Practical and analytical considerations when performing interim analyses in diagnostic test accuracy studies.

Interim analysis is a common methodology in randomised clinical trials but has received less attention in studies of diagnostic test accuracy. In such studies, early termination for futility may be beneficial if early evidence indicates that a diagnostic test is unlikely to achieve a clinically useful level of diagnostic performance, as measured by the sensitivity and specificity. In this paper, we describe relevant practical and analytical considerations when planning and performing interim analysis in diagnostic accuracy studies, focusing on stopping rules for futility. We present an adaptation of the exact group sequential method for diagnostic testing, with R code provided for implementing this method in practice. The method is illustrated using two simulated data sets and data from a published diagnostic accuracy study for point-of-care testing for SARS-CoV-2. The considerations described in this paper can be used to guide decisions as to when an interim analysis in a diagnostic accuracy study is suitable and highlight areas for further methodological development.

Evidence for differences in patterns of temporal trends in meta-analyses of diagnostic accuracy studies in the Cochrane Database of Systematic Reviews.

OBJECTIVES: Temporal trends in comparative meta-analyses of interventions are well-recognised in the medical literature. For studies of diagnostic test accuracy (DTA), evidence of temporal trends is growing and the importance of assessing and reporting them has been highlighted in recent guidelines on post-market surveillance in several jurisdictions. In this study we evaluate the prevalence and patterns of time trends using a larger and more up-to-date set of DTA systematic reviews than has previously been examined, from the Cochrane Database of Systematic Reviews. STUDY DESIGN AND SETTING: Cumulative meta-analysis was conducted on bivariate random effects meta-analysis estimates of sensitivity and specificity, after ranking studies by publication date. Trends for all studies were assessed graphically using plots of summary estimates by study rank, and using ROC plots of sensitivity vs. specificity. Linear trends were also described using weighted linear regression with autocorrelated errors of summary estimates against study rank. Various patterns of non-linear trends were characterised descriptively. RESULTS: The analysis included 46 reviews (92 meta-analyses) conducted between 2017 and 2022. The total number of studies within all reviews was 1,486, with a median [IQR] 7,134 [2,782, 16,406] participants per review. Reviews had a median [IQR] time span of 19 [15,25] publication years. Time trends in at least one DTA measure were observed in 40 (87%) reviews, and statistically significant linear trends in 32 (71%) reviews. Non-linear time trends were observed in 16 (35%) reviews. There was no evidence for a trend in either DTA measure in 27 (59%) reviews. CONCLUSION: The study contributes evidence on the variety in patterns of linear and non-linear temporal DTA trends which has not previously been described. We recommended researchers check statistical assumptions of trend analysis methods, for example using graphical methods. Further research into potential reasons for time trends could contribute to the robustness of future meta-analyses.

Serrated polyposis syndrome: defining the epidemiology and predicting the risk of dysplasia.

BACKGROUND: Serrated polyposis syndrome is the most common polyposis syndrome that has neoplastic potential. However, the natural history, genetic basis, and risk of dysplasia and neoplasia of serrated polyposis syndrome are incompletely understood. The objective of this study is to define the epidemiology of serrated polyposis syndrome. Using this data, we aim to evaluate candidate variables for predicting the risk of dysplasia and neoplasia in sessile serrated lesions found in serrated polyposis syndrome patients. Finally, we aim to use this data to create and evaluate clinical prediction models for accuracy in predicting dysplastic sessile serrated lesions in serrated polyposis syndrome patients. METHODS: This was a regional Australian single-centre retrospective cohort study. Data was prospectively collected data from the clinical record database of a regional Australian gastroenterology practice. All patients undergoing colonoscopy at Port Macquarie Gastroenterology between January 2015 and September 2021 were screened for this study. Collected data included patient demographic, endoscopic, and histopathological findings. Clinical and endoscopic multivariate logistic regression models were created to predict dysplastic sessile serrated lesions. Model performance was examined using the area under the receiver operating curve. RESULTS: In total 8401 patients underwent a colonoscopy procedure during the study period. Serrated polyposis syndrome was diagnosed in 247, representing a prevalence of 2.94% (mean age 67.15 years, 62.75% female). Logistic regression identified; older age at serrated polyposis syndrome diagnosis, a personal history of colorectal cancer, size of the largest sessile serrated lesions removed, and total sessile serrated lesions count as predictors of dysplastic sessile serrated lesions. The clinical and endoscopic model had an area under the receiver operating curve of 0.75. CONCLUSION: Serrated polyposis syndrome is more common than previously described. The clinical and endoscopic variables identified in logistic regression have acceptable accuracy in predicting the risk of dysplasia, however other populations need to be studied to achieve generalisability and improve model performance.

Infections diagnosed in children and young people screened for malaria in UK emergency departments: a retrospective multi-centre study.

