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Granulopoietic Dysregulation in a Patient-Tailored Mouse Model of Barth Syndrome
No full textBarth syndrome (BTHS) is an X-linked recessive disorder characterized by cardiomyopathy, skeletal muscle myopathy and fatigue, growth restriction, and neutropenia. Neutropenia increases the risk of life-threatening bacterial infections, a major cause of death in individuals with BTHS. Currently, there is no curative treatment for BTHS or associated neutropenia. The development of therapeutic strategies to correct BTHS-associated neutropenia has been hindered by a limited understanding of the underlying molecular mechanisms involved. BTHS is caused by a mutation in the Tafazzin gene encoding a transacylase required for the maturation of cardiolipin, an inner mitochondrial membrane phospholipid crucial for mitochondrial structure and function. We introduced a BTHS patient's point mutation (TAZD75H) into the mouse Tafazzin enzyme's critical acyltransferase site using CRISPR/Cas9-mediated genome editing, resulting in a patient-tailored point mutant knock-in BTHS model (TazD75H) that expresses a stable mutant TazD75H protein lacking transacylase activity. TazD75H mice were then used to investigate how loss of Tafazzin enzymatic activity impacts hematopoiesis. Male TazD75H mice exhibited impaired granulopoiesis and neutropenia secondary to impaired function of hematopoietic progenitors. Furthermore, they demonstrated age-dependent neutrophil maturation impairment reflecting the variable neutropenia observed in BTHS patients. Additionally, male TazD75H mice exhibit chronic lymphopenia that persists post TazD75H bone marrow transplantation. Mechanistically, the TAZD75H point mutation caused hematopoietic cell mitochondrial dysfunction in patient-derived immortalized TAZD75H lymphoblasts, increasing reactive oxygen species production and mitochondrial membrane depolarization. Likewise, Cyclosporine A treatment rescued these mitochondrial phenotypes in vitro, confirming TAZD75H mitochondrial dysfunction. Overall, our findings demonstrate that mitochondrial dysfunction secondary to TAFAZZIN loss of enzymatic function underlies BTHS-associated neutropenia and lymphopenia
Identification of type 2 diabetes- and obesity-associated human β-cells using deep transfer learning
No full textDiabetes affects >10% of adults worldwide and is caused by impaired production or response to insulin, resulting in chronic hyperglycemia. Pancreatic islet β-cells are the sole source of endogenous insulin, and our understanding of β-cell dysfunction and death in type 2 diabetes (T2D) is incomplete. Single-cell RNA-seq data supports heterogeneity as an important factor in β-cell function and survival. However, it is difficult to identify which β-cell phenotypes are critical for T2D etiology and progression. Our goal was to prioritize specific disease-related β-cell subpopulations to better understand T2D pathogenesis and identify relevant genes for targeted therapeutics. To address this, we applied a deep transfer learning tool, DEGAS, which maps disease associations onto single-cell RNA-seq data from bulk expression data. Independent runs of DEGAS using T2D or obesity status identified distinct β-cell subpopulations. A singular cluster of T2D-associated β-cells was identified; however, β-cells with high obese-DEGAS scores contained two subpopulations derived largely from either non-diabetic (ND) or T2D donors. The obesity-associated ND cells were enriched for translation and unfolded protein response genes compared to T2D cells. We selected CDKN1C and DLK1 for validation by immunostaining in human pancreas sections from healthy and T2D donors. Both CDKN1C and DLK1 were heterogeneously expressed among β-cells. CDKN1C was increased in β-cells from T2D donors, in agreement with the DEGAS predictions, while DLK1 appeared depleted from T2D islets of some donors. In conclusion, DEGAS has the potential to advance our holistic understanding of the β-cell transcriptomic phenotypes, including features that distinguish β-cells in obese ND or lean T2D states. Future work will expand this approach to additional human islet omics datasets to reveal the complex multicellular interactions driving T2D
Alzheimer Disease, Vascular Disease, and Blood-Brain Barrier Permeability Biomarkers in Middle-Aged Adults
No full textBackground and objectives: Cerebrovascular disease (CVD) influences Alzheimer disease (AD) risk and progression, but the link between vascular disease and AD pathophysiology remains unclear, particularly in midlife when the impact of CVD on AD risk may be strongest. This study examined the relationship of recently validated vascular cognitive impairment (VCI) plasma biomarker concentrations that reflect aspects of blood-brain barrier dysfunction with MRI markers of CVD and AD plasma biomarker concentrations.
