Publications by Year: 2026

PURPOSE: Translational Breast Cancer Research Consortium 048 was a proof-of-principle trial demonstrating responses to the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib in patients (pts) with metastatic breast cancer (MBC) with germline (g) PALB2 or somatic (s) BRCA mutations (sBRCAm). Here we report results from the expansion cohorts in a larger sample of pts with gPALB2m or sBRCAm.

METHODS: Eligible pts had MBC of any subtype with measurable disease and a gPALB2m or sBRCAm. Pts received olaparib 300 mg twice a day until progression. The primary end point was overall response rate. Secondary end points include clinical benefit rate (CBR) at 18 weeks, progression-free survival (PFS), duration of response (DOR), and whether among sBRCAm carriers the mutant allele frequency (MAF) is significantly higher in responders than in nonresponders.

RESULTS: Fifty-four pts with gPALB2m (N = 24) or sBRCAm (N = 30) were enrolled. Forty-two (78%) had estrogen receptor-positive human epidermal growth factor receptor 2-negative (HER2-) MBC, seven (13%) had triple-negative breast cancer, and five (9%) had HER2+ disease. Among pts with a gPALB2m, the overall response rate (ORR) was 75% (80% CI, 60.2 to 86.3), CBR was 83.3% (90% CI, 65.8 to 94.1), the median PFS was 9.4 months (90% CI, 8.3 to 13.1), and the median DOR was 7.0 months (90% CI, 5.6 to 10.4). Among pts with sBRCAm (15 sBRCA1 and 15 sBRCA2), the ORR was 36.7% (80% CI, 24.7 to 50), CBR was 53.3% (90% CI, 37 to 69.1), the median PFS was 5.5 months (90% CI, 2.8 to 8.3), and the median DOR was 11.2 months (90% CI, 4.4 to not reached). One additional pt had an unconfirmed partial response. Although clinically meaningful, the ORR in pts with sBRCAm did not achieve the prespecified target. Among sBRCAm carriers, the mean MAF did not differ significantly between responders (46%) and nonresponders (39%; P = .7).

CONCLUSION: Olaparib is active in pts with MBC with gPALB2m and sBRCAm, significantly expanding the population of pts with breast cancer likely to benefit from PARP inhibitors beyond gBRCA1/2m carriers.

OBJECTIVE: Undiagnosed diabetes leads to delayed treatment and increased risk of complications, exacerbating global disease burdens. In this study, we estimated the prevalence and absolute numbers of individuals with undiagnosed diabetes globally and across regions and quantified gaps in national diabetes detection efforts.

RESEARCH DESIGN AND METHODS: We systematically compiled estimates of biomarker-based diabetes prevalence and self-reported diabetes diagnosis using 2003-2024 data from all eligible population-based studies and gray literature. We calculated proportions of individuals with undiagnosed diabetes and case numbers among adults aged 20-79 years. For countries without data, we extrapolated estimates using available data within the same geographic region and country income group. Country-level estimates were benchmarked against the World Health Organization 80% diagnosis target.

RESULTS: We identified 193 data sources on undiagnosed diabetes from 109 countries. Across all 215 countries/territories, 42.8% of individuals with diabetes were undiagnosed in 2024, equating to 251.7 million (95% uncertainty interval [UI] 250.4-253.0 million) adults. Proportions undiagnosed ranged from 16.2% in Colombia to 90.4% in Burkina Faso and 29.1% in North America and the Caribbean to 72.6% in Africa. A larger proportion of individuals were undiagnosed in low-income (58.7%) compared with high-income countries (28.9%). Middle-income countries accounted for 206.0 million (95% UI 202.3-209.7 million) adults with undiagnosed diabetes (81.8% of all individuals), including 127.1 million (95% UI 121.2-133.0 million [or 50.5%]) adults in China, India, and Indonesia alone. Less than 5% of all countries attained diabetes diagnosis levels ≥80%.

CONCLUSIONS: Substantial global variability in undiagnosed diabetes indicates opportunities to close existing care gaps, likely requiring context-specific solutions and investments.

Patients with loss-of-function DOCK8 or dominant-negative STAT3 variants have hyper-IgE syndrome, although only DOCK8 deficiency consistently presents with elevated food-specific IgE and symptomatic allergy. We previously found in mice that DOCK8 restricts the differentiation of IL-13+ T follicular helper (Tfh13) cells that drive anaphylactic IgE, although the mechanisms were unclear. Here, we show that DOCK8 promotes STAT3 activity, which inhibits GATA3 in T cells. However, only patients with DOCK8, but not STAT3, deficiency had elevated Tfh13 cells. Cell-specific deletion of either Dock8 (T-Dock8-/-) or Stat3 (T-Stat3-/-) augmented peanut-specific IgE and Tfh13s when oral sensitization was promoted by adjuvants. However, the phenotypes diverged during adjuvant-free oral peanut exposure: only T-Dock8-/- mice developed Tfh13 cells and peanut-specific IgE, accompanied by reduced Foxp3+ Tregs. Treg depletion in T-Stat3-/- mice unmasked Tfh13 induction to oral antigen alone. Thus, DOCK8 and STAT3 cooperate to restrain Tfh13 differentiation to food allergens, and additional Treg impairment in DOCK8 deficiency allows for Tfh13 cell induction and allergy.

BACKGROUND: Many popular botulinum neurotoxin treatments are off-label, yet no review has comprehensively captured their effects. This study provides a systematic review of neurotoxin's off-label aesthetic applications, focusing on muscle targets, aesthetic goals, outcomes, and patient satisfaction.

