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Disruption of gut barrier integrity and host–microbiome interactions underlie MASLD severity in patients with type-2 diabetes mellitus

(2024)

Aberration of the "gut-liver axis" contributes to the development and progression of metabolic dysfunction-associated steatotic liver disease (MASLD). Here, we use multi-omics to analyze the gut microbiota composition and metabolic profile of patients with type-2 diabetes mellitus (T2DM). T2DM patients were screened for liver disease by blood tests, ultrasound, and liver stiffness measurements. Stool microbiota was analyzed by 16S rRNA gene sequencing; metabolomic profiling by Nuclear Magnetic Resonance spectroscopy and Ultra-High Performance-Mass Spectrometry. Microbiome and metabolic signatures were analyzed in the whole cohort and in matched subsets to identify signatures specific for steatosis (MASLD±) or fibrosis (Fibrosis±). Gut permeability was assessed in-vitro using monolayers of MDCK cells and trans-epithelial electric resistance (TEER). Cytokine profile was assessed in serum and stools.Overall, 285 patients were enrolled: 255 serum, 252 urine and 97 stool samples were analyzed. Anaeroplasma and Escherichia/Shigella ASVs were higher, while Butyricicoccus ASVs were lower in those with normal liver. In MASLD±, Butyricicoccus ASV was significantly higher in those with steatosis. In the Fibrosis±, Butyricicoccus ASV was significantly lower in those with fibrosis. Glycochenodeoxycholic acid-3-sulfate (G-UDCA-3S) appeared to be higher in MASLD with fibrosis. Fecal water from patients with MASLD and fibrosis caused the greatest drop in the TEER vs those with normal liver; this was reversed with protease inhibitors. Finally, fecal IL-13 was lower in MASLD with fibrosis. We identified microbiome signatures which were specific for steatosis and fibrosis and independent of other metabolic risk factors. Moreover, we conclude that protease-related gut permeability plays a role in those MASLD patients with fibrosis, and that disease progression is linked to a gut-liver axis which is at least partially independent of T2DM.

Cover page of A vascularized 3D model of the human pancreatic islet for ex vivo study of immune cell-islet interaction

A vascularized 3D model of the human pancreatic islet for ex vivo study of immune cell-islet interaction

(2024)

Insulin is an essential regulator of blood glucose homeostasis that is produced exclusively byβcells within the pancreatic islets of healthy individuals. In those affected by diabetes, immune inflammation, damage, and destruction of isletβcells leads to insulin deficiency and hyperglycemia. Current efforts to understand the mechanisms underlyingβcell damage in diabetes rely onin vitro-cultured cadaveric islets. However, isolation of these islets involves removal of crucial matrix and vasculature that supports islets in the intact pancreas. Unsurprisingly, these islets demonstrate reduced functionality over time in standard culture conditions, thereby limiting their value for understanding native islet biology. Leveraging a novel, vascularized micro-organ (VMO) approach, we have recapitulated elements of the native pancreas by incorporating isolated human islets within a three-dimensional matrix nourished by living, perfusable blood vessels. Importantly, these islets show long-term viability and maintain robust glucose-stimulated insulin responses. Furthermore, vessel-mediated delivery of immune cells to these tissues provides a model to assess islet-immune cell interactions and subsequent islet killing-key steps in type 1 diabetes pathogenesis. Together, these results establish the islet-VMO as a novel,ex vivoplatform for studying human islet biology in both health and disease.

Cover page of Incidental solitary fibrous tumor involving the seminal vesicle: A case report.

Incidental solitary fibrous tumor involving the seminal vesicle: A case report.

(2024)

Solitary fibrous tumors are rare mesenchymal neoplasms that can range from slow-growing to aggressive tumors. This report presents a unique case of a young male patient with a solitary fibrous tumor involving the seminal vesicle, a rare location, and reinforces incidental discovery of these tumors on imaging and physical exams. Detection of these tumors is imperative to identify and treat malignancy. In our case, a 39-year-old previously healthy Asian male presents to the emergency department as a trauma admission post bicycle crash and is incidentally found to have a pelvic mass on computed tomography imaging of the pelvis. The patient underwent trans-anal biopsy which showed spindle epithelioid cells positive for CD34 and STAT6 markers, with a morphological and immunohistochemical profile consistent with a solitary fibrous tumor. The patient underwent surgery with a robotic-assisted laparoscopic pelvic mass resection and now follows up annually with imaging for observation.

