James J. Peters VA Medical Center

Diabetic kidney disease (DKD) remains a major global health burden and the most common cause of ESKD. The therapeutic landscape has profoundly shifted from a glucocentric model to a multifaceted strategy focusing on the holistic management of cardiovascular-kidney-metabolic syndrome. This therapeutic paradigm is now anchored by four foundational pillars: renin-angiotensin-aldosterone system inhibitors, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists, which collectively target complementary pathogenic pathways to slow DKD progression and reduce cardiovascular morbidity. Despite these advances, a high residual risk persists, driving kidney disease research into novel therapeutic targets. A large body of mechanistic studies demonstrates the critical roles of genetic and epigenetic modifications, persistent metabolic dysfunction, and inflammatory and fibrotic processes in DKD pathogenesis. Consequently, emerging investigational therapies are focused on histone-modifying enzymes, drugs to restore metabolic/lipid disorders, new anti-inflammatory and anti-fibrosis therapies, as well as stem cell-based interventions for their regenerative and immunomodulatory potential. The future of DKD management hinges on the successful clinical translation of these novel therapeutic approaches, which will require overcoming challenges in clinical trial design alongside current therapies, patient stratification for different therapeutic regimens using predictive biomarkers, and the exploration of synergistic combination therapies to ultimately personalize treatment strategies and enhance long-term kidney outcomes.

Brain network architecture is anticipated to influence future grey matter loss in individuals at Clinical High Risk (CHR) for psychosis. However, existing studies on grey matter structural network properties in CHR are scarce and constrained by small sample sizes. Here, we examined network topology differences comparing a) CHR versus healthy controls (HC); b) CHR who transitioned to psychosis (CHR-T) versus those who did not (CHR-NT); and c) different subsyndromes. We included structural scans from 1842 CHR individuals and 1417 HC individuals from 31 sites within the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. At the global level, CHR individuals exhibited lower structural covariance (q < 0.001; Cohen's d = 0.164) and less optimal structural network configuration than HC (lower global efficiency and clustering coefficient, d = 0.100,0.087, qs <= 0.027). Though no global difference between CHR-T and CHR-NT, network distinctiveness of the frontal and temporal surface area networks was higher in CHR-T than CHR-NT (d = 0.223,0.237) and HC (d = 0.208,0.219) (qs < 0.001). Network distinctiveness of the frontal cortical thickness network was lower in CHR-T (d = 0.218, q < 0.001) than CHR-NT and HC (d = 0.165, q < 0.001). Importantly, higher network distinctiveness was associated with worse positive symptoms in CHR-NT (frontal surface area, q = 0.008, R2 = 0.013) and at trend with worse negative symptoms in CHR-T (frontal thickness, q = 0.063, R2 = 0.049). Further, the brief intermittent psychotic syndrome subgroup showed more severe network alterations. Together, brain structural networks inform symptoms and the risk of transition to psychosis in CHR individuals.

ImportanceGeneral responders of the World Trade Center (WTC) Health Program (WTCHP), who were uniquely exposed to chemical toxicants and extreme psychological stress during the 2001 terrorist attack, now experience a wide range of unusually prevalent health outcomes for a mid-aged population, including frailty, Post Traumatic Stress Disorder (PTSD), and depression.ObjectiveWe investigated whether these outcomes are associated with urban environmental exposures experienced in the two decades post 9/11.DesignProspective cohort study.SettingWTCHP general responders’ cohort.ParticipantsWe included 18,861 WTCHP general responders between the years 2003 to 2023 who took part in rescue, recovery, and clean-up tasks following the 9/11/2001 attack on the WTC.ExposuresWe evaluated the distinct and combined associations with annual fine particulate matter (PM2.5), temperature, and Green View Index (GVI) and assessed interactions with WTC-exposures.OutcomesWe assessed frailty using a validated index developed specifically for the WTCHP. We determined PTSD and depression status based on repeated test scores from validated tools administered during the monitoring visits.ResultsWe included 18,861 responders, 81.89% were males, and the mean age at entry was 47. Interquartile range increases in PM2.5and temperature were significantly associated with increased frailty, PTSD, and depression scores, while greenness (GVI) was protective. A decile increase in the overall exposure mixture was associated with a 0.50% (95% confidence interval 0.08; 0.94) increase in frailty and a 0.10 unit (0.02; 0.18) increase in PTSD scores, primarily driven by temperature. Importantly, the exposure-mixture was associated with an increased risk of reaching a clinical threshold for PTSD (odds ratio: 1.013[1.001,1.024]). Finally, the associations between the exposure-mixture and mental health were significantly amplified among responders with high WTC-exposures, though no such modification was observed for frailty.Conclusion and relevanceExposures to heat and PM2.5were associated with increased frailty, PTSD, and depression, while greenness exposure was protective. Responders who experienced more intense WTC exposures were more vulnerable to later-life environmental exposure-mixture effects on mental health. These findings may help explain the elevated burden of these conditions among WTCHP responders and suggest avenues for public health interventions including education on risk mitigation strategies.

