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Lyme disease, caused by spirochetes in the Borrelia burgdorferi sensu lato clade within the Borrelia genus, is transmitted by Ixodes ticks and is currently the most prevalent and rapidly expanding tick-borne disease in Europe and North America. We report complete genome sequences of 47 isolates that encompass all established species in this clade while highlighting the diversity of the widespread human pathogenic species B. burgdorferi . A similar set of plasmids has been maintained throughout Borrelia divergence, indicating that they are a key adaptive feature of this genus. Phylogenetic reconstruction of all sequenced Borrelia genomes revealed the original divergence of Eurasian and North American lineages and subsequent dispersals that introduced B. garinii, B. bavariensis, B. lusitaniae, B. valaisiana, and B. afzelii from East Asia to Europe and B. burgdorferi and B. finlandensis from North America to Europe. Molecular phylogenies of the universally present core replicons (chromosome and cp26 and lp54 plasmids) are highly consistent, revealing a strong clonal structure. Nonetheless, numerous inconsistencies between the genome and gene phylogenies indicate species dispersal, genetic exchanges, and rapid sequence evolution at plasmid-borne loci, including key host-interacting lipoprotein genes. While localized recombination occurs uniformly on the main chromosome at a rate comparable to mutation, lipoprotein-encoding loci are recombination hotspots on the plasmids, suggesting adaptive maintenance of recombinant alleles at loci directly interacting with the host. We conclude that within- and between-species recombination facilitates adaptive sequence evolution of host-interacting lipoprotein loci and contributes to human virulence despite a genome-wide clonal structure of its natural populations., Importance: Lyme disease (also called Lyme borreliosis in Europe), a condition caused by spirochete bacteria of the genus Borrelia , transmitted by hard-bodied Ixodes ticks, is currently the most prevalent and rapidly expanding tick-borne disease in the United States and Europe. Borrelia interspecies and intraspecies genome comparisons of Lyme disease-related bacteria are essential to reconstruct their evolutionary origins, track epidemiological spread, identify molecular mechanisms of human pathogenicity, and design molecular and ecological approaches to disease prevention, diagnosis, and treatment. These Lyme disease-associated bacteria harbor complex genomes that encode many genes that do not have homologs in other organisms and are distributed across multiple linear and circular plasmids. The functional significance of most of the plasmid-borne genes and the multipartite genome organization itself remains unknown. Here we sequenced, assembled, and analyzed whole genomes of 47 Borrelia isolates from around the world, including multiple isolates of the human pathogenic species. Our analysis elucidates the evolutionary origins, historical migration, and sources of genomic variability of these clinically important pathogens. We have developed web-based software tools (BorreliaBase.org) to facilitate dissemination and continued comparative analysis of Borrelia genomes to identify determinants of human pathogenicity., Competing Interests: The authors declare no conflict of interest.

Competing Interests: The authors have no conflicts of interest to declare.

Background: Posttraumatic stress disorder (PTSD) symptomatology and poorer pulmonary function are highly prevalent psychiatric and medical conditions. In the present study, we tested for the individual, additive, and modifying associations of PTSD symptomatology and pulmonary function with cognitive performance., Methods: In this cross-sectional study, a total of 1,401 World Trade Center (WTC) responders (mean age = 53, SD = 8 years, 92% males) participated in the study. Cogstate assessment measured cognitive performance. PTSD symptomatology was measured using the trauma-specific version of the posttraumatic stress disorder checklist (PCL-17) adapted for the WTC attacks. The 1-second forced expiratory volume and forced vital capacity (FEV1/FVC) ratio was used to measure pulmonary function. Linear regressions with cognitive performance as the outcome were conducted to assess individual, additive, and moderating associations of PTSD symptomatology and pulmonary function., Results: Higher PTSD symptomatology and poorer pulmonary function were negatively associated with cognitive performance. A 10% increase on the FEV1/FVC ratio moderated the association between PTSD symptomatology and cognition, whereby its association with cognition was stronger when PTSD symptomatology was higher (est. = 0.01, 95%CI = 0.004, 0.01, p < 0.001). When stratified by responder type, these associations persisted in trained (est. = 0.01, 95%CI = 0.01, 0.02, p < 0.001), but not in non-trained (est. = 0.004, 95% C.I. = -0.01, 0.02, p = 0.39) responders., Conclusions: In the presence of higher PTSD, better pulmonary functioning is associated with better cognitive performance. Early intervention efforts to mitigate preventable cognitive decline in high-risk populations should be studied, especially since intervention in one modality may have an impact on others., (© 2024 The Author(s). American Journal of Industrial Medicine published by Wiley Periodicals LLC.)

