Effectiveness of behavioural interventions with motivational interviewing on physical activity outcomes in adults: systematic review and meta-analysis.

OBJECTIVE: To evaluate the effectiveness of behavioural interventions that include motivational interviewing on physical activity outcomes in adults. DESIGN: Systematic review and meta-analysis. STUDY SELECTION: A search of seven databases for randomised controlled trials published from inception to 1 March 2023 comparing a behavioural intervention including motivational interviewing with a comparator without motivational interviewing on physical activity outcomes in adults. Outcomes of interest were differences in change in quantitative measures of total physical activity, moderate to vigorous physical activity (MVPA), and sedentary time. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted data and assessed risk of bias. Population characteristics, intervention components, comparison groups, and outcomes of studies were summarised. For overall main effects, random effects meta-analyses were used to report standardised mean differences (SMDs) and 95% confidence intervals (CIs). Differential effects based on duration of follow-up, comparator type, intervention duration, and disease or health condition of participants were also examined. RESULTS: 129 papers reporting 97 randomised controlled trials totalling 27 811 participants and 105 comparisons were included. Interventions including motivational interviewing were superior to comparators for increases in total physical activity (SMD 0.45, 95% CI 0.33 to 0.65, equivalent to 1323 extra steps/day; low certainty evidence) and MVPA (0.45, 0.19 to 0.71, equivalent to 95 extra min/week; very low certainty evidence) and for reductions in sedentary time (-0.58, -1.03 to -0.14, equivalent to -51 min/day; very low certainty evidence). Evidence for a difference in any outcome compared with comparators of similar intensity was lacking. The magnitude of effect diminished over time, and evidence of an effect of motivational interviewing beyond one year was lacking. Most interventions involved patients with a specific health condition, and evidence of an effect of motivational interviewing to increase MVPA or decrease sedentary time was lacking in general population samples. CONCLUSIONS: Certainty of the evidence using motivational interviewing as part of complex behavioural interventions for promoting total physical activity in adults was low, and for MVPA and sedentary time was very low. The totality of evidence suggests that although interventions with motivational interviewing increase physical activity and decrease sedentary behaviour, no difference was found in studies where the effect of motivational interviewing could be isolated. Effectiveness waned over time, with no evidence of a benefit of motivational interviewing to increase physical activity beyond one year. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020219881.

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.

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.

Clinician resistance to broaching the topic of weight in primary care: Digging deeper into weight management using strong structuration theory.

Clinical trials have shown that providing advice and support for people with excess weight can lead to meaningful weight loss. Despite this evidence and guidelines endorsing this approach, provision in real-world clinical settings remains low. We used Strong Structuration Theory (SST) to understand why people are often not offered weight management advice in primary care in England. Data from policy, clinical practice and focus groups were analysed using SST to consider how the interplay between weight stigma and structures of professional responsibilities influenced clinicians to raise (or not) the issue of excess weight with patients. We found that general practitioners (GPs) often accounted for their actions by referring to obesity as a health problem, consistent with policy documents and clinical guidelines. However, they were also aware of weight stigma as a social process that can be internalised by their patients. GPs identified addressing obesity as a priority in their work, but described wanting to care for their patients by avoiding unnecessary suffering, which they were concerned could be caused by talking about weight. We observed tensions between knowledge of clinical guidelines and understanding of the lived experience of their patients. We interpreted that the practice of 'caring by not offering care' produced the outcome of an absence of weight management advice in consultations. There is a risk that this outcome reinforces the external structure of weight stigma as a delicate topic to be avoided, while at the same time denying patients the offer of support to manage their weight.

Antidepressants for smoking cessation.

