Citations

Post-transplant lymphoproliferative disorder is a rare and serious complication of organ and stem cell transplant secondary to immunosuppressive therapies, most commonly of monomorphic B-cell subtype. Here we describe the first reported case of a pediatric heart transplant patient who developed both monomorphic B-cell and nondestructive PTLD with plasmacytic hyperplasia followed by an unrelated case of monomorphic T-cell and nondestructive PTLD with plasmacytic hyperplasia, which later relapsed. We detail the patient’s risk factors for development of PTLD and her successful treatment regimens. This case highlights the potential relationship between Epstein-Barr virus and/or cytomegalovirus and PTLD.

PURPOSE Gender bias against girls may affect health-seeking behavior and outcomes of childhood cancer. This study aimed to study the nature and extent of gender bias in health care among caregivers of childhood patients with cancer and also in community. METHODS This cross-sectional mixed-methods study was conducted in a tertiary cancer hospital and an urban community between July 2021 and July 2023. Qualitative component included 26 in-depth interviews (IDI) and four focus group discussions (FGDs) with caregivers of children with cancer. IDIs and FGDs were conducted by a psychologist and continued until thematic saturation was reached. For quantitative part, a gender-bias questionnaire was finalized which was administered to 230 caregivers in hospital and 311 participants from the community, with children in family. RESULTS Most participants did not perceive personal gender bias; however, many acknowledged noticing gender bias in others. This bias was linked to girls being considered financial burdens and having reduced marital prospects due to illness. Reducing treatment costs, improving access, and education targeting societal mindsets were suggested measures to mitigate bias. In community, no significant difference was observed among the respondents based on sex of youngest child in family. However, in hospital, caregivers of male children were less likely to offer similar care to a child of opposite sex than that reported by caregivers of female children ( P = .01) for ailments like fever/diarrhea. Similar difference was not observed for other health care scenarios. CONCLUSION Gender bias against girls, including that in health care access, is influenced by societal norms. Even with little personal perception of bias, there was a significant perceived bias observed in others by the participants. This study identified the existence of gender bias affecting health care choices, including cancer care.

Abstract Objective The objective of this study is to identify social/metabolic risk factors associated with subsequent diagnosis of adrenal adenoma Design The design is a population-based historical case–control study. Methods Cases were adult patients diagnosed with an adrenal adenoma between 2005 and 2017 with no overt hormone excess. Controls were age- and sex-matched individuals with (1) no diagnosis of adrenal adenoma and (2) no diagnosis of adrenal adenoma with cross-sectional imaging of the chest/abdomen performed within 5 years prior to index date. The frequency of various social/metabolic risk factors present 5-10 years prior to index date and odds ratios (ORs) for adrenal adenoma diagnosis were reported. Results Six hundred seventy cases identified (median age 63 years old, 56% women). During the 5-10 years prior to index date, patients with adrenal adenomas had higher prevalence of obesity (56.7% vs 49.3%, P = .007), low socioeconomic status (36.7% vs 31.1%, P = .039), tobacco use (70.2% vs 61.4%, P = .001), and diabetes (17.5% vs 11.7%, P = .003) compared to controls with prior imaging. No difference in prevalence of hypertension, substance use, chronic kidney disease, or combined cardiovascular events was observed. Based on a multivariable analysis, increased body mass index (BMI) and tobacco use were associated with increased odds of adrenal adenoma diagnosis with ORs 1.18 (95% confidence interval [CI] 1.07-1.32) and 1.41 (95% CI 1.06-1.87), respectively. Conclusions Compared to controls with prior imaging, patients with adrenal adenoma had higher prevalence of obesity, low socioeconomic status, tobacco use, and diabetes 5-10 years prior to index date. In particular, increased BMI and tobacco use were independent risk factors associated with increased odds of adrenal adenoma diagnosis.

Background & Aims: The clinical course and outcomes of alcohol-associated hepatitis (AH) remain poorly understood. Major adverse liver outcomes do not capture the added risk of return to drinking. We examined the natural history of AH and developed a composite endpoint using a contemporary observational cohort of AH. Approach & Results: A cohort of 1127 participants: 712 AH patients, 256 heavy drinking controls without clinically evident liver disease, and 159 healthy controls, were prospectively followed for 6 months at 8 United States centers as part of the Alcoholic Hepatitis Network (AlcHepNet) consortium. Outcomes included mortality and a composite endpoint (AlcHepNet composite index) that included death, liver transplantation, hepatic decompensation (new onset/worsening ascites, HE, variceal bleeding), liver-related hospital admission, MELD increase ≥5, and return to drinking. Of 712 AH patients (age 45±10.7 y; 59.1% male), 558 (79.0%) had severe and 148 (21.0%) had moderate AH, 232 (32.5%) died, and 86 (12.1%) underwent liver transplantation. Mortality rates in moderate AH and severe AH were 0.7% versus 17.2% (30 d), 3.4% versus 26.5% (90 d), and 8.8% versus 30.5% (180 d), respectively (all p <0.001). Composite liver/alcohol use events were noted in 459 (64.5%) AH patients. Higher MELD score, lower mean arterial pressure, and baseline leukocytosis were associated with higher 90-day mortality in AH (all p <0.05). College education and higher ALP were associated with lower mortality. Heavy drinking controls had low mortality (n=3; 1.2%). Conclusions: This large observational study showed a high incidence of composite liver and alcohol-use events within 6 months, reiterating the need for early interventions.

