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This cohort study characterizes heterogeneity in cardiac function prior to sepsis and describes associations with hospitalization outcomes and mortality.

BACKGROUND: Associations of early changes in vasoactive support with cardiogenic shock (CS) mortality remain incompletely defined. METHODS: The Critical Care Cardiology Trials Network is a multicenter registry of cardiac intensive care units. Patients admitted with CS (2018–2023) had vasoactive dosing assessed at 4 and 24 hours from cardiac intensive care unit admission and quantified by the vasoactive-inotropic score (VIS). Prognostic associations of VIS at both time points, as well as change in VIS from 4 to 24 hours, were examined. Interaction testing was performed based on mechanical circulatory support status. RESULTS: Among 3665 patients, 82% had a change in VIS <10, with 7% and 11% having a ≥10-point increase and decrease from 4 to 24 hours, respectively. The 4 and 24-hour VIS were each associated with cardiac intensive care unit mortality (13%–45% and 11%–73% for VIS <10 to ≥40, respectively; P trend <0.0001 for each). Stratifying by the 4-hour VIS, changes in VIS from 4 to 24 hours had a graded association with mortality, ranging from a 2- to >4-fold difference in mortality comparing those with a ≥10-point increase to ≥10-point decrease in VIS ( P trend <0.0001). The change in VIS alone provided good discrimination of cardiac intensive care unit mortality (C-statistic, 0.72 [95% CI, 0.70–0.75]) and improved discrimination of the 24-hour Sequential Organ Failure Assessment score (0.72 [95% CI, 0.69–0.74] to 0.76 [95% CI, 0.74–0.78]) and the clinician-assessed Society for Cardiovascular Angiography and Interventions shock stage (0.72 [95% CI, 0.70–0.74] to 0.77 [95% CI, 0.75–0.79]). Although present in both groups, the mortality risk associated with VIS was attenuated in patients managed with versus without mechanical circulatory support (odds ratio per 10-point higher 24-hour VIS, 1.36 [95% CI, 1.23–1.49] versus 1.84 [95% CI, 1.69–2.01]; P interaction <0.0001). CONCLUSIONS: Early changes in the magnitude of vasoactive support in CS are associated with a gradient of risk for mortality. These data suggest that early VIS trajectory may improve CS prognostication, with the potential to be leveraged for clinical decision-making and research applications in CS.

The immune system substantially influences age-related cognitive decline and Alzheimer’s disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 ( N = 298), we measured 365 CSF inflammatory molecules, finding age, sex, and diabetes status predominantly influencing their levels. We observed age-related correlations with AD biomarkers such as total tau, phosphorylated tau-181, neurofilament light chain (NfL), and YKL40. APOE4 was associated with lower Aβ42 and higher SNAP25 in CSF. We explored baseline variables predicting cognitive decline risk, finding age, CSF Aβ42, NfL, and REG4 to be independently correlated. Subjects with older age, lower Aβ42, higher NfL, and higher REG4 at baseline had increased cognitive impairment risk during follow-up. This suggests that assessing CSF inflammatory molecules and AD biomarkers could predict cognitive impairment risk in the elderly.

ImportanceFrontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD.ObjectiveTo evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations.Design, Setting, and ParticipantsIn this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)–based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes.ExposureParticipants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests.Main Outcomes and MeasuresInternal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy.ResultsIn the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized β range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, −2.49 [95% CI, −0.19 to −0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back β = −0.49 [95% CI, −0.72 to −0.25]; P &amp;lt; .001) but not a composite of traditional neuropsychological measures (β = −0.14 [95% CI, −0.42 to 0.14]; P = .32).Conclusions and RelevanceThe findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

Abstract The field of medicine continues to advance as new technologies emerge. These technological advancements include the science of sports prostheses and wheelchairs, in which there have been significant advancements over the past decades. The world of adaptive sports continues to expand, largely due to a combination of the increase in awareness, inclusion, and technology. As participation in sports for people with impairments increases, there has been an associated demand for new, innovative adaptive sporting equipment designs that help accommodate the physical deficits of the individual. Controversy has risen as persons with disabilities advance their skills with adaptive sports equipment to compete with individuals without disabilities. The controversy leads to the question: is the adaptive equipment allowing athletes with disability to regain the lost function from their baseline or does it allow them to exceed prior ability level? This narrative review provides information regarding the performance effects of advances in technology and biomechanics of adaptive sports equipment to help answer these questions.

OBJECTIVES: Extracorporeal cardiopulmonary resuscitation (ECPR) has been shown to improve neurologically favorable survival in patients with refractory out-of-hospital cardiac arrest (OHCA) caused by shockable rhythms. Further refinement of patient selection is needed to focus this resource-intensive therapy on those patients likely to benefit. This study sought to create a selection model using machine learning (ML) tools for refractory cardiac arrest patients undergoing ECPR. DESIGN: Retrospective cohort study. SETTING: Cardiac ICU in a Quaternary Care Center. PATIENTS: Adults 18–75 years old with refractory OHCA caused by a shockable rhythm. METHODS: Three hundred seventy-six consecutive patients with refractory OHCA and a shockable presenting rhythm were analyzed, of which 301 underwent ECPR and cannulation for venoarterial extracorporeal membrane oxygenation. Clinical variables that were widely available at the time of cannulation were analyzed and ranked on their ability to predict neurologically favorable survival. INTERVENTIONS: ML was used to train supervised models and predict favorable neurologic outcomes of ECPR. The best-performing models were internally validated using a holdout test set. MEASUREMENTS AND MAIN RESULTS: Neurologically favorable survival occurred in 119 of 301 patients (40%) receiving ECPR. Rhythm at the time of cannulation, intermittent or sustained return of spontaneous circulation, arrest to extracorporeal membrane oxygenation perfusion time, and lactic acid levels were the most predictive of the 11 variables analyzed. All variables were integrated into a training model that yielded an in-sample area under the receiver-operating characteristic curve (AUC) of 0.89 and a misclassification rate of 0.19. Out-of-sample validation of the model yielded an AUC of 0.80 and a misclassification rate of 0.23, demonstrating acceptable prediction ability. CONCLUSIONS: ML can develop a tiered risk model to guide ECPR patient selection with tailored arrest profiles.

