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BACKGROUND: Chronic Kidney Disease (CKD) is a common health problem, associated with increased risk of cardiovascular disease (CVD), end stage kidney disease (ESKD), and premature death. A third of people aged≥70 years have CKD, many of whom are undiagnosed, but little is known about the value of screening. AIM: To compare the risk of adverse health outcomes between people with an existing diagnosis of CKD and those identified on screening. To identify factors associated with mortality in CKD. DESIGN & SETTING: Prospective cohort study of 892 primary care patients aged≥60 years with CKD (existing and screening detected) in Oxfordshire, with data linkage to civil death registry and secondary care. METHOD: Hazard Ratios (HR) and 95% Confidence Intervals (CI) were estimated using Cox proportional-hazard models to compare the risk of all-cause mortality, hospitalisation, CVD, ESKD separately, and as a composite between CKD groups, as well as to identify factors associated with mortality. RESULTS: After a median follow-up of 3-5 years, 49 people died, 493 were hospitalised, 57 had an incident CVD event, and 0 had an ESKD event. There was no difference in the composite outcome between those existing CKD and those identified on screening (HR 0.94, CI 0.67-1.33). Older age (HR 1.10, CI 1.06-1.15), male sex (HR 2.31, CI 1.26-4.24), and heart failure (HR 5.18, CI 2.45-10.97) were associated with increased risk of death. CONCLUSION: Screening older people for CKD may be of value, as their risk of short-term mortality, hospitalisation, and CVD is comparable to people routinely diagnosed. Larger studies with longer follow-up in more diverse and representative populations of older adults are needed to corroborate these findings.

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BACKGROUND: Community acquired acute kidney injury (CA-acute kidney injury) is under-recognized in the outpatient setting and is associated with adverse outcomes. METHODS: We analyzed the incidence of CA-acute kidney injury in an academic primary care practice and community health center and assessed recognition/followup as determined by repeat creatinine measurement (loop-closed). We reviewed 93,259 specimens for 36,593 unique patients from 1/1/2018 through 12/31/2021. RESULTS: There were 220 unique patients with CA-acute kidney injury defined as a >75% increase in creatinine from baseline; incidence: 150/100,000 (0.15% per year). 137 patients (62.3%) had repeat serum creatinine performed within 30 days. Chart reviews of the 83 (37.72%) patients with open loops found there was no follow-up creatinine ordered in 69/83 (83.1%) patients. Mean baseline creatinine was higher and eGFR was lower in the loop-closed group (0.92±0.4mg/dl; 84.45±27.49mls/min) versus (0.63±0.34mg/dl; 105.19±26.67mls/min) in the loop-open group (p<.0001). Preexisting chronic kidney disease was more prevalent in loop-closed patients (35/137; 25.6%) compared to those with open-loops (3/83; 3.6%). Patients with baseline chronic kidney disease were more likely to have the loop-closed. Progression to new chronic kidney disease was common among CA-acute kidney injury patients, occurring in 23.94% of loop-open and 17.50% of loop-closed patients. New baseline eGFR was lower in all groups. CONCLUSIONS: Clinicians frequently overlooked a clinically significant change in eGFR, especially when the baseline creatinine and incident creatinine levels were in the "normal" range.

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Vaccines against COVID-19 and influenza can reduce the adverse outcomes caused by infections during pregnancy, but vaccine uptake among pregnant women has been suboptimal. We examined the COVID-19 and influenza vaccine uptake and disparities in pregnant women during the COVID-19 pandemic to inform vaccination interventions. We used data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre database in England and the Secure Anonymised Information Linkage Databank in Wales. The uptake of at least one dose of vaccine was 40.2% for COVID-19 and 41.8% for influenza among eligible pregnant women. We observed disparities in COVID-19 and influenza vaccine uptake, with socioeconomically deprived and ethnic minority groups showing lower vaccination rates. The suboptimal uptake of COVID-19 and influenza vaccines, especially in those from socioeconomically deprived backgrounds and Black, mixed or other ethnic groups, underscores the necessity for interventions to reduce vaccine hesitancy and enhance acceptance in pregnant women.