Background: Research into COVID-19-related cognitive decline has focused on individuals who are cognitively impaired following hospitalization for COVID-19. Our objective was to determine whether cognitive decline emerged after the onset of COVID-19 and was more pronounced in patients with postacute sequelae of SARS-CoV-2 infection (PASC)., Methods: We analyzed longitudinal cognitive data collected during a cohort study of essential workers at midlife that continued through the COVID-19 pandemic. We used longitudinal discontinuity models, a form of causal modeling, to examine the change in cognitive performance among 276 participants with COVID-19 in comparison to contemporaneously-collected information from 217 participants who did not have COVID-19. Cognitive performance across four domains was measured before and after the pandemic. Eligible study participants were those with validated COVID-19 diagnoses who were observed before having a verified COVID-19 infection who survived their initial infection, and for whom post-COVID-19 information was also available., Results: The mean age of the COVID-19 group was 56.0 ± 6.6 years old, while the control group was 58.1 ± 7.3 years old. Longitudinal models indicated a significant decline in cognitive throughput (β = -0.168, P = .001) following COVID-19, after adjustment for pre-COVID-19 functioning, demographics, and medical factors. Associations were larger in those with more severe COVID-19 and those who reported PASC. Observed changes in throughput were equivalent to 10.6 years of normal aging., Conclusion: Findings from this longitudinal causal modeling study revealed that COVID-19 and PASC appeared to cause clincially relevant cognitive deterioration., Competing Interests: We have no financial conflicts of interest to disclose., (© 2024 The Author(s).)

Background: The emergency personnel who responded to the World Trade Center (WTC) attacks endured severe occupational exposures, yet the prevalence of cognitive impairment remains unknown among WTC-exposed-FDNY-responders. The present study screened for mild and severe cognitive impairment in WTC-exposed FDNY responders using objective tests, compared prevalence rates to a cohort of non-FDNY WTC-exposed responders, and descriptively to meta-analytic estimates of MCI from global, community, and clinical populations., Methods: A sample of WTC-exposed-FDNY responders ( n = 343) was recruited to complete an extensive battery of cognitive, psychological, and physical tests. The prevalences of domain-specific impairments were estimated based on the results of norm-referenced tests, and the Montreal Cognitive Assessment (MoCA), Jak/Bondi criteria, Petersen criteria, and the National Institute on Aging and Alzheimer's Association (NIA-AA) criteria were used to diagnose MCI. NIA-AA criteria were also used to diagnose severe cognitive impairment. Generalized linear models were used to compare prevalence estimates of cognitive impairment to a large sample of WTC-exposed-non-FDNY responders from the General Responder Cohort (GRC; n = 7102) who completed the MoCA during a similar time frame., Result: Among FDNY responders under 65 years, the unadjusted prevalence of MCI varied from 52.57% to 71.37% depending on the operational definition of MCI, apart from using a conservative cut-off applied to MoCA total scores (18 < MoCA < 23), which yielded a markedly lower crude prevalence (24.31%) compared to alternative criteria. The prevalence of MCI was higher among WTC-exposed-FDNY-responders, compared to WTC-exposed-non-FDNY-GRC-responders (adjusted RR = 1.53, 95% C.I . = [1.24, 1.88], p < .001) and meta-analytic estimates from different global, community, and clinical populations. Following NIA-AA diagnostic guidelines, 4.96% of WTC-exposed-FDNY-responders met the criteria for severe impairments (95% CI = [2.91% to 7.82%]), a prevalence that remained largely unchanged after excluding responders over the age of 65 years., Discussion: There is a high prevalence of mild and severe cognitive impairment among WTC-responders highlighting the putative role of occupational/environmental and disaster-related exposures in the etiology of accelerated cognitive decline., Competing Interests: Statement of Competing Interests. The authors have no competing interests to report.