The finite dual coalgebra as a quantization of the maximal spectrum

(2024)

In pursuit of a noncommutative spectrum functor, we argue that the Heyneman-Sweedler finite dual coalgebra can be viewed as a quantization of the maximal spectrum of a commutative affine algebra, integrating prior perspectives of Takeuchi, Batchelor, Kontsevich-Soibelman, and Le Bruyn. We introduce fully residually finite-dimensional algebras A as those with enough finite-dimensional representations to let A∘ act as an appropriate depiction of the noncommutative maximal spectrum of A; importantly, this class includes affine noetherian PI algebras. In the case of prime affine algebras that are module-finite over their center, we describe how the Azumaya locus is represented in the finite dual. This is used to describe the finite dual of quantum planes at roots of unity as an endeavor to visualize the noncommutative space on which these algebras act as functions. Finally, we discuss how a similar analysis can be carried out for other maximal orders over surfaces.

Cover page of A two-sample Mendelian randomization study explores metabolic profiling of different glycemic traits.

A two-sample Mendelian randomization study explores metabolic profiling of different glycemic traits.

(2024)

We assessed the causal relation of four glycemic traits and type 2 diabetes liability with 167 metabolites using Mendelian randomization with various sensitivity analyses and a reverse Mendelian randomization analysis. We extracted instruments for fasting glucose, 2-h glucose, fasting insulin, and glycated hemoglobin from the Meta-Analyses of Glucose and Insulin-related traits Consortium (n = 200,622), and those for type 2 diabetes liability from a meta-analysis of multiple cohorts (148,726 cases, 965,732 controls) in Europeans. Outcome data were from summary statistics of 167 metabolites from the UK Biobank (n = 115,078). Fasting glucose and 2-h glucose were not associated with any metabolite. Higher glycated hemoglobin was associated with higher free cholesterol in small low-density lipoprotein. Type 2 diabetes liability and fasting insulin were inversely associated with apolipoprotein A1, total cholines, lipoprotein subfractions in high-density-lipoprotein and intermediate-density lipoproteins, and positively associated with aromatic amino acids. These findings indicate hyperglycemia-independent patterns and highlight the role of insulin in type 2 diabetes development. Further studies should evaluate these glycemic traits in type 2 diabetes diagnosis and clinical management.

Cover page of The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence.

The NUTRIENT Trial (NUTRitional Intervention among myEloproliferative Neoplasms): Results from a Randomized Phase I Pilot Study for Feasibility and Adherence.

(2024)

PURPOSE: Chronic inflammation is integral to myeloproliferative neoplasm (MPN) pathogenesis. JAK inhibitors reduce cytokine levels, but not without significant side effects. Nutrition is a low-risk approach to reduce inflammation and ameliorate symptoms in MPN. We performed a randomized, parallel-arm study to determine the feasibility of an education-focused Mediterranean diet intervention among patients with MPN. EXPERIMENTAL DESIGN: We randomly assigned patients with MPN to either a Mediterranean diet or standard U.S. Dietary Guidelines for Americans (USDA). Groups received equal but separate education with registered dietician counseling and written dietary resources. Patients were prospectively followed for feasibility, adherence, and symptom burden assessments. Biological samples were collected at four timepoints during the 15-week study to explore changes in inflammatory biomarkers and gut microbiome. RESULTS: The Mediterranean diet was as easy to follow for patients with MPN as the standard USDA diet. Approximately 80% of the patients in the Mediterranean diet group achieved a Mediterranean Diet Adherence Score of ≥8 throughout the entire active intervention period, whereas less than 50% of the USDA group achieved a score of ≥8 at any timepoint. Improvement in symptom burden was observed in both diet groups. No significant changes were observed in inflammatory cytokines. The diversity and composition of the gut microbiome remained stable throughout the duration of the intervention. CONCLUSIONS: With dietician counseling and written education, patients with MPN can adhere to a Mediterranean eating pattern. Diet interventions may be further developed as a component of MPN care, and potentially incorporated into the management of other hematologic conditions. SIGNIFICANCE: Diet is a central tenant of management of chronic conditions characterized by subclinical inflammation, such as cardiovascular disease, but has not entered the treatment algorithm for clonal hematologic disorders. Here, we establish that a Mediterranean diet intervention is feasible in the MPN patient population and can improve symptom burden. These findings warrant large dietary interventions in patients with hematologic disorders to test the impact of diet on clinical outcomes.

Cover page of Variability in the Integration of Peers in a Multi-site Digital Mental Health Innovation Project.

Variability in the Integration of Peers in a Multi-site Digital Mental Health Innovation Project.

