Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix 1 and Appendix 2). Updates are published regularly and can be found at www.asco.org/genitourinary-cancer-guidelines.

OBJECTIVES:To compare the efficacy and safety of belimumab and anifrolumab in adult patients with SLE. METHODS:We conducted a systematic review and network meta-analysis (NMA) of randomized controlled trials (RCTs) in SLE. We included RCTs comparing belimumab or anifrolumab plus standard of care versus placebo plus standard of care. Outcomes included SRI-4, BICLA, selected BILAG organ-domain responses, and safety endpoints; belimumab BICLA data were derived from post hoc analyses. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. Risk of bias was assessed with RoB 2; certainty in network estimates was evaluated using the GRADE approach as applied in the CINeMA framework. RESULTS:Eleven trials (n = 8607) were included (4 anifrolumab; 7 belimumab, including 2 safety-only trials). Both biologics were associated with higher odds of achieving an SRI-4 response than placebo: anifrolumab OR 1.78 (95% CI 1.41-2.24); belimumab OR 1.62 (95% CI 1.38-1.90), with no significant difference between active treatments. For BICLA, anifrolumab was superior to belimumab (OR 1.56, 95% CI 1.10-2.21). Mucocutaneous and musculoskeletal responses favored both biologics versus placebo, whereas renal and cardiovascular/respiratory effects were not statistically significantly different. In safety analyses, SAEs and serious infections were similar between biologics, whereas herpes zoster was higher with anifrolumab versus belimumab (OR 4.74, 95% CI 2.00-11.21). CONCLUSION:In this NMA, anifrolumab and belimumab achieved similar SRI-4 responses. Anifrolumab showed a higher BICLA response than belimumab, but this finding should be interpreted cautiously given reliance on indirect evidence and moderate certainty. Clinically, these data support individualized biologic selection, weighing potential benefit on BICLA against the consistently higher herpes zoster risk with anifrolumab.

BACKGROUND AND OBJECTIVES:Methodological studies critically evaluate how health research is designed, conducted, analyzed, and reported. Despite their growing importance, currently, there is no reporting tailored to this type of research, which hampers the visibility, reproducibility, and overall utility of the findings of methodological studies. METHODS:We administered a survey to researchers with expertise in designing and performing methodological studies to gather their opinions on appropriate terminology, how they should be categorized, and key reporting elements. Quantitative data were analyzed descriptively, with a content validity ratio applied to determine appropriateness. Qualitative survey responses were analyzed using inductive content analysis. RESULT:Of 499 invited, a total of 119 participants completed the survey (response rate 23%). None of the 13 proposed nomenclatures met the threshold for appropriateness. Of the four proposed study categories, two (study aim and study design) were retained based on expert ratings. Among 23 proposed reporting items, 15 were endorsed for further evaluation. Qualitative responses were condensed and categorized, identifying the importance of flexibility in terminology and concerns about categorization. CONCLUSION:There is substantial disagreement among experts regarding key aspects of methodological studies, particularly related to terminology. While some agreement was observed around study categories and reporting elements, diverse and sometimes conflicting perspectives underscore the complexity of standardizing methodological studies. These findings reinforce the need for a collaborative consensus process to develop reporting guidance that is both practical and adaptable to the nuances of this field.

BACKGROUND:The number of arthroplasty procedures and infection-related complications, including prosthetic joint infections (PJIs) and surgical site infections (SSIs), continues to rise. Although current guidelines recommend cefazolin or cefuroxime as the first-line perioperative prophylactic antibiotic, substitutions with non-cephalosporins remain common, especially among patients with reported β-lactam allergies. These substitutions may increase infection risk and healthcare costs. Evidence comparing outcomes across antibiotic classes remains variable. METHODS:We conducted a systematic review and meta-analysis of studies comparing single-agent cephalosporin versus single-agent non-cephalosporin prophylaxis in adults undergoing primary arthroplasty. Cochrane, Embase, Medline, Scopus, and Web of Science were searched from database inception through January 2025. Random-effect or fixed-effect models were used to estimate pooled odds ratios (OR) and 95% confidence intervals (CI). Subgroup analyses stratified results by cephalosporin type, study era, and risk of bias. RESULTS:Twenty-three studies (7 randomized controlled trials and 16 observational studies) were included, encompassing 191 527 arthroplasties in the cephalosporin arm and 20 058 in the non-cephalosporin arm. The odds of PJI were lower with cephalosporins (OR 0.59; 95% CI, .46-.75). No overall difference was observed for SSI (OR 0.70; 95% CI, .36-1.36), though post-2013 studies and the cefazolin subgroup demonstrated a significant protective effect. Randomized trial estimates were limited and heterogeneous and did not reach statistical significance. Certainty of evidence was graded as moderate. CONCLUSIONS:Cephalosporins, particularly cefazolin or cefuroxime, remain the preferred prophylactic agents for primary arthroplasty. This quantitative synthesis reinforces their protective association against prosthetic joint infection and supports adherence to guideline-endorsed prophylaxis.