BACKGROUND: The pharmacological profiles and mechanisms of antidepressants are varied. However, there are common reasons why they might help people to stop smoking tobacco: nicotine withdrawal can produce short-term low mood that antidepressants may relieve; and some antidepressants may have a specific effect on neural pathways or receptors that underlie nicotine addiction. OBJECTIVES: To assess the evidence for the efficacy, harms, and tolerability of medications with antidepressant properties in assisting long-term tobacco smoking cessation in people who smoke cigarettes. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group Specialised Register, most recently on 29 April 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) in people who smoked, comparing antidepressant medications with placebo or no pharmacological treatment, an alternative pharmacotherapy, or the same medication used differently. We excluded trials with fewer than six months of follow-up from efficacy analyses. We included trials with any follow-up length for our analyses of harms. DATA COLLECTION AND ANALYSIS: We extracted data and assessed risk of bias using standard Cochrane methods. Our primary outcome measure was smoking cessation after at least six months' follow-up. We used the most rigorous definition of abstinence available in each trial, and biochemically validated rates if available. Our secondary outcomes were harms and tolerance outcomes, including adverse events (AEs), serious adverse events (SAEs), psychiatric AEs, seizures, overdoses, suicide attempts, death by suicide, all-cause mortality, and trial dropouts due to treatment. We carried out meta-analyses where appropriate. MAIN RESULTS: We included a total of 124 studies (48,832 participants) in this review, with 10 new studies added to this update version. Most studies recruited adults from the community or from smoking cessation clinics; four studies focused on adolescents (with participants between 12 and 21 years old). We judged 34 studies to be at high risk of bias; however, restricting analyses only to studies at low or unclear risk of bias did not change clinical interpretation of the results.  There was high-certainty evidence that bupropion increased smoking cessation rates when compared to placebo or no pharmacological treatment (RR 1.60, 95% CI 1.49 to 1.72; I2 = 16%; 50 studies, 18,577 participants). There was moderate-certainty evidence that a combination of bupropion and varenicline may have resulted in superior quit rates to varenicline alone (RR 1.21, 95% CI 0.95 to 1.55; I2 = 15%; 3 studies, 1057 participants). However, there was insufficient evidence to establish whether a combination of bupropion and nicotine replacement therapy (NRT) resulted in superior quit rates to NRT alone (RR 1.17, 95% CI 0.95 to 1.44; I2 = 43%; 15 studies, 4117 participants; low-certainty evidence). There was moderate-certainty evidence that participants taking bupropion were more likely to report SAEs than those taking placebo or no pharmacological treatment. However, results were imprecise and the CI also encompassed no difference (RR 1.16, 95% CI 0.90 to 1.48; I2 = 0%; 23 studies, 10,958 participants). Results were also imprecise when comparing SAEs between people randomised to a combination of bupropion and NRT versus NRT alone (RR 1.52, 95% CI 0.26 to 8.89; I2 = 0%; 4 studies, 657 participants) and randomised to bupropion plus varenicline versus varenicline alone (RR 1.23, 95% CI 0.63 to 2.42; I2 = 0%; 5 studies, 1268 participants). In both cases, we judged evidence to be of low certainty. There was high-certainty evidence that bupropion resulted in more trial dropouts due to AEs than placebo or no pharmacological treatment (RR 1.44, 95% CI 1.27 to 1.65; I2 = 2%; 25 studies, 12,346 participants). However, there was insufficient evidence that bupropion combined with NRT versus NRT alone (RR 1.67, 95% CI 0.95 to 2.92; I2 = 0%; 3 studies, 737 participants) or bupropion combined with varenicline versus varenicline alone (RR 0.80, 95% CI 0.45 to 1.45; I2 = 0%; 4 studies, 1230 participants) had an impact on the number of dropouts due to treatment. In both cases, imprecision was substantial (we judged the evidence to be of low certainty for both comparisons). Bupropion resulted in inferior smoking cessation rates to varenicline (RR 0.73, 95% CI 0.67 to 0.80; I2 = 0%; 9 studies, 7564 participants), and to combination NRT (RR 0.74, 95% CI 0.55 to 0.98; I2 = 0%; 2 studies; 720 participants). However, there was no clear evidence of a difference in efficacy between bupropion and single-form NRT (RR 1.03, 95% CI 0.93 to 1.13; I2 = 0%; 10 studies, 7613 participants). We also found evidence that nortriptyline aided smoking cessation when compared with placebo (RR 2.03, 95% CI 1.48 to 2.78; I2 = 16%; 6 studies, 975 participants), and some evidence that bupropion resulted in superior quit rates to nortriptyline (RR 1.30, 95% CI 0.93 to 1.82; I2 = 0%; 3 studies, 417 participants), although this result was subject to imprecision. Findings were sparse and inconsistent as to whether antidepressants, primarily bupropion and nortriptyline, had a particular benefit for people with current or previous depression. AUTHORS' CONCLUSIONS: There is high-certainty evidence that bupropion can aid long-term smoking cessation. However, bupropion may increase SAEs (moderate-certainty evidence when compared to placebo/no pharmacological treatment). There is high-certainty evidence that people taking bupropion are more likely to discontinue treatment compared with people receiving placebo or no pharmacological treatment. Nortriptyline also appears to have a beneficial effect on smoking quit rates relative to placebo, although bupropion may be more effective. Evidence also suggests that bupropion may be as successful as single-form NRT in helping people to quit smoking, but less effective than combination NRT and varenicline. In most cases, a paucity of data made it difficult to draw conclusions regarding harms and tolerability. Further studies investigating the efficacy of bupropion versus placebo are unlikely to change our interpretation of the effect, providing no clear justification for pursuing bupropion for smoking cessation over other licensed smoking cessation treatments; namely, NRT and varenicline. However, it is important that future studies of antidepressants for smoking cessation measure and report on harms and tolerability.