BACKGROUND: Data on imported infections in children and young people (CYP) are sparse. AIMS: To describe imported infections in CYP arriving from malaria-endemic areas and presenting to UK emergency departments (ED) who were screened for malaria. METHODS: This is a retrospective, multi-centre, observational study nested in a diagnostic accuracy study for malaria rapid diagnostic tests. Any CYP < 16 years presenting to a participating ED with a history of fever and travel to a malaria-endemic area between 1 January 2016 and 31 December 2017 and who had a malaria screen as a part of standard care were included. Geographical risk was calculated for the most common tropical infections. RESULTS: Of the 1414 CYP screened for malaria, 44.0% (n = 622) arrived from South Asia and 33.3% (n = 471) from sub-Saharan Africa. Half (50.0%) had infections common in both tropical and non-tropical settings such as viral upper respiratory tract infection (URTI); 21.0% of infections were coded as tropical if gastro-enteritis is included, with a total of 4.2% (60) cases of malaria. CYP diagnosed with malaria were 7.44 times more likely to have arrived from sub-Saharan Africa than from South Asia (OR 7.44, 3.78-16.41). CONCLUSION: A fifth of CYP presenting to participating UK EDs with fever and a history of travel to a malaria-endemic area and who were screened for malaria had a tropical infection if diarrhoea is included. A third of CYP had no diagnosis. CYP arriving from sub-Saharan Africa had the greatest risk of malaria.Abbreviations: CYP: children and young people; ED: emergency department; PERUKI: Paediatric Emergency Research in the UK and Ireland; RDT: rapid diagnostic test; VFR: visiting friends and relatives.

Epidemiology and microbiology of recurrent UTI in women in the community in Oxfordshire, UK.

Background: Recurrent urinary tract infection (rUTI) contributes to significant morbidity and antibiotic usage. Objectives: To characterize the age of women experiencing rUTI, the microbiology of rUTIs, and the risk of further rUTIs in Oxfordshire, UK. Patients and methods: We retrospectively analysed de-identified linked microbiology and hospital admissions data (Infections in Oxfordshire Research Database), between 2008 and 2019, including positive urine cultures from women aged ≥16 years in community settings. We defined rUTI as ≥2 positive urine cultures within 6 months or ≥3 within 12 months. Results: Of 201 927 women with urine culture performed, 84 809 (42%) had ≥1 positive culture, and 15 617 (18%) of these experienced ≥1 rUTI over a median (IQR) follow-up of 6 (3-9) years. Women with rUTI were 17.0 (95% CI: 16.3-17.7) years older on average. rUTI was commonest (6204; 40%) in those aged 70-89 years. Post-rUTI, the risk of further UTI within 6 months was 29.4% (95% CI: 28.7-30.2). Escherichia coli was detected in 65% of positive cultures. Among rUTIs where the index UTI was E. coli associated, the second UTI was also E. coli associated in 81% of cases. Conclusions: rUTIs represent a substantial healthcare burden, particularly in women >60 years. One-third of women experiencing rUTI have a further microbiologically confirmed UTI within 6 months.

Urine tenofovir and dried blood spot tenofovir diphosphate concentrations and viraemia in people taking efavirenz and dolutegravir-based antiretroviral therapy.

OBJECTIVE: We aimed to determine whether urine tenofovir (TFV) and dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations are associated with concurrent HIV viraemia. DESIGN: Cross-sectional study among people with HIV (PWH) receiving tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy (ART). METHODS: We used dual tandem liquid chromatography and mass spectrometry to measure urine TFV and DBS TFV-DP concentrations, and evaluated their associations with concurrent viraemia at least 1000 copies/ml using logistic regression models. In exploratory analyses, we used receiver operating curves (ROCs) to estimate optimal urine TFV and DBS TFV-DP thresholds to predict concurrent viraemia. RESULTS: Among 124 participants, 68 (54.8%) were women, median age was 39 years [interquartile range (IQR) 34-45] and 74 (59.7%) were receiving efavirenz versus 50 (40.3%) receiving dolutegravir. Higher concentrations of urine TFV [1000 ng/ml increase, odds ratio (OR) 0.97 95% CI 0.94-0.99, P  = 0.005] and DBS TFV-DP (100 fmol/punch increase, OR 0.76, 95% CI 0.67-0.86, P  < 0.001) were associated with lower odds of viraemia. There was evidence that these associations were stronger among people receiving dolutegravir than among people receiving efavirenz (urine TFV, P  = 0.072; DBS TFV-DP, P  = 0.003). Nagelkerke pseudo- R2 for the DBS TFV-DP models was higher for the urine TFV models, demonstrating a stronger relationship between DBS TFV-DP and viraemia. Among people receiving dolutegravir, a DBS TFV-DP concentration of 483 fmol/punch had 88% sensitivity and 85% specificity to predict concurrent viraemia ≥1000 copies/ml. CONCLUSION: Among PWH receiving TDF-based ART, urine TFV concentrations, and in particular DBS TFV-DP concentrations, were strongly associated with concurrent viraemia, especially among people receiving dolutegravir.

Diagnostic accuracy of a point-of-care antigen test for SARS-CoV-2 and influenza in a primary care population (RAPTOR-C19).