[Box: see text]Living guidelines are developed for selected topic areas with rapidly evolving evidence that drives frequent change in recommended clinical practice. Living guidelines are updated on a regular schedule by a standing expert panel that systematically reviews the health literature on a continuous basis, as described in the ASCO Guidelines Methodology Manual. ASCO Living Guidelines follow the ASCO Conflict of Interest Policy Implementation for Clinical Practice Guidelines. Living Guidelines and updates are not intended to substitute for independent professional judgment of the treating clinician and do not account for individual variation among patients. See appendix for disclaimers and other important information (Appendix I and Appendix II). Updates are published regularly and can be found on the ASCO Publications website.

Introduction Increasing publication of fraudulent clinical trials poses a serious threat to evidence-based medicine. In the VITALITY Study I, we demonstrated that contamination by retracted trials significantly distorts evidence synthesis. The upcoming VITALITY Study II will take a step further and investigate how such problematic evidence undermines the credibility of guideline recommendations.Methods and analyses The VITALITY Study II will adopt a retrospective cohort design and will be structured as three work packages (WPs). To start with, a cohort of clinical practice guidelines (CPGs) that were contaminated by retracted trials and/or meta-analyses that included retracted trials will be established based on forward citation searching (WP1). Then, recommendations from these CPGs that used evidence from retracted trials and/or meta-analyses that synthesised these retracted trials will be re-evaluated after removing such problematic evidence, in terms of both the direction and strength of effect sizes (WP2). Finally, the subsequent impact on patient outcomes attributable to distorted recommendations will be estimated on a hypothetical population, measured by the number of expected benefit loss and the number of expected harm increment per 100 000 patients (WP3).Ethics and dissemination Formal ethical approval is not necessary for this study as it does not involve human or animal participants, nor does it involve the collection of primary data. We will disseminate the findings through publication in peer-reviewed journals and, whenever possible, presentations at academic conferences.

Background:Community-acquired pneumonia (CAP) is a significant public health concern associated with increased rates of hospital admissions and mortality. The purpose of the current study was to compare beta-lactam plus azithromycin or doxycycline vs fluoroquinolones in adults hospitalized with CAP. Methods:We searched several databases from inception to 10 June 2024. Two reviewers independently screened, selected, and extracted data. Disagreements were resolved by consensus or a third reviewer. Study quality was assessed in duplicate with the Cochrane Risk of Bias 2 for randomized studies and the Newcastle-Ottawa Scale for nonrandomized studies. Meta-analysis was conducted by a random effect model when feasible. Network meta-analysis was performed to compare direct and indirect evidence. The GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation) was followed to rate the certainty of evidence. Results:Twenty studies were included (20 beta-lactam + azithromycin, 7 beta-lactam + doxycycline, 12 levofloxacin, and 4 moxifloxacin): 6 were randomized, enrolling 861 participants (mean age, 61.8 years; 43.2% women), and 14 were nonrandomized, enrolling 185 928 participants (mean age, 65.2 years; 42.9% women). Direct comparison and network meta-analysis results showed no statistically significant differences and likely equal effectiveness between beta-lactam + azithromycin and beta-lactam + doxycycline in terms of in-hospital mortality, need for intensive care unit admission or invasive mechanical ventilation, or safety outcomes including Clostridioides difficile infection and QT prolongation. Conclusions:The current evidence demonstrated no likely difference in outcomes between azithromycin and doxycycline in adults hospitalized with CAP receiving beta-lactam. Head-to-head randomized clinical trials are needed to validate these results.