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.

Measures of Retention in HIV Care: A Study Within a Review.

People living with HIV (PLHIV) need lifelong medical care. However, retention in HIV care is not measured uniformly, making it challenging to compare or pool data. The objective of this study within a review (SWAR) is to describe the assortment of definitions used for retention in HIV care in randomized controlled trials (RCTs). We conducted a SWAR, drawing data from an overview of systematic reviews on interventions to improve the HIV care cascade. Ethics review was not required for this analysis of secondary data. We identified RCTs of interventions used to improve retention in care for PLHIV, including all age groups and extracted the definitions used and their characteristics. We identified 50 trials that measured retention published between 2007 and 2021 and provided 59 definitions for retention in care. The definitions consisted of nine different characteristics with follow-up time (n = 47), and clinical visits (n = 36) most used. The definitions of retention in HIV care are highly heterogeneous. In this study, we present the pros and cons of characteristics used to measure retention in HIV care.

Smoking cessation for secondary prevention of cardiovascular disease.

BACKGROUND: Smoking is a leading cause of cardiovascular disease (CVD), particularly coronary heart disease (CHD). However, quitting smoking may prevent secondary CVD events in people already diagnosed with CHD.  OBJECTIVES: To examine the impact of smoking cessation on death from CVD and major adverse cardiovascular events (MACE), in people with incident CHD. SEARCH METHODS: We searched the Cochrane Tobacco Addiction Group's Specialised Register, CENTRAL, MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, and the trials registries clinicaltrials.gov and the International Clinical Trials Registry Platform. We ran all searches from database inception to 15 April 2021.  SELECTION CRITERIA: We included cohort studies, and both cluster- and individually randomised controlled trials of at least six months' duration. We treated all included studies as cohort studies and analysed them by smoking status at follow-up. Eligible studies had to recruit adults (> 18 years) with diagnosed CHD and who smoked tobacco at diagnosis, and assess whether they quit or continued smoking during the study. Studies had to measure at least one of our included outcomes with at least six months' follow-up. Our primary outcomes were death from CVD and MACE. Secondary outcomes included all-cause mortality, non-fatal myocardial infarction, non-fatal stroke, new-onset angina and change in quality of life.  DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methods for screening and data extraction.  We assessed the risk of bias for the primary outcomes using the ROBINS-I tool. We compared the incidence of death from CVD and of MACE (primary outcomes) between participants who quit smoking versus those who continued to smoke for each included study that reported these outcomes. We also assessed differences in all-cause mortality, incidence of non-fatal myocardial infarction, incidence of non-fatal stroke and new onset angina. We calculated hazard ratios (HRs) and 95% confidence intervals (95% CI). For our outcome, change in quality of life, we calculated the pooled standardised mean difference (SMD) and 95% CI for the difference in change in quality of life from baseline to follow-up between those who had quit smoking and those who had continued to smoke. For all meta-analyses we used a generic inverse variance random-effects model and quantified statistical heterogeneity using the I²statistic. We assessed the certainty of evidence for our primary outcomes using the eight GRADE considerations relevant to non-randomised studies. MAIN RESULTS: We included 68 studies, consisting of 80,702 participants. For both primary outcomes, smoking cessation was associated with a decreased risk compared with continuous smoking: CVD death (HR 0.61, 95% CI 0.49 to 0.75; I² = 62%; 18 studies, 17,982 participants; moderate-certainty evidence) and MACE (HR 0.57, 95% CI 0.45 to 0.71; I² = 84%; 15 studies, 20,290 participants; low-certainty evidence). These findings were robust to our planned sensitivity analyses. Through subgroup analysis, for example comparing adjusted versus non-adjusted estimates, we found no evidence of differences in the effect size. While there was substantial heterogeneity, this was primarily in magnitude rather than the direction of the effect estimates. Overall, we judged 11 (16%) studies to be at moderate risk of bias and 18 (26%) at serious risk, primarily due to possible confounding. There was also some evidence of funnel plot asymmetry for MACE outcomes. For these reasons, we rated our certainty in the estimates for CVD death as moderate and MACE as low.  