OBJECTIVES: Limited evidence exists for the diagnostic performance of point-of-care tests for SARS-CoV-2 and influenza in community healthcare. We carried out a prospective diagnostic accuracy study of the LumiraDx™ SARS-CoV-2 and influenza A or B assay in primary care. METHODS: Total of 913 adults and children with symptoms of current SARS-CoV-2 infection were recruited from 18 UK primary care practices during a period when Omicron was the predominant COVID variant of concern (June 2022 to December 2022). Trained health care staff performed the index test, with diagnostic accuracy parameters estimated for SARS-CoV-2 and influenza against real-time reverse-transcription PCR (rtRT-PCR). RESULTS: 151/887 participants were SARS-CoV-2 rtRT-PCR positive, 109 positive for Influenza A, 6 for Influenza B. Index test sensitivity for SARS-CoV-2 was 80.8% (122 of the 151, 95% CI, 73.6-86.7%) and specificity 98.9% (728 of the 736, 95% CI, 97.9-99.5%). For influenza A, sensitivity was 61.5% (67 of the 109, 95% CI, 51.7-70.6%) and specificity 99.4% (771 of the 776, 95% CI, 98.5-99.8%). Sensitivity to detect SARS-CoV-2 and influenza dropped sharply at rtRT-PCR cycle thresholds (Ct) > 30. DISCUSSIONS: The LumiraDx™ SARS-CoV-2 and influenza A/B assay had moderate sensitivity for SARS-CoV-2 in symptomatic patients in primary care, with lower performance with high rtRT-PCR Ct. Negative results in this patient group cannot definitively rule out SARS-CoV-2 or influenza.

Pharmacological and electronic cigarette interventions for smoking cessation in adults: component network meta-analyses.

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.

Evaluation of the diagnostic accuracy of two point-of-care tests for COVID-19 when used in symptomatic patients in community settings in the UK primary care COVID diagnostic accuracy platform trial (RAPTOR-C19).

BACKGROUND AND OBJECTIVE: Point-of-care lateral flow device antigen testing has been used extensively to identify individuals with active SARS-CoV-2 infection in the community. This study aimed to evaluate the diagnostic accuracy of two point-of-care tests (POCTs) for SARS-CoV-2 in routine community care. METHODS: Adults and children with symptoms consistent with suspected current COVID-19 infection were prospectively recruited from 19 UK general practices and two COVID-19 testing centres between October 2020 and October 2021. Participants were tested by trained healthcare workers using at least one of two index POCTs (Roche-branded SD Biosensor Standard™ Q SARS-CoV-2 Rapid Antigen Test and/or BD Veritor™ System for Rapid Detection of SARS-CoV-2). The reference standard was laboratory triplex reverse transcription quantitative PCR (RT-PCR) using a combined nasal/oropharyngeal swab. Diagnostic accuracy parameters were estimated, with 95% confidence intervals (CIs), overall, in relation to RT-PCR cycle threshold and in pre-specified subgroups. RESULTS: Of 663 participants included in the primary analysis, 39.2% (260/663, 95% CI 35.5% to 43.0%) had a positive RT-PCR result. The SD Biosensor POCT had sensitivity 84.0% (178/212, 78.3% to 88.6%) and specificity 98.5% (328/333, 96.5% to 99.5%), and the BD Veritor POCT had sensitivity 76.5% (127/166, 69.3% to 82.7%) and specificity 98.8% (249/252, 96.6% to 99.8%) compared with RT-PCR. Sensitivity of both devices dropped substantially at cycle thresholds ≥30 and in participants more than 7 days after onset of symptoms. CONCLUSIONS: Both POCTs assessed exceed the Medicines and Healthcare products Regulatory Agency target product profile's minimum acceptable specificity of 95%. Confidence intervals for both tests include the minimum acceptable sensitivity of 80%. In symptomatic patients, negative results on these two POCTs do not preclude the possibility of infection. Tests should not be expected to reliably detect disease more than a week after symptom onset, when viral load may be reduced. REGISTRATION: ISRCTN142269.

Evidence-based appraisal of two guidelines for the diagnosis of suspected, uncomplicated urinary tract infections in primary care: a diagnostic accuracy validation study.