Traumatic brain injuries (TBI) frequently occur and can lead to lasting negative cognitive, physical, and mental health outcomes. The biological response to even mild TBIs (mTBI) includes well-characterized inflammatory sequelae that start immediately post-injury, remain for weeks, and can develop into long-term systemic inflammation. Studies have shown that TBI influences multiple physiological systems, including the gastrointestinal tract, through bidirectional communication modulated, in part, by the gut microbiome. Brainstem functioning post-TBI, as measured by acoustic startle sensorimotor processing, might play a role in this feedback loop. The current study investigated pre- to post-TBI (lateral fluid percussion injury model) changes in microbial communities and acoustic startle response in male and female rats. That is, the influence of mTBI on gut microbiome and sensorimotor processing was explored to examine: 1) overall and sex-specific differences in the gut microbiome and taxa in response to mTBI; 2) overall and sex-specific differences in sensorimotor processing following mTBI; and 3) associations between the gut microbiome and sensorimotor processing. Results showed mTBI had a limited effect on microbial diversity overall, and the same was observed in males and females independently. Yet, mTBI was associated with differences in 13 genus-level taxa. Further evaluation highlighted that 11 of the 13 genus-level taxa were sex-specific, with several being known to have short-chain fatty acid-producing capabilities. Alterations in sensorimotor processing were identified following mTBI; however, no sex-specific differences were evident. In addition, no associations were observed between sensorimotor processing and the gut microbiome. This study contributes longitudinal and sex-specific findings to the growing body of research examining the diverse effects of mTBI on the brain and gut microbial communities.

The COVID-19 pandemic has impacted millions of people worldwide, and recent studies have shown that SARS-CoV-2 infection can lead to an Alzheimer's-like neuropathological and biomarker phenotype, as well as clinical symptoms of "brain fog". This raises an intriguing question: "How and where might the molecular pathways underlying SARS-CoV-2 infection and Alzheimer's disease (AD) converge?" One common feature of both SARS-CoV-2 infection and AD is the alteration of the endomembrane system, particularly the fragmentation of the Golgi apparatus. In this review article, we summarize the existing literature on SARS-CoV-2 infection biology and speculate about the potential mechanisms linking Golgi defects, SARS-CoV-2 infection, and neurodegeneration.

Working memory (WM) deficits play a prominent role in schizophrenia and have been linked to aberrant frontal-parietal functional connectivity. Schizotypal personality disorder (SPD) is a schizophrenia-spectrum disorder that is biologically related to schizophrenia, but with less marked WM impairment. Comparing network dynamics during WM performance among individuals with schizophrenia-spectrum disorders could enhance our understanding of risk and resilience factors on a spectrum of illness severity. We used dynamiccausalmodeling (DCM) to identify changes in effective connectivity among the lateral-prefrontalcortex (lPFC), anterior-cingulate cortex (ACC) and parietalcortex (PC) associated with WM load during an N-back task in healthy controls (HC; N = 42), individuals with SPD (N = 28), and schizophrenia patients (N = 35). The main findings indicate that N-Back task difficulty (i.e. increasingWM load) significantly modulated connectivity between the ACC and PC, but in different directions depending on diagnostic group. In HC, WM load modulated PC-to-ACC effective connectivity, whereas in schizophrenia, WM load modulated effective connectivity in the opposite direction (i.e. ACC-to-PC). In SPD, no clear directionality emerged between ACC and PC, suggesting an intermediate or mixed pattern of connectivity. In schizophrenia, greater ACC-to-PC connectivity was associated with greater negative and positive symptom severity; a pattern that was also evident in the combined cohort of individuals with SPD and schizophrenia. These findings indicate that the normal pattern of PC-to-ACC effective connectivity modulated by WM load is abnormal in the schizophrenia spectrum which is consistent with abnormalities in processing that instigate early involvement of the ACC for conflict monitoring.