For our secondary outcomes, smoking cessation was associated with a decreased risk in all-cause mortality (HR 0.60, 95% CI 0.55 to 0.66; I² = 58%; 48 studies, 59,354 participants), non-fatal myocardial infarction (HR 0.64, 95% CI 0.58 to 0.72; I² = 2%; 24 studies, 23,264 participants) and non-fatal stroke (HR 0.70, 95% CI 0.53 to 0.90; I² = 0%; 9 studies, 11,352 participants). As only one study reported new onset of angina, we did not conduct meta-analysis, but this study reported a lower risk in people who stopped smoking. Quitting smoking was not associated with a worsening of quality of life and suggested improvement in quality of life, with the lower bound of the CI also consistent with no difference (SMD 0.12, 95% CI 0.01 to 0.24; I² = 48%; 8 studies, 3182 participants).  AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that smoking cessation is associated with a reduction of approximately one-third in the risk of recurrent cardiovascular disease in people who stop smoking at diagnosis. This association may be causal, based on the link between smoking cessation and restoration of endothelial and platelet function, where dysfunction of both can result in increased likelihood of CVD events.  Our results provide evidence that there is a decreased risk of secondary CVD events in those who quit smoking compared with those who continue, and that there is a suggested improvement in quality of life as a result of quitting smoking. Additional studies that account for confounding, such as use of secondary CVD prevention medication, would strengthen the evidence in this area.

Setting the top 10 priorities for obesity and weight-related research (POWeR): a stakeholder priority setting process.

OBJECTIVES: To identify and prioritise the most impactful, unanswered questions for obesity and weight-related research. DESIGN: Prioritisation exercise of research questions using online surveys and an independently facilitated workshop. SETTING: Online/virtual. PARTICIPANTS: We involved members of the public including people living with obesity, researchers, healthcare professionals and policy-makers in all stages of this study. PRIMARY OUTCOME MEASURES: Top 10 research questions to be prioritised in future obesity and weight-related research. RESULTS: Survey 1 produced 941 questions, from 278 respondents. Of these, 49 questions held satisfactory evidence in the scientific literature and 149 were out of scope. The remaining 743 questions were, where necessary, amalgamated and rephrased, into a list of 149 unique and unanswered questions. In the second survey, 405 respondents ranked the questions in order of importance. During the workshop, a subset of 38 survey respondents and stakeholders, agreed a final list of 10 priority research questions through small and large group consultation and consensus. The top 10 priority research questions covered: the role of the obesogenic environment; effective weight loss and maintenance strategies; prevention in children; effective prevention and treatment policies; the role of the food industry; access to and affordability of a healthy diet; sociocultural factors associated with weight; the biology of appetite and food intake; and long-term health modelling for obesity. CONCLUSIONS: This systematic and transparent process identified 149 unique and unanswered questions in the field of obesity and weight-related research culminating in a consensus among relevant stakeholders on 10 research priorities. Targeted research funding in these areas of top priority would lead to needed and impactful knowledge generation for the field of obesity and weight regulation and thereby improve population health.

In-Hospital Macro-, Meso-, and Micro-Drivers and Interventions for Antibiotic Use and Resistance: A Rapid Evidence Synthesis of Data from Canada and Other OECD Countries.