OBJECTIVES: Given the lack of accurate rapid diagnostics for urinary tract infection (UTI) in women, many countries have developed guidelines aiming to support appropriate antibiotic prescribing, but some guidelines have not been validated. We performed a diagnostic accuracy validation study of two guidelines: Public Health England (GW-1263) and Scottish Intercollegiate Guidelines Network (SIGN160). METHODS: We used data from women with symptoms suggestive of uncomplicated UTI from a randomized controlled trial comparing urine collection devices. Symptom information was recorded via baseline questionnaire and primary care assessment. Women provided urine samples for dipstick testing and culture. We calculated the number within each risk category of diagnostic flowcharts who had positive/mixed growth/no significant growth urine culture. Results were presented as positive/negative predictive values, with 95% CIs. RESULTS: Of women aged under 65 years, 311/509 (61.1%, 95% CI 56.7%-65.3%) classified to the highest risk category (recommended to consider immediate antibiotic prescribing) and 80/199 (40.2%, 95% CI 33.4%-47.4%) classified to the lowest risk category (recommended to reassure that UTI is less likely) by the GW-1263 guideline (n = 810) had positive culture. For the SIGN160 guideline (n = 814), the proportion with positive culture ranged from 60/82 (73.2%, 95% CI 62.1%-82.1%) in those for whom immediate treatment was indicated to 33/76 (43.4%, 95% CI 32.3%-55.3%) in those recommended a self-care/waiting strategy. CONCLUSIONS: Clinicians should be aware of the potential for diagnostic error when using diagnostic guidelines for managing uncomplicated UTI and making antimicrobial prescribing decisions. Infection cannot be excluded on the basis of symptoms and dipstick testing alone.

Risk of death by suicide following self-harm presentations to healthcare: development and validation of a multivariable clinical prediction rule (OxSATS).

BACKGROUND: Assessment of suicide risk in individuals who have self-harmed is common in emergency departments, but is often based on tools developed for other purposes. OBJECTIVE: We developed and validated a predictive model for suicide following self-harm. METHODS: We used data from Swedish population-based registers. A cohort of 53 172 individuals aged 10+ years, with healthcare episodes of self-harm, was split into development (37 523 individuals, of whom 391 died from suicide within 12 months) and validation (15 649 individuals, 178 suicides within 12 months) samples. We fitted a multivariable accelerated failure time model for the association between risk factors and time to suicide. The final model contains 11 factors: age, sex, and variables related to substance misuse, mental health and treatment, and history of self-harm. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis guidelines were followed for the design and reporting of this work. FINDINGS: An 11-item risk model to predict suicide was developed using sociodemographic and clinical risk factors, and showed good discrimination (c-index 0.77, 95% CI 0.75 to 0.78) and calibration in external validation. For risk of suicide within 12 months, using a 1% cut-off, sensitivity was 82% (75% to 87%) and specificity was 54% (53% to 55%). A web-based risk calculator is available (Oxford Suicide Assessment Tool for Self-harm or OxSATS). CONCLUSIONS: OxSATS accurately predicts 12-month risk of suicide. Further validations and linkage to effective interventions are required to examine clinical utility. CLINICAL IMPLICATIONS: Using a clinical prediction score may assist clinical decision-making and resource allocation.

Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation.

BACKGROUND: Nicotine replacement therapy (NRT) aims to replace nicotine from cigarettes. This helps to reduce cravings and withdrawal symptoms, and ease the transition from cigarette smoking to complete abstinence. Although there is high-certainty evidence that NRT is effective for achieving long-term smoking abstinence, it is unclear whether different forms, doses, durations of treatment or timing of use impacts its effects. OBJECTIVES: To determine the effectiveness and safety of different forms, deliveries, doses, durations and schedules of NRT, for achieving long-term smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group trials register for papers mentioning NRT in the title, abstract or keywords, most recently in April 2022. SELECTION CRITERIA: We included randomised trials in people motivated to quit, comparing one type of NRT use with another. We excluded studies that did not assess cessation as an outcome, with follow-up of fewer than six months, and with additional intervention components not matched between arms. Separate reviews cover studies comparing NRT to control, or to other pharmacotherapies. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. We measured smoking abstinence after at least six months, using the most rigorous definition available. We extracted data on cardiac adverse events (AEs), serious adverse events (SAEs) and study withdrawals due to treatment.  MAIN RESULTS: We identified 68 completed studies with 43,327 participants, five of which are new to this update. Most completed studies recruited adults either from the community or from healthcare clinics. We judged 28 of the 68 studies to be at high risk of bias. Restricting the analysis only to those studies at low or unclear risk of bias did not significantly alter results for any comparisons apart from the preloading comparison, which tested the effect of using NRT prior to quit day whilst still smoking.  There is high-certainty evidence that combination NRT (fast-acting form plus patch) results in higher long-term quit rates than single form (risk ratio (RR) 1.27, 95% confidence interval (CI) 1.17 to 1.37; I2 = 12%; 16 studies, 12,169 participants). Moderate-certainty evidence, limited by imprecision, indicates that 42/44 mg patches are as effective as 21/22 mg (24-hour) patches (RR 1.09, 95% CI 0.93 to 1.29; I2 = 38%; 5 studies, 1655 participants), and that 21 mg patches are more effective than 14 mg (24-hour) patches (RR 1.48, 95% CI 1.06 to 2.08; 1 study, 537 participants). Moderate-certainty evidence, again limited by imprecision, also suggests a benefit of 25 mg over 15 mg (16-hour) patches, but the lower limit of the CI encompassed no difference (RR 1.19, 95% CI 1.00 to 1.41; I2 = 0%; 3 studies, 3446 participants). Nine studies tested the effect of using NRT prior to quit day (preloading) in comparison to using it from quit day onward. There was moderate-certainty evidence, limited by risk of bias, of a favourable effect of preloading on abstinence (RR 1.25, 95% CI 1.08 to 1.44; I2 = 0%; 9 studies, 4395 participants). High-certainty evidence from eight studies suggests that using either a form of fast-acting NRT or a nicotine patch results in similar long-term quit rates (RR 0.90, 95% CI 0.77 to 1.05; I2 = 0%; 8 studies, 3319 participants). We found no clear evidence of an effect of duration of nicotine patch use (low-certainty evidence); duration of combination NRT use (low- and very low-certainty evidence); or fast-acting NRT type (very low-certainty evidence). Cardiac AEs, SAEs and withdrawals due to treatment were all measured variably and infrequently across studies, resulting in low- or very low-certainty evidence for all comparisons. Most comparisons found no clear evidence of an effect on these outcomes, and rates were low overall. More withdrawals due to treatment were reported in people using nasal spray compared to patches in one study (RR 3.47, 95% CI 1.15 to 10.46; 1 study, 922 participants; very low-certainty evidence) and in people using 42/44 mg patches in comparison to 21/22 mg patches across two studies (RR 4.99, 95% CI 1.60 to 15.50; I2 = 0%; 2 studies, 544 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: There is high-certainty evidence that using combination NRT versus single-form NRT and 4 mg versus 2 mg nicotine gum can result in an increase in the chances of successfully stopping smoking. Due to imprecision, evidence was of moderate certainty for patch dose comparisons. There is some indication that the lower-dose nicotine patches and gum may be less effective than higher-dose products. Using a fast-acting form of NRT, such as gum or lozenge, resulted in similar quit rates to nicotine patches. There is moderate-certainty evidence that using NRT before quitting may improve quit rates versus using it from quit date only; however, further research is needed to ensure the robustness of this finding. Evidence for the comparative safety and tolerability of different types of NRT use is limited. New studies should ensure that AEs, SAEs and withdrawals due to treatment are reported.

