Citations

Abstract Hemorrhagic shock is a common emergency that accounts for more than 10% of global mortality and up to 40% of trauma-related mortality. The Advanced Trauma Life Support (ATLS) guidelines outline resuscitation strategies in patients with massive hemorrhage based on clinical trial and observational data. Early intervention with fluids and/or blood products is recommended during resuscitation as key to maintaining vascular patency, stabilizing a patient’s blood pressure, maintaining tissue oxygenation, and limiting shock. From a transfusion perspective, there is wide heterogeneity in the quality of blood products due to donor and manufacturing variation. The optimal transfusion strategy for massive hemorrhage remains unclear. In silico models of resuscitation may offer a means to evaluate the effectiveness and safety of various resuscitation protocols. Here we describe a stochastic multicompartment model of fluid balance and resuscitation that includes (i) cardiovascular hemodynamics, (ii) body fluid compartments and capillary solute exchange, (iii) the ability to alter hemorrhage, resuscitation, and hemostasis parameters, and (iv) tissue oxygenation and capillary-alveolar gas exchange. Building upon deterministic frameworks, this stochastic model more faithfully reflects the clinical heterogeneity of bleeding patients at a level I trauma center. This allows for a proof of concept in silico trial comparing crystalloids, conventional component therapy (CCT), i.e. red cell, platelet and plasma components, to cold-stored low titer group O whole blood (LTOWB). In an in silico cohort of ATLS class III (>30% and ≤40% blood volume lost) hemorrhage, LTOWB resuscitation reduced the time spent in the critical hemostatic window (platelet count <50x109/L, INR≥2, hemoglobin (Hgb) <8 g/dL and fibrinogen <150 mg/dL) compared with CCT (90.59 vs. 147.62 minutes; p=0.04), with no difference in predicted event-free survival (t = 240 minutes; cardiac < 1.5, fluid overload > 10% or SBP > 150% of the starting SBP, or Hgb < 3.0 g/dL). In a separate cohort of ATLS class IV (>40% blood volume lost) hemorrhage, LTOWB yielded a higher predicted event-free survival (74%) versus the CCT arm (69%, p < 0.01). We demonstrate how this in silico platform can function as a digital twin for hemorrhagic trauma enabling precision transfusion strategies, and in parallel, an operational twin to support blood banks to forecast blood product demand and inform massive transfusion protocols and clinical trial design.

PURPOSE Social determinants of health (SDOH) shape cancer treatment access, adherence, and outcomes, yet their collection and use within National Clinical Trials Network (NCTN) studies remain poorly defined. This study examined how demographic and SDOH-related variables were historically collected and published to identify gaps that constrain the study of social context within NCTN trials. METHODS Participant-level data from completed phase III trials for gastrointestinal (GI) cancers conducted by the Alliance for Clinical Trials in Oncology (Alliance) or its legacy groups from 1999 to 2018 were pooled. Thirteen measures were assessed: four demographic and nine SDOH-related. The proportion of individual participants with data collected for each measure was evaluated. Data utilization was evaluated for all primary articles and via targeted review of related publications using the number either reporting subgroups or publishing analyses for each measure. RESULTS A total of 12,701 participants across 11 trials were included. All trials collected demographic measures (<2% of patients missing), insurance status (1% missing), and ZIP code (3% missing). Education level was collected in two trials (28% missing) with marital and employment status collected in one trial (41% missing for both). No trials collected data on other SDOH-related measures. Education level was the only SDOH-related measure reported in primary articles, and none reported analysis of SDOH-related measures. Of the 149 related publications, <2% reported or analyzed any SDOH-related measure. CONCLUSION Across Alliance and NCTN legacy group phase III trials for GI cancers, demographic variables have been consistently collected and frequently reported or analyzed, whereas SDOH-related measures are inconsistently collected and rarely published in the literature. These findings demonstrate a historical absence of routine SDOH data capture and utilization within NCTN trials.

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.

