UC San Diego Health is the academic health system of the University of California, San Diego in San Diego, California. It is the only academic health system serving San Diego and has one of only two adult Level I trauma centers in the region. In operation since 1966, it comprises the UC San Diego Medical Center in Hillcrest as well as the; Jacobs Medical Center; Moores Cancer Center; Shiley Eye Institute; Sulpizio Cardiovascular Center, and Koman Family Outpatient Pavilion, all in La Jolla. It also includes several outpatient sites located throughout San Diego County. The health system works closely with the university's School of Medicine and Skaggs School of Pharmacy to provide training to medical and pharmacy students and advanced clinical care to patients.It is the official health system of the San Diego Padres and UC San Diego Tritons.
BACKGROUND:Breast implant illness (BII) refers to a cluster of nonspecific systemic symptoms that some patients attribute to breast implants. This study compared long-term rates of "BII-compatible symptoms" among mastectomy patients who received implant-based reconstruction, autologous flap reconstruction, or no reconstruction. METHODS:A retrospective, propensity-matched cohort study was conducted in the TriNetX Global Collaborative Network. Women ≥18 years with breast cancer diagnosed between 2005 and 2025 who underwent mastectomy entered 3 mutually exclusive groups: implant-based reconstruction, autologous reconstruction without implants, or mastectomy only. Ten BII-compatible outcomes (fatigue, joint pain, anxiety, cognitive dysfunction, alopecia, major depression, rash, headache, abnormal weight loss, and abnormal weight gain) were captured 3 to 20 years postsurgery. Separate 1:1 nearest-neighbor matches balanced demographic, oncologic, and comorbidity covariates (standardized mean difference, <0.10). Risk ratios (RRs), absolute risk differences (RDs), 95% confidence intervals (CIs), and Kaplan-Meier hazard ratios were calculated within TriNetX; P < 0.05 signified significance. RESULTS:After matching, cohort sizes were 2536 (implant vs autologous), 1716 (autologous vs no reconstruction), and 8188 (implant vs no reconstruction), with a mean follow-up of around 3.8 years. First instance of any BII-compatible symptom incidence was higher with implants than autologous flaps (8.2% vs 5.1%; RR, 1.6 [95% CI, 1.2-2.1]), lower with autologous flaps than no reconstruction (6.7% vs 9.5%; RR, 0.71 [0.52-0.96], and similar between implants and mastectomy only (8.9% vs 8.1%; RR, 1.09 [0.96-1.25]). Implants carried higher risks than autologous flaps for fatigue (RR, 2.42), joint pain (RR, 2.08), and rash (RR, 1.86). Autologous flaps were protective versus no reconstruction for fatigue (RR, 0.60) and joint pain (RR, 0.66). Compared with mastectomy only, implants showed a modest excess of depressive diagnoses (RR, 1.26) but fewer rashes (RR, 0.61); other symptoms did not demonstrate significance. Kaplan-Meier curves confirmed earlier symptom onset with implants than autologous flaps (adjusted hazard ratio, 1.41). CONCLUSIONS:Autologous reconstruction confers the lowest long-term burden of BII-compatible symptoms, whereas implants increase fatigue, joint pain, and rash relative to autologous flaps but not relative to mastectomy alone. Systemic complaints after breast surgery appear multifactorial rather than implant-specific, supporting balanced patient counseling and prospective mechanistic research.
Importance:The Epic Sepsis Model version 2 (ESM v2) is a widely implemented proprietary sepsis prediction model, but no multicenter, external validation of its performance has been reported to guide adoption and use. Objective:To conduct a multicenter validation of the ESM v2 to compare performance against the original ESM v1, outline differences across heterogenous clinical sites, and compare model performance against clinician recognition of sepsis. Design, Setting, and Participants:This prognostic study included adult inpatient encounters at 4 large US health systems between August 31, 2023, and March 11, 2025. At each site, data were collected for a consecutive period immediately following new model implementation. Data were analyzed from July 23 to August 19, 2025. Main Outcomes and Measures:Sepsis was defined using Sepsis-3 clinical consensus criteria. Model discrimination was assessed using area under the receiver operating characteristic curve (AUROC) at the encounter level and prediction level with 4-hour, 12-hour, and hospitalization-wide time horizons. Performance against clinician recognition of sepsis was measured using antibiotics, lactate, and body culture orders. Results:Of 227 091 inpatient encounters, 7401 (3.3%; median [IQR] age, 65 [54-75] years; 3359 [45.4%] female; 2.7% Asian; 24.6% Black; 64.6% White; 7.1% Hispanic ethnicity) met sepsis criteria and 219 690 (96.7%; median [IQR] age, 48 [33-65] years; 123 563 [56.2%] female; 2.5% Asian; 38.8% Black; 49.6% White; 9.6% Hispanic ethnicity) did not. At the encounter level, the AUROC ranged from 0.82 (95% CI, 0.81-0.83) to 0.92 (95% CI, 0.92-0.93) across study sites. At the prediction level with a 12-hour time horizon, the AUROC ranged from 0.75 (95% CI, 0.74-0.75) to 0.85 (95% CI, 0.85-0.85). Comparison against clinician recognition of sepsis yielded a minor decrease in performance, with the resulting encounter-level AUROC ranging from 0.80 (95% CI, 0.79-0.81) to 0.90 (95% CI, 0.89-0.90) across sites. Positive predictive values remained low, from 0.13 (95% CI, 0.13-0.14) to 0.26 (95% CI, 0.25-0.27), with a high number needed to evaluate and high alert burden. Conclusions and Relevance:In this prognostic study of a new sepsis prediction model, a multicenter prospective validation performed across 4 major US health systems found improved discrimination for the early prediction of sepsis but noted high institutional variability, low positive predictive value, and high alert burden.