Blunt thoracic aortic injury (BTAI) remains a devastating and potentially fatal complication of major trauma that requires expedient diagnosis and management by a collaborative team of trauma and vascular specialists. Trauma patients with BTAI commonly have multiple associated injuries, including intracranial or truncal hemorrhage, that increase the complexity of factors related to timing and conduct of repair. Optimal outcomes for these patients require consideration of these factors and updated knowledge of the available evidence by all stakeholders of care in a collaborative fashion. In 2011, the Society for Vascular Surgery published its clinical practice guidelines on the management of BTAI. Based on the available evidence from published research at the time, seven specific key questions were formulated spanning areas including patient selection, timing and conduct of repair, considerations in the setting of specific high-risk associated injuries, and surveillance. A systematic review and evidence synthesis of each question was conducted by a dedicated methodology team. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used to describe the strength of each recommendation and the level of certainty of evidence. The review identified major gaps in evidence across most of the questions posed, highlighting opportunities for additional research. Since that publication in 2011, the cumulative experience in the diagnosis and management of BTAI has grown significantly. This provided an opportunity for a focused update based on the current evidence. We assembled a panel of experts who identified seven specific areas of investigation and commissioned a systematic review of the published literature. Thirteen recommendations are provided in the current update. They address indications for and timing of definitive treatment, use of perioperative anticoagulation, management of the left subclavian artery, and imaging surveillance. In addition, we discuss the use of anti-impulse therapy for medical management as well as BTAI management for patients with concomitant injuries such as traumatic brain injury and solid organ injury. The collaborative engagement of all stakeholders in care of these complex patients is considered fundamental to optimal care. Significant unmet research needs in the field are also outlined.

While medications are essential for preventing and treating disease, they can also cause harm. Evidence synthesis has been widely adopted for evaluating harms, but traditional methods are resource-intensive and may constrain timely decision-making. This study aims to validate a Trial Bank approach towards rapid evidence synthesis. A Trial Bank consisting of 13,650 RCTs of pharmaceutical or biopharmaceutical agents for children was established using artificial intelligence (AI) and humans, based on five databases (e.g., PubMed) up to February 14, 2023. The Trial Bank approach for evidence synthesis was validated in two ways: First, the percentage of trials within 1,996 Cochrane meta-analyses of drug safety in children that were also available in the Trial Bank was reported as the Trial Bank coverage (TBC). Second, the agreement of pooled effects from trials limited to those in the Trial Bank was compared to the full Cochrane meta-analyses in terms of their direction and statistical significance. Of 1,020 trials included in the Cochrane meta-analyses, there was an overall 80.2

Introduction:Syphilis rates have increased substantially across the U.S. over the past decade. In response, the Minnesota Department of Health reviewed and updated its screening recommendations. Methods:A scoping review was performed to identify published manuscripts and guidelines on syphilis screening. The Minnesota Department of Health reviewed national and local syphilis data (2016-2024), published evidence, and screening approaches from other jurisdictions. The final recommendation was based on decisional factors derived from the GRADE evidence-to-decision framework and an adaptation of evidence-to-decision that is specific to screening. Multiple factors were considered, including disease burden, treatment availability, screening accessibility, implementation feasibility, and access to health care. Results:Evidence shows that early detection and treatment of syphilis are highly effective. Opt-out screening models achieve greater uptake and case detection than risk-based screening approaches. On the basis of the findings, the Minnesota Department of Health endorsed a new universal, opt-out syphilis screening recommendation for all nonpregnant individuals aged 18-49 years. Conclusions:Universal opt-out screening for syphilis has the potential to reduce the syphilis disease burden in Minnesota. Other jurisdictions may wish to adopt similar policies and may do so by modeling this approach.

Despite published guidance by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) Working Group on the use of good practice statements (GPSs), their appropriate development remains challenging. This article provides updated guidance with nuanced operationalization. The updated guidance was developed on the basis of examples and iterative discussions. The lead authors refined the approach according to the feedback from GRADE Working Group meetings and presented the summary of the results to all attendees of the GRADE Working Group meeting for feedback in September 2023 and for final approval in September 2024. The 5 signaling questions from the original guidance were leveraged, and the authors recommend that guideline developers select relevant Evidence to Decision criteria to assess the potential downstream consequences of implementing the statement. They have updated the definition of a GPS, classifying GPSs into the following 3 categories: those grounded in ethics and human rights; those grounded in essential principles, practices, and protocols; and those grounded in established scientific evidence. Practical examples accompany the steps as they relate to each type of GPS. In addition, the authors introduce a tool to streamline GPS development and enhance the reporting process. This GRADE guidance article provides an update on when and how to develop a GPS. Adherence to the guidance will add to the trustworthiness of guidelines and may facilitate reducing the inappropriate use or overuse of the GPS.