Background: The occurrence of post-traumatic stress disorder (PTSD) following a traumatic event is associated with biological differences that can represent the susceptibility to PTSD, the impact of trauma, or the sequelae of PTSD itself. These effects include differences in DNA methylation (DNAm), an important form of epigenetic gene regulation, at multiple CpG loci across the genome. Moreover, these effects can be shared or specific to both central and peripheral tissues. Here, we aim to identify blood DNAm differences associated with PTSD and characterize the underlying biological mechanisms by examining the extent to which they mirror associations across multiple brain regions., Methods: As the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup, we conducted the largest cross-sectional meta-analysis of epigenome-wide association studies (EWASs) of PTSD to date, involving 5077 participants (2156 PTSD cases and 2921 trauma-exposed controls) from 23 civilian and military studies. PTSD diagnosis assessments were harmonized following the standardized guidelines established by the PGC-PTSD Workgroup. DNAm was assayed from blood using either Illumina HumanMethylation450 or MethylationEPIC (850K) BeadChips. A common QC pipeline was applied. Within each cohort, DNA methylation was regressed on PTSD, sex (if applicable), age, blood cell proportions, and ancestry. An inverse variance-weighted meta-analysis was performed. We conducted replication analyses in tissue from multiple brain regions, neuronal nuclei, and a cellular model of prolonged stress., Results: We identified 11 CpG sites associated with PTSD in the overall meta-analysis (1.44e-09 < p < 5.30e-08), as well as 14 associated in analyses of specific strata (military vs civilian cohort, sex, and ancestry), including CpGs in AHRR and CDC42BPB . Many of these loci exhibit blood-brain correlation in methylation levels and cross-tissue associations with PTSD in multiple brain regions. Methylation at most CpGs correlated with their annotated gene expression levels., Conclusions: This study identifies 11 PTSD-associated CpGs, also leverages data from postmortem brain samples, GWAS, and genome-wide expression data to interpret the biology underlying these associations and prioritize genes whose regulation differs in those with PTSD., Competing Interests: Competing interests CYC is an employee of Biogen. NPD has served on scientific advisory boards for BioVie Pharma, Circular Genomics and Sentio Solutions for unrelated work. NRN serves as an unpaid member of the Ilumivu advisory board. SAMR receives support from the Wounded Warrior Project (WWP), Department of Veterans Affairs (VA), National Institute of Health (NIH), McCormick Foundation, Tonix Pharmaceuticals, Woodruff Foundation, and Department of Defense (DOD). Dr. Rauch receives royalties from Oxford University Press and American. KJR serves as a consultant for Acer, Bionomics, and Jazz Pharma; SABs for Sage, Boehringer Ingelheim, and Senseye. DJS has received consultancy honoraria from Discovery Vitality, Johnson & Johnson, Kanna, L’Oreal, Lundbeck, Orion, Sanofi, Servier, Takeda and Vistagen. MBS has in the past 3 years received consulting income from Acadia Pharmaceuticals, Aptinyx, atai Life Sciences, BigHealth, Biogen, Bionomics, BioXcel Therapeutics, Boehringer Ingelheim, Clexio, Delix Therapeutics, Eisai, EmpowerPharm, Engrail Therapeutics, Janssen, Jazz Pharmaceuticals, NeuroTrauma Sciences, PureTech Health, Sage Therapeutics, Sumitomo Pharma, and Roche/Genentech. MBS has stock options in Oxeia Biopharmaceuticals and EpiVario. MBS has been paid for his editorial work on Depression and Anxiety (Editor-in-Chief), Biological Psychiatry (Deputy Editor), and UpToDate (Co-Editor-in-Chief for Psychiatry). MBS has also received research support from NIH, Department of Veterans Affairs, and the Department of Defense. MBS is on the scientific advisory board for the Brain and Behavior Research Foundation and the Anxiety and Depression Association of America.

Importance: Reports suggest that the individuals who served in rescue operations following the terrorist attacks on the World Trade Center (WTC) have poorer brain health than expected., Objective: To assess the incidence of dementia before age 65 years in a prospective study of WTC responders and to compare incidence among responders with severe exposures to debris vs responders not exposed to building debris or who wore personalized protective equipment (PPE)., Design, Setting, and Participants: This prospective cohort study was conducted from November 1, 2014, to January 1, 2023, in an academic medical monitoring program available to verified WTC responders residing on Long Island, New York. Responders 60 years of age or younger without dementia at the time of their first cognitive assessment were followed up every 18 months, on average, for up to 5 years., Exposures: Exposure severity was based on responses to a detailed questionnaire of WTC exposures and exposure-related activities that included exposures to fine particulate dust and potentially neurotoxic debris, duration of work, and the use of PPE. Exposure level was divided into 5 categories ranging from low to severe., Main Outcomes and Measures: Incidence of all-cause dementia before age 65 years was the primary outcome. Dementia was diagnosed following standard guidelines relying on repeated measures of cognition., Results: Of 9891 responders, 5010 were eligible for inclusion in this study of cognitive function (median [IQR] age, 53 [48-57] years; 4573 [91.3%] male). There were 228 cases of dementia identified during 15 913.1 person-years of follow-up. Increasing WTC exposure severity was associated with incremental increases in the incidence rate of dementia per 1000 person-years (low, 2.95 [95% CI, 1.07-11.18]; mild, 12.16 [95% CI, 10.09-14.79]; moderate, 16.53 [95% CI, 13.30-20.81]; high, 30.09 [95% CI, 21.35-43.79]; and severe, 42.37 [95% CI, 24.86-78.24]). Adjusting for social, demographic, and relevant medical factors, each unit increase in exposure severity was associated with increased incidence of dementia (adjusted hazard ratio, 1.42 [95% CI, 1.18-1.71]; P < .001; mean risk difference, 9.74 [95% CI, 2.94-32.32] per 1000 person-years; P < .001)., Conclusions and Relevance: In this cohort study of WTC responders who survived these unique exposures and participated in a longitudinal follow-up study of cognition from 2014 through 2022, when compared with responders with the lowest exposure levels or responders who used PPE, more severe exposure to dust or debris was significantly associated with a higher risk of dementia before 65 years of age. This study suggests that the reliable use of PPE might help prevent the onset of dementia before age 65 years among individuals exposed to an uncontrolled building collapse. Future research is warranted to determine cerebral biomarkers for individuals with exposure-associated dementia.