Methods: The study included middle-aged participants from the Offspring Study of Racial and Ethnic Disparities in AD who had MRI and plasma biomarker data available. Biomarker concentrations of vascular endothelial growth factor (VEGF) family members (VEGF-D, placental growth factor [PlGF], and basic fibroblast growth factor [bFGF]) were measured using the Meso Scale Discovery platform. β-Amyloid (Aβ42, Aβ40), phosphorylated tau 181 (p-tau181), astrocytosis (glial fibrillary acidic protein [GFAP]), and neurodegeneration (neurofilament light chain [NfL]) biomarkers were measured with Simoa immunoassays. White matter hyperintensity (WMH) volumes were derived from T2-weighted MRI scans. Bivariate relationships of WMH, Aβ42/Aβ40 ratio, p-tau181, GFAP, and NfL with VEGF biomarkers were tested, and path analyses examined potential causal pathways linking each VEGF biomarker concentration to WMH and GFAP, as well as their downstream associations with tau pathology and neurodegeneration.
Results: We analyzed data from 488 participants (mean [SD] age = 54.3 [10.5]; 66.8% women). Higher PlGF levels were associated with older age (R [CI] = 0.25 [0.17-0.33]); greater WMH volume (R [CI] = 0.2 [0.11-0.29]); and higher levels of GFAP (R [CI] = 0.11 [0.02-0.2]), p-tau181 (R [CI] = 0.12 [0.03-0.21]), and NfL (R [CI] = 0.19 [0.1-0.27]). Higher VEGF-D was associated with increased GFAP (R [CI] = 0.11 [0.02-0.19]) and NfL (R [CI] = 0.16 [0.07-0.25]) levels. bFGF concentration was associated with a lower Aβ42/40 ratio (R [CI] = -0.1 [-0.19 to -0.02]) and higher p-tau181 levels (R [CI] = 0.13 [0.04-0.21]). The best fitting path model showed that PlGF had an indirect effect on GFAP levels mediated by WMH. GFAP subsequently had a direct positive effect on p-tau181, which in turn had a positive effect on NfL levels. VEGF-D and bFGF levels also had a positive direct effect on NfL.
Discussion: The findings suggest that permeability of the blood-brain barrier is linked to AD pathophysiology, contributes to cerebrovascular lesions observed on MRI, and is associated with neuroinflammation in middle age
NEXT STEPs: Evidence-Based Recruitment and Retention for Nursing Home Clinical Trials
No full textThe National Institute on Aging funded NEXT STEPs (Nursing home EXplanatory clinical Trials: Supporting Transformation by Enhancing Partnerships) to promote the successful conduct of nursing home clinical trials. Three of NEXT STEPs’ key elements recognize the importance of the relationship between researchers and those participating in research: recruiting nursing homes and participants; cultivating engagement throughout the process; and following up and following through on communication to share results and promote sustainable implementation. NEXT STEPs’ Recruitment and Retention Core focuses on these areas, a key effort being the development of a range of evidence-based best practice resources for use by those who conduct research and participate in research. To begin this effort, Core members searched the literature and conferred with experts to develop an extensive and evolving list of best practice topics – such as strategies to help researchers convey the importance of research, and participants to understand their rights as a research partner – and determine the optimal format to convey the best practices (e.g., checklists, short videos). The first document created for researchers is entitled “Words Matter,” employing a “use this/not that” format (e.g., use “choose not to” rather than “noncompliant”). Feedback on materials are obtained from diverse partner workgroups before they are finalized, and their utility is evaluated as they are used in NEXT STEPs’ efforts. This session will overview the topics identified important for recruitment and retention, the process of topic selection and material development, and materials developed to date; audience feedback and recommendations will be solicited
Serum Metabolomics Reveals Potential Differences in Gut Microbiota-Associated Metabolites in Twins Discordant for Type 1 Diabetes
No full textWe investigated serum metabolites in monozygotic (MZ) and dizygotic (DZ) twins discordant for type 1 diabetes (T1D) to explore potential environmental factors, with a focus on differences in gut microbiota-associated metabolites that may influence T1D. Serum samples from 39 twins discordant for T1D were analyzed using a semi-targeted metabolomics approach via liquid chromatography-high-resolution tandem mass spectrometry. Statistical analyses identified significant metabolites (P < 0.1) within three groups: all twins (combined group [All]), MZ twins, and DZ twins. Thirteen metabolites exhibited significant differences between individuals with T1D and those without T1D. Across all groups, 3-indoxyl sulfate and 5-hydroxyindole were significantly reduced in individuals with T1D. Carnitine was reduced, and threonine, muramic acid, and 2-oxobutyric acid were significantly elevated in both All and MZ groups. Allantoin was significantly reduced and 3-methylhistidine was significantly elevated in All and DZ groups. These findings suggest metabolite dysregulation associated with gut dysbiosis was observed. However, further validation of our findings in a larger cohort is needed.
