Citations

Abstract Background Partial breast irradiation (PBI) is an effective treatment for early-stage breast cancer. However, evidence comparing different PBI modalities is limited. Methods This trial emulation uses electronic health records from a multi-state large tertiary health system. Three PBI modalities were compared: proton radiation therapy, photon radiation therapy, and applicator-based brachytherapy. Inverse probability weighting (IPW) was used to balance confounders. The primary outcome was ipsilateral breast recurrence (IBR). Results Between 2013 and 2023, 1041 women with early-stage breast cancer were treated with PBI. Of these, 1026 patients were included in the analyses. The median age was 66 years; 22.51% had ductal carcinoma in situ (DCIS), and 97.56% were estrogen receptor positive. With median follow-up of 38.2 months, the rate of IBR in the overall group was 3.05% (95% confidence interval [CI] = 1.99% to 4.65%) at 3 years. After IPW, compared with photon PBI, the hazard ratio for IBR for proton PBI was 2.11 (95% CI = 0.70 to 6.33) and for brachytherapy, 3.86 (95% CI = 1.39 to 10.69). Compared with proton PBI, the hazard ratio for IBR for brachytherapy was 1.83 (95% CI = 0.88 to 3.81). IBR risk was similar across PBI modalities for patients with tumor size ≤ 10 mm and in patients treated for DCIS. Among patients with tumor size >10 mm, the hazard ratio for IBR for brachytherapy was 7.64 (95% CI = 1.64 to 35.58) and 3.59 (95% CI = 1.22 to 10.56) relative to photons and protons, respectively. Conclusion PBI with applicator-based brachytherapy was associated with higher IBR than photon or proton PBI in patients with tumor size > 10 mm, suggesting the need for more careful PBI patient selection for this modality.

Background The natural history of asymptomatic moderate or severe aortic regurgitation (AR) remains uncertain, with conflicting reports about its progression and surgical timing. We aimed to quantify adverse outcomes under conservative management and evaluate the association of aortic valve replacement/repair (AVR) with mortality. Methods Systematic searches (inception–July 2025) identified cohort studies of asymptomatic moderate/severe AR. Random-effects models estimated pooled incidence rates of adverse events; fixed-effects models were used for hazard ratios (HRs) of AVR vs conservative management. Results Twenty-seven studies (4720 patients; mean age 49 years; mean follow-up 3.9 years) were included. Pooled incidence rates per 100 person-years were 1.75 (95% CI 1.27 to 2.41) for all-cause mortality, 1.29 for cardiac death, 0.29 for sudden death, 4.30 for new symptoms and 7.01 for AVR. Asymptomatic low left ventricular ejection fraction occurred in only 0.9 per 100 person-years. Mortality rates were more than double those of the general population across age groups—2.45 (1.90 to 3.18) per 100 person-years for cohorts with mean age ≥50 years versus 0.59 (0.29 to 1.21) for younger cohorts. Early AVR was associated with lower mortality (pooled HR 0.33; 95% CI 0.30 to 0.37). Conclusion Asymptomatic moderate/severe AR carries significant excess mortality irrespective of age, contradicting its historically benign reputation. Given the rarity of asymptomatic LV dysfunction, earlier intervention guided by more sensitive markers of LV damage may improve outcomes, although heterogeneity and study quality warrant cautious interpretation. PROSPERO registration number CRD42024522683.

Abstract Disclosure: A. Al Nofal: None. K. Benkhadra: None. M. Nduwimana: None. A. Mohammad: None. A. Abbas: None. Z. Wang: None. M. Murad: None. Background: Hybrid closed-loop (HCL) systems for automated insulin delivery are increasingly used in diabetes management. However, their safety and efficacy in pregnant women with pre-existing type 1 diabetes remain uncertain. Aim: To assess the safety and effectiveness of HCL systems in pregnant women with pre-existing type 1 diabetes compared to current standard of care. Methods: A comprehensive search of several databases was conducted from inception to January 3rd, 2024. Pairs of independent reviewers screened abstracts. Abstracts included by at least one reviewer were reviewed in full text by a pair of independent reviewers. The DerSimonian and Laird random effects model with the Hartung-Knapp-Sidik-Jonkman method was used to pool effect sizes across the included studies. Results: Five randomized controlled trials (RCTs) with 274 pregnant women with type I diabetes met the inclusion criteria. Our meta-analysis showed no significant difference between HCL and standard of care regarding overall time in range (TIR), time above range (TAR), and time below range (TBR). However, overnight, women using HCL showed significantly higher TIR (mean difference: 10.18%, CI 7.42-12.94%) and lower TBR (mean difference: -0.67%, CI -0.91 to -0.43%) compared to those using standard care. Additionally, there were no significant differences between HCL and standard of care in term of LGA, SGA, neonatal hypoglycemia, and maternal severe hypoglycemia or hyperglycemia. Conclusion: HCL systems for management of pre-existing type I diabetes during pregnancy are associated with similar outcomes without increased risk of complications when compared to standard of care. This is derived from limited number of RCTs with low risk of bias but significant imprecision, which warrant low confidence. Presentation: Sunday, July 13, 2025