Post-traumatic stress disorder (PTSD) genetics are characterized by lower discoverability than most other psychiatric disorders. The contribution to biological understanding from previous genetic studies has thus been limited. We performed a multi-ancestry meta-analysis of genome-wide association studies across 1,222,882 individuals of European ancestry (137,136 cases) and 58,051 admixed individuals with African and Native American ancestry (13,624 cases). We identified 95 genome-wide significant loci (80 new). Convergent multi-omic approaches identified 43 potential causal genes, broadly classified as neurotransmitter and ion channel synaptic modulators (for example, GRIA1, GRM8 and CACNA1E), developmental, axon guidance and transcription factors (for example, FOXP2, EFNA5 and DCC), synaptic structure and function genes (for example, PCLO, NCAM1 and PDE4B) and endocrine or immune regulators (for example, ESR1, TRAF3 and TANK). Additional top genes influence stress, immune, fear and threat-related processes, previously hypothesized to underlie PTSD neurobiology. These findings strengthen our understanding of neurobiological systems relevant to PTSD pathophysiology, while also opening new areas for investigation., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: World Trade Center (WTC) responders are susceptible to both cognitive and neuropsychiatric impairments, particularly chronic posttraumatic stress disorder. The present study examined self-reported behavioral impairments in a sample of 732 WTC responders, 199 of whom were determined to have high risk of WTC-related cortical atrophy by an artificial neural network. Results: We found that responders at increased risk of cortical atrophy showed behavioral impairment across five domains: motivation, mood, disinhibition, empathy, and psychosis (14.6% vs 3.9% in the low-risk group; P = 3.90 × 10 -7 ). Factor analysis models revealed that responders at high risk of cortical atrophy tended to have deficits generalized across all aspects of behavioral impairment with focal dysfunction in sensory psychosis. We additionally describe how relationships are modulated by exposure severity and pharmacological treatments. Discussion: Our findings suggest a potential link between sensory deficits and the development of cortical atrophy in WTC responders and may indicate symptoms consistent with a clinical portrait of parietal dominant Alzheimer's disease or a related dementia (ADRD). Results underscore the importance of investigating neuropsychiatric symptomatology in clinical evaluations of possible ADRD., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

World Trade Center (WTC) responders exposed to traumatic and environmental stressors during rescue and recovery efforts have a high prevalence of chronic WTC-related post-traumatic stress disorder (WTC-PTSD). We investigated neural mechanisms underlying WTC-PTSD by applying eigenvector centrality (EC) metrics and data-driven methods on resting state functional magnetic resonance (fMRI). We identified how EC differences relate to WTC-exposure and behavioral symptoms. We found that connectivity differentiated significantly between WTC-PTSD and non-PTSD responders in nine brain regions, as these differences allowed an effective discrimination of PTSD and non-PTSD responders based solely on analysis of resting state data. Further, we found that WTC exposure duration (months on site) moderates the association between PTSD and EC values in two of the nine brain regions; the right anterior parahippocampal gyrus and the left amygdala (p = 0.010; p = 0.005, respectively, adjusted for multiple comparisons). Within WTC-PTSD, a dimensional measure of symptom severity was positively associated with EC values in the right anterior parahippocampal gyrus and brainstem. Functional neuroimaging can provide effective tools to identify neural correlates of diagnostic and dimensional indicators of PTSD., (© 2023. The Author(s).)