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Nanoscale dislocation loops formed by irradiation can significantly contribute to both irradiation hardening and embrittlement of materials when subjected to extreme nuclear reactor environments. This study explores the application of weak-beam dark-field (WBDF) scanning transmission electron microscopy (STEM) methods for quantitative irradiation-induced defect analysis in crystalline materials, with a specific focus on dislocation loop imaging and analysis. A high-purity Fe-5 wt% Cr model alloy was irradiated with 8 MeV Fe2+ ions at 450°C to a fluence of 8.8 × 1019 m-2, inducing dislocation loops for analysis. While transmission electron microscopy (TEM) has traditionally been the primary tool for dislocation imaging, recent advancements in STEM technology have reignited interest in using STEM for defect imaging. This study introduces and compares three WBDF STEM methods, demonstrating their effectiveness in suppressing background contrasts, isolating defect information for dislocation loop type classification, providing finer dislocation line images for small loop analysis, and presenting inside-outside contrast for identifying loop nature. Experimental findings indicate that WBDF STEM methods surpass traditional TEM approaches, yielding clearer and more detailed images of dislocation loops. The study concludes by discussing the potential applications of WBDF STEM techniques in defect analysis, emphasizing their adaptability across various material systems beyond nuclear materials.

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BACKGROUND: Globally, there are marked inconsistencies in how immunosuppression is characterized and subdivided into clinical risk groups. This is detrimental to the precision and comparability of disease surveillance efforts-which has negative implications for the care of those who are immunosuppressed and their health outcomes. This was particularly apparent during the COVID-19 pandemic; despite collective motivation to protect these patients, conflicting clinical definitions created international rifts in how those who were immunosuppressed were monitored and managed during this period. We propose that international clinical consensus be built around the conditions that lead to immunosuppression and their gradations of severity concerning COVID-19. Such information can then be formalized into a digital phenotype to enhance disease surveillance and provide much-needed intelligence on risk-prioritizing these patients. OBJECTIVE: We aim to demonstrate how electronic Delphi objectives, methodology, and statistical approaches will help address this lack of consensus internationally and deliver a COVID-19 risk-stratified phenotype for "adult immunosuppression." METHODS: Leveraging existing evidence for heterogeneous COVID-19 outcomes in adults who are immunosuppressed, this work will recruit over 50 world-leading clinical, research, or policy experts in the area of immunology or clinical risk prioritization. After 2 rounds of clinical consensus building and 1 round of concluding debate, these panelists will confirm the medical conditions that should be classed as immunosuppressed and their differential vulnerability to COVID-19. Consensus statements on the time and dose dependencies of these risks will also be presented. This work will be conducted iteratively, with opportunities for panelists to ask clarifying questions between rounds and provide ongoing feedback to improve questionnaire items. Statistical analysis will focus on levels of agreement between responses. RESULTS: This protocol outlines a robust method for improving consensus on the definition and meaningful subdivision of adult immunosuppression concerning COVID-19. Panelist recruitment took place between April and May of 2024; the target set for over 50 panelists was achieved. The study launched at the end of May and data collection is projected to end in July 2024. CONCLUSIONS: This protocol, if fully implemented, will deliver a universally acceptable, clinically relevant, and electronic health record-compatible phenotype for adult immunosuppression. As well as having immediate value for COVID-19 resource prioritization, this exercise and its output hold prospective value for clinical decision-making across all diseases that disproportionately affect those who are immunosuppressed. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/56271.

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Electric fields are commonly used to control the orientation and motion of microscopic metal particles in aqueous suspensions. For example, metallodielectric Janus spheres are propelled by the induced-charge electro-osmotic flow occurring on their metallic side, the most common case in electrokinetics of exploiting symmetry breaking of surface properties for achieving net particle motion. In this work, we demonstrate that a homogeneous metal rod can translate parallel to a dielectric wall as a result of the hydrodynamic wall-particle interaction arising from the induced-charge electro-osmosis on the rod surface. The applied electric field could be either dc or low-frequency ac. The only requirement for a nonvanishing particle velocity is that the axis of the rod be inclined with respect to the wall, i.e., it cannot be neither parallel nor perpendicular. We show numerical results of the rod velocity as a function of rod orientation and distance to the wall. The maximum particle velocity is found for an orientation of between ∼30^{∘} and ∼50^{∘}, depending on the position and aspect ratio of the cylinder. Particle velocities of up to tens of µm/s are predicted for typical conditions in electrokinetic experiments.

