Citations

ABSTRACT Introduction Postoperative mortality commonly follows complications that are not prevented, recognised or managed effectively. Ward‐based nursing care is central to surveillance, escalation and rescue, but population‐level evidence using shift‐level staffing data is limited. This national population‐based cohort study examined the association between surgical ward nurse staffing and postoperative outcomes. Methods Adults aged 18 years or older undergoing inpatient surgery under general or neuraxial anaesthesia in public hospitals in Aotearoa New Zealand between 2022 and 2024 were included. Prospectively recorded TrendCare staffing data were linked to administrative health datasets. The exposure was shift‐level staffing variance, defined as the difference between required and available nursing care hours on surgical wards in the treating hospital during admission. The primary outcome was 90‐day postoperative mortality. Secondary outcomes were postoperative complications and failure to rescue. Results The cohort included 202 428 patients undergoing 223 415 surgical admissions. Within 90 days, 6296 admissions resulted in death (2.8%). Complications occurred in 41 722 admissions (18.7%), with failure to rescue in 15.1%. Of 281 147 surgical ward shifts, 122 186 (43.5%) were understaffed. After adjustment, each one‐nurse reduction in staffing per shift was associated with higher odds of mortality (aOR: 1.13, 95% CI: 1.07–1.18), complications (aOR: 1.07, 95% CI: 1.05–1.10) and failure to rescue (aOR: 1.07, 95% CI: 1.00–1.14). Modelling estimated that correcting observed staffing deficits was associated with 182 fewer deaths annually. Conclusion Lower surgical ward nurse staffing was associated with increased postoperative mortality, complications and failure to rescue. Nurse staffing is a modifiable system factor associated with postoperative safety and should be prioritised to improve surgical outcomes.

Despite advances in pharmacogenomics that have led to innovative therapeutic strategies, substantial interindividual variability in drug efficacy and toxicity persists. Both endogenous and exogenous factors contribute to this unexplained variation, resulting in suboptimal treatment effectiveness, unnecessary healthcare costs, preventable mortality, and significant human suffering. The emerging field of exposomics is aimed at addressing the complex exposures that impact human health and offers an opportunity to interrogate how these exposures influence drug actions and outcomes. Here, we introduce pharmacoexposomics as a complementary framework that systematically quantifies the body's metabolic response to drug and environmental exposures using high-resolution mass spectrometry. We then present IndiPHARM (Individualized Pharmacology), a multi-institution, Advanced Research Projects Agency for Health–supported platform designed to integrate population-scale pharmacoexposomics with pharmacogenomics and clinical data to elucidate interindividual variability in drug response, identify adverse reactions, and inform tailored, effective treatment strategies that advance precision medicine.

Background Prognostic staging systems in transthyretin amyloid (ATTR) cardiomyopathy were developed before the introduction of disease‐modifying treatment. We therefore evaluated contemporary risk stratification according to different staging systems in patients with ATTR cardiomyopathy. Methods All patients with newly diagnosed ATTR cardiomyopathy and baseline biomarker measurements from 2019 to 2023 were included from Mayo Clinic, Rochester, MN. Prognostic outcomes were calculated with Kaplan–Meier analysis for 3e staging systems in the main analysis: the National Amyloidosis Centre (NAC) staging system; a modified Mayo staging system using hsTNT (high‐sensitivity troponin T) cutoff >65 ng/L; the extended NAC model with a fourth stage (NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide] >10 000 ng/L). Results The study population consisted of 441 patients with a median age of 76 years, 93% were men, 85% were initiated on tafamidis, and 94% had wild‐type ATTR. Median follow‐up was 3.4 years, and 109 deaths occurred during follow‐up. The 3‐year survival for the Mayo stages were 92.3% (88.7–95.9) for stage I, 71.6% (63.0–81.3) for stage II, and 43.5% (32.4–58.5) for stage III. For the NAC system, 3‐year survival were 92.0% (89.0–95.7), 67.5% (59.0–77.3), and 47.0% (34.7–63.5) for stages I, II, and III, respectively. The 3‐year survival by the extended NAC system was 92.0 (69.0–79.2), 69.0% (60.1–79.2), 53.2% (39.9–70.8) and 34.4% (17.4–68.0) for stages I, II, III, and IV, respectively. Conclusions In a contemporary cohort of patients with ATTR cardiomyopathy, the NAC and modified Mayo staging systems remained equally effective in delineating clinically meaningful prognostic groups, whereas the extended NAC system identified a stage IV subgroup with high mortality.