Background: How sleep is impacted by stress ("sleep reactivity to stress") and how stress is impacted by sleep ("stress reactivity to sleep") are trait-like characteristics of individuals that predict depression, anxiety, and insomnia. However, pathways between reactivity and functional impairment (e.g., impairment in social relationships and interpersonal functioning) have not been explored, which may be a critical pathway in understanding the link between reactivity and the development of psychological disorders., Purpose: We examined associations between reactivity and changes in functional impairment among a cohort of 9/11 World Trade Center responders., Methods: Data from 452 responders (Mage = 55.22 years; 89.4% male) were collected between 2014 and 2016. Four baseline sleep and stress reactivity indices (i.e., sleep duration and efficiency reactivity to stress; stress reactivity to sleep duration and efficiency) were calculated from 14 days of sleep and stress data using random slopes from multilevel models. Functional impairment was assessed approximately 1 year and 2 years after baseline via semi-structured interviews. Latent change score analyses examined associations between baseline reactivity indices and changes in functional impairment., Results: Greater baseline sleep efficiency reactivity to stress was associated with decreases in functioning (β = -0.05, p = .039). In addition, greater stress reactivity to sleep duration (β = -0.08, p = .017) and sleep efficiency (β = -0.22, p < .001) was associated with lower functioning at timepoint one., Conclusion: People who are more reactive to daily fluctuations in stress and sleep have poorer interpersonal relationships and social functioning. Identifying individuals with high reactivity who could benefit from preventative treatment may foster better social integration., (© Society of Behavioral Medicine 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: The clock drawing task (CDT) is frequently used to aid in detecting cognitive impairment, but current scoring techniques are time-consuming and miss relevant features, justifying the creation of an automated quantitative scoring approach., Methods: We used computer vision methods to analyze the stored scanned images ( N  = 7,109), and an intelligent system was created to examine these files in a study of aging World Trade Center responders. Outcomes were CDT, Montreal Cognitive Assessment (MoCA) score, and incidence of mild cognitive impairment (MCI)., Results: The system accurately distinguished between previously scored CDTs in three CDT scoring categories: contour (accuracy = 92.2%), digits (accuracy = 89.1%), and clock hands (accuracy = 69.1%). The system reliably predicted MoCA score with CDT scores removed. Predictive analyses of the incidence of MCI at follow-up outperformed human-assigned CDT scores., Discussion: We created an automated scoring method using scanned and stored CDTs that provided additional information that might not be considered in human scoring., Competing Interests: No conflicts of interest to disclose., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Chronically re-experiencing the memory of a traumatic event might cause a glial response. This study examined whether glial activation would be associated with PTSD in a study of responders present after the 9/11 World Trade Center attacks without comorbid cerebrovascular disease., Methods: Plasma was retrieved from 1,520 WTC responders and stored for a cross-sectional sample of responders of varying levels of exposure and PTSD. Plasma levels (pg/ml) of glial fibrillary acidic protein (GFAP) were assayed. Because stroke and other cerebrovascular diseases cause distributional shifts in GFAP levels, multivariable-adjusted finite mixture models analyzed GFAP distributions in responders with and without possible cerebrovascular disease., Results: Responders were aged 56.3 years and primarily male; 11.07% (n = 154) had chronic PTSD. Older age was associated with increased GFAP, whereas higher body mass was associated with decreased GFAP. Multivariable-adjusted finite mixture models revealed that severe re-experiencing trauma from 9/11 was associated with lower GFAP (B = -0.558, p = 0.003)., Conclusion: This study presents evidence of reduced plasma GFAP levels among WTC responders with PTSD. Results suggest re-experiencing traumatic events might cause glial suppression., Competing Interests: This is an epidemiological study examining biomarkers associated with posttraumatic stress disorder. The authors have no conflicts of interest to disclose., (© 2023 The Authors.)