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Objective: To evaluate Phenotype Execution and Modelling Architecture (PhEMA), to express sharable phenotypes using Clinical Quality Language (CQL) and intensional Systematised Nomenclature of Medicine (SNOMED) Clinical Terms (CT) Fast Healthcare Interoperability Resources (FHIR) valuesets, for exemplar chronic disease, sociodemographic risk factor, and surveillance phenotypes. Method: We curated 3 phenotypes: Type 2 diabetes mellitus (T2DM), excessive alcohol use, and incident influenza-like illness (ILI) using CQL to define clinical and administrative logic. We defined our phenotypes with valuesets, using SNOMED's hierarchy and expression constraint language, and CQL, combining valuesets and adding temporal elements where needed. We compared the count of cases found using PhEMA with our existing approach using convenience datasets. We assessed our new approach against published desiderata for phenotypes. Results: The T2DM phenotype could be defined as 2 intensionally defined SNOMED valuesets and a CQL script. It increased the prevalence from 7.2% to 7.3%. Excess alcohol phenotype was defined by valuesets that added qualitative clinical terms to the quantitative conceptual definitions we currently use; this change increased prevalence by 58%, from 1.2% to 1.9%. We created an ILI valueset with SNOMED concepts, adding a temporal element using CQL to differentiate new episodes. This increased the weekly incidence in our convenience sample (weeks 26-38) from 0.95 cases to 1.11 cases per 100 000 people. Conclusions: Phenotypes for surveillance and research can be described fully and comprehensibly using CQL and intensional FHIR valuesets. Our use case phenotypes identified a greater number of cases, whilst anticipated from excessive alcohol this was not for our other variable. This may have been due to our use of SNOMED CT hierarchy. Our new process fulfilled a greater number of phenotype desiderata than the one that we had used previously, mostly in the modeling domain. More work is needed to implement that sharing and warehousing domains.

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Density functional theory (DFT) calculations and an atomistic thermodynamic approach were used to study the geometric rearrangement of sulfur atoms on the Ni- and Cu-doped MoS2 S-edge upon hydrogen adsorption. Under HDS conditions, thermodynamically stable hydrogenated structures were identified as SH groups on the undoped S-edge with 100% sulfur coverage, on the Ni-doped S-edge with 50% sulfur coverage and on the Cu-doped S-edge with 25% sulfur coverage. It was found that the rearrangement of the S atoms is essential to reach the most stable state at the edge for the undoped and Ni-doped S-edge. Hydrogen adsorption on the Ni-doped S-edge leads to the greatest amount of S rearrangement (ΔERearrang = 0.93 eV/H2). Our results suggest that under the reaction conditions, the H2 dissociative adsorption process is strongly coupled to the rearrangement of the sulfur atoms. By examining the differential hydrogen adsorption energy on the most stable edge structures, we found a plausible explanation for the trend in the hydrogenation activity of the doped edges. Our results suggest that Ni enhances the hydrogenation activity of the S-edge by decreasing the S-H bond strength, while Cu poisons it by increasing the S-H bond strength.

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OBJECTIVE: Offering advice and support for smoking, obesity, excess alcohol, and physical inactivity is an evidence-based component of primary care. The objective was to quantify the impact of the pandemic on the rate of advice or referral for these four risk factors. METHODS: A retrospective cohort study using primary care data from 1847 practices in England and 21,191,389 patients contributing to the Oxford Clinical Informatics Digital Hub. An interrupted time series analysis was undertaken with a single change point (March 2020). Monthly trends were modelled from 1st January 2018 - 30th June 2022 using segmented linear regression. RESULTS: There was an initial step reduction in advice and referrals for smoking, obesity, excess alcohol, and physical inactivity in March 2020. By June 2022, advice on smoking (slope change -0.02 events per hundred patient years/month (EPH/month); 95% confidence interval (CI) -0.17, 0.21), obesity (0.06 EPH/month; 95% CI 0.01, 0.12), alcohol (0.02 EPH/month; 95% CI -0.01, 0.05) and physical inactivity (0.05 EPH/month; 95% CI 0.01, 0.09) had not returned to pre-pandemic levels. Similarly, smoking cessation referral remained lower (0.01 EPH/month; 95% CI -0.01, 0.09), excess alcohol referral returned to similar levels (0.0005 EPH/month; 95% CI 0.0002, 0.0008), while referral for obesity (0.14 EPH/month; 95% CI 0.10, 0.19) and physical inactivity (0.01 EPH/month; 95% CI 0.01, 0.02) increased relative to pre-pandemic rates. CONCLUSION: Advice and support for smoking, and advice for weight, excess alcohol and physical inactivity have not returned to pre-pandemic levels. Clinicians and policy makers should prioritise preventive care in COVID-19 recovery plans.