Article highlights: We believed this cohort of twins discordant for type 1 diabetes (T1D) would allow for control over genetic variability to examine environmental factors. We aimed to identify differences in microbial and microbiota-associated metabolites in twins discordant for T1D to examine the effect of the gut microbiome on T1D. Thirteen metabolites were identified as significantly different. Our results show dysregulation of several microbial metabolites in twin pairs, suggesting the role of the gut microbiome in T1D pathogenesis
A Comparative Analysis of Injuries related to Self-Harm, Assault, and Intimate Partner Violence: Insights from U.S. Emergency Departments (2005–2021)
No full textBackground: Emergency departments are on the front lines of non-fatal self-harm injury (SHI). This study identifies patterns in patients presenting to emergency departments with SHI compared with patients presenting with assault and intimate partner violence.
Methods: Using the National Electronic Injury Surveillance System All Injury Program database, we analyzed SHI cases in the emergency department from 2005 to 2021 and examined demographic characteristics, injury mechanism and anatomic location, emergency department disposition and temporal patterns relative to cases involving assault and intimate partner violence.
Results: Of all injury-related emergency department visits, 1.5% (7 774 900) were due to SHI, 4.8% (24 165 696) due to assault and 0.6% (3 188 790) due to intimate partner violence. SHI peaked in ages 15-19 (18.3%), assault in ages 20-24 (17.3%) and intimate partner violence in ages 25-29 (19.2%). Patients with SHI were 41.0% males, compared with assault (66.3%) and intimate partner violence (19.3%) groups (p<0.0001). Most SHIs involved white patients (75.2%), compared with assaults (46.2%) and intimate partner violence (40.4%) (p<0.0001). Lacerations (20.6%) were the most common injury for SHI, while contusions/abrasions were the most common injuries for both assaults (27.8%) and intimate partner violence (39.1%) (p<0.0001). The upper extremity was the most common injury location in SHI (71.11%), while the head/neck was the most injured area in assaults (58.4%) and intimate partner violence (59.7%). Of adolescents sustaining SHI, 76.7% were women, compared with 59.0% of emerging adults and 53.2% of adults (p<0.0001). Among adolescents, the prevalence of SHI was lowest on weekends and during the summer.
Conclusions: Our findings highlight distinct demographic, injury and temporal patterns observed in patients with SHI
COVID-19 and sexual assault: trends in US emergency department visits—a cross-sectional analysis
No full textBackground: Sexual assault often increases during crises, yet trends in United States (US) emergency department (ED) visits for sexual assault during COVID-19 remain unclear.
Objective: To examine demographic, incident and injury trends in US sexual assault presentations during early and late COVID-19 compared with pre-COVID-19.
Methods: This study analysed National Electronic Injury Surveillance System All Injury Programme (2014-2021) retrospective data. ED visits for assault (n=246 499) and sexual assault (n=22 752) were compared across pre-COVID-19 (January 2014-March 2020), early COVID-19 (March 2020-January 2021) and late COVID-19 (February 2021-December 2021). Demographic and injury trends were analysed via t-tests, analysis of variance or χ² tests, with national trends assessed using Joinpoint regression and weighted data in SUDAAN.
Results: From 2017 to 2021, while assault-related ED visits declined (-5.05% annually; p=0.003), sexual assault ED visits remained stable (-1.15% annually; p=0.57). During COVID-19, sexual assault cases decreased among 0-19 years (46.1% pre-COVID-19 to 37.3% late COVID-19) but increased among 20-34 years (36.0% to 40.3%) and 35-64 years (17.2% to 21.0%). From early to late COVID-19, cases increased among black (31.7% to 32.8%) and Hispanic (13.8% to 15.6%) populations but declined among white populations (49.5% to 47.7%). Assaults by parents (9.0% to 11.2%) and partners (10.9% to 13.5%) increased, as did poisoning-related (1.4% to 5.5%) and anoxia-related injuries (0.1% to 0.7%).
