The Indiana University School of Medicine has nine campuses throughout Indiana; the principal research and medical center is located on the Indiana University – Purdue University Indianapolis campus in Indianapolis. With 1,409 M.D. Program students and 158 Ph.D. students in 2017, IU is one of the largest allopathic medical schools in the United States. The school offers several joint-degree programs, including an MD/MBA, MD/MA, MD/MPH, and an MD-PhD Medical Scientist Training Program. The school has pioneered research in multiple specialties, including oncology, immunology, substance use, neuroscience, and endocrinology. Research discoveries include a curative therapy for testicular cancer, the development of echocardiography, the identification of several genes linked to Alzheimer's disease, and the creation of inner ear sensory cells from pluripotent stem cells.In the 2021 U.S. News & World Report rankings of the best graduate schools for medicine, the school ranked 20th in the nation for primary care and 47th for research out of about 150 medical schools. In the U.S. News & World Report rankings of the best hospitals, the Indiana University Health Medical Center had seventeen nationally ranked clinical programs. The Riley Hospital for Children at Indiana University Health is nationally ranked in 9 of 10 designated specialties for children in the U.S. News & World Report. The IU School of Medicine is also home to the Melvin and Bren Simon Cancer Center, a National Cancer Institute-designated Comprehensive Cancer Center.
BACKGROUND:Paediatric acute kidney injury (AKI) is a complication of severe malaria, but its long-term outcomes remain poorly defined in low-income and middle-income countries. We aimed to evaluate the long-term association between paediatric AKI and kidney outcomes and mortality following severe malaria. METHODS:We pooled data from two prospective cohorts of Ugandan children (ie, those aged 6 months-12 years) admitted to hospital with severe malaria between 2008 and 2017. Children with stored admission blood samples available for creatinine measurement were included in the analysis. Surviving participants were enrolled in a follow-up study conducted from 2020 to 2023, when kidney function and survival were assessed, using Cox regression with age as the timescale to model mortality risk. Logistic regression was used to estimate the odds of chronic kidney disease (CKD), defined as two or more consecutive low estimated glomerular filtration rates 90 days or more apart, and long-term major adverse kidney events, defined as CKD or death. Adjusted analyses included the following enrolment characteristics: age, sex, height-for-age Z score, study site, study cohort, severe malaria group (ie, cerebral malaria, severe malarial anaemia, respiratory distress, complicated seizures, or prostration), and HIV status. FINDINGS:At enrolment, the median age was 2·5 years (IQR 1·8-3·5), 622 (57·8%) of 1077 were male and 455 (42·2%) were female, with Kidney Disease: Improving Global Outcomes-defined AKI occurring in 431 (40·0%) children. Over a median of 6·5 years (3·7-8·8), 147 (13·6%) of children died, with nearly half of deaths (71 of 147) occurring after hospital discharge. Adjusted odds of long-term major adverse kidney events were higher among children with AKI (adjusted odds ratio [aOR] 3·14, 95% CI 2·23-4·43), driven by a higher mortality risk (adjusted hazard ratio [aHR] 3·36, 95% CI 2·22-5·10) that remained elevated beyond 2 years after the acute episode (aHR 4·53, 1·80-11·37). AKI survivors had higher odds of chronic kidney disease over follow-up (odds ratio 1·77, 1·07-2·93), although not significant after adjustment (aOR 1·47, 95% CI 0·84-2·56; p=0·18). INTERPRETATION:In this paediatric population, AKI was associated with excess long-term mortality, suggesting AKI is a sentinel event that marks sustained vulnerability to death and highlights limitations of acute-care models in malaria-endemic settings. FUNDING:The US National Institute of Neurological Disorders and Stroke, the Fogarty International Center, the US National Institutes of Allergy and Infectious Diseases, and a Ralph W and Grace M Showalter Young Investigator Award.
This manuscript reviews the clinical spectrum and management of Fontan-associated liver disease (FALD) and protein-losing enteropathy (PLE), examining how chronic venous hypertension leads to multisystem injury. Liver fibrosis is now recognized as an early and nearly universal complication after the Fontan procedure, with cirrhosis affecting approximately 43
One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.
Human enteric viruses frequently encounter diverse microbial communities in wastewater, where interactions with bacteria and other microorganisms can profoundly influence their environmental persistence and transmission. Increasing evidence demonstrates that bacteria can bind and stabilize enteric viruses, thereby enhancing thermal inactivation and prolonging infectivity. These interactions not only shape viral fate during wastewater treatment but also may affect the sensitivity and interpretation of wastewater-based epidemiology, an essential tool for public health surveillance. Yet significant knowledge gaps remain regarding the molecular mechanisms that govern bacterial-viral interactions and their roles in broader wastewater microbiomes. Together, advancing our understanding of transkingdom interactions in wastewater is essential for improving treatment processes, strengthening environmental surveillance, and reducing the risk of virus transmission through contaminated water systems.
CONTEXT:Maternal (vs paternal) type 1 diabetes is associated with a relative reduction in type 1 diabetes risk in offspring during early life. OBJECTIVE:To determine whether this effect extends into later life. To clarify the importance of intrauterine exposure to maternal type 1 diabetes, and baseline genetic susceptibility in this context. METHODS:We compared the proportion of individuals with type 1 diabetes diagnosed aged 0 to 88 years of age with affected mothers and fathers across 5 observational studies (n = 11 475), and used random-effects meta-analyses to generate overall effect estimates. We examined this by age at diagnosis, and timing of parental diagnosis relative to offspring birth. We compared the type 1 diabetes genetic risk score (T1D-GRS2) of individuals with affected mothers and fathers. RESULTS:Almost half as many individuals with type 1 diabetes had an affected mother vs father (odds ratio [OR], 0.55; 95% CI, 0.48-0.64; P < .0001). A lower proportion of individuals with affected mothers than fathers was apparent even among individuals diagnosed as adults (>18 years) (OR, 0.63; 95% CI, 0.43-0.91; P = .01). The lower proportion of individuals with maternal vs paternal type 1 diabetes was only observed if maternal diagnosis preceded offspring birth (OR, 0.51; 95% CI, 0.37-0.70; P < .001 vs OR 0.97; 95% CI, 0.69-1.38; P = .87 after birth). T1D-GRS2 was similar between individuals with affected mothers and fathers (P = .25). CONCLUSION:Our analyses suggest intrauterine exposure to maternal type 1 diabetes is associated with long-lasting relative protection against offspring type 1 diabetes, which is independent of genetic susceptibility as measured by T1D-GRS2.