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BACKGROUND/HYPOTHESIS: Observational studies suggest sodium-glucose co-transporter-2 (SGLT2) inhibitor kidney outcome trials are not representative of the broader population of people with chronic kidney disease (CKD). However, there are limited data on the generalisability to those without co-existing type 2 diabetes (T2D), and the representativeness of the EMPA-KIDNEY trial has not been adequately explored. We hypothesised that SGLT2 inhibitor kidney outcome trials are more representative of people with co-existing T2D than those without, and that EMPA-KIDNEY is more representative than previous trials. METHODS: A cross-sectional analysis of adults with CKD in English primary care was conducted using the Oxford-Royal College of General Practitioners Clinical Information Digital Hub. The proportions that met the eligibility criteria of SGLT2 inhibitor kidney outcome trials were determined, and their characteristics described. Logistic regression analyses were performed to identify factors associated with trial eligibility. RESULTS: Of 6,670,829 adults, 516,491 (7.7%) with CKD were identified. In the real-world CKD population, 0.9%, 2.2%, and 8.0% met the CREDENCE, DAPA-CKD, and EMPA-KIDNEY eligibility criteria, respectively. All trials were more representative of people with co-existing T2D than those without T2D. Trial participants were 9-14 years younger than the real-world CKD population, and had more advanced CKD, including higher levels of albuminuria. A higher proportion of the CREDENCE (100%), DAPA-CKD (67.6%) and EMPA-KIDNEY (44.5%) trial participants had T2D compared to the real-world CKD population (32.8%). Renin-angiotensin system inhibitors were prescribed in almost all trial participants, compared to less than half of the real-world CKD population. Females were under-represented and less likely to be eligible for the trials. CONCLUSION: SGLT2 inhibitor kidney outcome trials represent a sub-group of people with CKD at high risk of adverse kidney events. Out study highlights the importance of complementing trials with real-world studies, exploring the effectiveness of SGLT2 inhibitors in the broader population of people with CKD.

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Background: The cardiovascular and kidney benefits of sodium-glucose co-transporter-2 (SGLT2) inhibitors in people with chronic kidney disease (CKD) are well established. The implementation of updated SGLT2 inhibitor guidelines and prescribing in the real-world CKD population remains largely unknown. Methods: A cross-sectional study of adults with CKD registered with UK primary care practices in the Oxford-Royal College of General Practitioners Research and Surveillance Centre network on the 31st December 2022 was undertaken. Pseudonymised data from electronic health records held securely within the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub (ORCHID) were extracted. An update to a previously described ontological approach was used to identify the study population, using a combination of Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) indicating a diagnosis of CKD and laboratory confirmed CKD based on Kidney Disease: Improving Global Outcomes (KDIGO) diagnostic criteria. We examined the extent to which SGLT2 inhibitor guidelines apply to and are then implemented in adults with CKD. A logistic regression model was used to identify factors associated with SGLT2 inhibitor prescribing, reported as odds ratios (ORs) with 95% confidence intervals (CI). The four guidelines under investigation were the United Kingdom Kidney Association (UKKA) Clinical Practice Guideline SGLT2 Inhibition in Adults with Kidney Disease (October 2021), American Diabetes Association (ADA) and KDIGO Consensus Report on Diabetes Management in CKD (October 2022), National Institute for Health and Care Excellence (NICE) Guideline Type 2 Diabetes in Adults: Management (June 2022), and NICE Technology Appraisal Dapagliflozin for Treating CKD (March 2022). Findings: Of 6,670,829 adults, we identified 516,491 (7.7%) with CKD, including 32.8% (n = 169,443) who had co-existing type 2 diabetes (T2D). 26.8% (n = 138,183) of the overall CKD population had a guideline directed indication for SGLT2 inhibitor treatment. A higher proportion of people with CKD and co-existing T2D were indicated for treatment, compared to those without T2D (62.8% [n = 106,468] vs. 9.1% [n = 31,715]). SGLT2 inhibitors were prescribed to 17.0% (n = 23,466) of those with an indication for treatment, and prescriptions were predominantly in those with co-existing T2D; 22.0% (n = 23,464) in those with T2D, and <0.1% (n = 2) in those without T2D. In adjusted multivariable analysis of people with CKD and T2D, females (OR 0.69, 95% CI 0.67-0.72, p <0.0001), individuals of Black ethnicity (OR 0.84, 95% CI 0.77-0.91, p <0.0001) and those of lower socio-economic status (OR 0.72, 95% CI 0.68-0.76, p <0.0001) were less likely to be prescribed an SGLT2 inhibitor. Those with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 had a lower likelihood of receiving an SGLT2 inhibitor, compared to those with an eGFR ≥60 mL/min/1.73 m2 (eGFR 45-60 mL/min/1.73 m2 OR 0.65, 95% CI 0.62-0.68, p <0.0001, eGFR 30-45 mL/min/1.73 m2 OR 0.73, 95% CI 0.69-0.78, p <0.0001, eGFR 15-30 mL/min/1.73 m2 OR 0.52, 95% CI 0.46-0.60, p <0.0001, eGFR <15 mL/min/1.73 m2 OR 0.03, 95% CI 0.00-0.23, p = 0.0037, respectively). Those with albuminuria (urine albumin-to-creatinine ratio 3-30 mg/mmol) were less likely to be prescribed an SGLT2 inhibitor, compared to those without albuminuria (OR 0.78, 95% CI 0.75-0.82, p <0.0001). Interpretation: SGLT2 inhibitor guidelines in CKD have not yet been successfully implemented into clinical practice, most notably in those without co-existing T2D. Individuals at higher risk of adverse outcomes are paradoxically less likely to receive SGLT2 inhibitor treatment. The timeframe between the publication of guidelines and data extraction may have been too short to observe changes in clinical practice. Enhanced efforts to embed SGLT2 inhibitors equitably into routine care for people with CKD are urgently needed, particularly in those at highest risk of adverse outcomes and in the absence of T2D. Funding: None.