Background: Genetic factors contribute to individual differences in the severity of coronavirus disease 2019 (COVID-19). A portion of genetic predisposition can be captured using polygenic risk scores (PRS). Relatively little is known about the associations between PRS and COVID-19 severity or post-acute COVID-19 in community-dwelling individuals., Methods: Participants in this study were 983 World Trade Center responders infected for the first time with SARS-CoV-2 (mean age at infection = 56.06; 93.4% male; 82.7% European ancestry). Seventy-five (7.6%) responders were in the severe COVID-19 category; 306 (31.1%) reported at least one post-acute COVID-19 symptom at 4-week follow-up. Analyses were adjusted for population stratification and demographic covariates., Findings: The asthma PRS was associated with severe COVID-19 category (odds ratio [OR] = 1.61, 95% confidence interval: 1.17-2.21) and more severe COVID-19 symptomatology (β = .09, p = .01), independently of respiratory disease diagnosis. Severe COVID-19 category was also associated with the allergic disease PRS (OR = 1.97, [1.26-3.07]) and the PRS for COVID-19 hospitalization (OR = 1.35, [1.01-1.82]). PRS for coronary artery disease and type II diabetes were not associated with COVID-19 severity., Conclusion: Recently developed polygenic biomarkers for asthma, allergic disease, and COVID-19 hospitalization capture some of the individual differences in severity and clinical course of COVID-19 illness in a community population., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Waszczuk et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: World Trade Center (WTC) responders are experiencing a high risk of mild cognitive impairment (MCI) and dementia, though the etiology remains inadequately characterized. This study investigated whether WTC exposures and chronic post-traumatic stress disorder (PTSD) were correlated with plasma biomarkers characteristic of Alzheimer's disease (AD) neuropathology., Methods: Eligible participants included WTC-exposed individuals with a baseline cognitive assessment and available plasma sample. We examined levels of the amyloid beta (Aβ)40/42 ratio, phosphorylated tau 181 (p-tau181), and neurofilament light chain (NfL) and associations with a WTC exposures (duration on site ≥15 weeks, dust cloud), the PTSD Symptom Checklist for Diagnostic and Statistical Manual of Mental Disorders, 4th edition PTSD, and classification of amyloid/tau/neurodegeneration (AT[N]) profiles. Multinomial logistic regressions assessed whether biomarkers predicted increased risk of MCI or dementia., Results: Of 1179 eligible responders, 93.0% were male, mean (standard deviation) age 56.6 years (7.8). Aβ40/42, p-tau181, and NfL intercorrelated and increased with age. In subgroup analyses of responders with available neuroimaging data ( n = 75), Aβ40/42 and p-tau181 were further associated with decreased hippocampal volume (Spearman's  ρ = -0.3). Overall, 58.08% of responders with dementia had ≥1 elevated biomarker, and 3.45% had elevations across all biomarkers. In total, 248 (21.05%) had MCI and 70 (5.94%) had dementia. Increased risk of dementia was associated with plasma AT(N) profile T+ or A+N+. Exposure on site ≥15 weeks was independently associated with T+ (adjusted risk ratio [aRR] = 1.03 [1.01-1.05], P = 0.009), and T+N+ profile (aRR = 2.34 [1.12-4.87]). The presence of PTSD was independently associated with risk of A+ (aRR = 1.77 [1.11-2.82])., Discussion: WTC exposures and chronic PTSD are associated with plasma biomarkers consistent with neurodegenerative disease., Competing Interests: The authors declare no conflicts of interest. Author disclosures are available in the supporting information., (© 2023 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: Oral histories from 9/11 responders to the World Trade Center (WTC) attacks provide rich narratives about distress and resilience. Artificial Intelligence (AI) models promise to detect psychopathology in natural language, but they have been evaluated primarily in non-clinical settings using social media. This study sought to test the ability of AI-based language assessments to predict PTSD symptom trajectories among responders., Methods: Participants were 124 responders whose health was monitored at the Stony Brook WTC Health and Wellness Program who completed oral history interviews about their initial WTC experiences. PTSD symptom severity was measured longitudinally using the PTSD Checklist (PCL) for up to 7 years post-interview. AI-based indicators were computed for depression, anxiety, neuroticism, and extraversion along with dictionary-based measures of linguistic and interpersonal style. Linear regression and multilevel models estimated associations of AI indicators with concurrent and subsequent PTSD symptom severity (significance adjusted by false discovery rate)., Results: Cross-sectionally, greater depressive language ( β = 0.32; p = 0.049) and first-person singular usage ( β = 0.31; p = 0.049) were associated with increased symptom severity. Longitudinally, anxious language predicted future worsening in PCL scores ( β = 0.30; p = 0.049), whereas first-person plural usage ( β = -0.36; p = 0.014) and longer words usage ( β = -0.35; p = 0.014) predicted improvement., Conclusions: This is the first study to demonstrate the value of AI in understanding PTSD in a vulnerable population. Future studies should extend this application to other trauma exposures and to other demographic groups, especially under-represented minorities.

Proteomics provides an opportunity to develop biomarkers for the early detection and monitoring of post-traumatic stress disorder (PTSD). However, research to date has been limited by small sample sizes and a lack of replication. This study performed Olink Proseek Multiplex Platform profiling of 81 proteins involved in neurological processes in 936 responders to the 9/11 disaster (mean age at blood draw = 55.41 years (SD = 7.93), 94.1% white, all men). Bivariate correlations and elastic net regressions were used in a discovery subsample to identify concurrent associations between PTSD symptom severity and the profiled proteins, and to create a multiprotein composite score. In hold-out subsamples, nine bivariate associations between PTSD symptoms and differentially expressed proteins were replicated: SKR3, NCAN, BCAN, MSR1, PVR, TNFRSF21, DRAXIN, CLM6, and SCARB2 (|r| = 0.08-0.17, p < 0.05). There were three replicated bivariate associations between lifetime PTSD diagnosis and differentially expressed proteins: SKR3, SIGLEC, and CPM (OR = 1.38-1.50, p < 0.05). The multiprotein composite score retained 38 proteins, including 10/11 proteins that replicated in bivariate tests. The composite score was significantly associated with PTSD symptom severity (β = 0.27, p < 0.001) and PTSD diagnosis (OR = 1.60, 95% CI: 1.17-2.19, p = 0.003) in the hold-out subsample. Overall, these findings suggest that PTSD is characterized by altered expression of several proteins implicated in neurological processes. Replicated associations with TNFRSF21, CLM6, and PVR support the neuroinflammatory signature of PTSD. The multiprotein composite score substantially increased associations with PTSD symptom severity over individual proteins. If generalizable to other populations, the current findings may inform the development of PTSD biomarkers., (© 2023. The Author(s).)

