Henry Ford Health System

RET fusions appear in 1%-2% of non-small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET-altered NSCLC and RET fusion-positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion-positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion-positive NSCLCs, confirming previous findings with longer follow-up.

Conventional type 1 dendritic cells (cDC1s) are specialized for cross-presenting tumor antigens and determining the efficacy of immunotherapies, including immune checkpoint blockade and adoptive cell therapy. However, their rarity and tumor-induced dysfunction severely limit CD8 T cell priming and represent a central bottleneck to therapeutic efficacy. While strategies such as anti-DEC-205-mediated antigen delivery and Flt3L-driven DC expansion can enhance host DC function, their reliance on functional cDC1s remains a significant constraint. We developed Tim-3-targeted vaccines by conjugating tumor antigens or neoantigens to anti-Tim-3 antibodies. These vaccines delivered antigens to both cDC1s and cDC2s, and elicited robust, durable CD8 T cell responses. Remarkably, Tim-3-targeted vaccines endowed cDC2s with efficient cross-presentation capacity that matched that of cDC1s. In tumor-bearing mice or in CD11c-β-cateninactive mice, which model β-catenin-driven DC dysfunction, Tim-3-targeted vaccination restored cross-priming and counteracted tumor- and DC-mediated immunosuppression. In Batf3-/- mice lacking cDC1s, anti-Tim-3-based vaccines still elicited significant CD8 T cell cross-priming and tumor control-albeit both were reduced compared to wild-type mice- demonstrating that cDC1s contribute to but are not essential for Tim-3-targeted vaccine-induced CD8 T cell priming and anti-tumor efficacy. Strikingly, a single dose of anti-Tim-3-neoantigen vaccination eradicated large established MC38 tumors in a CD8 T cell-dependent manner. Together, these data identify Tim-3-targeted vaccines as a next-generation cancer vaccine platform that broadens DC engagement, reduces reliance on cDC1s, and overcomes tumor- and DC-mediated immunosuppression, addressing key limitations of current DC-based cancer vaccines.

Research suggests fear of sleep (FoS) may be an important consequence of trauma that increases risk for posttraumatic stress disorder (PTSD), especially among patients experiencing ongoing threat after their trauma has ended. Community violence exposure may reinforce perceptions of threat, compounding the pathogenic effect of FoS after trauma. The current study investigated whether FoS increases within the acute aftermath of trauma, and if such increases in FoS predict future PTSD severity. Further, we tested whether community violence exposure moderates the prospective relationship between FoS and PTSD. We recruited patients from an urban Level I trauma center (N = 88; Mage = 39.53 ± SD 14.31, 67.0% male, 67.0% Black). Patients reported FoS within one week of trauma (T1) and again one month later (T2), and PTSD symptoms two months later (T3). We operationalized community violence exposure as the frequency of hearing gunshots in the 90 days prior to trauma. FoS significantly increased from T1 (M = 8.80) to T2 (M = 11.98), p = 0.015, g = 0.28. Change in FoS significantly predicted PTSD symptoms at T3, and this effect was most pronounced among patients who frequently heard gunshots in their community (β = 0.61, SE = 0.35, p = 0.005). Exploratory analyses in a subsample of patients revealed preliminary associations between skin conductance reactivity and sleep fears at T1, tentatively suggesting heightened sympathetic activation as a corollary of fear of sleep. This study provides novel evidence that FoS increases in response to acute trauma exposure and, in turn, predicts future PTSD severity. Moreover, patients exposed to community violence may be especially vulnerable to these effects, perhaps due in part to continued threats to safety. Acute trauma patients who develop sleep fears may be vulnerable to PTSD, particularly those returning to neighborhoods marked by high levels of community violence.

To evaluate trends in neonatal intensive care unit (NICU) admissions, illness acuity, and hospitalization costs among U.S. children's hospitals from 2017 to 2022. This retrospective cohort study used data from the Pediatric Health Information System (PHIS) and included all NICU admissions. We examined trends in patient characteristics (e.g., gestational age, complex chronic conditions), illness severity scores, and standardized hospital costs. Interrupted time series analyses assessed changes in NICU costs over time. There were 234,571 infants admitted to NICUs in US children's hospitals between 2017 and 2022. NICU admissions shifted significantly by gestational age with admissions increasing by 10-18% among extremely, very, and late preterm infants. Term infants remained the largest admission group, averaging 45% annually (p < 0.001). Infants with ≥1 complex chronic condition increased from 46.6% in 2017 to 50.9% in 2022 (p < 0.001). NICU-specific illness severity increased modestly over time (1.14-1.24, p < 0.001). Median standardized NICU hospital costs rose by approximately 20% over the study period, with notable inflections in early 2020 and 2021. Among US children's hospitals in the PHIS database, NICU admissions were increasingly complex and costly. These findings highlight the importance of ongoing monitoring of resource use and patient mix in specialized NICU settings.