BackgroundDuring and after the 9/11 rescue and recovery efforts, World Trade Center (WTC) responders were exposed to environmental hazards that may accelerate aging and increase frailty. This study examines the relationship between polypharmacy and frailty among WTC responders to inform strategies that mitigate medication-related risks in high-risk, aging populations.MethodsWe included WTC responders aged 50 and older who attended at least one clinical monitoring visit at WTC Health Program between 2017–2019. Frailty was assessed using the WTC-specific Clinical Frailty Index, and associations with polypharmacy (concurrent use of 5 or more medications) and fall-risk increasing drugs (FRIDs) use were evaluated through multivariable logistic regression models adjusting for demographic, employment, health, and WTC exposure data.ResultsAmong 6,966 WTC responders, 55% met the criteria for polypharmacy and 7.6% used FRIDs. Frailty was independently associated with both polypharmacy (OR 1.15, p < 0.001) and FRID use (OR 1.11, p < 0.001). Older age (OR 1.08, p < 0.001), obesity (OR 1.92, p < 0.001 for BMI ≥ 30), protective service occupations (OR 1.30, p = 0.002), and chronic conditions such as gastroesophageal reflux disease (OR 1.71, p < 0.001), obstructive airway disease (OR 2.24, p < 0.001), and upper respiratory disease (OR 1.85, p < 0.001) were associated with higher odds of polypharmacy. In contrast, male sex (OR 0.81, p = 0.018) and construction occupations (OR 0.73, p = 0.001) were associated with lower odds of polypharmacy. Female sex (OR 1.64, p < 0.001), smoking (current: OR 1.55, p = 0.013; former: OR 1.30, p = 0.014), and mental health conditions such as anxiety (OR 1.66, p = 0.004), depression (OR 2.85, p < 0.001), and post-traumatic stress disorder (OR 1.72, p < 0.001) were associated with higher odds of FRID use.ConclusionsWe found a high prevalence of polypharmacy and FRID use among aging WTC responders, with frailty significantly associated with both. Our findings underscore the need to optimize medication management for aging WTC responders, which may impact their healthy aging.

Suicidal ideation (SI) and behavior are complex phenotypes, with multiple contributing risk-factors. This study used longitudinal data from the Million Veteran Program Mental Health Survey to identify SI profiles among Veterans based on trajectories of ideation and depression severity and compared them to a non-suicidal (no-SI) control group. Latent profile analysis (LPA) was performed to identify SI profiles using data from Veterans (n = 34,322) endorsing SI in their electronic health record. LPA identified four highly reproducible SI profiles: mild ideators with and without depression, variable ideators, and persistent ideators. Veterans across the SI profiles were significantly more likely to have diagnoses of suicidal ideation or behavior, mental disorders, and TBI compared to Veterans with no-SI. The variable ideators showed higher rates of comorbid conditions. The mild ideators without depression and persistent ideators had a significantly higher proportion of deaths by suicide than the no-SI Veterans. European and African American GWAS and pan-ancestry meta-analyses of SI profiles compared to no-SI controls were also performed, which identified genome-wide significant loci across all SI profiles proximal to genes implicated in auditory and vestibular functioning, Alzheimer's, diabetes, and asthma. In summary, SI profiles identified were associated with novel genetic variants not identified by previous suicide GWAS studies. Additionally, Veterans within the mild SI profile that did not present with high-risk comorbidities had the highest rate of suicide deaths, indicating the need for upstream suicide risk prevention interventions across the SI risk continuum.

Abstract World Trade Center (WTC) responders are a unique cohort whose environmental exposures place them at increased risk for earlier onset of aging-related conditions, including frailty. Detecting frailty in this group is critical for guiding interventions to support healthy aging. The WTC Clinical Frailty Index (WTC FI-Clinical) is a continuous measure constructed from 30 health items routinely collected during responder monitoring visits. We aimed to use the frailty phenotype to validate and establish a meaningful cutoff for identifying frailty using the WTC FI-Clinical. We enrolled WTC responders aged 50 and older who received annual health monitoring at Mount Sinai’s WTC Health Program (WTCHP). Frailty was measured using both the frailty phenotype and WTC FI-Clinical. ROC (Receiver Operation Characteristic) analysis, with the frailty phenotype as reference, was used to assess discrimination and identify an optimal cutoff for the WTC FI-Clinical. Among 390 responders (median age 62, IQR 57–67), the frailty phenotype classified 54.1% robust, 40.8% pre-frail, and 5.1% frail. The WTC FI-Clinical demonstrated good discrimination for frailty (AUC 0.907, 95% CI: 0.858–0.952), and ROC analysis identified an optimal cutoff of 0.237, corresponding to 85% sensitivity and 76% specificity. Using this cutoff, 27.2% were classified as frail by the WTC FI-Clinical (versus 5.1% by the phenotype). These findings support its use as a practical screening tool to identify at-risk responders and guide healthy aging interventions within the WTCHP. It also extends frailty detection beyond traditional older cohorts, offering insight into how frailty can emerge earlier in populations with unique environmental exposures.