PURPOSE:To evaluate the safety and effectiveness of the second-generation CVAC® Aspiration System. METHODS:A prospective study of steerable ureteroscopic renal evacuation using the second-generation CVAC was performed. Stone clearance (percent stone volume removed), residual stone volume (RSV), and stone-free rate (SFR) at postoperative day 30 were assessed using noncontrast CT (NCCT). Adverse events were recorded. RESULTS:Twenty-six out of 30 subjects had POD 30 NCCT. Mean baseline stone volume and density were 703.6 mm3 and 1203 HU, respectively. Mean stone clearance was 96.2%; average RSV was 14.1 mm3, and SFR (zero residual fragments) was 46.4%. Stone clearance remained high, and RSV remained low with increasing baseline stone volume. There were two instances of urinary tract infection (Clavien-Dindo grade II) and no subjects requiring intervention or retreatment. CONCLUSIONS:The CVAC Aspiration System safely delivers high stone clearance and low RSV.
Alzheimer disease (AD) has a strong genetic basis, yet previously derived polygenic risk scores (PRS) are heavily weighted by the APOE locus and perform inconsistently across diverse ancestries. We developed an APOE-independent multi-ancestry AD PRS using genome-wide association study summary statistics from cohorts in the United States, Europe and East Asia that were applied to European ancestry (EA), African American (AA), Caribbean Hispanic (CH), and East Asian cohorts from the Alzheimer's Disease Genetics Consortium. PRS performance was evaluated in the multi-ancestry Alzheimer's Disease Sequencing Project (ADSP) dataset and validated in several additional multi-ancestry cohorts. The PRS was significantly associated with AD in the ADSP EA, AA, CH, and Native American Hispanic groups with adjusted odds ratios (ORs) between 1.14 and 1.52 per standard deviation of the PRS. PRS performance was validated in the replication cohorts (ORs 1.21-1.65). The PRS was also associated with poorer memory, executive function, and language performance; greater AD-related neuropathological burden (including CERAD, Braak stage, and Thal phase scores); reduced hippocampal volume; lower CSF Aβ42; and elevated total tau and phosphorylated tau (p-tau), with stronger p-tau associations observed in women. Longitudinal analyses revealed that individuals in the highest PRS decile exhibited the steepest cognitive decline, particularly among those who progressed to AD. Our findings demonstrate the utility of an ancestry-aware and APOE-independent PRS for advancing understanding of the genetic basis of AD across diverse populations. Associations observed with early biological and cognitive changes and potential sex-specific differences support the incorporation of a PRS in clinical trials and personalized intervention and prevention strategies.
Pancreatic ductal adenocarcinoma (PDAC) is the deadliest major cancer and has a profoundly immunosuppressive tumor microenvironment (TME). Previous studies have shown that inhibition of the E1 enzyme, which catalyzes the small ubiquitin-like modifiers (SUMO), with the small molecule TAK-981, can reprogram the TME to enhance immune activation and suppress tumor growth. We found that the CD-155/TIGIT pathway, a key regulator of immune evasion in PDAC, is influenced by SUMOylation. We hypothesized that the combination of SUMO E1 and TIGIT inhibition would synergistically induce antitumor immune effects. We used a clinically relevant orthotopic mouse model that consistently develops liver metastases to study this combination therapy alone and in the perioperative setting with surgical resection. The combination of SUMO E1 and TIGIT inhibition significantly prolonged survival. Complete responders exhibited protective immunity and enhanced T-cell reactivity to model-specific alloantigens. Complementary immune analyses of resected tumors demonstrated that combination therapy more significantly reduces the abundance of regulatory FoxP3+CD4+ T cells than either monotherapy alone. Mechanistic studies suggest that SUMO E1 inhibition enhances antibody-mediated elimination of regulatory T cells through innate immune cells, potentially by activation of type I IFN responses. Our results highlight a mechanism to enhance the efficacy of anti-TIGIT therapy.