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BACKGROUND: Effective disease surveillance, including that for COVID-19, is compromised without a standardised method for categorising the immunosuppressed as a clinical risk group. METHODS: We conducted a systematic review and meta-analysis to evaluate whether excess COVID-associated mortality compared to the immunocompetent could meaningfully subdivide the immunosuppressed. Our study adhered to UK Immunisation against infectious disease (Green Book) criteria for defining and categorising immunosuppression. Using OVID (EMBASE, MEDLINE, Transplant Library, and Global Health), PubMed, and Google Scholar, we examined relevant literature between the entirety of 2020 and 2022. We selected for cohort studies that provided mortality data for immunosuppressed subgroups and immunocompetent comparators. Meta-analyses, grey literature and any original works that failed to provide comparator data or reported all-cause or paediatric outcomes were excluded. Odds Ratios (OR) and 95% confidence intervals (CI) of COVID-19 mortality were meta-analysed by immunosuppressed category and subcategory. Subgroup analyses differentiated estimates by effect measure, country income, study setting, level of adjustment, use of matching and publication year. Study screening, extraction and bias assessment were performed blinded and independently by two researchers; conflicts were resolved with the oversight of a third researcher. PROSPERO registration number is CRD42022360755. FINDINGS: We identified 99 unique studies, incorporating data from 1,542,097 and 56,248,181 unique immunosuppressed and immunocompetent patients with COVID-19 infection, respectively. Compared to immunocompetent people (pooled OR, 95%CI), solid organ transplants (2.12, 1.50-2.99) and malignancy (2.02, 1.69-2.42) patients had a very high risk of COVID-19 mortality. Patients with rheumatological conditions (1.28, 1.13-1.45) and HIV (1.20, 1.05-1.36) had just slightly higher risks than the immunocompetent baseline. Case type, setting income and mortality data matching and adjustment were significant modifiers of excess immunosuppressed mortality for some immunosuppressed subgroups. INTERPRETATION: Excess COVID-associated mortality among the immunosuppressed compared to the immunocompetent was seen to vary significantly across subgroups. This novel means of subdivision has prospective benefit for targeting patient triage, shielding and vaccination policies during periods of high disease transmission.

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Peru ranks among the three countries with the highest bird species diversity globally and a majority of those species are found in the Peruvian Amazon. However, birds in this area are currently facing serious anthropogenic threats. Genetic and genomic methods are becoming important tools for avian biodiversity monitoring and conservation planning. Comprehensive molecular libraries that are publicly available are key to the effective deployment of these tools. We analyze the information gaps for four molecular markers in the most important genetic sequence databases, Barcode of Life Data Systems (BOLD) and NCBI GenBank, for bird species of the Peruvian Amazonia. We found that 64% of Peruvian Amazonian bird species have gene sequences for COI, 59.5% have CYTB sequences, 16.4% have 12S sequences, and only 0.6% have 18S sequences. However, these numbers decrease drastically to 4.3% for COI sequences when we only consider specimens sampled in Peru. Our data also showed that 43.8% of Peruvian Amazonian endemic species (n = 32) are missing sequences of any screened marker uploaded to GenBank or BOLD. Our results will encourage and guide efforts of the scientific community to complete reference libraries for Peruvian avian species that will be useful for future DNA-based monitoring projects that include birds.