Hospitals continue to face challenges in reducing incorrect antibiotic use due to social and cultural factors at the level of the health system, the care facility, the provider, and the patient. The objective of this paper is to highlight the social and cultural drivers of antimicrobial use and resistance and targeted interventions for secondary and tertiary care settings in Canada and other OECD countries. This paper is an extension of the synthesis conducted for the Public Health Agency of Canada's 2019 Spotlight Report: Preserving Antibiotics Now and Into the Future. We conducted a systematic review with a few modifications to meet rapid timelines. We conducted a search in Ovid MEDLINE and McMaster University's evidence databases for systematic reviews and then for individual Canadian studies. To cast a wider net, we searched OECD organization websites and screened reference lists from systematic reviews. We synthesized the evidence narratively and categorized the evidence into macro-, meso-, and microlevel. A total of 70 studies were (a) from OCED countries and summarized evidence of potential sociocultural antimicrobial resistance and use barriers or facilitators and/or interventions addressing these challenges; (b) systematic reviews with 50% of included studies that are situated in secondary and tertiary settings; and (c) published in Canada's two official languages, English and French. We found that hospital structures and policies may influence antibiotic utilization and variations in antimicrobial management. Microlevel factors may sway inappropriate prescribing among clinicians. The amount and type of antibiotics used may affect resistance rates. Interventions were mainly comprised of antibiotic stewardship and training that modify clinician behavior and that educate patients and carers. This evidence synthesis illustrates the various drivers of, and interventions for, antimicrobial use and resistance at the macro-, meso-, and microlevel in secondary and tertiary settings. We demonstrate that upstream drivers may lead to downstream events that influence antimicrobial resistance.

Comparing the usability of the World Health Organization's conventional tuberculosis guidelines to the eTB recommendations map: A two-arm superiority randomised controlled trial.

Best practices for the dissemination of global health guidelines has not undergone rigorous research. We used a new approach to digitizing World Health Organization (WHO) global tuberculosis guideline recommendations (eTB RecMap) and compared its usability to the conventional method of accessing TB recommendations using the WHO website. We conducted a two-arm superiority randomised controlled trial using a survey among global stakeholders who were past or planned future users of TB guidelines, recommendations, or policy advice. We assigned participants randomly (1:1) to complete an activity using the WHO eTB RecMap or the conventional website. The primary outcome was the accessibility of information and secondary outcomes understanding, satisfaction, and preference for one of the two formats. Between February 26 and August 29, 2021, we received 478 responses from stakeholders, of whom 244 (122 per group) were eligible and provided analysable results. Participants rated the eTB RecMap as more accessible, on average, when compared to the conventional website (on a seven-point scale, the mean difference {MD} was 0.9; 95% confidence interval {CI}: 0.6, 1.2; p < 0.001) and were more likely to correctly answer understanding questions. This is the first trial comparing digitized dissemination formats of health guideline recommendations. Stakeholders rated the WHO eTB RecMap as more accessible than the conventional WHO website for the tested recommendations. They also understood presented information better. The findings support better usability of TB information through the eTB RecMap and contribute to the effort to end the TB epidemic. Trial registration: This trial was registered with ClinicalTrials.gov (NCT04745897) on February 9, 2021.

A taxonomy and framework for identifying and developing actionable statements in guidelines suggests avoiding informal recommendations.

OBJECTIVE: To propose a taxonomy and framework that identifies and presents actionable statements in guidelines. STUDY DESIGN AND SETTING: We took an iterative approach reviewing case studies of guidelines produced by the World Health Organization and the American Society of Hematology to develop an initial conceptual framework. We then tested it using randomly selected recommendations from published guidelines addressing COVID-19 from different organizations, evaluated its results, and refined it before retesting. The urgency and availability of evidence for development of these recommendations varied. We consulted with experts in research methodology and guideline developers to improve the final framework. RESULTS: The resulting taxonomy and framework distinguishes five types of actional statements: formal recommendations; research recommendations; good practice statements; implementation considerations, tools and tips; and informal recommendations. These statements should respond to a priori established criteria and require a clear structure and recognizable presentation in a guideline. Most importantly, this framework identifies informal recommendations that differ from formal recommendations by how they consider evidence and in their development process. CONCLUSION: The identification, standardization and explicit labelling of actionable statements according to the framework may support guideline developers to create actionable statements with clear intent, avoid informal recommendations and improve their understanding and implementation by users.