Abstract Standard of care RPT may result in dose-limiting side effects of the salivary glands include sialadenitis and xerostomia that are inconsistent with outcomes from external beam for equivalent ADs. This work develops a parametrizable ‘Macro-to-Micro’ (M2μ) model that demonstrates the consideration of small-scale dosimetry in comparison to conventional methods that typically assume uniform voxel or organ-level uptake. Anatomical features of the salivary gland are represented by annular structures (a centralized branching network of ducts, including excretory, lobar, interlobular) and small-scale voxels (intralobular ducts and acinar cells) with dimensions set to reproduce ex-vivo murine histopathology measurements and scaled up in size for extrapolation to humans. Simulations were performed by scoring and recording S-value histograms to the target ductal and acinar cells, for two beta emitters (177Lu, 131I) and one alpha emitter (225Ac). Four idealized activity distributions were created to assign activity to surface and volumes of the annuli, and GEANT4 v11 was used for radiation transport calculations. Comparisons against whole gland uniform spherical self-dose S-value calculations were conducted to validate the radiation transport and to highlight differences between M2μ and conventional dosimetry approaches. Analyses for both models showed greater S-value variation in comparison to the homogeneously distributed activity S-value calculation. The most notable result was that the calculated S-values differed between different branches, depending on the geometric size of the annuli. For the surrounding acinar cells, S-values from ductal cells decreased as a function of distance from the branching structures. High variability of S-values, depending on ductal cell dimensions as well as within the acinar cell distribution of the salivary gland highlights the potential clinical utility of small-scale approaches to RPT salivary gland dosimetry, contingent on clinical translation and validation. To this end, future work should further refine the model and incorporate small-scale activity distributions from pre-clinical and translational studies.

Accurate estimation of Alzheimer’s disease (AD) severity from structural magnetic resonance imaging (MRI) remains difficult, as disease-associated anatomical alterations are often subtle and publicly available datasets are typically too small to support robust deep learning model training. This feasibility study sought to determine how much Alzheimer’s disease spectrum-related information could be extracted from a small structural MRI cohort using a deliberately lightweight two-dimensional convolutional neural network (2D CNN), and whether transfer learning improves model performance. This study was intended as a methodological proof of concept rather than the development of a clinically deployable diagnostic tool. Structural scans and Clinical Dementia Rating (CDR) labels from the OASIS-1 dataset were filtered to 214 subjects: 124 cognitively normal (CN), 65 with mild cognitive impairment (MCI; CDR = 0.5), and 25 with AD-level impairment (CDR ≥ 1). A compact 2D CNN trained from scratch and a transfer learning model (frozen ImageNet MobileNetV2 features) were evaluated on four binary tasks (CN vs. AD, MCI vs. AD, CN vs. MCI, and CN vs. any impairment) under identical pre-processing and subject-level repeated 5-fold cross-validation (10 repeats), with the decision threshold tuned only on an inner split. Discrimination was summarized by ROC-AUC with 95% confidence intervals (CIs), permutation tests against chance, and per-task sensitivity and specificity. The from-scratch CNN recovered only a broad normal-versus-impaired signal (CN vs. any impairment AUC 0.59) and was at chance on adjacent-stage tasks (MCI vs. AD 0.41; CN vs. MCI 0.51). Transfer learning improved every task: CN vs. AD AUC 0.745 (95% CI 0.730–0.763), CN vs. any impairment 0.642, CN vs. MCI 0.601, and MCI vs. AD 0.599. On an independent OASIS-2 cohort, the transfer learning CN vs. AD model retained AUC 0.748. In this small-data regime, transfer learning recovers substantially more Alzheimer-spectrum signals than a from-scratch CNN, but performance remains modest because it is bounded by CDR-based, non-biomarker-confirmed labels, suggesting the model separates CDR-defined cognitive-status groups rather than detecting AD pathology.