Objectives It is crucial, when using Grading of Recommendations Assessment, Development and Evaluation (GRADE), that authors are clear about what it is in which they are rating the certainty of evidence (ie, the target of certainty of evidence rating). This article addresses challenges GRADE users face in choosing a target of certainty rating for any value-based threshold (ie, little or no difference; an important effect; small, moderate or large difference) when the point estimate is close to that threshold. Study Design and Setting Using an iterative process, authors generated and refined possible solutions to the identified challenges. Results The challenges GRADE users face when point estimates prove close to the initially chosen value-based threshold include (1) the intuitive interpretation of the point estimate is similar whichever side of the threshold the point estimate lies on but the formal interpretation differs greatly and (2) rating down for imprecision due to the confidence interval (CI) crossing the threshold when the CI is very narrow. This paper provides four possible solutions. The first is continuing to rate certainty in an important or unimportant effect and rating down for imprecision when the CI crosses the MID. The second is to consider uncertainty around the MID, rating certainty in relation to a range of plausible MIDs (ie, a range formed by the smallest plausible MID and the largest plausible MID), and rate down for imprecision when the CI crosses either plausibility bound. The third solution is considering both the null and moderate effect thresholds, rating certainty in a trivial or small effect, and rating down for imprecision when the CI crosses either threshold. The fourth solution is using more than one of the above solutions and presenting two or more certainty of evidence ratings. Conclusions GRADE users should note these challenges and apply their chosen solution to transparently determine the target of their certainty rating. Plain Language Summary When point estimates prove to be close to the initially chosen value-based threshold, to decide on what it is in which GRADE users rate their certainty (ie, the target of certainty rating), GRADE users face challenges. This paper provides four possible solutions related to the minimal important difference (MID) that are also applicable to other value-based thresholds. (1) Continuing to rate certainty in an important or unimportant effect and rate down for imprecision when the CI crosses the MID; (2) Considering a plausible range of MIDs, rating certainty in an effect that is close to the MID, and rating down for imprecision when the CI crosses either or both plausibility bounds; (3) Considering both the null and moderate effect thresholds, rating certainty in a trivial or small effect, and rating down for imprecision when the CI crosses either threshold; and (4) presenting more than one certainty of evidence rating. GRADE users may note these challenges and consider applying the solutions to transparently determine the target of their certainty rating and to make certainty assessments accordingly.

CONTEXT:Central precocious puberty (CPP). OBJECTIVE:To summarize the available supporting evidence for the Endocrine Society guidelines about the management of CPP. METHODS:Multiple databases (MEDLINE, EMBASE, Scopus) were searched to identify studies that addressed the Endocrine Society Guideline Development Panel's 10 clinical questions. Identified studies were selected and appraised, and data were extracted by pairs of independent trained reviewers. RESULTS:The systematic review yielded 3796 citations, of which 32 citations were included. The systematic review and meta-analysis demonstrate that in children with CPP, with no central nervous system symptoms, the rate of magnetic resonance imaging identification of pathogenic lesions (ie, hamartomas and brain tumors) was 6% (35 noncomparative studies with 5541 children with CPP). For girls with idiopathic CPP, gonadotropin-releasing hormone agonist (GnRHa) treatment was associated with +2.7 cm adult height gain compared to those who did not receive treatment (21 comparative observational studies with 1835 girls [mean age 8.20 ± 1.08 years]). The review did not identify any studies that assessed the clinical questions on: benefits of additional evaluation in cases of early thelarche, differentiation of slowly vs rapidly progressing CPP, order of biochemical testing to establish and monitor the diagnosis of CPP, genetic testing for individuals diagnosed with CPP, and chronological age and/or bone age for discontinuation of GnRHa treatment. CONCLUSION:This systematic review addresses various aspects of CPP evaluation and treatment of CPP and will support the development of the Endocrine Society guidelines.

