Citations

Abstract 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.

Abstract 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.

ABSTRACT Background Journal clubs provide opportunities for discussion of new and evolving practices and technologies. Objective We sought to evaluate the utility and effectiveness of a monthly web‐based cosmetic dermatology journal club facilitated by faculty, residents, and medical students. Results From May 2025 to September 2025, 16 articles were discussed and 41 responses were recorded (response rate: 60%). Most respondents found the journal club was an appropriate length, engaging, and very useful. Relevance, frequency, and likelihood to participate in the future varied significantly by participant type. Medical students and residents collectively considered the journal club too infrequent ( p = 0.03) and reported it had less relevance to their practice ( p < 0.001). Conclusion A monthly web‐based cosmetic dermatology journal club was generally positively received by respondents.

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.

ABSTRACT 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.

Abstract 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.

ABSTRACT Objectives Systematic evidence reviews (SERs) produced by the U.S. Agency for Healthcare Research and Quality (AHRQ) Evidence‐based Practice Center (EPC) Program use contextual questions to provide context and background information on the topic. There is currently no standardized approach to address contextual questions in systematic reviews. This study explored the use of publicly available large language models (LLMs) in addressing contextual questions. Study Design Using a set of 20 published and 5 yet to be published SERs, we selected one contextual question per report and used it as a prompt to elicit answers from an LLM (ChatGPT, Bard, Claude, or Perplexity). Two independent reviewers rated the results using a priori established evaluation criteria ( https://osf.io/4k3cu/ ), comparing the response in the SER to LLM‐generated responses. The study was guided by six research questions addressing feasibility, validity of content, validity of structure, mistakes, congruence between responses, and incremental validity of using LLMs to address contextual questions. Results Using minimal prompt engineering produced relevant responses and documented the feasibility of LLM‐generated answers to contextual questions. Responses differed in content and format and are not reproducible (e.g., LLMs update regularly), but LLMs were able to produce articulate, clinically plausible, and well‐structured responses. We detected few factual errors, contradictions, and no instance of suspected bias, but citations supporting LLM‐generated responses could often not be produced or could not be verified (‘confabulations’). Congruence with human generated responses varied, with LLM‐generated responses providing more background on the topic and SERs providing more nuanced answers in response to the contextual question. Results regarding incremental validity were mixed and may depend on the tool. Conclusion LLMs are potentially helpful in addressing contextual questions in systematic reviews but human expertise remains essential for using the generated information in a meaningful way.

Abstract Background The ability of large language models (LLMs) to work collaboratively and screen studies in a systematic review (SR) is under-explored. Hence, we aimed to evaluate the effectiveness of LLMs in automating the process of screening in systematic reviews. Methods This is an observational study which included labeled data (title and abstracts) for five SRs. Originally, two reviewers screened the citations independently for eligibility. A third reviewer cross-checked each citation for quality assurance. GPT-4, Claude-3-Sonnet, and Gemini-Pro-1.0 were used using zero-shot chain-of-thought prompting. Collaborative approaches included (i): conflict resolution using benefit of the doubt, (ii) majority voting using an independent third LLM and (iii) conflict resolution using an informed third LLM. Performance was assessed using accuracy, precision for exclusion, and recall for inclusion. Work saved over samples (WSS) was computed to estimate the reduction in manual human effort. Results A total of 11300 articles were included in this study. The individual models, GPT-4, Claude-3-Sonnet, and Gemini-Pro-1.0 exhibited a high precision for exclusion, achieving 99.7%, 99.7%, and 99.2% and high recall for inclusion achieving 95.5%, 96.6% and 85.7%, respectively. However, the collaborative approach utilizing the two best-performing models (GPT-4 and Claude-3S) achieved an average precision of 99.9% and a recall of 98.5% (across all collaborative approaches). Furthermore, the proposed collaborative approach resulted in an average WSS of 63.5%, compared to the average WSS of 45.2% for individual models. Conversational LLM interactions showed a consistent pattern of results. Limitations This study was limited due to reliance on proprietary models, and evaluation on oncology datasets. Conclusion Evidence shows that collaborative LLMs enable efficient, high-performing screening in systematic reviews, supporting continuous evidence updates. Primary funding source NIH (U24CA265879-01-1) and Carolyn-Ann-Kennedy-Bacon Fund.