Long-established prostate cancer cell lines provide limited insight into how contemporary early prostate cancer evolves into drug-resistant and neuroendocrine-like refractory disease. Patient-derived three-dimensional (3D) ex vivo models may better preserve this transition. Here, we found that 8 of 10 magnetic resonance imaging-guided biopsy specimens from patients with early-stage prostate cancer generated sustained 3D tumor spheroid cultures. After 12 weeks of enzalutamide selection, only one patient-derived culture acquired a resistant phenotype with treatment-emergent neuroendocrine prostate cancer (t-NEPC)-like features, including increased chromogranin A (CgA) and synaptophysin (SYP); reduced androgen receptor (AR), prostate-specific antigen (PSA), and prostate-specific membrane antigen (PSMA); and conversion from compact spheroids into irregular resistant aggregates. During this transition, WD repeat and SOCS box-containing protein 1 (WSB1) increased, whereas PSMA progressively decreased. WSB1 silencing restored PSMA, AR, and PSA expression and reduced neuroendocrine-associated features. A similar WSB1 dependency was observed in enzalutamide-resistant LNCaP cells, the castration-resistant prostate cancer model 22Rv1, and the neuroendocrine/small-cell prostate cancer model NCI-H660. Mechanistically, WSB1 functioned as a SOCS box-dependent E3 ubiquitin ligase adaptor that promoted PSMA ubiquitination and degradation. SOCS box deletion or T380A mutation impaired this process, while Aurora kinase A (AURKA) inhibition reduced WSB1-dependent PSMA ubiquitination. WSB1 depletion, AURKA inhibition with alisertib, and combined AURKA inhibition with EZH2 suppression reduced resistant aggregate growth and increased apoptosis-associated markers in patient-derived enzalutamide-resistant neuroendocrine-like spheroids and related models. These findings nominate the AURKA–WSB1–PSMA axis as a therapeutic vulnerability in refractory prostate cancer.

Abstract Background: Glioma diagnosed during pregnancy and pregnancy following glioma treatment present complex management challenges. The safety of glioma treatment during pregnancy is not well established. The ability to counsel patients on timing of conception after treatment remains limited. The aim of this study was to review our institution’s experience with glioma during and before pregnancy. Methods: In this single-institution study, we retrospectively identified patients diagnosed with glioma during or prior to pregnancy and reviewed treatment course and maternal and neonatal outcomes. Results: Twenty-one female patients were included in our study. Glioma diagnoses included 12 high-grade tumors and 9 low-grade tumors. Cohort A consisted of 8 patients who presented with glioma during pregnancy, of which, 7 underwent glioma treatment during pregnancy. All pregnancies in cohort A were without significant maternal complications and resulted in delivery of a healthy neonate. Cohort B consisted of 13 patients who experienced pregnancy after a prior diagnosis of glioma, totaling 23 pregnancies. Antepartum course was complicated by seizure in three pregnancies. Functionally inconsequential anatomic abnormalities in childhood offspring of cohort B occurred in 5 (27.8%) of the pregnancies. Four of the offspring with anatomic abnormalities had exposure to TMZ prior to conception. Conclusions: In this retrospective series, diagnosis of glioma before or during pregnancy was associated with generally favorable maternal, fetal and childhood outcomes. We observed a higher-than-expected rate of anatomic abnormalities in the post-diagnosis cohort, though none carried meaningful functional consequences. These findings add to the limited literature exploring maternal and fetal outcomes in patients with glioma.