BACKGROUND:Central precocious puberty (CPP), which is traditionally defined as the development of secondary sexual characteristics before age 8 years in girls and age 9 years in boys, results from the premature activation of the hypothalamic-pituitary-gonadal (HPG) axis. CPP can be associated with short adult stature, adverse psychosocial outcomes, and increased cardiometabolic and cancer risks in adulthood. Gonadotropin-releasing hormone (GnRH) agonists can effectively suppress premature activation of the HPG axis and have the potential to increase adult height as well as improve psychosocial and long-term health outcomes among patients with CPP. However, as secular trends have continued to shift toward earlier age of pubertal onset, some subpopulations of children with CPP, as it is currently defined, may not require the same extent of diagnostic evaluation and treatment. OBJECTIVE:Develop evidence-based recommendations related to the diagnosis and treatment of CPP. METHODS:A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, used the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to address 10 clinical questions related to the diagnosis and treatment of CPP. Systematic reviews of health-related benefits and harms were conducted for each clinical question. The guideline development panel (GDP) also used the GRADE evidence-to-decision (EtD) framework to address stakeholder values and preferences, costs and required resources, cost-effectiveness, acceptability, feasibility, and potential impacts on health equity. RESULTS:In girls with thelarche (Tanner stage B2) between ages 7.0 and 8.0 years, the GDP suggests watchful waiting via periodic physical examinations (every 4-6 months) rather than immediately performing evaluation with laboratory testing or radiologic imaging. In addition, the GDP suggests that all girls with breast development (ie, Tanner stage B2) before age 7 years should first be observed for 4 to 6 months to differentiate unsustained or slowly progressive puberty vs rapidly progressive puberty. These recommendations are largely based on evidence that girls with slowly progressive puberty attain a normal adult height without treatment. When hormonal evaluation is performed to confirm central (GnRH-dependent) activation as the cause of precocious puberty, the GDP suggests starting the evaluation with ultrasensitive basal luteinizing hormone (LH) concentration rather than routine GnRH/GnRH agonist (GnRHa) stimulation testing for all patients. While brain magnetic resonance imaging has been a traditional part of CPP evaluation, the GDP suggests that it should not be routinely performed in girls ages 6.0 to 8.0 years and boys ages 8.0 to 9.0 years without central nervous system (eg, neuro-ophthalmologic) symptoms, largely based on a low prevalence of pathologic intracranial findings in these age groups. The GDP suggests against routine genetic testing for patients with CPP, although they judged that genetic testing (eg, MKRN3 sequencing) should be considered for patients with familial CPP through a shared decision-making process. The GDP suggests GnRHa treatment for many children with CPP, although available evidence suggests that some patient subgroups (eg, older girls with slowly progressive CPP) may be less likely to receive a net benefit with this treatment. Rather than always starting GnRHa treatment with a monthly injectable formulation, the GDP suggests that treatment should be initiated with the formulation (such as a longer-acting formulation) that is anticipated to be used long-term. The GDP suggests against routine addition of growth hormone therapy to increase adult height. They also suggest against the routine biochemical testing (eg, LH, sex steroids) to monitor pubertal suppression while receiving GnRHa, instead reserving biochemical testing to confirm clinically suspected treatment failure. Finally, the GDP suggests against routinely continuing GnRHa treatment beyond chronologic age 10.0 to 11.0 years (girls) or 11.0 to 12.0 years (boys) and/or bone age 11.0 to 12.0 years (girls) or 12.0 to 13.0 years (boys). CONCLUSION:These clinical recommendations were developed to address important uncertainties in the diagnosis and treatment of children with CPP. They are based on the best available scientific evidence regarding clinical outcomes judged to be most important to patients and families. The GDP's overarching goal was to suggest diagnostic and therapeutic strategies that will most likely provide net clinical benefits while simultaneously considering important contextual factors such as cost and feasibility. The guideline-development process highlighted important knowledge gaps and the substantial need for additional research.