(2024)

Peer support specialists (peers) who have the lived experience of, and are in recovery from, mental health challenges are increasingly being integrated into mental health care as a reimbursable service across the US. This study describes the ways peers were integrated into Help@Hand, a multi-site innovation project that engaged peers throughout efforts to develop and offer digital mental health interventions across counties/cities (sites) in California. Using a mixed methods design, we collected quantitative data via quarterly online surveys, and qualitative data via semi-annual semi-structured phone interviews with key informants from Help@Hand sites. Quantitative data were summarized as descriptive findings and qualitative data from interviews were analyzed using rapid qualitative analysis methods. In the final analytic phase, interview quotes were used to illustrate the complex realities underlying quantitative responses. 117 quarterly surveys and 46 semi-annual interviews were completed by key informants from 14 sites between September 2020 and January 2023. Peers were integrated across diverse activities for support and implementation of digital mental health interventions, including development of training and educational materials (78.6% of sites), community outreach (64.3%), technology testing (85.7%), technology piloting (90.9%), digital literacy training (71.4%), device distribution (63.6%), technical assistance (72.7%), and cross-site collaboration (66.7%). Peer-engaged activities shifted over time, reflecting project phases. Peer-provided digital literacy training and technology-related support were key ingredients for project implementations. This study indicates the wide range of ways peers can be integrated into digital mental health intervention implementations. Considering contextual readiness for peer integration may enhance their engagement into programmatic activities.

Cover page of Characterization of ATG8-family protein phosphorylation by Phos-tag gel for autophagy study

Characterization of ATG8-family protein phosphorylation by Phos-tag gel for autophagy study

(2024)

Autophagy supports cell survival under different stress conditions, where ATG8-family proteins are required for autophagosome biogenesis/maturation and selective autophagy. Here, we present a protocol for studying ATG8-family protein phosphorylation using Phos-tag gel, a modified SDS-PAGE system, when the related phosphorylation site information and/or specific phospho-antibody are unavailable. We describe steps for generating GST-ATG8 proteins in bacteria, purifying S protein-Flag-SBP protein (SFB)-tagged kinasefrom cells, preparing gel, and an in vitro kinase assay. We then detail procedures for western blotting and image processing. For complete details on the use and execution of this protocol, please refer to Seo et al.1.

Cover page of Female genital mutilation: Overview and dermatologic relevance.

Female genital mutilation: Overview and dermatologic relevance.

(2024)

Female genital mutilation (FGM) is a common cultural practice, which involves the partial or complete removal of the external female genitalia. With increasing immigration from regions where the practice is endemic, there has been a growing prevalence of FGM in the United States and other developed nations. However, most medical professionals lack the baseline knowledge regarding FGM and its associated health complications. Given this increasing trend, dermatologists should anticipate an increasing number of patients with a history of FGM in their practice. While some of the obstetric, gynecologic, and psychologic consequences of FGM have been well-reported, the dermatologic findings are less characterized. Thus, this review article aims to provide dermatologists with a fundamental understanding of the prevalence, cultural significance, and health implications of FGM with a focus on the associated dermatological findings and provides recommendations on how dermatologists can address this sensitive matter.

Cover page of Family cash transfers in childhood and birthing persons and birth outcomes later in life.

Family cash transfers in childhood and birthing persons and birth outcomes later in life.

(2024)

Much literature in the US documents an intergenerational transmission of birthing person and perinatal morbidity in socioeconomically disadvantaged groups. A separate line of work indicates that family cash transfers may improve life chances of low-income families well into adulthood. By exploiting a quasi-random natural experiment of a large family cash transfer among a southeastern American Indian (AI) tribe in rural North Carolina, we examine whether a perturbation in socioeconomic status during childhood improves birthing person/perinatal outcomes when they become parents themselves. We acquired birth records on 6805 AI and non-AI infants born from 1995 to 2018. Regression methods to examine effect modification tested whether the birthing persons American Indian (AI) status and exposure to the family cash transfer during their childhood years corresponds with improvements in birthing person and perinatal outcomes. Findings show an increase in age at childbearing (coef: 0.15 years, 95% confidence interval [CI]: 0.05, 0.25) and a decrease in pre-pregnancy body mass index (BMI; coef: -0.42, 95% CI: -0.76, -0.09) with increased duration of cash transfer exposure during childhood. The odds of large-for-gestational age at delivery, as well as mean infant birthweight, is also reduced among AI births whose birthing person had relatively longer duration of exposure to the cash transfer. We, however, observe no relation with other birthing person/perinatal outcomes (e.g., tobacco use during pregnancy, preterm birth). In this rural AI population, cash transfers in one generation correspond with improved birthing person and infant health in the next generation.