Objective/background: Post-traumatic stress disorder (PTSD) is characterized by substantial disruptions in sleep quality, continuity, and depth. Sleep problems also may exacerbate PTSD symptom severity. Understanding how PTSD and sleep may reinforce one another is critical for informing effective treatments., Patients/methods: In a sample of 452 World Trade Center 9/11 responders (mean age = 55.22, 89.4% male, 66.1% current or former police), we examined concurrent and cross-lagged associations between PTSD symptom severity, insomnia symptoms, nightmares, and sleep quality at 3 time points ∼1 year apart. Data were analyzed using random intercept cross-lagged panel models., Results: PTSD symptom severity and sleep variables were relatively stable across time (intraclass correlation coefficients: 0.63 to 0.84). Individuals with more insomnia symptoms, more nightmares, and poorer sleep quality had greater PTSD symptom severity, on average. Within-person results revealed that greater insomnia symptoms and nightmares at Time 1 were concurrently associated with greater PTSD symptoms at Time 1. Insomnia symptoms were also concurrently associated with PTSD symptoms at Times 2 and 3, respectively. Cross-lagged and autoregressive results revealed that PTSD symptoms and nightmares predicted nightmares at the next timepoint., Conclusions: Overall, results suggest PTSD and sleep problems may be linked at the same point in time but may not always influence each other longitudinally. Further, individuals who experience more sleep disturbances on average may suffer from more debilitating PTSD. Evidence-based treatments for PTSD may consider incorporating treatment of underlying sleep disturbances and nightmares., Competing Interests: Declaration of competing interest This research was supported by the National Institute for Occupational Safety and Health (NIOSH) under Award Number U01OH011321 (PI: Roman Kotov). NIOSH had no role in the conduct of the study or preparation of the manuscript. Findings and conclusions in this article are those of the authors and do not represent official positions of NIOSH., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: There is a high incidence of cognitive impairment among World Trade Center (WTC) responders, comorbid with post-traumatic stress disorder (PTSD). Yet, it remains unknown whether genetic liability for Alzheimer's disease, PTSD, educational attainment, or for a combination of these phenotypes, is associated with cognitive impairment in this high-risk population. Similarly, whether the effects of genetic liability are comparable to PTSD and indicators of exposure severity remains unknown., Objective: In a study of 3,997 WTC responders, polygenic scores for Alzheimer's disease, PTSD, and educational attainment were used to test whether genome-wide risk for one or more of these phenotypes is associated with cognitive impairment, controlling for population stratification, while simultaneously estimating the effects of demographic factors and indicators of 9/11 exposure severity, including symptoms of PTSD., Results: Polygenic scores for Alzheimer's disease and educational attainment were significantly associated with an increase and decrease, respectively, in the hazard rate of mild cognitive impairment. The polygenic score for Alzheimer's disease was marginally associated with an increase in the hazard rate of severe cognitive impairment, but only age, exposure severity, and symptoms of PTSD were statistically significant predictors., Conclusion: These results add to the emerging evidence that many WTC responders are suffering from mild cognitive impairments that resemble symptoms of Alzheimer's disease, as genetic liability for Alzheimer's disease predicted incidence of mild cognitive impairment. However, compared to polygenic scores, effect sizes were larger for PTSD and the type of work that responders completed during rescue and recovery efforts.

Lyme disease is a multisystem disorder primarily caused by Borrelia burgdorferi sensu lato. However, B. garinii, which has been identified on islands off the coast of Newfoundland and Labrador, Canada, is a cause of Lyme disease in Eurasia. We report isolation and whole-genome nucleotide sequencing of a B. garinii isolate from a cotton mouse (Peromyscus gossypinus) in South Carolina, USA. We identified a second B. garinii isolate from the same repository. Phylogenetic analysis does not associate these isolates with the previously described isolates of B. garinii from Canada.