BACKGROUND AND AIMS:Pruritus is a frequent and debilitating symptom in primary biliary cholangitis (PBC), substantially impairing sleep, mood and quality of life. Peroxisome proliferator-activated receptor (PPAR) agonists are promising second-line therapies for patients with an inadequate response to ursodeoxycholic acid (UDCA). We conducted a systematic review and meta-analysis to evaluate the efficacy of PPAR agonists on pruritus and health-related quality of life (HRQoL) in PBC. METHODS:We systematically searched for randomised placebo-controlled trials (RCTs) of PPAR agonists in PBC through December 2025. Eligible studies reported validated pruritus or HRQoL outcomes. Main outcomes were NRS and PBC-40 total score. Pooled estimates were calculated using random-effects models and expressed as mean differences (MD) with 95% confidence intervals (CI). RESULTS:Five RCTs evaluating bezafibrate, elafibranor and seladelpar (n = 660; 390 PPAR agonist; 270 placebo) met the inclusion criteria. For pruritus intensity analyses, data were restricted to participants with moderate-to-severe baseline symptoms (NRS ≥ 4) when available. PPAR agonists significantly reduced NRS scores at 3 months (MD, -1.39; 95% CI: -2.49 to -0.29), 6 months (MD, -1.17; 95% CI: -1.96 to -0.38) and 12 months (MD, -1.73; 95% CI, -3.00 to -0.46); in individual agent analyses, bezafibrate and seladelpar reached statistical significance at two or more time points. While improvements were also noted in PBC-40 itch-domain and 5D-itch score, an impact on overall HRQoL as reflected by PBC-40 total score could not be demonstrated, with a lower level of certainty. CONCLUSIONS:PPAR agonists, notably bezafibrate and seladelpar, reduce pruritus severity in PBC patients with moderate-to-severe symptoms and consistently improve itch-specific outcomes. However, effects on global HRQoL remain uncertain. These findings underscore the incorporation of validated, symptom-focused endpoints in future PBC trials.

Background. Epidemiological studies have shown inconsistent findings regarding the effect of dietary digestible carbohydrate intake on the risk of cardiovascular disease and type 2 diabetes (T2D). Synthesis of such evidence is important for determining the Dietary Reference Intakes (DRI) for carbohydrates, which can have consequences on incidence and morbidity of chronic conditions. Methods. Two systematic reviews were conducted, one addressing cardiovascular outcomes and the second addressing incidence of T2D, body weight, and composition. We searched several databases from January 1, 2000, to July 19, 2024, and searched gray literature. Eligible studies evaluated the outcomes of interest in healthy individuals over 2 years old and isolated the effect of digestible carbohydrate intake from other macronutrients in grams per day or percent of total energy intake. Random-effects dose-response meta-analyses were conducted when feasible. Results. The systematic review on cardiovascular outcome included 21 prospective cohort studies with 1,277,621 participants. The majority of the studies reported inadequate confounding adjustment (73%) and were deemed to have serious risks of bias (80%). No eligible studies evaluated children under 18 years. The association between digestible carbohydrate intake and cardiovascular outcomes was nonlinear and was supported by low strength of evidence. When carbohydrate intake was analyzed as the percentage of total energy intake, the risk of incident cardiovascular disease significantly increased when carbohydrate intake exceeded 65 percent total energy intake, compared with the carbohydrate intake reference level of 50 percent total energy intake. The lowest risk was at a carbohydrate intake level of 50 percent total energy intake. The risk of incident coronary heart disease increased starting at a carbohydrate intake level of 45 percent total energy intake. When carbohydrate intake was analyzed as grams per day, the risk of incident cardiovascular disease significantly increased when carbohydrate intake exceeded 300 grams per day, compared with a reference level of 300 grams per day. The lowest risk was at a carbohydrate intake level of 250 grams per day. The risk of incident coronary heart disease increased starting at 250 grams per day of carbohydrates. The nonlinear relationships were overall similar based on sex or geographic location but with variable intake range associated with the lowest risk. Higher carbohydrate intake was associated with lower levels of high-density lipoprotein-cholesterol and higher levels of triglycerides. The systematic review on diabetes and body composition included 17 studies with 497,941 participants. The majority of the studies reported inadequate confounding adjustment (79%) and were deemed to have serious risks of bias (92%). No eligible studies evaluated children under 18 years. The association between carbohydrate intake and incident T2D was nonlinear and was supported by low strength of evidence. Analyzing carbohydrate intake as a percentage of total energy intake showed a gradual reduction in the risk of incident T2D up to 45 percent total energy intake. The risk then plateaued between 45 percent and 55 percent total energy intake before rising with higher carbohydrate intake levels. Similarly, analyzing carbohydrate intake in grams per day revealed a gradually reduced risk up to 270 grams per day, followed by a plateau between 270–350 grams per day and increased risk after 350 grams per day. The evidence was insufficient to determine an association between carbohydrate intake and weight or body composition. The nonlinear relationships were overall similar based on sex but with variable intake range associated with the lowest risk. Very few studies evaluated intermediate outcomes. Conclusion. Dose-response meta-analyses suggest a nonlinear relationship between the intake of digestible carbohydrates and cardiovascular disease and incident T2D. These associations appear to be U-shaped and suggest certain ranges of carbohydrate intake that were associated with the lowest risk. Such ranges can help in establishing future DRI for carbohydrates, which can have important consequences on incidence and morbidity of chronic conditions and public health.