Interventions for preventing weight gain after smoking cessation.

BACKGROUND: Most people who stop smoking gain weight. This can discourage some people from making a quit attempt and risks offsetting some, but not all, of the health advantages of quitting. Interventions to prevent weight gain could improve health outcomes, but there is a concern that they may undermine quitting. OBJECTIVES: To systematically review the effects of: (1) interventions targeting post-cessation weight gain on weight change and smoking cessation (referred to as 'Part 1') and (2) interventions designed to aid smoking cessation that plausibly affect post-cessation weight gain (referred to as 'Part 2'). SEARCH METHODS: Part 1 - We searched the Cochrane Tobacco Addiction Group's Specialized Register and CENTRAL; latest search 16 October 2020. Part 2 - We searched included studies in the following 'parent' Cochrane reviews: nicotine replacement therapy (NRT), antidepressants, nicotine receptor partial agonists, e-cigarettes, and exercise interventions for smoking cessation published in Issue 10, 2020 of the Cochrane Library. We updated register searches for the review of nicotine receptor partial agonists. SELECTION CRITERIA: Part 1 - trials of interventions that targeted post-cessation weight gain and had measured weight at any follow-up point or smoking cessation, or both, six or more months after quit day. Part 2 - trials included in the selected parent Cochrane reviews reporting weight change at any time point. DATA COLLECTION AND ANALYSIS: Screening and data extraction followed standard Cochrane methods. Change in weight was expressed as difference in weight change from baseline to follow-up between trial arms and was reported only in people abstinent from smoking. Abstinence from smoking was expressed as a risk ratio (RR). Where appropriate, we performed meta-analysis using the inverse variance method for weight, and Mantel-Haenszel method for smoking. MAIN RESULTS: Part 1: We include 37 completed studies; 21 are new to this update. We judged five studies to be at low risk of bias, 17 to be at unclear risk and the remainder at high risk.  An intermittent very low calorie diet (VLCD) comprising full meal replacement provided free of charge and accompanied by intensive dietitian support significantly reduced weight gain at end of treatment compared with education on how to avoid weight gain (mean difference (MD) -3.70 kg, 95% confidence interval (CI) -4.82 to -2.58; 1 study, 121 participants), but there was no evidence of benefit at 12 months (MD -1.30 kg, 95% CI -3.49 to 0.89; 1 study, 62 participants). The VLCD increased the chances of abstinence at 12 months (RR 1.73, 95% CI 1.10 to 2.73; 1 study, 287 participants). However, a second study  found that no-one completed the VLCD intervention or achieved abstinence. Interventions aimed at increasing acceptance of weight gain reported mixed effects at end of treatment, 6 months and 12 months with confidence intervals including both increases and decreases in weight gain compared with no advice or health education. Due to high heterogeneity, we did not combine the data. These interventions increased quit rates at 6 months (RR 1.42, 95% CI 1.03 to 1.96; 4 studies, 619 participants; I2 = 21%), but there was no evidence at 12 months (RR 1.25, 95% CI 0.76 to 2.06; 2 studies, 496 participants; I2 = 26%). Some pharmacological interventions tested for limiting post-cessation weight gain (PCWG) reduced weight gain at the end of treatment (dexfenfluramine, phenylpropanolamine, naltrexone). The effects of ephedrine and caffeine combined, lorcaserin, and chromium were too imprecise to give useful estimates of treatment effects. There was very low-certainty evidence that personalized weight management support reduced weight gain at end of treatment (MD -1.11 kg, 95% CI -1.93 to -0.29; 3 studies, 121 participants; I2 = 0%), but no evidence in the longer-term 12 months (MD -0.44 kg, 95% CI -2.34 to 1.46; 4 studies, 530 participants; I2 = 41%). There was low to very low-certainty evidence that detailed weight management education without personalized assessment, planning and feedback did not reduce weight gain and may have reduced smoking cessation rates (12 months: MD -0.21 kg, 95% CI -2.28 to 1.86; 2 studies, 61 participants; I2 = 0%; RR for smoking cessation 0.66, 95% CI 0.48 to 0.90; 2 studies, 522 participants; I2 = 0%). Part 2: We include 83 completed studies, 27 of which are new to this update. There was low certainty that exercise interventions led to minimal or no weight reduction compared with standard care at end of treatment (MD -0.25 kg, 95% CI -0.78 to 0.29; 4 studies, 404 participants; I2 = 0%). However, weight was reduced at 12 months (MD -2.07 kg, 95% CI -3.78 to -0.36; 3 studies, 182 participants; I2 = 0%). Both bupropion and fluoxetine limited weight gain at end of treatment (bupropion MD -1.01 kg, 95% CI -1.35 to -0.67; 10 studies, 1098 participants; I2 = 3%); (fluoxetine MD -1.01 kg, 95% CI -1.49 to -0.53; 2 studies, 144 participants; I2 = 38%; low- and very low-certainty evidence, respectively). There was no evidence of benefit at 12 months for bupropion, but estimates were imprecise (bupropion MD -0.26 kg, 95% CI -1.31 to 0.78; 7 studies, 471 participants; I2 = 0%). No studies of fluoxetine provided data at 12 months. There was moderate-certainty that NRT reduced weight at end of treatment (MD -0.52 kg, 95% CI -0.99 to -0.05; 21 studies, 2784 participants; I2 = 81%) and moderate-certainty that the effect may be similar at 12 months (MD -0.37 kg, 95% CI -0.86 to 0.11; 17 studies, 1463 participants; I2 = 0%), although the estimates are too imprecise to assess long-term benefit. There was mixed evidence of the effect of varenicline on weight, with high-certainty evidence that weight change was very modestly lower at the end of treatment (MD -0.23 kg, 95% CI -0.53 to 0.06; 14 studies, 2566 participants; I2 = 32%); a low-certainty estimate gave an imprecise estimate of higher weight at 12 months (MD 1.05 kg, 95% CI -0.58 to 2.69; 3 studies, 237 participants; I2 = 0%). AUTHORS' CONCLUSIONS: Overall, there is no intervention for which there is moderate certainty of a clinically useful effect on long-term weight gain. There is also no moderate- or high-certainty evidence that interventions designed to limit weight gain reduce the chances of people achieving abstinence from smoking.