Objective: To compare postoperative complications between staged versus unstaged tympanoplasty and subtotal petrosectomy (STP) in adults undergoing cochlear implants with noncholesteatoma chronic otitis media (NCCOM) and tympanic membrane perforation. Databases reviewed: PubMed/MEDLINE, Cochrane CENTRAL, Embase, CINAHL, Web of Science, WHO Global Index Medicus, ClinicalTrials.gov, and WHO ICTRP. Materials and methods: A systematic search of databases was conducted by a research librarian from inception through November 18, 2024. Eligible studies for inclusion must have reported on adult cochlear implant recipients undergoing surgical management of NCCOM with perforation. Using a random effects model, complication rates were pooled and compared between staged and unstaged surgeries using relative risk (RR) with 95% CI. Results: Of 1265 studies identified, 19 met inclusion criteria (n = 84). Fifty three (63.1%) patients underwent unstaged surgery. Amongst all patients, STP was performed more than tympanoplasty (72.6%, 61/84 vs 27.4%, 23/84), and the overall complication rate was 11.9% (10/84). There was no significant difference in complication rates between combined staged and unstaged surgeries [RR: 1.13 (95% CI, 0.18-7.04)] as well staged and unstaged tympanoplasty [RR: 0.34 (95% CI, 0.11-0.1.01)]. However, complication rates were lower for staged than unstaged STP [RR: 0 (95% CI, 0.0-0.07)]. Conclusion: Staged and unstaged surgery for NCCOM and cochlear implant may result in comparable complication rates, however the wide CIs for RR statistics in comparisons between combined staged and unstaged procedures as well as staged and unstaged tympanoplasty indicate a need for similar studies of larger populations.

572 Background: Neoadjuvant endocrine therapy (NET) is sometimes used to shrink hormone receptor-positive (HR+) breast cancers to improve breast conservation rates and reduce axillary nodal burden. At the beginning of the COVID-19 pandemic, several organizations endorsed NET use to mitigate the harm of surgery delay when cancer operations were less available due to infection transmission concerns. However, the real-world patterns of NET during this period are understudied. This study investigated the alteration of NET utilization patterns during the COVID-19 pandemic in the United States using the National Cancer Database (NCDB). Methods: We identified patients diagnosed with stage I-III invasive HR+/human epidermal growth factor receptor 2-negative (HER2-) breast cancer between 2018-2022 in the NCDB. Estrogen receptor and/or progesterone receptor positivity was required for inclusion in the cohort. Receipt of NET was defined as initiation of endocrine therapy ≥ 14 days before the patient’s first surgical procedure. The study cohort generation and statistical analysis were conducted using Stata and R 4.4.3. A two-tailed p value < 0.05 was considered statistically significant. Results: 495,098 patients were included in the cohort, 195,371 in 2018-2019 (pre-pandemic), 91,686 in 2020 (early pandemic), 106,157 in 2021 (mid-pandemic), and 101,884 in 2022 (late pandemic). NET utilization was increased in the early pandemic compared to the pre-pandemic (seen in 5.8% vs 2.4% of the cohort, Chi-square p value < 0.001), but this use fell back to 3.4% in the mid-pandemic and 3.5% in the late-pandemic. The median (IQR) duration of NET was 15.7 (6.4-26.6) weeks in the pre-pandemic, 9.3 (5.4-18.7) weeks in the early pandemic, 13.2 (5.8-25.7) weeks in the mid-pandemic, and 12.0 (6-24.6) weeks in late pandemic (Kruskal-Wallis p value = 0.001). The transient increase in NET utilization during the early pandemic was more pronounced among patients with tumors < 5 cm and node-negative disease. Conclusions: Our study identified a significant shift in the utilization of NET for HR+/HER2- breast cancer during the COVID-19 pandemic. Pandemic-era NET policies produced a short-lived practice change that was only partially sustained once surgical access normalized. NET utilization (%) by subgroup and year for stage I-III HR+/HER2- breast cancer. Variable Category 2018-2019 2020 2021 2022 Overall NET Use 2.4 5.8 3.4 3.5 Age Group (years old) <50 2.2 4.9 3.9 4.0 >=50 2.4 6.0 3.3 3.4 Tumor Size <5 cm 2.0 5.5 2.9 3.1 >=5 cm 9.0 9.7 11.2 11.6 Histology Subtype Ductal 2.2 5.5 3.3 3.4 Lobular 3.6 7.1 4.4 4.8 Ductal/Lobular 2.6 6.2 4.3 3.6 Other 1.9 6.7 2.5 2.6 KI67 <20% 2.5 6.4 3.4 3.3 >=20% 2.3 5.5 3.5 3.7 Tumor Grade Well differentiated 1.9 5.8 2.4 2.6 Moderately differentiated 2.7 6.1 3.9 3.9 Poorly differentiated/undifferentiated 2.9 4.8 4.3 4.8 Node Positivity Positive 5.2 5.6 9.3 9.5 Negative 2.0 5.8 2.6 2.7