OBJECTIVES:We aimed to determine whether the existing risk of bias assessment tools addressed constructs other than risk of bias or internal validity and whether they used numerical scores to express quality, which is discouraged and may be a misleading approach. METHODS:We searched Ovid MEDLINE and Embase to identify quality appraisal tools across all disciplines in human health research. Tools designed specifically to evaluate reporting quality were excluded. Potentially eligible tools were screened by independent pairs of reviewers. We categorized tools according to conceptual constructs and evaluated their scoring methods. RESULTS:We included 230 tools published from 1995 to 2023. Access to the tool was limited to a peer-reviewed journal article in 63% of the sample. Most tools (76%) provided signaling questions, whereas 39% produced an overall judgment across multiple domains. Most tools (93%) addressed concepts other than risk of bias, such as the appropriateness of statistical analysis (65%), reporting quality (64%), indirectness (41%), imprecision (38%), and ethical considerations and funding (22%). Numerical scoring was used in 25% of tools. CONCLUSION:Currently available study quality assessment tools were not explicit about the constructs addressed by their items or signaling questions and addressed multiple constructs in addition to risk of bias. Many tools used numerical scoring systems, which can be misleading. Limitations of the existing tools make the process of rating the certainty of evidence more difficult. PLAIN LANGUAGE SUMMARY:Many tools have been made to assess how well a scientific study was designed, conducted, and written. We searched for these tools to better understand the types of questions they ask and the types of studies to which they apply. We found 230 tools published between 1995 and 2023. One in every four tools used a numerical scoring system. This approach is not recommended because it does not distinguish well between different ways quality can be assessed. Tools assessed quality in a number of different ways, with the most common ways being risk of bias (how a study is designed and run to reduce biased results; 98%), statistical analysis (how the data were analyzed; 65%), and reporting quality (whether important details were included in the article; 64%). People who make tools in the future should carefully consider the aspects of quality that they want the tool to address and distinguish between questions of study design, conduct, analysis, ethics, and reporting.

BACKGROUND:Bile acid diarrhoea, a common cause of diarrhoea-predominant irritable bowel syndrome, has a similar prevalence to coeliac disease and inflammatory bowel diseases. The mainstay of treatment is bile acid sequestrants (BAS). The effectiveness of using bile acid-targeted therapies remains unclear. AIM:To compare BAS with placebo for bile acid diarrhoea. METHODS:We conducted a systematic review and meta-analysis of randomised controlled trials comparing BAS to placebo using a comprehensive search of databases from inception to 8/1/2023. Inclusion required unequivocal diagnosis using serum or faecal biochemical parameters, or 75SeHCAT. Co-primary endpoints were ≥ 30% improvement in bowel movement consistency and frequency averaged over 7 days. Adverse effects were also summarised. RESULTS:Database search resulted in 1152 citations; 1 additional study was added. Ultimately, 6 trials (5 parallel arm, 1 crossover) involving 182 participants evaluated the effectiveness of BAS over 1-8 weeks. Participants were between the third and seventh decades of life and mostly female. The risk of bias was low except in one parallel and one crossover trial. Meta-analysis of parallel-design trials of sequestrants only showed a clinically significant reduction in stool consistency and frequency with pooled relative risks of 1.50 (95% CI: 1.14-1.96) and 2.80 (95% CI: 1.68-4.67), respectively. There was no observable heterogeneity (I2 = 0%), and the certainty of evidence was moderate. There was no statistically significant difference in adverse effects. CONCLUSIONS:This study quantifies the significant and rapid improvement in both stool consistency and frequency with BAS in patients with objective diagnosis of bile acid diarrhoea. Sequestrants also appear well tolerated.