer leader programming prevented vaping initiation. DISCUSSION: Some individual- and school-based interventions showed promise for preventing e-cigarette initiation among children and youth.

Incretin-based drugs and the risk of diabetic retinopathy among individuals with type 2 diabetes: A systematic review and meta-analysis of observational studies.

AIM: The results from the SUSTAIN-6 trial generated some uncertainty regarding the association between incretin-based drugs [dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs)] and the risk of diabetic retinopathy. Our objective was to synthesize the available evidence from observational studies regarding the use of incretin-based drugs and the risk of diabetic retinopathy among individuals with type 2 diabetes. MATERIALS AND METHODS: We systemically searched Cochrane Library, Embase and Medline to identify observational studies of interest. Risk of bias was assessed using the ROBINS-I tool. Data from included studies were pooled using the DerSimonian and Laird random-effect model with the Hartung-Knapp extension. RESULTS: We included 14 studies in the systematic review, with 10 examining DPP-4 inhibitors and seven examining GLP-1 RAs. Nine studies investigated incident diabetic retinopathy, six investigated diabetic retinopathy progression and two investigated both outcomes. Seven studies were at moderate risk of bias, four at serious risk of bias and three at critical risk of bias. Data pooled across studies showed no association between the use of DPP-4 inhibitors (risk ratio: 0.98, 95% confidence interval: 0.83, 1.17) or GLP-1 RAs (risk ratio: 0.87, 95% confidence interval: 0.56, 1.34) and the risk of diabetic retinopathy. CONCLUSION: This study suggests that the use of incretin-based drugs is not associated with the risk of diabetic retinopathy among individuals with type 2 diabetes. However, these findings should be interpreted with caution considering the limited quality of some of the available evidence.

Structural differences of cell walls in earlywood and latewood of Pinus sylvestris and their contribution to biomass recalcitrance.

Scots pine (Pinus sylvestris L.) is an evergreen coniferous tree with wide distribution and good growth performance in a range of habitats. Therefore, wood from P. sylvestris is produced in many managed forests and is frequently used in industry. Despite the importance of pine wood, we still do not fully understand its molecular structure what limits improvements in its processing. One of the basic features leading to variation in wood properties is the presence of earlywood and latewood which form annual growth rings. Here, we characterise biochemical traits that differentiate cell walls of earlywood and latewood in Scots pine. We discover that latewood is less recalcitrant to enzymatic digestion, with galactoglucomannan showing particularly pronounced difference in accessibility. Interestingly, characterisation of lignin reveals a higher proportion of coniferaldehydes in pine latewood and suggests the presence of a different linkage landscape in this wood type. With complementary analysis of wood polysaccharides this enabled us to propose the first detailed molecular model of earlywood and latewood and to conclude that the variation in lignin structure is likely the main determinant of differences in recalcitrance observed between the two wood types in pine. Our discoveries lay the foundation for improvements in industrial processes that use pine wood since we show clear pathways for increasing the efficiency of enzymatic processing of this renewable material. Our work will help guide future breeding of pine trees with desired timber properties and can help link molecular structure of softwood cell walls to function of the different types of xylem in conifers.

Outcomes of SGLT-2i and GLP-1RA Therapy Among Patients With Type 2 Diabetes and Varying NAFLD Status.