Nicotine receptor partial agonists for smoking cessation.

BACKGROUND: Nicotine receptor partial agonists may help people to stop smoking by a combination of maintaining moderate levels of dopamine to counteract withdrawal symptoms (acting as an agonist) and reducing smoking satisfaction (acting as an antagonist). This is an update of a Cochrane Review first published in 2007. OBJECTIVES: To assess the effectiveness of nicotine receptor partial agonists, including varenicline and cytisine, for smoking cessation. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialised Register in April 2022 for trials, using relevant terms in the title or abstract, or as keywords. The register is compiled from searches of CENTRAL, MEDLINE, Embase, and PsycINFO.  SELECTION CRITERIA: We included randomised controlled trials that compared the treatment drug with placebo, another smoking cessation drug, e-cigarettes, or no medication. We excluded trials that did not report a minimum follow-up period of six months from baseline. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods. Our main outcome was abstinence from smoking at longest follow-up using the most rigorous definition of abstinence, preferring biochemically validated rates where reported. We pooled risk ratios (RRs), using the Mantel-Haenszel fixed-effect model. We also reported the number of people reporting serious adverse events (SAEs). MAIN RESULTS: We included 75 trials of 45,049 people; 45 were new for this update. We rated 22 at low risk of bias, 18 at high risk, and 35 at unclear risk. We found moderate-certainty evidence (limited by heterogeneity) that cytisine helps more people to quit smoking than placebo (RR 1.30, 95% confidence interval (CI) 1.15 to 1.47; I2 = 83%; 4 studies, 4623 participants), and no evidence of a difference in the number reporting SAEs (RR 1.04, 95% CI 0.78 to 1.37; I2 = 0%; 3 studies, 3781 participants; low-certainty evidence). SAE evidence was limited by imprecision. We found no data on neuropsychiatric or cardiac SAEs. We found high-certainty evidence that varenicline helps more people to quit than placebo (RR 2.32, 95% CI 2.15 to 2.51; I2 = 60%, 41 studies, 17,395 participants), and moderate-certainty evidence that people taking varenicline are more likely to report SAEs than those not taking it (RR 1.23, 95% CI 1.01 to 1.48; I2 = 0%; 26 studies, 14,356 participants). While point estimates suggested increased risk of cardiac SAEs (RR 1.20, 95% CI 0.79 to 1.84; I2 = 0%; 18 studies, 7151 participants; low-certainty evidence), and decreased risk of neuropsychiatric SAEs (RR 0.89, 95% CI 0.61 to 1.29; I2 = 0%; 22 studies, 7846 participants; low-certainty evidence), in both cases evidence was limited by imprecision, and confidence intervals were compatible with both benefit and harm. Pooled results from studies that randomised people to receive cytisine or varenicline showed that more people in the varenicline arm quit smoking (RR 0.83, 95% CI 0.66 to 1.05; I2 = 0%; 2 studies, 2131 participants; moderate-certainty evidence) and reported SAEs (RR 0.67, 95% CI 0.44 to 1.03; I2 = 45%; 2 studies, 2017 participants; low-certainty evidence). However, the evidence was limited by imprecision, and confidence intervals incorporated the potential for benefit from either cytisine or varenicline. We found no data on neuropsychiatric or cardiac SAEs. We found high-certainty evidence that varenicline helps more people to quit than bupropion (RR 1.36, 95% CI 1.25 to 1.49; I2 = 0%; 9 studies, 7560 participants), and no clear evidence of difference in rates of SAEs (RR 0.89, 95% CI 0.61 to 1.31; I2 = 0%; 5 studies, 5317 participants), neuropsychiatric SAEs (RR 1.05, 95% CI 0.16 to 7.04; I2 = 10%; 2 studies, 866 participants), or cardiac SAEs (RR 3.17, 95% CI 0.33 to 30.18; I2 = 0%; 2 studies, 866 participants). Evidence of harms was of low certainty, limited by imprecision. We found high-certainty evidence that varenicline helps more people to quit than a single form of nicotine replacement therapy (NRT) (RR 1.25, 95% CI 1.14 to 1.37; I2 = 28%; 11 studies, 7572 participants), and low-certainty