Objective: To estimate the relative risk of meningitis after repair of spontaneous lateral skull base cerebrospinal fluid (CSF) leaks through meta-analysis of published studies. Databases Reviewed: PubMed, Medline, Embase, Cochrane, SCI-EXPANDED, ESCI, Epistemonikos, and WHO Global Index Medicus were queried for terms including and related to meningitis, CSF leak, surgery, and spontaneous from inception to April 02, 2024. Methods: Prospective and retrospective studies in any language reporting either preoperative or postoperative rates of meningitis in adults with spontaneous lateral skull base CSF leaks were included. Two reviewers independently screened 2,564 studies and extracted data and evaluated risk of bias in 57 studies that met inclusion criteria. A random effects generalized linear mixed model was used to pool and compare logit transformed risk of meningitis before and after repair. Results: Of 1,310 patients who met inclusion criteria, 1,239 underwent CSF leak repair. Fifty-two studies reported rates of preoperative meningitis, and 27 studies reported rates of postoperative meningitis. Twenty-two studies with a total of 511 patients reported both rates. The average follow-up period of 17 studies reporting duration of follow-up was 23.1 months. The preoperative pooled risk of meningitis was 0.16 (95% CI: 0.13–0.25, I 2 = 40.57%). The postoperative pooled risk was considerably lower at 0.01 (95% CI: 0.01–0.14, I 2 = 4.16%). With substantial heterogeneity (I 2 = 62.94%), we observed a relative risk of meningitis after repair of 0.02 (95% CI: 0.00–0.79, p = 0.04). Conclusion: Surgical repair of spontaneous lateral skull base CSF leaks may significantly reduce the risk of adult meningitis.

Importance Suicide is a leading cause of death among young people and an escalating public health crisis. Objective To assess the effectiveness and harms of available treatments for suicidal thoughts and behaviors among youths at heightened risk for suicide. Evidence Review A systematic review was conducted searching databases including MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and various gray literature sources from January 1, 2000, to September 26, 2024. We included randomized clinical trials, comparative observational studies, and before-after studies of psychosocial interventions, pharmacologic interventions, neurotherapeutics, emerging therapies, and combination therapies. Eligible patients were youths (aged 5-24 years) with heightened risk for suicide, adolescents from racial and ethnic minority groups known to be at increased risk of suicide, or those exposed to crime or violence. Pairs of independent reviewers selected and appraised studies. Findings This review included 65 studies (33 randomized clinical trials, 13 comparative observational studies, and 19 before-after studies) reporting on 14 534 patients (median age, 15.1 years; 75.1% female patients). Psychosocial interventions comprised psychotherapy interventions (33 studies; cognitive behavioral therapy, dialectical behavioral therapy, collaborative assessment and management of suicidality, dynamic deconstructive psychotherapy, attachment-based family therapy, and family-focused therapy), acute (ie, 1-4 sessions or contacts) psychosocial interventions (19 studies; safety planning, family-based crisis management, motivational interviewing crisis interventions, continuity of care after crisis, and brief adjunctive treatments), and school- or community-based psychosocial interventions (13 studies; social network interventions, school-based skills interventions, suicide awareness or gatekeeper programs, and community-based, culturally tailored adjunct programs). Dialectical behavior therapy showed moderate strength of evidence for reducing suicidal ideation. Other categories of psychosocial treatments showed insufficient to low strength of evidence for reducing suicidal outcomes. None of the studies evaluated adverse events. The evidence base on pharmacologic treatment for youths at risk of suicide was largely nonexistent. Conclusions and Relevance This systematic review found that the current evidence on available interventions targeting youths at heightened risk of suicide is uncertain. Medication, neurotherapeutics, and emerging therapies remain unstudied among this population. The limited evidence base calls for the development of novel, developmentally and trauma-informed treatments, as well as multilevel interventions to target the increasing suicide risk among youths.