Importance: Nonalcoholic fatty liver disease (NAFLD) is a cardiovascular risk factor, but whether sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) are associated with reduced cardiovascular risk in patients with type 2 diabetes (T2D) and concomitant NAFLD remains uncertain. Objective: To investigate the outcomes of SGLT-2i and GLP-1RA therapy among patients with T2D varied by the presence or absence of NAFLD. Design, Setting, and Participants: This retrospective, population-based, nationwide cohort study used an active-comparator new-user design. Two distinct new-user active-comparator cohorts of patients aged 40 years and older who initiated SGLT-2i or GLP-1RA were propensity score matched to patients who initiated dipeptidyl peptidase-4 inhibitors (DPP-4i). The study was conducted in South Korea from January 2013 to December 2020, and data analysis was conducted from October 2022 to March 2023. Main Outcomes and Measures: The main outcomes were (1) major adverse cardiovascular events (MACE), a composite end point of hospitalization for myocardial infarction, hospitalization for stroke, and cardiovascular death, and (2) hospitalization for heart failure (HHF). Cox proportional hazards models were used to estimate hazard ratios (HRs). The Wald test was applied to assess heterogeneity by NAFLD. Results: After 1:1 propensity score matching, 140 438 patients were retrieved in the first cohort (SGLT-2i vs DPP-4i; mean [SD] age, 57.5 [10.3] years; 79 633 [56.7%] male) and 34 886 patients were identified in the second cohort (GLP-1RA vs DPP-4i; mean [SD] age, 59.5 [10.5] years; 17 894 [51.3%] male). Compared with DPP-4i, SGLT-2i therapy was associated with a lower risk of MACE (HR, 0.78 [95% CI, 0.71-0.85]) and HHF (HR, 0.62 [95% CI, 0.48-0.81]). GLP-1RA therapy was associated with a decreased risk of MACE (HR, 0.49 [95% CI, 0.39-0.62]) but had statistically nonsignificant findings regarding HHF (HR, 0.64 [95% CI, 0.39-1.07]). Stratified analysis by NAFLD status yielded consistent results for SGLT-2i (MACE with NAFLD: HR, 0.73 [95% CI, 0.62-0.86]; without NAFLD: HR, 0.81 [95% CI, 0.72-0.91]; HHF with NAFLD: HR, 0.76 [95% CI, 0.49-1.17]; without NAFLD: HR, 0.56 [95% CI, 0.40-0.78]) and for GLP-1RA (MACE with NAFLD: HR, 0.49 [95% CI, 0.32-0.77]; without NAFLD: HR, 0.49 [95% CI, 0.37-0.65]; HHF with NAFLD: HR, 0.82 [95% CI, 0.38-1.76]; without NAFLD: HR, 0.54 [95% CI, 0.27-1.06]). Conclusions and Relevance: In this population-based cohort study, SGLT-2i therapy was associated with a decreased risk of MACE and HHF, while GLP-1RA therapy was associated with a decreased risk of MACE among patients with T2D, irrespective of baseline NAFLD status.

Levothyroxine initiation and the risk of pregnancy loss among pregnant women with subclinical hypothyroidism: An observational study emulating a target trial.

BACKGROUND: While the benefits of levothyroxine are well-established for overt hypothyroidism, they are unclear for subclinical hypothyroidism (SCH) among pregnant women. OBJECTIVE: To estimate the effect of initiation of levothyroxine on pregnancy loss among women with SCH with an emulated target trial using observational data. METHODS: We emulated a target trial using the United Kingdom's Clinical Practice Research Datalink to account for the staggered timing of diagnosis and treatment of SCH and the time of entry of women into prenatal care. We emulated multiple nested trials (at each gestational week) and used an intention-to-treat approach to define levothyroxine use (≥1 prescription in the 7 days prior to trial entry), with eligible users matched to non-users (1:4) on time of diagnosis, gestational week of the first eligible trial and high-dimensional propensity score. Pregnancy losses included spontaneous abortion and stillbirth. A pooled logistic regression model with bootstrap resampling was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Based on 159,177 eligible person-trials (5781 women), the matched cohort included 181 initiators and 640 non-initiators of levothyroxine, with 57 pregnancy losses occurring during follow-up. Overall, the mean age of women was 32.2 years (SD 5.4), 25% were obese, 8% had type 2 diabetes and about 50% were nulliparous. After matching, women who initiated levothyroxine versus not had higher thyroid-stimulating levels during pregnancy and were more likely to have a history of hypothyroidism. The cumulative incidence of pregnancy loss was lower in initiators versus non-initiators of levothyroxine. The adjusted HR for pregnancy loss was 0.87 (95% CI 0.22, 1.56). CONCLUSIONS: Although our assessment of the effect of initiation of levothyroxine for SCH in pregnancy precludes any definitive conclusions due to wide confidence intervals, this study illustrates the feasibility of using the target trial emulation framework to examine the effectiveness of medication use in pregnancy.

Evaluating the impact of varying expired carbon monoxide thresholds on smoking relapse identification: insights from the E3 trial on e-cigarette efficacy for smoking cessation.