Abstract Background: Conventional null hypothesis significance testing, which relies heavily on p-values and confidence intervals, remains central to scientific research. However, both measures are subject to variability and may yield fragile or misleading conclusions. This has contributed to reproducibility concerns and the need for more informative inferential tools. Methods: We propose the Replicative Significance Index (RSI), a simulation-based metric that estimates the proportion of hypothetical replications that achieve statistical significance under identical design assumptions. The RSI directly models the stability of observed significance, in contrast to post hoc p-value interpretation or traditional power analysis. We further introduce a tail-augmented RSI (RSI*), which incorporates the depth of significant p-values through a tail-dominance adjustment. RSI and RSI* were implemented in R and demonstrated via conceptual examples, simulations under varying precision, and illustrative case scenarios of fragile significance and hidden robustness. Results: The simulations revealed that the RSI discriminates between superficially similar p-values that differ markedly in replicability and highlights cases where confidence intervals and p-values may overstate or understate robustness. RSI* further rewards distributions concentrated in the lower tail, distinguishing robustly reproducible findings from borderline significance. An R package and interactive Shiny web application are provided to facilitate implementation.

Abstract May-Thurner physiology (MTP) can lead to various congestion syndromes due to compression of the left common iliac vein (LCIV) by the right common iliac artery (RCIA). This compression may result in venous reflux through the lumbar vein, leading to congestion of the spinal epidural venous plexus (EVP), which could contribute to refractory headaches. This case report details the clinical course of a patient with severe refractory new daily persistent headache associated with MTP who underwent ascending lumbar vein (ALV) embolization. The patient is a 59-year-old female with a 3-year history of daily persistent headache which failed multiple migraine prevention therapies and minimally invasive procedures. Imaging studies revealed significant LCIV compression by the RCIA, retrograde ALV flow, and EVP congestion. The patient underwent ALV embolization, resulting in significant symptomatic relief. At the 22-month follow-up, headache severity reduced by 80%, with the patient no longer requiring routine headache medications. Additionally, treatment of associated pelvic congestion syndrome through gonadal vein embolization resolved longstanding associated pelvic pain and pressure. This case highlights the role of venous congestion in refractory headache syndromes and underscores the potential of targeted venous interventions, such as embolization, in their management. The findings expand on emerging evidence linking venous compression syndromes to headache pathophysiology and support exploring interventional strategies as viable treatment options for selected patients. Further research is needed to validate these findings and establish evidence-based guidelines for clinical practice.

Abstract Insulin resistance (IR) is a modifiable risk factor for dementia, yet its effects on brain metabolism and function remain unclear. In older adults, greater IR was associated with reduced cerebral glucose uptake (indicating impaired mitochondrial metabolism), atrophy, and weakened connectivity between brain regions critical for cognition. In neuron-specific insulin receptor knockout mice, brain IR produced deficits in hippocampal- and prefrontal-dependent tasks accompanied by reduced brain mitochondrial ATP and elevated reactive oxygen species. To evaluate reversibility of IR-induced brain deficits, forty older adults with IR were randomized to 40-weeks of metformin or placebo. Metformin improved insulin sensitivity, increased brain glucose uptake, strengthened cognitive network connectivity, and preserved whole-brain and regional volumes implicated in decision-making and learning. Metformin also improved processing speed and working memory. Collectively, these findings highlight IR as a driver of brain metabolism and support the concept that insulin sensitization can prevent neurobiological deficits in older people with IR.

Key Points ift140 -deficient zebrafish exhibited phenotypes observed in mammals, including skeletal defects and kidney cysts. Beyond ciliogenesis, ift140 also regulated cell polarity and intracellular microtubule stability, potentially contributing to cystogenesis. Microhomology-mediated end joining–induced mosaic ift140 crispants enabled evaluation of cystogenesis in adult fish and F0-based screening for modifiers of kidney cysts. Background Genetic modifiers are believed to play an important role in the onset and severity of polycystic kidney disease, but identifying these modifiers has been challenging due to the lack of effective methodologies. Methods We generated zebrafish mutants of IFT140 , a skeletal ciliopathy gene and newly identified autosomal dominant polycystic kidney disease gene, to examine skeletal development and kidney cyst formation in larval and juvenile mutants. In addition, we used ift140 crispants, generated through efficient microhomology-mediated end joining–based genome editing, to compare phenotypes with mutants and conduct a pilot genetic modifier screen. Results ift140 mutants developed kidney cysts and bone defects similar to those seen in mammalian models. ift140 crispants recapitulated mutant phenotypes while bypassing the early lethality of the mutants, enabling the analysis of kidney cyst formation in adult fish. In addition to cilia defects, we identified nonciliary phenotypes, including disrupted cell polarity and aberrant cytoplasmic microtubule stabilization in kidney epithelial cells, as potential contributors to ift140 -associated cystogenesis. The ability to detect ift140 -associated kidney cysts with ease allowed us to develop an F0-based genetic screen to identify potential protective modifiers. A pilot screen of 16 genes previously implicated in dysregulated signaling pathways in autosomal dominant polycystic kidney disease revealed both known and novel modifiers, including mtor and ulk1a . We further found that inhibition of mtor and ulk1a reversed both cilia-related and non–cilia-related abnormalities in the kidney. Conclusions By establishing a zebrafish model of ift140 -associated cystic kidney disease, we recapitulated ift140 ’s ciliary role and uncovered a nonciliary function in kidney cystogenesis. Importantly, we demonstrated the feasibility of using ift140 mosaic crispants to evaluate cystogenesis in adult fish and to perform F0-based screening for identifying genetic modifiers of kidney cysts.