evidence, limited by imprecision, of fewer reported SAEs (RR 0.70, 95% CI 0.50 to 0.99; I2 = 24%; 6 studies, 6535 participants). We found no data on neuropsychiatric or cardiac SAEs. We found no clear evidence of a difference in quit rates between varenicline and dual-form NRT (RR 1.02, 95% CI 0.87 to 1.20; I2 = 0%; 5 studies, 2344 participants; low-certainty evidence, downgraded because of imprecision). While pooled point estimates suggested increased risk of SAEs (RR 2.15, 95% CI 0.49 to 9.46; I2 = 0%; 4 studies, 1852 participants) and neuropsychiatric SAEs (RR 4.69, 95% CI 0.23 to 96.50; I2 not estimable as events only in 1 study; 2 studies, 764 participants), and reduced risk of cardiac SAEs (RR 0.32, 95% CI 0.01 to 7.88; I2 not estimable as events only in 1 study; 2 studies, 819 participants), in all three cases evidence was of low certainty and confidence intervals were very wide, encompassing both substantial harm and benefit. AUTHORS' CONCLUSIONS: Cytisine and varenicline both help more people to quit smoking than placebo or no medication. Varenicline is more effective at helping people to quit smoking than bupropion, or a single form of NRT, and may be as or more effective than dual-form NRT. People taking varenicline are probably more likely to experience SAEs than those not taking it, and while there may be increased risk of cardiac SAEs and decreased risk of neuropsychiatric SAEs, evidence was compatible with both benefit and harm. Cytisine may lead to fewer people reporting SAEs than varenicline. Based on studies that directly compared cytisine and varenicline, there may be a benefit from varenicline for quitting smoking, however further evidence could strengthen this finding or demonstrate a benefit from cytisine. Future trials should test the effectiveness and safety of cytisine compared with varenicline and other pharmacotherapies, and should also test variations in dose and duration. There is limited benefit to be gained from more trials testing the effect of standard-dose varenicline compared with placebo for smoking cessation. Further trials on varenicline should test variations in dose and duration, and compare varenicline with e-cigarettes for smoking cessation.

A Diagnostic Accuracy Study to Evaluate Standard Rapid Diagnostic Test (RDT) Alone to Safely Rule Out Imported Malaria in Children Presenting to UK Emergency Departments.

BACKGROUND: Microscopy is the gold standard for malaria diagnosis but is dependent on trained personnel. Rapid diagnostic tests (RDTs) form the mainstay of diagnosis in endemic areas without access to high-quality microscopy. We aimed to evaluate whether RDT alone could rule out imported malaria in children presenting to UK emergency departments (EDs). METHODS: UK-based, multi-center, retrospective, diagnostic accuracy study. Included: any child <16 years presenting to ED with history of fever and travel to a malaria-endemic country, between 01/01/2016 and 31/12/2017. Diagnosis: microscopy for malarial parasites (clinical reference standard) and RDT (index test). UK Health Research Authority approval: 20/HRA/1341. RESULTS: There were 47 cases of malaria out of 1,414 eligible cases (prevalence 3.3%) in a cohort of children whose median age was 4 years (IQR 2-9), of whom 43% were female. Cases of Plasmodium falciparum totaled 36 (77%, prevalence 2.5%). The sensitivity of RDT alone to detect malaria infection due to any Plasmodium species was 93.6% (95% CI 82.5-98.7%), specificity 99.4% (95% CI 98.9-99.7%), positive predictive value 84.6% (95% CI 71.9-93.1%) and negative predictive value 99.8% (95% CI 99.4-100.0%). Sensitivity of RDT to detect P. falciparum infection was 100% (90.3-100%), specificity 98.8% (98.1-99.3%), positive predictive value 69.2% (54.9-81.2%, n = 46/52) and negative predictive value 100% (99.7-100%, n = 1,362/1,362). CONCLUSIONS: RDTs were 100% sensitive in detecting P. falciparum malaria. However, lower sensitivity for other malaria species and the rise of pfhrp2 and pfhrp3 (pfhrp2/3) gene deletions in the P. falciparum parasite mandate the continued use of microscopy for diagnosing malaria.