Abstract Introduction Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen (ER), progesterone (PR), and HER2 expression. It accounts for ∼15% of breast cancers and is more common in Black women, younger patients, and those with BRCA1 mutations. TNBC carries a poor prognosis with 5-year survival rates of 92% (localized), 66.8% (regional), and 14.3% (metastatic). Patients with high-risk of recurrence can be treated with different adjuvant therapies based on results of 3 trials (capecitabine, pembrolizumab, olaparib), but data on adverse events (AE) on their combination is limited.High-risk, stage II-III TNBC is treated with curative intent using neoadjuvant chemotherapy with pembrolizumab, followed by surgery and radiation. Pembrolizumab, an anti-PD-1 checkpoint inhibitor, was FDA-approved in 2021 based on KEYNOTE-522. This phase III trial showed that pembrolizumab plus chemotherapy significantly improved pathologic complete response (pCR) and event-free survival (EFS). 3-year EFS was 84.5% vs. 76.8% with placebo (HR 0.63); 5-year follow-up confirmed sustained benefit, with OS of 86.6%. Patients achieving pCR had better outcomes, while those with residual disease remained at high risk for recurrence, justifying further adjuvant therapy.In KEYNOTE-522, grade ≥3 treatment-related (AEs occurred in 77.1% receiving pembrolizumab-chemotherapy vs. 73.3% with placebo-chemotherapy. Pembrolizumab was linked to more serious AEs (34.1% vs. 20.1%) and higher discontinuation rates (23.3% vs. 12.3%). Before pembrolizumab, capecitabine was standard of care for TNBC with residual disease, based on the CREATE-X trial (HR 0.52 for OS benefit). Common AEs included hand-foot syndrome, fatigue, and liver enzyme elevation. Notably, KEYNOTE-522 excluded adjuvant capecitabine, and CREATE-X predated the use of pembrolizumab. Olaparib, a PARP inhibitor, was FDA-approved in 2022 for high-risk early TNBC with germline BRCA mutations, based on OlympiA. It improved invasive disease-free and OS. Grade ≥3 AEs included anemia, neutropenia, and fatigue. OlympiA did not include pembrolizumab or capecitabine, limiting insight into optimal sequencing or combination. Currently, no trials compare pembrolizumab, capecitabine, or olaparib directly, nor do they guide how to sequence or combine these therapies. Despite NCCN guidelines allowing combined/sequential use in high-risk patients, real-world safety and outcome data are lacking. This study aims to evaluate and compare the safety and effectiveness of capecitabine, olaparib, pembrolizumab, and their combinations. We will describe AE rates, onset, discontinuation, and dose modifications to inform clinical management and help reduce early termination of effective therapies. Methods We conducted a retrospective observational study across all Mayo Clinic sites. Eligible patients were ≥18 years with early-stage TNBC who initiated adjuvant therapy with capecitabine, pembrolizumab, olaparib, or combinations (capecitabine + pembrolizumab or olaparib + pembrolizumab) from October 2018 to September 2024. Patients with metastatic disease, other active malignancies, or receiving concurrent investigational therapy were excluded. The primary outcomes were incidence and timing of treatment-related AEs. Secondary outcomes included time to AE resolution, immune-related AEs, treatment interruptions/modifications, early discontinuation, and EFS. Time-to-event data will be analyzed using Kaplan-Meier and Cox proportional hazards models. Subgroup analyses by age, DPYD status, regimen, and dosing will be conducted. Data was abstracted from electronic health records and managed using REDCap. Results Data collection is completed. Final analyses are being conducted, and results will be presented at SABCS 2025. Citation Format: R. Garza-Morales, F. Raheem, D. Alton, S. Sharma, B. Murad, W. Harris, E. Terwilliger, F. Batalini. Analysis of Adverse Events and Outcomes of Adjuvant Therapies in TNBC as Monotherapy and Combination: Pembrolizumab, Capecitabine, and Olaparib [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-10-06.