Citations

AbstractBackgroundLewy body dementia (LBD) is one of the most common causes of dementia and is characterized by the deposition of extracellular amyloid plaques and intracellular accumulation of alpha‐synuclein in the form of Lewy bodies and neurites. Many of these individuals also have concomitant neuropathological changes such as vascular disease, tangles, and TDP‐43. Like in Alzheimer’s disease, APOE4 is the most significant genetic risk factor for the development of LBD. We sought to survey the landscape of transcriptional changes in the cingulate cortex from a large cohort of LBD cases (>400) compared to normal controls of both sexes.MethodWe performed bulk tissue RNAseq and aligned reads to a human reference genome that is informed on the sex chromosome complement of the sample. Differentially expressed genes were determined after genome‐wide correction.ResultWe found a core set of transcriptional changes that were shared between both sexes in pathways related to neuronal functions and inflammation. However, we also identified numerous changes in genetic female samples that were not significantly altered in genetic males, or that were significantly altered but in the opposite direction. Similar male‐specific changes were also found. These alterations were present for genes on both sex chromosomes as well as autosomes. Though cohort sizes were smaller, we also compared this dataset to Alzheimer’s disease and found shared but unique transcriptional alterations.ConclusionOverall, genetic males and females exhibit sex‐shared and sex‐specific gene expression patterns in dementia with Lewy bodies. We are currently assessing splice alterations, running causal gene network analysis, and performing histological validation.

ABSTRACT Post-transplantation diabetes mellitus (PTDM) remains a leading complication after solid organ transplantation. Previous international PTDM consensus meetings in 2003 and 2013 provided standardized frameworks to reduce heterogeneity in diagnosis, risk stratification and management. However, the last decade has seen significant advancements in our PTDM knowledge complemented by rapidly changing treatment algorithms for management of diabetes in the general population. In view of these developments, and to ensure reduced variation in clinical practice, a 3rd international PTDM Consensus Meeting was planned and held from 6–8 May 2022 in Vienna, Austria involving global delegates with PTDM expertise to update the previous reports. This update includes opinion statements concerning optimal diagnostic tools, recognition of prediabetes (impaired fasting glucose and/or impaired glucose tolerance), new mechanistic insights, immunosuppression modification, evidence-based strategies to prevent PTDM, treatment hierarchy for incorporating novel glucose-lowering agents and suggestions for the future direction of PTDM research to address unmet needs. Due to the paucity of good quality evidence, consensus meeting participants agreed that making GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) recommendations would be flawed. Although kidney-allograft centric, we suggest that these opinion statements can be appraised by the transplantation community for implementation across different solid organ transplant cohorts. Acknowledging the paucity of published literature, this report reflects consensus expert opinion. Attaining evidence is desirable to ensure establishment of optimized care for any solid organ transplant recipient at risk of, or who develops, PTDM as we strive to improve long-term outcomes.

AbstractPancreas transplantation alone (PTA) is a β cell replacement option for selected patients with type 1 diabetes mellitus; concerns have been raised regarding deterioration in kidney function (KF) after PTA. This retrospective multicenter study assessed actual impact of transplantation and immunosuppression on KF in PTA recipients at three Transplant Centers. The primary composite endpoint 10 years after PTA was >50% eGFR decline, eGFR < 30 mL/min/1.73 m2, and/or receiving a kidney transplant (KT). Overall, 822 PTA recipients met eligibility. Median baseline and 10‐year eGFR (mL/min/1.73 m2) were 76.3 (58.1–100.8) and 51.3 (35.3–65.9), respectively. Primary composite endpoint occurred in 98 patients (53.5%) with 45 experiencing a >50% decrease in eGFR by 10 years post‐transplant, 38 eGFR < 30 mL/min/1.73 m2 and 49 requiring KT. KF declined most significantly within 6 months post‐PTA, more often in females and patients with better preserved GFR up to 5 years with 11.6% kidney failure at 10 years. Patient survival and death‐censored graft survival were both 68% at 10 years with overall graft thrombosis rate 8%. KF declined initially after PTA but stabilized with further slow progression. In conclusion, prospective intervention studies are needed to test renal sparing interventions while gathering more granular data.