Background Inhaled treprostinil (iTre) is the only treatment approved for pulmonary hypertension due to interstitial lung disease (PH-ILD) to improve exercise capacity. This post hoc analysis evaluated clinical worsening and PH-ILD exacerbations from the 16-week INCREASE study and change in 6-minute walking distance (6MWD) in the INCREASE open-label extension (OLE) in patients with less severe haemodynamics. Methods Patients were stratified by baseline pulmonary vascular resistance (PVR) of <4 Wood units (WU) versus ≥4 WU and ≤5 WU versus >5 WU. Exacerbations of underlying lung disease, clinical worsening and change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in INCREASE were evaluated. For the OLE, patients previously assigned to placebo were considered to have a 16-week treatment delay. 6MWD and clinical events in the OLE were evaluated by PVR subgroup. Results Of the 326 patients enrolled in INCREASE, patients with less severe haemodynamics receiving iTre had fewer exacerbations of underlying lung disease and clinical worsening events. This was supported by the Bayesian analysis of the risk of disease progression (HR<1), and significant decreases in NT-proBNP levels. In the OLE, patients without a treatment delay had improved exercise capacity after 1-year compared with those with a 16-week treatment delay (22.1 m vs −10.3 m). Patients with a PVR of ≤5 WU without a treatment delay had a change of 5.5 m compared with −8.2 m for those with a treatment delay. Patients without a treatment delay had a prolonged time to hospitalisation, lung disease exacerbation and death. Conclusion Treatment with iTre led to consistent benefits in clinical outcomes in patients with PH-ILD and less severe haemodynamics. Earlier treatment in less severe PH-ILD may lead to better exercise capacity long-term, however, the subgroup analyses in this post hoc study were underpowered and confirmation of these findings is needed.

Abstract Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of patients with deficient DNA mismatch repair (d-MMR) cancers, yet less than half of patients with metastatic colorectal cancer (mCRC) receive clinical benefit. We analyzed heterogeneity within d-MMR tumors using a multi-omics approach inclusive of percent unstable microsatellite loci (MS). Methods: We studied consecutive patients with d-MMR mCRC with available primary tumors (N=32) that were treated with an anti-PD-1 antibody at Mayo Clinic (2015-2022). Tumors were profiled using a whole exome and transcriptome platform (ImmunoID NeXT®). MSIsensor was used to calculate percent unstable microsatellite loci from whole exome sequencing data. CIBERSORT and ssGSEA were used to analyze immune gene expression in relationship to percent unstable microsatellite loci. An immune checkpoint gene expression signature was calculated as the mean expression of CD274, CTLA-4, HAVCR2, LAG-3, PDCD1, PDCD1LG2, TIGIT. Aforementioned variables were analyzed in relationship to objective tumor response (RECIST version 1.1). A Cox proportional hazards model was fit to predict progression-free survival (PFS). Results: Among 32 patients with d-MMR mCRC treated with PD-1 blockade, 16 (50%) received first-line anti-PD-1 therapy; others had &gt; 1 prior chemotherapy regimen. Eighteen (56.3%) tumors harbored BRAFV600E, 4 (12.5%) had mutant KRAS, and median PFS was 24.6 months (95% CI: 8.4, NR) with 18 events. Neither tumor mutation burden (TMB) nor PD-L1 mRNA expression predicted PFS. Median percent unstable MS loci was 14.38 (IQR: 2.6-23.2). Patients whose tumors had higher percent unstable MS loci had significantly better PFS (Q2-4 vs Q1; HR: 0.22, 95%CI: 0.06, 0.62; P=0.003), and were associated with increased objective response (P=0.049). Tumors with higher unstable loci also had higher neoantigen clonality (R= 0.64; P= 0.0003) and increased M0 (resting) macrophages (P=0.02). Nonresponders (vs responders) to PD-1 blockade had an increased immune checkpoint expression signature (P= 0.005). Conclusion: A higher percentage of unstable microsatellite loci, associated with higher neoantigen clonality and resting macrophages, was predictive of anti-PD-1 efficacy. Furthermore, an immune checkpoint gene expression signature was associated with objective response. Citation Format: Bahar Saberzadeh-Ardestani, Oluwadunni E. Emiloju, Rondell P. Graham, Jason T. Lewis, Charles W. Abbott, Sean M. Boyle, Frank A. Sinicrope. Prediction of PD-1 treatment outcome in mismatch repair deficient metastatic colorectal cancer using a multi-omic approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 578.