Diagnostic accuracy of natriuretic peptide screening for left ventricular systolic dysfunction in the community: systematic review and meta-analysis.

AIMS: Heart failure (HF) is a global health burden and new strategies to achieve timely diagnosis and early intervention are urgently needed. Natriuretic peptide (NP) testing can be used to screen for left ventricular systolic dysfunction (LVSD), but evidence on test performance is mixed, and international HF guidelines differ in their recommendations. Our aim was to summarize the evidence on diagnostic accuracy of NP screening for LVSD in general and high-risk community populations and estimate optimal screening thresholds. METHODS: We searched relevant databases up to August 2020 for studies with a screened community population of over 100 adults reporting NP performance to diagnose LVSD. Study inclusion, quality assessment, and data extraction were conducted independently and in duplicate. Diagnostic test meta-analysis used hierarchical summary receiver operating characteristic curves to obtain estimates of pooled accuracy to detect LVSD, with optimal thresholds obtained to maximize the sum of sensitivity and specificity. RESULTS: Twenty-four studies were identified, involving 26 565 participants: eight studies in high-risk populations (at least one cardiovascular risk factor), 12 studies in general populations, and four in both high-risk and general populations combined. For detecting LVSD in screened high-risk populations with N-terminal prohormone brain natriuretic peptide (NT-proBNP), the pooled sensitivity was 0.87 [95% confidence interval (CI) 0.73-0.94] and specificity 0.84 (95% CI 0.55-0.96); for BNP, sensitivity was 0.75 (95% CI 0.65-0.83) and specificity 0.78 (95% CI 0.72-0.84). Heterogeneity between studies was high with variations in positivity threshold. Due to a paucity of high-risk studies that assessed NP performance at multiple thresholds, it was not possible to calculate optimal thresholds for LVSD screening in high-risk populations alone. To provide an indication of where the positivity threshold might lie, the pooled accuracy for LVSD screening in high-risk and general community populations were combined and gave an optimal cut-off of 311 pg/mL [sensitivity 0.74 (95% CI 0.53-0.88), specificity 0.85 (95% CI 0.68-0.93)] for NT-proBNP and 49 pg/mL [sensitivity 0.68 (95% CI 0.45-0.85), specificity 0.81 (0.67-0.90)] for BNP. CONCLUSIONS: Our findings suggest that in high-risk community populations NP screening may accurately detect LVSD, potentially providing an important opportunity for diagnosis and early intervention. Our study highlights an urgent need for further prospective studies, as well as an individual participant data meta-analysis, to more precisely evaluate diagnostic accuracy and identify optimal screening thresholds in specifically defined community-based populations to inform future guideline recommendations.

Electronic cigarettes for smoking cessation.