Purpose of review Photon-counting detector computed tomography (PCD-CT) represents a major technological advancement in computed tomography, offering improved spatial resolution, reduced image noise, and increased dose efficiency compared with conventional energy-integrating detector CT (EID-CT). Because many clinically relevant structures within the temporal bone are submillimeter in size, the temporal bone represents an ideal region for determining whether these technical improvements translate into meaningful clinical benefits. This review evaluates the emerging literature on PCD-CT in temporal bone imaging and examines whether higher spatial resolution meaningfully impacts clinical decision-making. Recent findings Recent studies demonstrate improved visualization of middle ear anatomy, ossicular prostheses, cochlear implant electrode arrays, and superior semicircular canal dehiscence with PCD-CT compared with conventional CT. Improved spatial resolution and reduced metal artifact have been shown to enhance assessment of prosthesis positioning, cochlear duct measurements, and differentiation of true versus near semicircular canal dehiscence. However, given the recent availability of PCD-CT, most studies to date have focused on cadaveric studies, phantom studies, or patient studies evaluating image quality rather than diagnostic accuracy or clinical outcomes. Summary PCD-CT provides substantially improved visualization of submillimeter temporal bone structures and may improve diagnostic confidence in select clinical scenarios. Nevertheless, evidence demonstrating improved clinical outcomes remains limited, and further clinical studies are needed to define the role of PCD-CT in routine temporal bone imaging.

Importance Tofersen is a disease-modifying antisense oligonucleotide therapeutic for people living with SOD1 –amyotrophic lateral sclerosis ( SOD1 -ALS). Autopsy tissue donors have provided the first opportunity to study the distribution of intrathecally administered tofersen in human central nervous system tissues. Objectives To determine the tissue distribution of tofersen and to provide the first estimates of SOD1 reduction in human somatic motor systems tissues. Design, Setting, and Participants This was a cross-sectional autopsy tissue case series conducted between 2018 and 2026. Autopsies were performed at 3 US academic medical institutions. Tissue samples from 8 deceased patients who lived with SOD1 -ALS, participated in tofersen clinical trials (ClinicalTrials.gov Identifiers NCT02623699 [An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)] and NCT03070119 [Long-Term Evaluation of BIIB067 (Tofersen)]) or the Expanded Access Program, and whose families authorized autopsies were eligible for this study. All autopsy tissue donors known at the time of this study were included (none were excluded). Analyses were conducted between August 2020 and January 2026. Exposures Participants received multiple intrathecal 20- to 100-mg tofersen doses. Main Outcomes and Measures Tofersen tissue concentrations were measured using hybridization enzyme-linked immunosorbent assay (ELISA). SOD1 messenger RNA (mRNA) and protein reduction estimates, defined as percentage SOD1 levels in this study’s recently treated autopsy tissue donors compared to a cohort of samples from tofersen-naive SOD1 -ALS autopsy tissue donors, were measured using quantitative reverse transcription polymerase chain reaction (PCR) and ELISA. Histological localization of tofersen and SOD1 transcripts were studied using immunohistochemistry and in situ hybridization assays. Results In 8 tofersen-treated autopsy tissue donors (5 male and 3 female donors; age range, 42-66 years), spinal cord and motor cortical tissue tofersen concentrations strongly correlated with predictions based on individual dosing histories and a preclinical pharmacokinetic model. For 3 recently treated autopsy tissue donors, reductions in lumbar spinal cord tissue SOD1 mRNA and protein levels ranged from 45% to 84% despite not having been administered 1 to 2 scheduled doses before autopsy. Residual somatic motor neurons demonstrated tofersen transduction and low SOD1 mRNA probe hybridization. Misfolded SOD1 protein inclusions were detected in residual motor neurons of tofersen-naive SOD1- ALS tissue donor controls and tofersen-treated tissue donors. Meningeal and perivascular lymphocytic immune responses were observed in 5 recently treated tissue donors but were not apparent in tissue donors with remote final tofersen doses. Conclusions and Relevance This case series presents the first emerging autopsy tissue data confirming the predicted distribution of tofersen and robust SOD1 protein reduction in human somatic motor systems tissues.