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Mercury (Hg) endangers human and wildlife health globally, primarily due to its release from artisanal small-scale gold mining (ASGM). During gold extraction, Hg is emitted into the environment and converted to highly toxic methylmercury by microorganisms. In Madre de Dios (MDD), Peru, ASGM dominates the economy and has transformed rainforests into expansive deforested areas punctuated by abandoned mining ponds. The aim of this study was to evaluate the use of bats as bioindicators for mercury pollution intensity in tropical terrestrial ecosystems impacted by ASGM. We collected 290 bat fur samples from three post-ASGM sites and one control site in Madre de Dios. Our results showed a wide Hg distribution in bats (0.001 to 117.71 mg/kg) strongly influenced by feeding habits. Insectivorous and piscivorous bats from ASGM sites presented elevated levels of Hg surpassing the mercury small mammal threshold for small mammals (10 mg/kg). We observed the highest reported fur mercury concentrations for insectivorous Neotropical bats reported to date (Rhynchonycteris naso, 117 mg/kg). Our findings further confirm that Hg emissions from ASGM are entering local food webs and exposing wildlife species at several trophic levels to higher levels of Hg than in areas not impacted by mining. We also found that three bat genera consistently showed increased Hg levels in ASGM sites relative to controls indicating potential usefulness as bioindicators of mercury loading in terrestrial ecosystems impacted by artisanal and small-scale gold mining.

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BACKGROUND: Resistance to antibiotics is rising and threatens future antibiotic effectiveness. 'Antibiotic targeting' ensures patients who may benefit from antibiotics receive them, while being safely withheld from those who may not. Point-of-care tests may assist with antibiotic targeting by allowing primary care clinicians to establish if symptomatic patients have a viral, bacterial, combined, or no infection. However, because organisms can be harmlessly carried, it is important to know if the presence of the virus/bacteria is related to the illness for which the patient is being assessed. One way to do this is to look for associations with more severe/prolonged symptoms and test results. Previous research to answer this question for acute respiratory tract infections has given conflicting results with studies has not having enough participants to provide statistical confidence. AIM: To undertake a synthesis of IPD from both randomised controlled trials (RCTs) and observational cohort studies of respiratory tract infections (RTI) in order to investigate the prognostic value of microbiological data in addition to, or instead of, clinical symptoms and signs. METHODS: A systematic search of Cochrane Central Register of Controlled Trials, Ovid Medline and Ovid Embase will be carried out for studies of acute respiratory infection in primary care settings. The outcomes of interest are duration of disease, severity of disease, repeated consultation with new/worsening illness and complications requiring hospitalisation. Authors of eligible studies will be contacted to provide anonymised individual participant data. The data will be harmonised and aggregated. Multilevel regression analysis will be conducted to determine key outcome measures for different potential pathogens and whether these offer any additional information on prognosis beyond clinical symptoms and signs. TRIAL REGISTRATION: PROSPERO Registration number: CRD42023376769.