OBJECTIVES: Expired carbon monoxide (ECO) is often used in smoking cessation trials to biochemically validate self-reported smoking status. The optimal ECO threshold to distinguish individuals who smoke from those who do not is debated. DESIGN: The data from the 'Evaluating the Efficacy of E-Cigarette use for Smoking Cessation (E3) Trial' were used; the E3 trial was a randomised controlled trial that examined e-cigarettes efficacy for smoking cessation. SETTINGS: Participants were recruited from 17 Canadian sites across 4 provinces. PARTICIPANTS: This substudy included data from participants who returned for at least one of the clinical visits at week 4 (291), 12 (257) or 24 (218) and provided both self-reported smoking status and ECO measures. Analyses were based on 766 paired measures (ie, self-reported smoking status with corresponding ECO). RESULTS: The ability of ECO measurements to discriminate between adults who reported smoking and those who reported abstinence varied with the threshold used. ECO thresholds of 6, 7, 8 and 9 parts per million (ppm) yielded the greatest area under the receiver operating characteristic curve (0.84). These thresholds produced sensitivities of 84%, 82%, 78% and 76% and specificities of 84%, 87%, 90% and 91%, respectively. However, at a threshold of 6 ppm, intersecting sensitivity (84%) and specificity (84%) were maximised with respect to each other. Biochemical validation had the highest agreement with self-report at an ECO threshold of 6 ppm (κ=0.57; 95% CI, 0.51 to 0.64). CONCLUSION: The classification of participants' smoking status depends on the ECO threshold used for biochemical validation. We recommend that future smoking cessation trial investigators analyse and report the impact that varying ECO thresholds has on trial results. TRIAL REGISTRATION NUMBER: NCT02417467.

The Cardiovascular Safety of Five-Alpha-Reductase Inhibitors Among Men with Benign Prostatic Hyperplasia: A Population-Based Cohort Study.

BACKGROUND: Five-alpha reductase inhibitors (5αRIs) are used to treat benign prostatic hyperplasia (BPH). However, the cardiovascular effects of 5αRIs remain poorly understood. The study objective was to compare the rate of hospitalization for heart failure among men with BPH prescribed 5αRIs to that of men with BPH not prescribed BPH medications. METHODS: Using the Clinical Practice Research Datalink linked with hospitalization and vital statistics data, we conducted a population-based cohort study among patients newly diagnosed with BPH. We defined exposure as the current use of 5αRIs, current use of alpha-blockers, and no current use of BPH medications in a time-varying approach. The primary endpoint was hospitalization for heart failure, and secondary endpoints were myocardial infarction, stroke, and cardiovascular death. We used time-dependent Cox-proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Our cohort included 94,440 men with incident BPH. A total of 3893 hospitalizations for heart failure occurred over 527,660 person-years of follow-up (incidence rate 7.38; 95% CI, 7.15-7.61, per 1000 person-years). Compared with no current use of BPH medications, current use of 5αRIs was not associated with an increased risk of hospitalization for heart failure (HR 0.94; 95% CI, 0.86-1.03), myocardial infarction (HR 0.92; 95% CI, 0.81-1.05), stroke (HR 0.94; 95% CI, 0.85-1.05), or cardiovascular death (HR 0.89; 95% CI, 0.80-0.99). CONCLUSIONS: The use of 5αRIs was not associated with an increased risk of hospitalization for heart failure, myocardial infarction, stroke, or cardiovascular death compared with non-use.

Sensitivity and specificity of alternative screening methods for systematic reviews using text mining tools.

OBJECTIVES: To evaluate the impact of text mining (TM) on the sensitivity and specificity of title and abstract screening strategies for systematic reviews (SRs). STUDY DESIGN AND SETTING: Twenty reviewers each evaluated a 500-citation set. We compared five screening methods: conventional double screen (CDS), single screen, double screen with TM, combined double screen and single screen with TM, and single screen with TM. Rayyan, Abstrackr, and SWIFT-Review were used for each TM method. The results of a published SR were used as the reference standard. RESULTS: The mean sensitivity and specificity achieved by CDS were 97.0% (95% confidence interval [CI]: 94.7, 99.3) and 95.0% (95% CI: 93.0, 97.1). When compared with single screen, CDS provided a greater sensitivity without a decrease in specificity. Rayyan, Abstrackr, and SWIFT-Review identified all relevant studies. Specificity was often higher for TM-assisted methods than that for CDS, although with mean differences of only one-to-two percentage points. For every 500 citations not requiring manual screening, 216 minutes (95% CI: 169, 264) could be saved. CONCLUSION: TM-assisted screening methods resulted in similar sensitivity and modestly improved specificity as compared to CDS. The time saved with TM makes this a promising new tool for SR.

Assessing Serious Infections in Children Exposed In Utero to Ustekinumab.

Chronic inflammatory conditions, including inflammatory bowel disease (IBD), psoriasis (PsO), and psoriatic arthritis (PsA), have a high burden among women of reproductive age. There has been significant interest in finding safe ways of controlling disease activity during pregnancy without adversely affecting the pregnancy or offspring.