Abstract Context Women with preexisting diabetes mellitus (PDM) are at increased risk of pregnancy-related complications. Objective To summarize the available supporting evidence for the Endocrine Society guidelines about management of PDM in pregnancy. Data Sources MEDLINE, EMBASE, Scopus, and other sources through February 2025. Study Selection Studies were selected by pairs of independent reviewers. Data Extraction Data were extracted by pairs of independent reviewers. Data Synthesis We included 17 studies. Meta-analysis showed no significant difference between hybrid closed-loop insulin pump (HCL) and standard of care regarding time in range (TIR), time above range (TAR), and time below range (TBR). HCL had better overnight TIR and TBR. For women with type 2 diabetes mellitus (T2DM), intermittent use of continuous glucose monitoring (CGM) was not associated with a significant change in the risk of large for gestational age (LGA) neonates (2 randomized controlled trials [RCTs], 102 patients). Adding metformin to insulin was associated with a lower risk of LGA (2 RCTs, 1126 patients). Three retrospective studies (1724 patients) suggested increased neonatal complications when delivery was induced before 39 weeks of gestation (particularly before 38 weeks) in women with preexisting type 1 (T1DM) and T2DM, although this evidence was subject to likely confounding. One retrospective study showed no increase in neonatal complications with periconceptional exposure to glucagon-like peptide-1 receptor agonists. We could not identify comparative studies assessing a screening question about the possibility of pregnancy or a carbohydrate restrictive diet. Conclusion This systematic review addresses various aspects of managing PDM in pregnancy and will support the development of the Endocrine Society guidelines.

Importance The role and safety of transcranial electrical stimulation (tES) for treating depressive disorders remain under evaluation. Objective To evaluate tES treatment in patients with major depressive disorder (MDD) and comorbid depressive conditions. Data Sources A search of MEDLINE, Embase, Cochrane, APA PsycINFO, and Scopus databases was conducted from inception to September 17, 2024. Study Selection Randomized clinical trials (RCTs) of adults with MDD, depression with psychiatric comorbidities (DPC), or depression with medical comorbidities (DMC), treated with transcranial direct current stimulation (tDCS), transcranial alternating current stimulation (tACS), or transcranial random noise stimulation (tRNS), compared with sham or other treatments were included. Data Extraction and Synthesis Independent reviewers extracted data in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guidelines, with random-effects meta-analysis used for pooling. Main Outcomes and Measures Primary outcomes were depression severity, response and remission rates, and adverse events. Standardized mean differences (SMDs) were reported for continuous outcomes, and odds ratios (ORs) were reported for categorical outcomes. Quality of evidence (QOE) was assessed using the Grading of Recommendations Assessment, Development, and Evaluation criteria. Results The meta-analysis included 5522 participants from 114 study groups from 88 RCTs (3198 female [58.9%]; mean [range] age, 43.1 [19.4-76.9] years). Most studies (104 study groups from 79 RCTs [91.2%]) evaluated tDCS, while 7 study groups from 6 RCTs (6.1%) evaluated tACS, and 3 study groups from 3 RCTs (2.7%) evaluated tRNS. tES was associated with reduced depressive symptoms (SMD = −0.59; 95% CI, −0.83 to −0.35; low QOE) and improvement in DMC (SMD = −1.05; 95% CI, −1.67 to −0.43; low QOE) and DPC (SMD = −0.78; 95% CI, −1.27 to −0.29; low QOE) compared with MDD (SMD = −0.22; 95% CI, −0.44 to 0.01; low QOE). tDCS was associated with reduced depression in DMC (SMD = −1.05; 95% CI, −1.70 to −0.40; very low QOE) and DPC (SMD = −0.88; 95% CI, −1.40 to −0.36; low QOE) but not MDD. tACS was associated with improved MDD symptoms (SMD = −0.58; 95% CI, −0.96 to −0.20; high QOE) and response rates (OR, 2.07; 95% CI, 1.34 to 3.19; high QOE). Combined tDCS and medication was associated with reduced symptoms (SMD = −0.51; 95% CI, −0.90 to −0.13; moderate QOE) and increased response (OR, 2.25; 95% CI, 1.08 to 4.65; high QOE) in MDD. tDCS combined with psychotherapy was not associated with improvement. Subgroup analysis showed that anodal left dorsolateral prefrontal cortex DCS was associated with improved outcomes. Mild to moderate adverse events were more frequent in tES groups. Conclusions and Relevance In this systematic review and meta-analysis, tDCS was associated with improvement in depression among patients with DMC and DPC (with smaller benefits in MDD), tACS was associated with improved MDD outcomes (while tRNS had insufficient evidence) in smaller samples, and combined tDCS and medication was associated with improvement in depression. These findings suggest that tES is well-tolerated overall, with only mild to moderate adverse events, and that future research should optimize stimulation parameters and individualize tES interventions.