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BACKGROUND: Tobacco smoking is the leading preventable cause of death and disease worldwide. Stopping smoking can reduce this harm and many people would like to stop. There are a number of medicines licenced to help people quit globally, and e-cigarettes are used for this purpose in many countries. Typically treatments work by reducing cravings to smoke, thus aiding initial abstinence and preventing relapse. More information on comparative effects of these treatments is needed to inform treatment decisions and policies. OBJECTIVES: To investigate the comparative benefits, harms and tolerability of different smoking cessation pharmacotherapies and e-cigarettes, when used to help people stop smoking tobacco. SEARCH METHODS: We identified studies from recent updates of Cochrane Reviews investigating our interventions of interest. We updated the searches for each review using the Cochrane Tobacco Addiction Group (TAG) specialised register to 29 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-RCTs and factorial RCTs, which measured smoking cessation at six months or longer, recruited adults who smoked combustible cigarettes at enrolment (excluding pregnant people) and randomised them to approved pharmacotherapies and technologies used for smoking cessation worldwide (varenicline, cytisine, nortriptyline, bupropion, nicotine replacement therapy (NRT) and e-cigarettes) versus no pharmacological intervention, placebo (control) or another approved pharmacotherapy. Studies providing co-interventions (e.g. behavioural support) were eligible if the co-intervention was provided equally to study arms. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods for screening, data extraction and risk of bias (RoB) assessment (using the RoB 1 tool). Primary outcome measures were smoking cessation at six months or longer, and the number of people reporting serious adverse events (SAEs). We also measured withdrawals due to treatment. We used Bayesian component network meta-analyses (cNMA) to examine intervention type, delivery mode, dose, duration, timing in relation to quit day and tapering of nicotine dose, using odds ratios (OR) and 95% credibility intervals (CrIs). We calculated an effect estimate for combination NRT using an additive model. We evaluated the influence of population and study characteristics, provision of behavioural support and control arm rates using meta-regression. We evaluated certainty using GRADE. MAIN RESULTS: Of our 332 eligible RCTs, 319 (835 study arms, 157,179 participants) provided sufficient data to be included in our cNMA. Of these, we judged 51 to be at low risk of bias overall, 104 at high risk and 164 at unclear risk, and 118 reported pharmaceutical or e-cigarette/tobacco industry funding. Removing studies at high risk of bias did not change our interpretation of the results. Benefits We found high-certainty evidence that nicotine e-cigarettes (OR 2.37, 95% CrI 1.73 to 3.24; 16 RCTs, 3828 participants), varenicline (OR 2.33, 95% CrI 2.02 to 2.68; 67 RCTs, 16,430 participants) and cytisine (OR 2.21, 95% CrI 1.66 to 2.97; 7 RCTs, 3848 participants) were associated with higher quit rates than control. In absolute terms, this might lead to an additional eight (95% CrI 4 to 13), eight (95% CrI 6 to 10) and seven additional quitters per 100 (95% CrI 4 to 12), respectively. These interventions appeared to be more effective than the other interventions apart from combination NRT (patch and a fast-acting form of NRT), which had a lower point estimate (calculated additive effect) but overlapping 95% CrIs (OR 1.93, 95% CrI 1.61 to 2.34). There was also high-certainty evidence that nicotine patch alone (OR 1.37, 95% CrI 1.20 to 1.56; 105 RCTs, 37,319 participants), fast-acting NRT alone (OR 1.41, 95% CrI 1.29 to 1.55; 120 RCTs, 31,756 participants) and bupropion (OR 1.43, 95% CrI 1.26 to 1.62; 71 RCTs, 14,759 participants) were more effective than control, resulting in two (95% CrI 1 to 3), three (95% CrI 2 to 3) and three (95% CrI 2 to 4) additional quitters per 100 respectively. Nortriptyline is probably associated with higher quit rates than control (OR 1.35, 95% CrI 1.02 to 1.81; 10 RCTs, 1290 participants; moderate-certainty evidence), resulting in two (CrI 0 to 5) additional quitters per 100. Non-nicotine/placebo e-cigarettes (OR 1.16, 95% CrI 0.74 to 1.80; 8 RCTs, 1094 participants; low-certainty evidence), equating to one additional quitter (95% CrI -2 to 5), had point estimates favouring the intervention over control, but CrIs encompassed the potential for no difference and harm. There was low-certainty evidence that tapering the dose of NRT prior to stopping treatment may improve effectiveness; however, 95% CrIs also incorporated the null (OR 1.14, 95% CrI 1.00 to 1.29; 111 RCTs, 33,156 participants). This might lead to an additional one quitter per 100 (95% CrI 0 to 2). Harms There were insufficient data to include nortriptyline and non-nicotine EC in the final SAE model. Overall rates of SAEs for the remaining treatments were low (average 3%). Low-certainty evidence did not show a clear difference in the number of people reporting SAEs for nicotine e-cigarettes, varenicline, cytisine or NRT when compared to no pharmacotherapy/e-cigarettes or placebo. Bupropion may slightly increase rates of SAEs, although the CrI also incorporated no difference (moderate certainty). In absolute terms bupropion may cause one more person in 100 to experience an SAE (95% CrI 0 to 2). AUTHORS' CONCLUSIONS: The most effective interventions were nicotine e-cigarettes, varenicline and cytisine (all high certainty), as well as combination NRT (additive effect, certainty not rated). There was also high-certainty evidence for the effectiveness of nicotine patch, fast-acting NRT and bupropion. Less certain evidence of benefit was present for nortriptyline (moderate certainty), non-nicotine e-cigarettes and tapering of nicotine dose (both low certainty). There was moderate-certainty evidence that bupropion may slightly increase the frequency of SAEs, although there was also the possibility of no increased risk. There was no clear evidence that any other tested interventions increased SAEs. Overall, SAE data were sparse with very low numbers of SAEs, and so further evidence may change our interpretation and certainty. Future studies should report SAEs to strengthen certainty in this outcome. More head-to-head comparisons of the most effective interventions are needed, as are tests of combinations of these. Future work should unify data from behavioural and pharmacological interventions to inform approaches to combined support for smoking cessation.

