Citations

Cytotoxic T cells produce the cytokine interferon-γ (IFN-γ). We sought to determine whether IFN-γ directly kills target cells and found that T cells used IFN-γ to kill murine melanoma cells lacking the kinases TBK1 and IKKε. In the absence of both kinases, IFN-γ induced the production of TNF receptor 1 (TNFR1) and the sensor Z-DNA binding protein 1 (ZBP1) in the tumor cells to stimulate receptor-interacting protein kinase 1 (RIPK1)–dependent apoptosis in a cell-autonomous manner. IFN-γ also enhanced the activation of nuclear factor κB (NF-κB) signaling in a TNFR1-dependent manner in cells deficient in both TBK1 and IKKε. Because IFN-γ–induced apoptosis occurred in a transcription-dependent manner with slow kinetics, STAT1 and NF-κB cooperated to activate the expression of inflammatory genes in the dying cells. Thus, IFN-γ–induced cell death was accompanied by an inflammatory signature in the absence of TBK1 and IKKε. TBK1 and IKKε not only mediated the induction of type I IFN but also inhibited RIPK1-dependent death and NF-κB–dependent inflammation. Therefore, we propose that these kinases may have gained these intertwined functions so that cells infected by pathogens that produce antagonists of TBK1 and IKKε are eliminated by IFN-γ–secreting T cells in an inflammatory manner to compensate for the inhibition of type I IFN production.

Ehlers-Danlos syndrome (EDS) is a heritable collagen disorder characterized by joint hypermobility and tissue fragility, with hypermobile Ehlers-Danlos syndrome (hEDS) as the most common subtype. Rates of gastroesophageal reflux disease (GERD) symptoms are reportedly higher in the hEDS population than the general population. This could be caused by increased esophageal hypersensitivity and/or connective tissue laxity leading to hiatal hernias or increased relaxations of the lower esophageal sphincter. Despite this, Barrett’s esophagus rates in hEDS do not appear to be higher than in the general population. This review examines the epidemiology, pathophysiology, and unique considerations for management of GERD in hEDS.

Importance Transvaginal pelvic imaging is an integral and sensitive aspect of gynecologic care that individuals find both invasive and burdensome. At-home transvaginal imaging provides an opportunity to navigate these barriers to care. Objective To evaluate the use of at-home transvaginal ultrasonography for gynecologic assessment, as measured by diagnostic imaging quality and participant satisfaction, in a broad sampling of women aged 22 to 50 years. Design, Setting, and Participants Prospective, interventional, single group nonrandomized clinical trial with blinded review of collected images from premenopausal women aged 22 to 50 from Florida, Massachusetts, Maryland, Maine, Minnesota, New Hampshire, Texas, Utah, Virginia, Vermont, and Washington, DC. Images were gathered between July 2022 and July 2023, and data were analyzed from April to September 2025. Intervention At-home pelvic ultrasonography guided by verbal communication with a fully trained remote sonographer who had real-time access to study images. Cine clips were used to capture standard views of the uterus, ovaries, cervix, and posterior cul-de-sac. Main Outcomes and Measures Primary outcomes were image quality and participant net promoter score (NPS), reflecting participants' likelihood of recommending the procedure, with higher scores indicating greater likelihood. Secondary outcomes included minor pain or discomfort, sonographer reported experience and/or pain, and all other adverse events. Results A total of 265 participants (mean [SD] age, 32 [6.7] years; mean [SD] body mass index, 27.0 [5.6]) enrolled in the trial, and 263 ultrasonographic scans were completed. Image quality showed that 253 at-home ultrasonographic scans (96.2%) met diagnostic quality while 10 (3.8%) did not. NPS was significantly higher with use of the at-home ultrasonography (59) compared with in-clinic scans (24), with an adjusted difference of 33.7 (95% CI, 23.3-44.0; z = 6.35; P < .001). No adverse events were reported. Conclusions and Relevance This nonrandomized clinical trial of at-home pelvic ultrasonography in premenopausal women demonstrated that broad use of at-home gynecologic ultrasonography technology is feasible, safe, and preferred by participants and sonographers compared with in-clinic ultrasonography. At-home ultrasonographic imaging presented an innovative and clinically acceptable alternative to in-clinic care, providing opportunities for improved access to and decreased burden of gynecologic and reproductive care. Registration ClinicalTrials.gov NCT05443698

Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is characterized by chronic progressive pulmonary fibrosis and high mortality. Genetic markers, summarized into a polygenic risk score (PRS), associate with IPF in well-phenotyped research cohorts. Objectives To evaluate the performance of the PRS using real-world data from routinely captured electronic healthcare records. Methods We conducted an observational study evaluating the association of a PRS for IPF with electronic healthcare record diagnosis of IPF as well as lung transplant-free survival in four independent cohorts; the Mass General Brigham Biobank (MGBB), Mayo Clinic Biobank (MCBB), Mayo Clinic Tapestry Cohort (Tapestry), and U.K. Biobank (UKBB). We used multivariable logistic regression and multivariable Cox proportional hazards models adjusting for age, gender, and principal components of ancestry. The cohorts then underwent fixed and random effects meta-analysis. Measurements and Main Results Of 37,709; 44,195; 43,202; and 447,422 participants from MGBB, MCBB, Tapestry and UKBB respectively, 1,015 (2.7%) 2,879 (6.5%), 1,310 (3.0%), and 2,742 (0.6%) participants had an IPF diagnosis. Meta-analysis demonstrated a high-risk PRS associated with IPF diagnosis, OR 2.88 (95%CI 2.41-3.44) compared to all other individuals. A high-risk PRS also associated with the composite endpoint of mortality or lung transplant among those with an IPF diagnosis, HR 1.23(95%CI 1.11-1.35) compared to all other individuals. Conclusions A PRS can identify those at risk for an IPF diagnosis and mortality in biobank-scale data, which may have implications for clinical decisions. Further work is necessary to evaluate the utility of adding genetics in clinical settings.

Background: Hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), and preterm delivery are associated with higher long-term cardiovascular, metabolic, and kidney disease risk. Their implications for living kidney donation remain uncertain. Methods: We conducted a retrospective cohort study of 498 female living kidney donors (2000–2017) from the Mayo Clinic Living Donor Program with documented pregnancy histories, pre-donation CT angiography, implantation kidney biopsy, and measured GFR. Donors with prior HDP (n=45), GDM (n=18), or preterm delivery (n=65) were compared with donors without adverse pregnancy outcomes (APO; n=385). Kidney morphometry, histology, and function were analyzed with adjustment for age at donation and first pregnancy, parity, and hypertension. Post-donation kidney outcomes were assessed using surveys and medical record review. Results: Donors with prior HDP and GDM had higher BMI at donation (+7.9% and +8.9%; p=0.006 and 0.04), whereas donors with preterm delivery had lower BMI (−4.8%; p=0.03) compared with donors with no APO. After adjustment, donors with HDP showed no differences in kidney volumes, biopsy features, or kidney function at donation or during follow-up. Donors with GDM had larger total and cortical kidney volumes (9.5–10%), less arterial luminal stenosis, and higher 5-year post-donation eGFR (+15%; p=0.03). Donors with preterm delivery had a lower risk of eGFR <45 mL/min/1.73 m 2 (HR 0.28; p=0.03). Conclusions: Prior adverse pregnancy outcomes were not associated with adverse kidney structure at donation or accelerated kidney function decline post-donation. These findings support that APO history alone should not preclude living kidney donation when other eligibility criteria are met.

Importance Anhydramnios from fetal kidney failure causes lethal pulmonary hypoplasia. Serial amnioinfusions have shown promise in mitigating pulmonary disease from bilateral renal agenesis, but efficacy and safety for other causes of fetal kidney failure are unproven. Objective To assess the efficacy of serial amnioinfusions initiated before 26 weeks’ gestation to mitigate lethal pulmonary hypoplasia in cases of anhydramnios due to fetal kidney failure. Design, Setting, and Participants Prospective, nonrandomized clinical trial conducted at 13 US fetal therapy centers from December 2018 to February 2025. Outcomes for maternal-fetal pairs with anhydramnios before 22 weeks’ gestation due to fetal kidney failure without bilateral renal agenesis are reported; data collection for surviving infants continued until February 13, 2026. Exposure Thirty-two participants underwent serial amnioinfusions with isotonic fluid beginning before 26 weeks’ gestation. Main Outcomes and Measures The primary end point was neonatal survival for 14 days or longer with dialysis access placement. Secondary outcome measures of survival to discharge home and kidney transplant are reported. Results Twenty-nine of 32 participants (91%) had a live birth, with a median (IQR) gestational age at delivery of 34 weeks 1 day (31 weeks 5 days to 34 weeks 6 days). All participants delivered before 37 weeks’ gestation. No unexpected serious maternal adverse events occurred, and the most common maternal complications were preterm prelabor rupture of membranes in 19 participants (56%) and chorioamniotic separation in 10 (29%). The primary outcome occurred in 19 (65.5%) of 29 live-born neonates (95% CI, 45.7%-82.1%). Factors associated with survival to the primary outcome included receiving more amnioinfusions (median [IQR], 14 [9-18] in survivors vs 7 [4-11] in nonsurvivors; P = .01), longer time interval from first amnioinfusion to preterm prelabor rupture of membranes (63.5 [60.5-74.5] days in survivors vs 29.0 [22.0-56.0] days in nonsurvivors; P = .01), gestational age greater than 32 weeks (79% of survivors vs 38% of nonsurvivors; P = .03), and higher birth weight (2029 [1770-2250] g in survivors vs 1635 [1185-1915] g in nonsurvivors; P = .01). Fourteen live-born infants (48%) survived to hospital discharge at a median (IQR) age of 4.7 (3.4-5.7) months. Of the 11 infants surviving to date, 7 (64%) have undergone kidney transplant between ages 2 years to 5 years. Conclusions and Relevance Serial amnioinfusions mitigated lethal pulmonary hypoplasia in neonates with anhydramnios due to fetal kidney failure. Significant neonatal morbidity and mortality independent of early lung function was noted. Factors associated with survival were consistent with the Renal Anhydramnios Fetal Therapy trial’s bilateral renal agenesis cohort, suggesting common mechanistic pathways for mitigating pulmonary hypoplasia. Trial Registration ClinicalTrials.gov Identifier: NCT03101891