BACKGROUND: Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol by heating an e-liquid. Some people who smoke use ECs to stop or reduce smoking, although some organizations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit smoking, and if they are safe to use for this purpose. This is a review update conducted as part of a living systematic review. OBJECTIVES: To examine the effectiveness, tolerability, and safety of using electronic cigarettes (ECs) to help people who smoke tobacco achieve long-term smoking abstinence. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 July 2022, and reference-checked and contacted study authors.  SELECTION CRITERIA: We included randomized controlled trials (RCTs) and randomized cross-over trials, in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. Studies had to report abstinence from cigarettes at six months or longer or data on safety markers at one week or longer, or both. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow-up, adverse events (AEs), and serious adverse events (SAEs). Secondary outcomes included the proportion of people still using study product (EC or pharmacotherapy) at six or more months after randomization or starting EC use, changes in carbon monoxide (CO), blood pressure (BP), heart rate, arterial oxygen saturation, lung function, and levels of carcinogens or toxicants, or both. We used a fixed-effect Mantel-Haenszel model to calculate risk ratios (RRs) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data in meta-analyses. MAIN RESULTS: We included 78 completed studies, representing 22,052 participants, of which 40 were RCTs. Seventeen of the 78 included studies were new to this review update. Of the included studies, we rated ten (all but one contributing to our main comparisons) at low risk of bias overall, 50 at high risk overall (including all non-randomized studies), and the remainder at unclear risk. There was high certainty that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (RR 1.63, 95% CI 1.30 to 2.04; I2 = 10%; 6 studies, 2378 participants). In absolute terms, this might translate to an additional four quitters per 100 (95% CI 2 to 6). There was moderate-certainty evidence (limited by imprecision) that the rate of occurrence of AEs was similar between groups (RR 1.02, 95% CI 0.88 to 1.19; I2 = 0%; 4 studies, 1702 participants). SAEs were rare, but there was insufficient evidence to determine whether rates differed between groups due to very serious imprecision (RR 1.12, 95% CI 0.82 to 1.52; I2 = 34%; 5 studies, 2411 participants). There was moderate-certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non-nicotine EC (RR 1.94, 95% CI 1.21 to 3.13; I2 = 0%; 5 studies, 1447 participants). In absolute terms, this might lead to an additional seven quitters per 100 (95% CI 2 to 16). There was moderate-certainty evidence of no difference in the rate of AEs between these groups (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 5 studies, 1840 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 1.00, 95% CI 0.56 to 1.79; I2 = 0%; 8 studies, 1272 participants). Compared to behavioural support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.66, 95% CI 1.52 to 4.65; I2 = 0%; 7 studies, 3126 participants). In absolute terms, this represents an additional two quitters per 100 (95% CI 1 to 3). However, this finding was of very low certainty, due to issues with imprecision and risk of bias. There was some evidence that (non-serious) AEs were more common in people randomized to nicotine EC (RR 1.22, 95% CI 1.12 to 1.32; I2 = 41%, low certainty; 4 studies, 765 participants) and, again, insufficient evidence to determine whether rates of SAEs differed between groups (RR 1.03, 95% CI 0.54 to 1.97; I2 = 38%; 9 studies, 1993 participants).  Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued EC use. Very few studies reported data on other outcomes or comparisons, hence evidence for these is limited, with CIs often encompassing clinically significant harm and benefit. AUTHORS' CONCLUSIONS: There is high-certainty evidence that ECs with nicotine increase quit rates compared to NRT and moderate-certainty evidence that they increase quit rates compared to ECs without nicotine. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the effect size. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, with no difference in AEs between nicotine and non-nicotine ECs nor between nicotine ECs and NRT. Overall incidence of SAEs was low across all study arms. We did not detect evidence of serious harm from nicotine EC, but longest follow-up was two years and the number of studies was small. The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates, but further RCTs are underway. To ensure the review continues to provide up-to-date information to decision-makers, this review is a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.

Longer-term use of electronic cigarettes when provided as a stop smoking aid: Systematic review with meta-analyses.

Moderate certainty evidence supports use of nicotine electronic cigarettes to quit smoking combustible cigarettes. However, there is less certainty regarding how long people continue to use e-cigarettes after smoking cessation attempts. We set out to synthesise data on the proportion of people still using e-cigarettes or other study products at 6 months or longer in studies of e-cigarettes for smoking cessation. We updated Cochrane searches (November 2021). For the first time, we meta-analysed prevalence of continued e-cigarette use among individuals allocated to e-cigarette conditions, and among those individuals who had successfully quit smoking. We updated meta-analyses comparing proportions continuing product use among individuals allocated to use nicotine e-cigarettes and other treatments. We included 19 studies (n = 7787). The pooled prevalence of continued e-cigarette use at 6 months or longer was 54% (95% CI: 46% to 61%, I2 86%, N = 1482) in participants assigned to e-cigarette conditions. Of participants who had quit combustible cigarettes overall 70% were still using e-cigarettes at six months or longer (95% CI: 53% to 82%, I2 73%, N = 215). Heterogeneity in direction of effect precluded meta-analysis comparing long-term use of nicotine e-cigarettes with NRT. More people were using nicotine e-cigarettes at longest follow-up compared to non-nicotine e-cigarettes, but CIs included no difference (risk ratio 1.15, 95% CI: 0.94 to 1.41, n = 601). The levels of continued e-cigarette use observed may reflect the success of e-cigarettes as a quitting tool. Further research is needed to establish drivers of variation in and implications of continued use of e-cigarettes.

The Impact of Point-of-Care Blood C-Reactive Protein Testing on Prescribing Antibiotics in Out-of-Hours Primary Care: A Mixed Methods Evaluation.

Improving prescribing antibiotics appropriately for respiratory infections in primary care is an antimicrobial stewardship priority. There is limited evidence to support interventions to reduce prescribing antibiotics in out-of-hours (OOH) primary care. Herein, we report a service innovation where point-of-care C-Reactive Protein (CRP) machines were introduced to three out-of-hours primary care clinical bases in England from August 2018-December 2019, which were compared with four control bases that did not have point-of-care CRP testing. We undertook a mixed-method evaluation, including a comparative interrupted time series analysis to compare monthly antibiotic prescription rates between bases with CRP machines and those without, an analysis of the number of and reasons for the tests performed, and qualitative interviews with clinicians. Antibiotic prescription rates declined during follow-up, but with no clear difference between the two groups of out-of-hours practices. A single base contributed 217 of the 248 CRP tests performed. Clinicians reported that the tests supported decision making and communication about not prescribing antibiotics, where having 'objective' numbers were helpful in navigating non-prescribing decisions and highlighted the challenges of training a fluctuant staff group and practical concerns about using the CRP machine. Service improvements to reduce prescribing antibiotics in out-of-hours primary care need to be developed with an understanding of the needs and context of this service.