Recommendation mapping of the World Health Organization's guidelines on tuberculosis: A new approach to digitizing and presenting recommendations.

OBJECTIVE: Having up-to-date health policy recommendations accessible in one location is in high demand by guideline users. We developed an easy to navigate interactive approach to organize recommendations and applied it to tuberculosis (TB) guidelines of the World Health Organization (WHO). STUDY DESIGN: We used a mixed-methods study design to develop a framework for recommendation mapping with seven key methodological considerations. We define a recommendation map as an online repository of recommendations from several guidelines on a condition, providing links to the underlying evidence and expert judgments that inform them, allowing users to filter and cross-tabulate the search results. We engaged guideline developers, users, and health software engineers in an iterative process to elaborate the WHO eTB recommendation map. RESULTS: Applying the seven-step framework, we included 228 recommendations, linked to 103 guideline questions and organized the recommendation map according to key components of the health question, including the original recommendations and rationale (https://who.tuberculosis.recmap.org/). CONCLUSION: The recommendation mapping framework provides the entire continuum of evidence mapping by framing recommendations within a guideline questions' population, interventions, and comparators domains. Recommendation maps should allow guideline developers to organize their work meaningfully, standardize the automated publication of guidelines through links to the GRADEpro guideline development tool, and increase their accessibility and usability.

Overview of systematic reviews on strategies to improve treatment initiation, adherence to antiretroviral therapy and retention in care for people living with HIV: part 1.