METHODS: A systematic review of PubMed, MEDLINE, and Web of Science was conducted per Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Eligible studies were published between 2014 and 2024, describing nonwrinkle aesthetic uses of botulinum toxin type A in adults. Data extracted included patient demographics, muscle targets, aesthetic goals, procedural approaches, outcome measures, and patient satisfaction. Proportion meta-analyses were performed using Stata software.

RESULTS: Of 531 search-identified studies, 38 met inclusion criteria, totaling 1903 patients aged 17 to 93 years. Patients were primarily female (94.3%, P < 0.0001), with a mean age of 43.7 years. Most interventions targeted the lower face (70.3%, P < 0.0001). Facial aesthetic goals included eyebrow lift, forehead fat graft retention, nasal flare reduction, nasal tip sculpting, facial slimming, and correction of gummy smile, downturned mouth, chin retrusion, mentalis strain, and lower-face descent. Nonfacial aesthetic goals included neck, arm, and calf contouring and scrotal relaxation. Interventions focused on reducing volume/bulk (n = 21, 61.8%) or reshaping (eg, lifts and smile correction) (n = 16, 47.1%). Overall satisfaction was high (94%; 95% confidence interval, 88%-98%). Studies with quantitative measurements during the first follow-up (n = 23) reported sustained results (75.0%, P < 0.0001), with minimal reported complications.

CONCLUSION: Beyond rhytid reduction, botulinum toxin type A demonstrates versatile aesthetic utility in facial and body contouring, with high patient satisfaction and minimal adverse effects. Standardized protocols and refined evaluation methods are needed to inform decision-making, expand clinical guidance, and optimize outcomes.

Alzheimer's disease (AD) risk is strongly influenced by genetic variants that converge on pathways regulating endosomal homeostasis. Among these, BIN1 and RIN3 have emerged as susceptibility genes, yet their functional relationship in AD remains largely unknown. Here, we investigated how BIN1 and RIN3 interaction regulates RAB5 activity and endosomal pathology. RIN3 has been shown to bind BIN1, and we previously reported that this interaction modulates amyloid-β (Aβ) precursor protein (APP) trafficking and Aβ generation in vitro. To extend these findings, we used Rin3 constitutive knockout (Rin3-CKO) mice and CRISPR-Cas9-edited human induced pluripotent stem cell-derived neurons carrying either BIN1 knockout or rare familial AD RIN3 missense mutations within the BIN1-binding domain. We found that disruption of BIN1-RIN3 binding, through either genetic deletion or pathogenic RIN3 variants, resulted in RIN3-mediated RAB5 hyperactivation and enlargement of neuronal endosomes, a hallmark of early AD pathology. Transcriptomic profiling further revealed dysregulated expression of AD-related genes. Together, these findings establish BIN1 as a critical regulator of RIN3-driven RAB5 activation and neuronal endosomal homeostasis.

OBJECTIVES: Prehospital blood transfusion by emergency medical services (EMS) is associated with improved outcomes in trauma patients, but little is known about the statewide protocols that influence the availability and use of prehospital blood. This study aimed to describe statewide EMS protocols regarding field-initiated prehospital blood and blood product transfusion across the U.S.

METHODS: This was a cross-sectional analysis of publicly available statewide EMS protocols pertaining to field-initiated blood or blood product use during ground transport by advanced life support (ALS) clinicians. We excluded protocols specific to critical care or interfacility transport. We used a standardized data collection tool to compare clinical indications, blood product type, and considerations for pediatrics and biologically female patients who may bear children in the future. Descriptive statistics were used to describe the protocols.

RESULTS: We identified 31 states and the District of Columbia with publicly available statewide EMS protocols. Thirteen (42%) of these protocols allowed for field-initiated prehospital blood transfusion. There was variability regarding recommendations for transfusion indications and the details of administration in the protocols. All protocols allowed for transfusion in traumatic emergencies, and nine (69%) allowed for transfusion in medical emergencies. Three (23%) protocols specifically recommended low titer group O whole blood, and three (23%) protocols allowed transfusion during cardiac arrest. Nine (69%) protocols allowed for transfusion in pediatric patients. Only four (31%) protocols included special considerations for transfusing blood to biologically female patients.

CONCLUSIONS: While most statewide EMS protocols in the US did not include field-initiated blood transfusion, the protocols that do exist vary widely. With the increasing implementation of prehospital blood programs, these findings suggest an opportunity to provide more robust evidence-based guidelines for prehospital blood transfusion to improve patient care and outcomes.

The cognitive phenomenon, known as task-unrelated thought, reflects the attention shift of one's mind away from the task at hand. Evidence suggests that task-unrelated thought occurs in 30-50% of people's waking time. Previous research using the metronome response task shows that task-unrelated thought is related to variability in response time magnitude. However, those studies did not account for the time varying characteristics of an individual's tapping behavior. In the current study, three research questions were investigated: (1) What is the relationship between task-unrelated thought and movement dynamics (finger tapping dynamics)? (2) How does the statistical structure of external stimuli influence task-unrelated thought? (3) Does this structure moderate the relationship between task-unrelated thought and finger tapping dynamics? Participants performed the metronome response task under four different metronome structures: NoTone, Persistent, Periodic, and Random. Participants synchronized their finger to the metronome tone for each condition and self-reported the occurrence of task-unrelated thought. Overall, an increase of the Hurst exponent resulted in a decrease of task-unrelated thought probability. The findings have implications that behavioral variability has value in detecting task-unrelated thought. Additionally, studies using the metronome response task should account for the impact of the tone structure being used. Future research is warranted in this field to truly understand the mechanism behind task-unrelated thought and its link to human movement variability.