To assess the performance of an AI algorithm, an independent dataset is needed that matches the intended clinical claim and intended population (e.g., patient characteristics) for which the algorithm is meant. Using all available data for performance assessment may not be practical or optimal; to reduce the risk of sampling bias, the user is expected to utilize training and test data that are representative of the intended population. This work outlines a computational method for task-based sampling of data from a large repository and demonstrates its use, utilizing demographic characteristics and disease states as examples of the clinical attributes to match to an intended population. To run our developed task-based sampling algorithm, the user defines the initial cohort from which to sample, a target distribution profile, and a maximum allowable deviation in any subcategory. The functionality and results of the developed workflow are described in the context of sampling the Medical Imaging and Data Resource Center (MIDRC) data commons for algorithm performance assessment. An initial cohort of over 4000 patients was selected from the MIDRC public data commons. The task-based sampling algorithm was used to select samples matched to an approximate CDC demographic distribution with maximum allowable deviations of 5% and 10%. Resulting final cohorts of 542 and 870 unique patients with average clinical attribute differences of 1.0% and 2.1% were sampled, respectively. This investigation demonstrates that the developed task-based sampling algorithm can generate matched samples from a large dataset for reducing sampling bias in algorithm training and performance assessment.

Coronary Artery Bypass Grafting (CABG) and Percutaneous Coronary Intervention (PCI) are standard treatments for Multivessel Coronary Artery Disease (MVD). Their long-term comparative effectiveness remains debated. A systematic review and meta-analysis of randomized and observational studies was conducted, including patients with MVD followed for ≥5 years. Data were pooled using randomor fixed-effects models, depending on the level of heterogeneity. Thirteen studies met the inclusion criteria. CABG was associated with reduced all-cause mortality (RR 0.82, 95% CI 0.72-0.91) and fewer repeat revascularizations (RR 1.98, 95% CI 1.74-2.26) compared with PCI. Stroke risk was slightly higher after CABG. Findings suggest CABG provides superior survival and event reduction in long-term follow-up, particularly in higher-risk subgroups. However, the modestly increased stroke risk highlights the need for individualized decision-making, taking into account patient comorbidities, anatomy, and surgical suitability. CABG offers long-term survival and durability advantages over PCI in MVD, while PCI remains suitable for patients with lower-risk anatomy or when surgery is contraindicated.

Introduction Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczematous lesions, intense itch, and skin pain. The chronic nature of the disease requires safe and effective long term treatment options. Upadacitinib (UPA) is a Janus kinase inhibitor approved for the treatment of moderate-to-severe AD in adults and adolescents. Materials and Methods Patients in the randomized, double-blind, multicenter, placebo-controlled, phase 3 Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and AD Up (NCT03568318) trials were pooled for analysis. Adolescents and adults (aged 12–75 years) with moderate-to-severe AD were randomized 1:1:1 to receive once-daily oral monotherapy with UPA 15 mg, UPA 30 mg, or placebo (Measure Up 1, Measure Up 2) or in conjunction with topical corticosteroids (AD Up). The first 16 weeks of each study were placebo-controlled, double-blinded with a blinded extension period of up to 524 weeks. Patients who were initially randomized to UPA maintained their original treatment. Patients initially randomized to placebo were rerandomized (1:1) to blinded UPA 15 mg or UPA 30 mg. Treatment-emergent adverse events (TEAEs) and adverse events of special interest (AESI) were assessed by exposure-adjusted rates per 100 patient-years (PY) for the entire treatment period. Results A total of 2683 patients were treated with either 15 mg (N = 1337) or 30 mg (N=1346) of UPA with a total of 9623.7 PYs of exposure. Overall rates for TEAEs were higher with UPA 30 mg than UPA 15 mg. Serious AE, and AE leading to discontinuation were generally similar between UPA 15 mg and 30 mg. Rates of TEAEs leading to death remained low in both groups (both UPA 15 mg and 30 mg, 0.1 events per 100PY [E/100PY]). Rates of AESIs were: serious infections (UPA 15 mg, 2.2E/100PY; UPA 30 mg, 2.7 E/100 PY), herpes zoster (UPA 15 mg, 3.2 E/100PY; UPA 30 mg, 5.1 E/100PY), nonmelanoma skin cancer (NMSC; UPA 15 mg, 0.4 patients per 100 patient-years [n/100PY]; UPA 30 mg 0.5 n/100PY), malignancy excluding NMSC (UPA 15 mg, 0.3 n/100PY; UPA 30 mg, 0.4 n/100PY), adjudicated major adverse cardiovascular events (UPA 15 mg, 0.2 n/100PY; UPA 30 mg, &lt; 0.1 n/100PY), and adjudicated venous thromboembolic events (UPA 15 mg, 0.1 n/100PY; UPA 30 mg, 0.2 n/100PY). Incidence rates for MACE, VTE and malignancy were similar or below background rates observed in real-world AD populations. Conclusions This integrated analysis of three phase 3 trials with over 9600 patient-years of exposure demonstrates consistently low rates of adverse events of special interest throughout 7 years of upadacitinib treatment. Rates were generally similar between doses and did not exceed background incidence rates in real-world atopic dermatitis populations, supporting the established benefit-risk profile of upadacitinib for moderate-to-severe atopic dermatitis.