Abstract Current genomic assays provide prognostic information and guide chemotherapy decisions in early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2−) breast cancer, but limited tissue sampling may incompletely capture tumor heterogeneity. We developed and validated an image-based artificial intelligence (AI) model integrating dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and clinicopathologic features to predict recurrence risk in early-stage HR+/HER2 − breast cancer. In this retrospective multi-institutional study, the model was trained using pre-treatment imaging and clinicopathologic data from 522 patients and independently validated in 550 additional patients treated between 2010 and 2023. By analyzing spatial tumor characteristics, the model generated individualized recurrence risk scores that outperformed clinicopathologic features alone. In the validation cohort, median age was 53 years (range, 24–90), 15.6% of patients self-identified as African American, 89.7% had clinical T1–T2 disease, and 34.4% had 1–3 positive lymph nodes. Five-year recurrence-free survival was 93.8% (95% CI, 90.0–96.2%) among patients classified as low risk compared with 82.6% (95% CI, 74.8–88.1%) among those classified as high risk, corresponding to an adjusted hazard ratio of 2.28. Prognostic performance was maintained across clinically relevant subgroups, including age and nodal status. These findings support the potential of a noninvasive image-based AI approach for real-time prognostication and treatment personalization in early-stage HR+/HER2 − breast cancer.

Abstract Dermatomyositis is driven by overactivation of type I and II interferons and other proinflammatory cytokines that signal via the JAK-STAT pathway. We conducted a 12-week, open-label study of brepocitinib, an oral TYK2/JAK1 inhibitor, in five adults with severe cutaneous dermatomyositis. Treatment was associated with rapid, clinically meaningful improvement in cutaneous disease activity. Single-cell and spatial transcriptomic profiling of lesional skin showed marked suppression of interferon-responsive pathways and inflammatory cell states by week 4. Together with findings from a Phase 3 randomized trial in DM patients with skin and muscle involvement (VALOR, NCT05437263 ), these data support TYK2/JAK1 inhibition as a promising therapeutic strategy for DM.

Summary Background Postoperative nausea and vomiting (PONV) is a common consequence of anaesthesia, affecting up to 30% of postoperative patients. Female sex is one of the strongest risk factors for PONV, yet no dedicated analysis has examined how this association varies across surgical settings and timepoints. This systematic review and meta-analysis aimed to quantify sex differences in PONV incidence across different surgical contexts. Methods A systematic search was conducted using PRISMA guidelines across Medline and Embase from inception to September 1, 2025. Eligible studies were observational cohort studies (n≥500) of adult patients that conducted multivariate regression analyses including sex as a variable. Two reviewers independently screened, extracted data, and assessed risk of bias using ROBINS-E. A random-effects meta-analysis was performed. Subgroup analyses and multiple sensitivity analyses were completed. Results From 4620 identified studies, 23 met the inclusion criteria, including 462,828 patients across various surgical settings and specialties (52% female). The pooled incidence of PONV was 21% (95% CI[16-27%]), with high heterogeneity (I 2 =99.9%). Meta-analysis confirmed females had a higher risk of developing PONV compared to males (pooled OR=2.40, 95% CI[2.06-2.79], I 2 =93.1%, p<0.0001). Sensitivity analyses confirmed robustness of pooled estimates. Subgroup analyses demonstrated consistently elevated risk of PONV for females at all three timepoints (PACU, 24-hour, 48-hour post-operative) and across studies including and excluding female-only surgeries. Studies were generally at high risk of bias. Discussion Female sex is a strong risk factor for PONV across surgical settings. Further research into precise subgroups, underlying mechanisms of sex-differences, and the use of prophylaxis may help improve this inequity.