Conclusions: Despite the pandemic, ED visits for sexual assault persisted, with demographic shifts and increased injury severity (eg, drug-facilitated violence, strangulation-related anoxia). These findings highlight the need for targeted interventions during public health crises
KLK15 alters connective tissues in hypermobile Ehlers-Danlos syndrome
No full textHypermobile Ehlers-Danlos syndrome (hEDS) is a debilitating multisystem condition characterized by joint hypermobility, chronic pain, and diverse comorbidities, yet its genetic basis remains undefined. Whole-exome sequencing (WES) of 200 patients with hEDS revealed rare and low frequency variants in 14 of 15 kallikrein (KLK) genes, including a recurrent KLK15 missense variant (p.Gly226Asp) segregating in multiple families. KLK15, a secreted serine protease, is expressed in connective and immune tissues and interacts with extracellular matrix (ECM) components, including fibronectin and lysyl oxidase (LOX). A KLK15 knock-in mouse model recapitulated hEDS features in tendons and cardiac valves and exhibited dysregulated cytokine profiles. The variant altered KLK15 and LOX compartmentalization within the ECM, consistent with a dominant-negative effect. These findings identify KLK15 as a contributor to hEDS and reveal broader roles for KLK protease-ECM-immune crosstalk in connective tissue regulation. This study reframes hEDS as a condition involving matrix remodeling and immune signaling beyond collagen defects
Forward Mentoring: A Reverse Mentoring-Inspired Initiative to Enhance Cultural Humility and Promote Academic Leadership Capacity
No full textBuilding relationships and broadening perspectives promotes cultural competence, inclusion, and belonging. At Indiana University School of Medicine, we created an innovative reverse mentoring-inspired program (Forward Mentoring) to connect individuals across academic hierarchies with the goal of fostering relationships, cultural humility, and leadership capacity through honest, personal, and reflective discourse-all to build more inclusive and welcoming workplaces. Here we describe the novel Forward Mentoring framework, outline the initial programmatic design and implementation, and present an evaluation plan that assesses learning, growth, satisfaction, and program efficacy. Evaluation data from a limited pilot is presented and future directions discussed
Predicting onset of Alzheimer disease symptoms with a plasma %p‐tau217 clock
No full textBackground:
Time proxies based on blood biomarkers may facilitate understanding of the timing of biomarker change and symptom onset in Alzheimer's disease (AD) and could potentially enable biological staging of AD. Compared to CSF biomarkers or brain imaging, blood biomarkers are more accessible and less burdensome, making a “plasma clock” a practical and useful tool.
Method:
Longitudinal plasma %p‐tau217 (p‐tau217 concentration divided by np‐tau217 concentration x 100) measurements from individuals enrolled in the Knight ADRC (n = 420) or ADNI (n = 392) cohorts were analyzed to develop plasma clocks for each cohort. The %p‐tau217 values were transformed into a time scale by integrating the inverse of the modeled rate of change. A %p‐tau217 value of 4.06%, which corresponds to amyloid PET Centiloid=20, was considered the threshold for positivity and set as time zero. The estimated age at %p‐tau217 positivity was then used to predict symptom onset, defined as a change in Clinical Dementia Rating® (CDR) from CDR=0 to CDR>0.
Result:
The rate of change for plasma %p‐tau217 was relatively consistent between 0.65‐8.16% (Figure 1) and was used to construct independent plasma %p‐tau217 clocks for the Knight ADRC and ADNI cohorts (Figure 2). For individuals with plasma %p‐tau217 measured before and after positivity (4.06%), the estimated age at positivity based on the clock was strongly correlated with the actual age at conversion (Knight ADRC: R2=0.646, r=0.807; ADNI: R2=0.790, r=0.891). The Knight ADRC and ADNI plasma clocks provided highly similar estimates of the age at %p‐tau217 positivity for individuals in either study (adjusted R2=0.993, Pearson r=0.997, Figure 2). The estimated age at plasma %p‐tau217 positivity predicted the age at symptom onset (Figure 3) in the Knight ADRC (Spearman r=0.421, adjusted R2=0.151) and ADNI cohorts (Spearman r=0.648, adjusted R2=0.397).
Conclusion:
Two independently constructed %p‐tau217 plasma clocks had strong correlations with actual time measures and were consistent across the two cohorts. Additionally, the age at %p‐tau217 positivity predicted symptom onset. Overall, these findings suggest that plasma %p‐tau217 may be useful in predicting symptom onset and in biological staging of AD