Citations

Abstract Obesity accelerates the onset and progression of age-related conditions. In preclinical models, obesity drives cellular senescence, a cell fate that compromises tissue health and function, in part through a robust and diverse secretome. In humans, components of the secretome have been used as senescence biomarkers that are predictive of age-related disease, disability, and mortality. Here, using biospecimens and clinical data from two large and independent cohorts of older adults, we tested the hypothesis that the circulating concentrations of senescence biomarkers are influenced by body mass index. After adjusting for age, sex, and race, we observed significant increases in activin A, Fas, MDC, PAI1, PARC, TNFR1, and VEGFA, and a significant decrease in RAGE, from normal weight, to overweight, to obesity body mass index categories by linear regression in both cohorts (all p < .05). These results highlight the influence of body mass index on circulating concentrations of senescence biomarkers.

Abstract Many patients in the emergency department present with signs and symptoms that arouse concern for sepsis; however, other explanations are also possible. There are currently no rapid tests used in clinical practice that reliably distinguish the presence of a bacterial or viral infection vs. a non-infectious etiology and can predict a patient’s likelihood to decompensate. The diagnostic and prognostic uncertainty in “gray zone” patients complicates the decision to begin therapy as clinicians need to balance the risk of withholding therapy vs. the risk of the therapy itself (e.g., overtreatment with antibiotics and hospitalization, which is costly, potentially harmful, and contributes to antibiotic resistance). The TriVerity™ Test uses isothermal amplification and machine-learning algorithms to quantify and interpret mRNA expression levels to determine both likelihood of bacterial infection, viral infection, or no infection, and whether the patient will likely require one or more critical interventions within 7 days. The three scores each fall into one of five interpretation bands ranging from Very high to Very low. Testing takes approximately 30 minutes using the proprietary Myrna™ Instrument with an operator hands-on-time of under one minute. We enrolled 1,222 patients from 22 emergency departments (ED) to validate the performance of the TriVerity Test. Patients were treated as per local standard of care and were followed for 28 days. Bacterial and viral TriVerity results were validated against clinically adjudicated infection status; the illness severity TriVerity result was validated against the need for at least one critical interventions within 7 days. The bacterial TriVerity result had high AUROC for the diagnosis of bacterial infection (0.83; 80% CI 0.81–0.85) and divided bacterial infection likelihood scores into five interpretation bands with increasing likelihood ratios of infection ranging from Very low (LR- 0.08, 80% CI 0.06–0.11) to Very high (LR + 8.04, 80% CI 5.72–11.78). The AUROC for the bacterial TriVerity result was significantly higher compared to AUROCs for C-reactive protein, procalcitonin or white blood cell count. Similarly, the viral TriVerity score showed high AUROC for the diagnosis of viral infection (0.91; 80% CI 0.90–0.93) and likelihood ratios from Very low (LR- 0.09, 80% CI 0.05–0.14) to Very high (LR + 40.93; 80% CI 29.11–79.23). The TriVerity Illness Severity score showed a high AUROC for the prediction of illness severity (0.77; 80% CI 0.77–0.81) with scores divided into five interpretation bands with increasing likelihood ratios ranging from Very low (LR- 0.22; 80% CI 0.14–0.33) to Very high (LR + 11.33; 80% CI 7.31–17.00). TriVerity illness severity results allowed marked re-classification of the risk for “ICU-level care” as compared to clinical assessment (qSOFA scores) alone. In conclusion, TriVerity provides rapid, highly accurate and actionable results for the diagnosis and prognosis of patients with suspected acute infection and/or sepsis, supporting a major unmet medical need. TriVerity may improve personalized management of patients with suspected acute infections and suspected sepsis for improved overall healthcare outcomes.

Since 1988 the demand for the pancreas transplantation has continued to increase. This has been accompanied by a growth in the number of centers offering the procedure, and an increase in the number of transplants performed. The National Cooperative Transplantation Study was undertaken to document the costs of all transplants, including pancreas transplantation. Data on transplantation procedure charges, from date of transplant to discharge, were obtained from 66.7% of all pancreas transplantation programs active in 1988. These programs accounted for 72% of all transplants performed that year. Valid sample survey data (no more than 25 transplants per center) were obtained for 133 randomly selected patients. This constituted 54% of all procedures done in the United States in 1988. Detailed data were also collected on sources of payment and amount reimbursed. Due to outlier data, we report statistical medians, rather than means, as our measure of central tendency. The median charge for a pancreas transplant with or without a kidney was $66 917, with a hospital length of stay of 21 days, compared with a kidney transplant alone at $39 625 and a hospital length of stay of 14 days. Total pancreas transplant charges fell between $45 260 and $105 375 for 50% of the cases studied. Half of the patients had a hospital length of stay between 16 and 33 days. Due to the small number of cases available for analysis, it was not meaningful to cross‐classify the data according to various prognostic variables. Fifty percent of the transplants studied were paid for by private insurers, and reimbursement exceeded 80% of billed charges for 50.6% of the cases analyzed. Insurance reimbursement for pancreas transplantation is not uniform, but is favorable for those covered. While the number of procedures performed annually has increased since 1980, with the largest increases occurring since 1988, sustained growth may well be a function of insurance coverage. Many transplant centers are unable to bear the expense of pancreas transplants insurers fail to cover. As a result, access will be a problem for some patients.