Abstract Oxidative phosphorylation (OXPHOS) is a central function and a key indicator of mitochondrial fitness, yet studies in human tissue remain limited. Inclusion body myositis (IBM) is a progressive myopathy that lies at the intersection of aging, inflammation and mitochondrial dysfunction. We aimed to perform a comprehensive profiling of mitochondrial respiration in muscle tissue from patients with IBM. A wide battery of complementary approaches from RNA level to high-resolution respirometry on permeabilized muscle fibers was employed. The relationship between mitochondrial respiration, mitochondrial content, mitochondrial DNA (mtDNA) abnormalities and mitophagy was examined, along with the correlation with various clinical parameters to determine their clinical relevance. The study included a total of 67 patients with IBM and 45 controls. On high resolution respirometry of permeabilized muscle fibers, IBM samples exhibited reduced maximal mitochondrial respiration per tissue weight in State 3 (high substrates, high ADP) and uncoupled state with decreased coupling efficiency and higher leak control ratios. When adjusting for citrate synthase reflecting mitochondrial content, male patients had decreased State 3 intrinsic respiration, whereas female patients had greater intrinsic respiration under leak states. Complex I activity was decreased mainly in female patients, in whom complex II control ratio positively correlated with disease duration and severity. IBM was further associated with decreased RNA levels of all complexes, and lower protein expression of complex I, III, IV and V, likely related to the lower mtDNA content seen in IBM samples. Regarding the production of reactive oxygen species, IBM samples exhibited lower maximal H2O2 emission, accompanied by a higher total antioxidant capacity that positively correlated with disease duration in female patients. Lastly, correlation analyses suggested that impaired mitochondrial respiration, altered mitophagy, and reduced mtDNA content are interconnected in IBM and maybe of clinical significance. IBM is characterized by multifaceted, clinically relevant impairments in mitochondrial respiration. Future studies should further explore underlying pathomechanisms and the variation of mitochondrial respiration by disease stage.

Abstract Introduction Glioblastoma (GBM), the most aggressive primary brain tumor in adults, is marked by profound immune suppression. Tumor-derived extracellular vesicles (TEVs) are increasingly recognized as key mediators of this immunosuppressive environment. Methods In this study, we examined the tumor-immune microenvironment using ultrasonic aspirate samples from GBM patients (n = 14). Results Several immune checkpoint molecules, including PDL1, B7-H3, and VISTA, were notably elevated. TIGIT, a receptor typically associated with T cells, was widely expressed across multiple myeloid subsets, including monocytic myeloid-derived suppressor cells (mMDSCs; 64.27±7.99%) and non-classical monocytes (NCM; 39.8±4.37%). Co-culture of healthy donor CD11b+ cells (n = 10) with TEVs replicated similar effects (mMDSCs; control 11.691.87 vs EV treated 23.322.0). We found CD155, a primary TIGIT ligand, to be heavily enriched in TEVs and co-localized with TIGIT in co-culture, suggesting the TIGIT/CD155 axis may be involved in promoting immune suppression. induced MDSCs markedly suppressed T cell proliferation (30.65 ± 5.97% vs. control 86.47 ± 2.94, p = 0.0001), accompanied by elevated Th2 cytokine production and increased NLRP3 and IL-1β expression. Interestingly, TIGIT knockdown did not affect NLRP3 expression, but did restore T cell proliferation (64.13±1.33%; p = 0.02) and pro-inflammatory cytokine production. However, this effect was lost upon NLRP3 knockdown, indicating its essential role in mediating immune rescue. Furthermore, IL-13 (a Th2 cytokine) blockade, in this model, enhanced pro-inflammatory response by suppressing phosphorylation of STAT-6 protein. Conclusion Overall, our findings highlight a crucial role for the TIGIT/CD155 axis in driving myeloid-mediated immune suppression in GBM. Furthermore, TIGIT inhibition may unmask NLRP3 function, potentially contributing to immune rescue. Funding Source Neurosurgery Research & Education Foundation through the B*CURED & NREF Young Clinician Investigator Award, as well as intramural K12 funding through the Institute for Clinical and Translational Research and the NCI Paul Calabresi Career Development Award (1K12CA279871). Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)