OBJECTIVES: We sought to map the evidence and identify interventions that increase initiation of antiretroviral therapy, adherence to antiretroviral therapy and retention in care for people living with HIV at high risk for poor engagement in care. METHODS: We conducted an overview of systematic reviews and sought for evidence on vulnerable populations (men who have sex with men (MSM), African, Caribbean and Black (ACB) people, sex workers (SWs), people who inject drugs (PWID) and indigenous people). We searched PubMed, Excerpta Medica dataBASE, Cumulative Index to Nursing and Allied Health Literature, PsycINFO, Web of Science and the Cochrane Library in November 2018. We screened, extracted data and assessed methodological quality in duplicate and present a narrative synthesis. RESULTS: We identified 2420 records of which only 98 systematic reviews were eligible. Overall, 65/98 (66.3%) were at low risk of bias. Systematic reviews focused on ACB (66/98; 67.3%), MSM (32/98; 32.7%), PWID (6/98; 6.1%), SWs and prisoners (both 4/98; 4.1%). Interventions were: mixed (37/98; 37.8%), digital (22/98; 22.4%), behavioural or educational (9/98; 9.2%), peer or community based (8/98; 8.2%), health system (7/98; 7.1%), medication modification (6/98; 6.1%), economic (4/98; 4.1%), pharmacy based (3/98; 3.1%) or task-shifting (2/98; 2.0%). Most of the reviews concluded that the interventions effective (69/98; 70.4%), 17.3% (17/98) were neutral or were indeterminate 12.2% (12/98). Knowledge gaps were the types of participants included in primary studies (vulnerable populations not included), poor research quality of primary studies and poorly tailored interventions (not designed for vulnerable populations). Digital, mixed and peer/community-based interventions were reported to be effective across the continuum of care. CONCLUSIONS: Interventions along the care cascade are mostly focused on adherence and do not sufficiently address all vulnerable populations.

Ventilation Techniques and Risk for Transmission of Coronavirus Disease, Including COVID-19: A Living Systematic Review of Multiple Streams of Evidence.

BACKGROUND: Mechanical ventilation is used to treat respiratory failure in coronavirus disease 2019 (COVID-19). PURPOSE: To review multiple streams of evidence regarding the benefits and harms of ventilation techniques for coronavirus infections, including that causing COVID-19. DATA SOURCES: 21 standard, World Health Organization-specific and COVID-19-specific databases, without language restrictions, until 1 May 2020. STUDY SELECTION: Studies of any design and language comparing different oxygenation approaches in patients with coronavirus infections, including severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS), or with hypoxemic respiratory failure. Animal, mechanistic, laboratory, and preclinical evidence was gathered regarding aerosol dispersion of coronavirus. Studies evaluating risk for virus transmission to health care workers from aerosol-generating procedures (AGPs) were included. DATA EXTRACTION: Independent and duplicate screening, data abstraction, and risk-of-bias assessment (GRADE for certainty of evidence and AMSTAR 2 for included systematic reviews). DATA SYNTHESIS: 123 studies were eligible (45 on COVID-19, 70 on SARS, 8 on MERS), but only 5 studies (1 on COVID-19, 3 on SARS, 1 on MERS) adjusted for important confounders. A study in hospitalized patients with COVID-19 reported slightly higher mortality with noninvasive ventilation (NIV) than with invasive mechanical ventilation (IMV), but 2 opposing studies, 1 in patients with MERS and 1 in patients with SARS, suggest a reduction in mortality with NIV (very-low-certainty evidence). Two studies in patients with SARS report a reduction in mortality with NIV compared with no mechanical ventilation (low-certainty evidence). Two systematic reviews suggest a large reduction in mortality with NIV compared with conventional oxygen therapy. Other included studies suggest increased odds of transmission from AGPs. LIMITATION: Direct studies in COVID-19 are limited and poorly reported. CONCLUSION: Indirect and low-certainty evidence suggests that use of NIV, similar to IMV, probably reduces mortality but may increase the risk for transmission of COVID-19 to health care workers. PRIMARY FUNDING SOURCE: World Health Organization. (PROSPERO: CRD42020178187).

Supplemental Vitamins and Minerals for CVD Prevention and Treatment.

The authors identified individual randomized controlled trials from previous meta-analyses and additional searches, and then performed meta-analyses on cardiovascular disease outcomes and all-cause mortality. The authors assessed publications from 2012, both before and including the U.S. Preventive Service Task Force review. Their systematic reviews and meta-analyses showed generally moderate- or low-quality evidence for preventive benefits (folic acid for total cardiovascular disease, folic acid and B-vitamins for stroke), no effect (multivitamins, vitamins C, D, ß-carotene, calcium, and selenium), or increased risk (antioxidant mixtures and niacin [with a statin] for all-cause mortality). Conclusive evidence for the benefit of any supplement across all dietary backgrounds (including deficiency and sufficiency) was not demonstrated; therefore, any benefits seen must be balanced against possible risks.