Background/Objectives: Patients with Non-Alcoholic Fatty Liver Disease (NAFLD) are reported to have an increased risk of developing severe infections, leading to hospitalizations with sepsis. However, data regarding the impact of comorbid NAFLD on in-hospital outcomes of patients with sepsis is scarce. Methods: This nationwide retrospective observational study using discharge data from the National Inpatient Sample (NIS), Healthcare Cost and Utilization Project (HCUP), and Agency for Healthcare Research and Quality included 21,057,911 adult patients who were admitted to hospitals in the United States between 2000 and 2019 with a primary discharge diagnosis of sepsis. These patients were categorized according to the presence or absence of comorbid NAFLD. The twenty-year trend of nationwide NAFLD prevalence among sepsis inpatients was elucidated. Multivariable logistic regression analysis was used to analyze NAFLD’s impact on sepsis outcomes. Results: In the twenty-year study period, the prevalence of NALFD among sepsis inpatients trended up from 1.2% in 2000 to 4.2% in 2019. Similar trends were observed in regional analysis. While overall sepsis mortality decreased, comorbid NAFLD in sepsis patients was consistently associated with a higher adjusted in-hospital all-cause mortality rate (adjusted odds ratio (OR), 1.19; 95% confidence interval (CI), 1.07–1.32), higher odds of developing septic shock, and higher likelihood of development of multi–organ dysfunction. Conclusions: Comorbid NAFLD in the stage of NASH or cirrhosis is associated with higher in-hospital all-cause mortality and worse clinical outcomes in sepsis inpatients. Addressing this rising epidemic will be of paramount importance to improve sepsis in-hospital outcomes.

ABSTRACTAimsThis study aimed to determine the efficacy and safety of iltamiocel investigational autologous muscle cell therapy in females with stress urinary incontinence (SUI).MethodsAdult females were randomized 2:1 to iltamiocel (150 × 106 cells) or placebo and stratified by severity and prior SUI surgery. The primary objective was efficacy based on the frequency of stress incontinence episodes (SIE) recorded in a 3‐day diary at 12 months posttreatment. After 12 months, placebo participants could elect to receive open‐label iltamiocel. Efficacy and safety analyses were performed using all patients as treated populations.ResultsThe study enrolled 311 patients, 297 were randomized to either iltamiocel (n = 199) or placebo (n = 98). Of the 295 participants that completed 12 months blinded follow‐up, the proportion achieving the primary endpoint of ≥ 50% SIE reduction was not statistically different between treatment groups (52% vs. 53.6%; p = 0.798). A significantly greater proportion of iltamiocel participants in the prior SUI surgery stratum group achieved ≥ 75% SIE reduction compared with placebo, (40% vs. 16%; p = 0.037). Treatment response was maintained at 24 months in 78.4% and 64.9% of iltamiocel participants who achieved ≥ 50% and ≥ 75% SIE reduction, respectively, at Month 12. Adverse events related to the treatment were reported in 19 (9.5%) iltamiocel participants and 6 (6.1%) placebo participants.ConclusionThe study did not meet its primary endpoint however, iltamiocel cell therapy is safe and may be ideally suited to female patients who have undergone prior surgery for SUI. Additional study in this group of patients with high unmet medical needs is warranted.Trial RegistrationClinicalTrials.gov identifier: NCT01893138; EudraCT number: 2014‐002919‐41.

Abstract BACKGROUND Few rare variants have been identified in genetic loci from genome‐wide association studies (GWAS) of Alzheimer's disease (AD), limiting understanding of mechanisms, risk assessment, and genetic counseling. METHODS Using genome sequencing data from 197 families in the National Institute on Aging Alzheimer's Disease Family Based Study and 214 Caribbean Hispanic families, we searched for rare coding variants within known GWAS loci from the largest published study. RESULTS Eighty‐six rare missense or loss‐of‐function (LoF) variants completely segregated in 17.5% of families, but in 91 (22.1%) families Apolipoprotein E ( APOE)‐ 𝜀4 was the only variant segregating. However, in 60.3% of families, APOE 𝜀4, missense, and LoF variants were not found within the GWAS loci. DISCUSSION Although APOE 𝜀4and several rare variants were found to segregate in both family datasets, many families had no variant accounting for their disease. This suggests that familial AD may be the result of unidentified rare variants. Highlights Rare coding variants from GWAS loci segregate in familial Alzheimer's disease. Missense or loss of function variants were found segregating in nearly 7% of families. APOE‐𝜀4 was the only segregating variant in 29.7% in familial Alzheimer's disease. In Hispanic and non‐Hispanic families, different variants were found in segregating genes. No coding variants were found segregating in many Hispanic and non‐Hispanic families.