Abstract Background Early diagnosis, prognostication, and treatment initiation are the cornerstones of sepsis management. There remains an immense interest in exploring the diagnostic and prognostic roles of neutrophil-lymphocyte ratio (NLR) in the sepsis population. Methods We performed a retrospective multi-center observational study including patients admitted to different Mayo Clinic sites with a diagnosis of sepsis between October 2018 and August 2022. Patients were excluded if they were aged &lt; 18 years, lacked research authorization, or had missing Neutrophil or Lymphocyte count at admission. Data were collected from an existing sepsis database and Mayo Data Explorer (MDE). Categorical variables were summarized as percentages and continuous variables were summarized as medians. Chi-square test for significance, independent sample t-test, and multivariate Cox Proportional Hazard models were performed on IBM SPSS Statistics v28.0. Results Our study cohort consisted of 13968 patients, of which the majority were males (55.9%), Caucasian (91.6%), and non-Hispanic or Latino (94.3%). The median age of the cohort was 71 (60, 80) years, and the median BMI was 27.7 (23.4, 33.3) kg/m2. Among all sepsis patients, 6.0% had a positive blood culture and the most common organisms were E. coli (26.5%), Klebsiella sp. (15.6%), Streptococcus sp. (12.8%) and Staphylococcus aureus (9.9%). 13131 patients (94.1%) survived the hospital stay and 837 (5.9%) did not. There was no difference in mortality based on blood culture positivity status (6.0% vs 6.6%, p=0.41). However, the median NLR was higher among patients with a positive blood culture (16.4 vs. 12.1, p&lt; 0.001) and among non-survivors (14.3 vs 12.2, p&lt; 0.001). NLR did not significantly vary based on the type of organism growing in the blood culture. A multivariate model revealed NLR as an independent predictor of mortality (HR 1.003, 95% CI: 1.000-1.006, p=0.029) after adjusting for comorbidities, baseline clinical and laboratory variables. (Tables 1 & 2) Conclusion Our retrospective multicentric study showed that the Neutrophil-Lymphocyte ratio at admission was higher among bacteremic sepsis patients and non-survivors. Further prospective studies are needed to explore its diagnostic and prognostic utility. Disclosures All Authors: No reported disclosures

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder associated with chronic abdominal pain along with recurrent diarrhea, constipation, or both that afflicts millions of people worldwide. Currently, the etiological foundation of the disorder remains enigmatic. However, there is mounting evidence suggesting that serotonin may play a critical role in the pathophysiology of IBS. DNA microarrays analyzing the transcriptomes of 11 IBS patients versus 13 asymptomatic control patients have identified a series of 858 differentially‐expressed genes that may characterize the IBS pathological state. Gene ontology (GO) analysis of this subset of genes revealed that nodes featuring serotonin‐related pathways displayed the highest number of functions relative to other GO groups. Quantitative real‐time polymerase chain reaction (qRT‐PCR) analysis of IBS patient‐derived RNA displayed reduced expression of the rate‐limiting enzyme of the serotonin biosynthetic pathway, tryptophan hydroxylase 1 (TPH1), relative to a pool of RNA comprised of eight control patients. Further, this analysis revealed potential compensatory regulation of several other genes integral to the maintenance of serotonin metabolism. In addition, concentrations of serum 25‐hydroxyvitamin D in both the IBS and control sampled populations indicated a trend towards decreased vitamin D levels within the IBS cohort, regardless of IBS subtype. Finally, vitamin D was shown to be effective in regulating the expression of several key serotonin metabolism genes, alluding to a potential link between vitamin D and serotonin pathways modulating IBS. These findings suggest that the pathogenesis of IBS may be associated with abnormal serotonin metabolism and/or vitamin D deficiency, and provide novel insight into possible treatment regimes. Support or Funding Information Wisconsin Network for Health Research

Chronic liver diseases can lead to fibrotic changes that may progress to the development of cirrhosis, which poses a significant risk for morbidity and increased mortality rates. Metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and viral hepatitis are prevalent liver diseases that may lead to cirrhosis. The advanced stages of cirrhosis can be further complicated by cancer development or end-stage liver disease and liver failure. Hence, early detection and diagnosis of liver fibrosis is crucial for preventing the progression to cirrhosis and improving patient outcomes. Traditionally, invasive liver biopsy has been considered the gold standard for diagnosing and staging liver fibrosis. In the last decade, research has focused on non-invasive methods, known as liquid biopsies, which involve the identification of disease-specific biomarkers in human fluids, such as blood. Among these alternative approaches, extracellular vesicles (EVs) have emerged as promising diagnostic and therapeutic tools for various diseases, including chronic liver diseases. EVs are released from stressed or damaged cells and can be isolated and quantified. Moreover, EVs facilitate cell-to-cell communication by transporting various cargo, and they have shown the potential to reduce the expression of profibrogenic markers, making them appealing tools for novel anti-fibrotic treatments. This review focuses on the impact of EVs in chronic liver diseases and exploring their potential applications in innovative therapeutic and diagnostic approaches.

A large number of variants identified through clinical genetic testing in disease susceptibility genes are of uncertain significance (VUS). Following the recommendations of the American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP), the frequency in case-control datasets (PS4 criterion) can inform their interpretation. We present a novel case-control likelihood ratio-based method that incorporates gene-specific age-related penetrance. We demonstrate the utility of this method in the analysis of simulated and real datasets. In the analysis of simulated data, the likelihood ratio method was more powerful compared to other methods. Likelihood ratios were calculated for a case-control dataset of BRCA1 and BRCA2 variants from the Breast Cancer Association Consortium (BCAC) and compared with logistic regression results. A larger number of variants reached evidence in favor of pathogenicity, and a substantial number of variants had evidence against pathogenicity—findings that would not have been reached using other case-control analysis methods. Our novel method provides greater power to classify rare variants compared with classical case-control methods. As an initiative from the ENIGMA Analytical Working Group, we provide user-friendly scripts and preformatted Excel calculators for implementation of the method for rare variants in BRCA1, BRCA2, and other high-risk genes with known penetrance.