ABSTRACT Background Eosinophilic esophagitis is associated with epithelial barrier dysfunction. Epidemiologic studies suggest environmental factors promote disease pathogenesis. The common household detergent sodium dodecyl sulfate (SDS) induces epithelial barrier dysfunction and eosinophilic inflammation in mice. We hypothesized that acute SDS exposure would compromise the esophageal mucosal barrier in humans. Methods Healthy adults brushed with 2 g of an SDS‐containing toothpaste. Esophageal impedance was measured continuously pre‐/post‐toothbrushing to assess the effect of toothpaste on epithelial barrier function. SDS was measured in saliva using a methylene blue anionic substances assay. Participants completed 1‐h esophageal string tests (ESTs) pre‐/post‐toothbrushing and protein isolates from EST eluates from the proximal and distal esophagus were analyzed by tandem mass tag mass spectrometry. Results Ten of twelve subjects completed the clinical study. SDS in the initial expectorate measured immediately after toothbrushing varied markedly (median: 321.40 μg/mL; range: 169.90–1243.00 μg/mL) and was detectable in saliva in 80% of subjects (median: 9.55 μg/mL; range: 0–123.40 μg/mL) at 60 min post toothbrushing. Esophageal mucosal impedance decreased within 30 min of toothbrushing ( p < 0.01). Toothbrushing increased salivary viscosity and proteins associated with mucosal defense in EST eluates. The tight junction pathway was downregulated while the salivary secretion and complement and coagulation cascades pathways were upregulated in the proximal esophagus. Conclusion In healthy individuals, SDS remained detectable in saliva for a prolonged period after toothbrushing at concentrations previously shown to disrupt esophageal epithelial barrier function in vitro. Toothbrushing with an SDS‐containing toothpaste was associated with reduced esophageal mucosal impedance, altered salivary properties, and activated mucosal immune responses.

Abstract Unvetted scientific claims about vaccines can spread rapidly and undermine decades of progress in immunization and public trust. A recent non-peer-reviewed analysis, promoted at political hearings, in the documentary “An Inconvenient Study,” and on social media, has been used to suggest that vaccinated children experience higher rates of chronic illness than unvaccinated peers. Despite standard regression models, critical flaws - uncontrolled confounding, exposure misclassification, unequal follow-up, and outcome multiplicity, invalidate causal inference. An independent group of international experts critically appraises this analysis and contrast its claims with the consistent evidence confirming vaccine safety and effectiveness. We also show how poorly designed studies can distort public discourse, amplify misinformation, and fuel vaccine hesitancy. We outline actions to strengthen research integrity, such as transparent data sharing, labeling of non-peer-reviewed content, and evidence-based communication. Safeguarding public health demands that vaccine evidence be methodologically sound, reviewed, and interpreted by qualified experts.

Peritoneal coccidioidomycosis is a rare, disseminated manifestation of Coccidioides infection with limited representation in the literature. We report 37 proven or probable cases from a single institution, including 12 patients (32%) with immunosuppression. Thirty-six patients received antifungal therapy, all of whom demonstrated clinical response. Among 11 (29.7%) patients who completed and stopped therapy after a median duration of 26 months, 2 (5%) experienced a relapse and were successfully retreated. Nine patients (24%) had no known relapse. Thirteen patients (35%) required modification of antifungal regimens, primarily due to azole adverse effects. Treatment approaches and median duration of therapy (57 months) were similar between immunosuppressed and non-immunosuppressed groups. No deaths were attributable to infection. Overall, outcomes were favorable, with strong clinical responses to azole therapy. Patients without identifiable immunologic deficits or additional sites of dissemination, when managed with antifungal therapy and close clinical, radiologic, and serologic monitoring, may achieve good prognosis, particularly when indefinite azole therapy is not feasible.

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.