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BACKGROUND: Health and social care interventions are often complex and can be decomposed into multiple components. Multicomponent interventions are often evaluated in randomised controlled trials. Across trials, interventions often have components in common which are given alongside other components which differ across trials. Multicomponent interventions can be synthesised using component NMA (CNMA). CNMA is limited by the structure of the available evidence, but it is not always straightforward to visualise such complex evidence networks. The aim of this paper is to develop tools to visualise the structure of complex evidence networks to support CNMA. METHODS: We performed a citation review of two key CNMA methods papers to identify existing published CNMA analyses and reviewed how they graphically represent intervention complexity and comparisons across trials. Building on identified shortcomings of existing visualisation approaches, we propose three approaches to standardise visualising the data structure and/or availability of data: CNMA-UpSet plot, CNMA heat map, CNMA-circle plot. We use a motivating example to illustrate these plots. RESULTS: We identified 34 articles reporting CNMAs. A network diagram was the most common plot type used to visualise the data structure for CNMA (26/34 papers), but was unable to express the complex data structures and large number of components and potential combinations of components associated with CNMA. Therefore, we focused visualisation development around representing the data structure of a CNMA more completely. The CNMA-UpSet plot presents arm-level data and is suitable for networks with large numbers of components or combinations of components. Heat maps can be utilised to inform decisions about which pairwise interactions to consider for inclusion in a CNMA model. The CNMA-circle plot visualises the combinations of components which differ between trial arms and offers flexibility in presenting additional information such as the number of patients experiencing the outcome of interest in each arm. CONCLUSIONS: As CNMA becomes more widely used for the evaluation of multicomponent interventions, the novel CNMA-specific visualisations presented in this paper, which improve on the limitations of existing visualisations, will be important to aid understanding of the complex data structure and facilitate interpretation of the CNMA results.

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Background: Thrombosis associated with thrombocytopenia was a matter of concern post first and second doses of BNT162b2 and ChAdOx1 COVID-19 vaccines. Therefore, it is important to investigate the risk of thrombocytopenic, thromboembolic and haemorrhagic events following a second dose of BNT162b2 and ChAdOx1 COVID-19 vaccines. Methods: We conducted a large-scale self-controlled case series analysis, using routine primary care data linked to hospital data, among 12.3 million individuals (16 years old and above) in England. We used the nationally representative Oxford-Royal College of General Practitioners (RCGP) sentinel network database with baseline and risk periods between 8th December 2020 and 11th June 2022. We included individuals who received two vaccine (primary) doses of the BNT162b2 mRNA (Pfizer-BioNTech) and two vaccine doses of ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccines in our analyses. We carried out a self-controlled case series (SCCS) analysis for each outcome using a conditional Poisson regression model with an offset for the length of risk period. We reported the incidence rate ratios (IRRs) and 95% confidence intervals (CI) of thrombocytopenic, thromboembolic (including arterial and venous events) and haemorrhagic events, in the period of 0-27 days after receiving a second dose of BNT162b2 or ChAdOx1 vaccines compared to the baseline period (14 or more days prior to first dose, 28 or more days after the second dose and the time between 28 or more days after the first and 14 or more days prior to the second dose). We adjusted for a range of potential confounders, including age, sex, comorbidities and deprivation. Findings: Between December 8, 2020 and February 11, 2022, 6,306,306 individuals were vaccinated with two doses of BNT162b2 and 6,046,785 individuals were vaccinated with two doses of ChAdOx1. Compared to the baseline, our analysis show no increased risk of venous thromboembolic events (VTE) for both BNT162b2 (IRR 0.71, 95% CI: 0.65-0.770) and ChAdOx1 (IRR 0.91, 95% CI: 0.84-0.98); and similarly there was no increased risk for cerebral venous sinus thrombosis (CVST) for both BNT162b2 (IRR 0.87, 95% CI: 0.41-1.85) and ChAdOx1 (IRR 1.73, 95% CI: 0.82-3.68). We additionally report no difference in IRR for pulmonary embolus, and deep vein thrombosis, thrombocytopenia, including idiopathic thrombocytopenic purpura (ITP), and haemorrhagic events post second dose for both BNT162b2. Interpretation: Reassuringly, we found no associations between increased risk of thrombocytopenic, thromboembolic and haemorrhagic events post vaccination with second dose for either of these vaccines. Funding: Data and Connectivity: COVID-19 Vaccines Pharmacovigilance study.