More than 20 years have elapsed since the September 11, 2001 (9/11) terrorist attacks on the World Trade Center (WTC), Pentagon and at Shanksville, PA. Many persons continue to suffer a variety of physical and mental health conditions following their exposures to a mixture of incompletely characterized toxicants and psychological stressors at the terrorist attack sites. Primary care and specialized clinicians should ask patients who may have been present at any of the 9/11 sites about their 9/11 exposures, especially patients with cancer, respiratory symptoms, chronic rhinosinusitis, gastroesophageal reflux disease, psychiatric symptoms, and substance use disorders. Clinicians, especially those in the NY metropolitan area, should know how to evaluate, diagnose, and treat patients with conditions that could be associated with exposure to the 9/11 attacks and its aftermath. As such, this issue of Archives contains a series of updates to clinical best practices relevant to medical conditions whose treatment is covered by the WTC Health Program. This first paper in the 14-part series describes the purpose of this series, defines the WTC Health Program and its beneficiaries, and explains how relevant Clinical Practice Guidelines were identified. This paper also reminds readers that because physical and mental health conditions are often intertwined, a coordinated approach to care usually works best and referral to health centers affiliated with the WTC Health Program may be necessary, since all such Centers offer multidisciplinary care.

Responders to the World Trade Center (WTC) attacks on 9/11/2001 inhaled toxic dust and experienced severe trauma for a prolonged period. Studies report that WTC site exposure duration is associated with peripheral inflammation and risk for developing early-onset dementia (EOD). Free Water Fraction (FWF) can serve as a biomarker for neuroinflammation by measuring in vivo movement of free water across neurons. The present case-controlled study aimed to examine associations between WTC site exposure duration as well as EOD status with increased hippocampal and cerebral neuroinflammation. Ninety-nine WTC responders (mean age of 56) were recruited between 2017 and 2019 (N = 48 with EOD and 51 cognitively unimpaired). Participants were matched on age, sex, occupation, race, education, and post-traumatic stress disorder (PTSD) status. Participants underwent neuroimaging using diffusion tensor imaging protocols for FWF extraction. Region of interest (ROI) analysis and correlational tractography explored topographical distributions of FWF associations. Apolipoprotein-e4 allele (APOEε4) status was available for most responders (N = 91). Hippocampal FWF was significantly associated with WTC site exposure duration (r = 0.30, p = 0.003), as was cerebral white matter FWF (r = 0.20, p = 0.044). ROI analysis and correlational tractography identified regions within the limbic, frontal, and temporal lobes. Hippocampal FWF and its association with WTC exposure duration were highest when the APOEε4 allele was present (r = 0.48, p = 0.039). Our findings demonstrate that prolonged WTC site exposure is associated with increased hippocampal and cerebral white matter neuroinflammation in WTC responders, possibly exacerbated by possession of the APOEε4 allele., (© 2022. The Author(s).)

Background and Objectives: Posttraumatic stress disorder (PTSD) has been linked to increased risk of cognitive dysfunction and physical functional impairment (PFI). The objective of this prospective cohort study was to examine whether PFI was associated with increased risk of incident mild cognitive impairment (MCI) among World Trade Center (WTC) responders with PTSD. We hypothesized that responders with PTSD would have an elevated risk of incident MCI and that PFI would mediate this increase., Methods: We examined responder participants in the WTC Aging Study whose baseline physical assessments were completed by May 2016-April 2017 and were followed up at least once before December 2019. Those without complete demographic, medical, or behavioral data were excluded. PFI was assessed using measures of upper body strength (maximal handgrip strength [HGS]) and lower extremity physical functioning (Short Physical Performance Battery). PTSD was rated using a diagnostic interview and symptom checklist; MCI and dementia were assessed using the Montreal Cognitive Assessment and diagnosed using the National Institute on Aging-Alzheimer's Association criteria. Group differences and longitudinal comparisons were examined. Cox proportional hazards models were evaluated from time to incident MCI and conversion to dementia. A mediation analysis examined whether PFI mediated associations between PTSD and MCI., Results: Within the sample of 2,687 WTC responders, 324 (12.06%, 95% CI = [10.83-13.29]) had lower extremity PFI. Responders with lower extremity PFI were older, had lower education and higher body mass, and were at a higher risk of pulmonary embolisms and PTSD. Responders with lower extremity PFI demonstrated lower baseline cognition and had increased hazards of MCI (multivariable-adjusted hazards ratio [aHR] = 1.55 [95% CI 1.21-1.98]); those with MCI converted to dementia more rapidly than those without PFI (2.73 [1.38-5.39] p = 0.004). In addition, each standard deviation decrease in HGS was associated with increased hazards of developing MCI (aHR = 1.35 [95% CI 1.10-1.66]). A mediation model suggested PFI played an intermediary role in the relationship between PTSD and MCI., Discussion: WTC responders with PFI demonstrated worse cognitive and behavioral outcomes, and PFI played an intermediary role in the relationship between PTSD and incident MCI, suggesting that PFI may be an early indicator of MCI in responders with PTSD. Regular monitoring of PFI should be considered among PTSD populations., (© 2022 American Academy of Neurology.)

Chronic pain is a significant public health problem and is exacerbated by stress. The World Trade Center (WTC) Disaster represents a unique stressor, and responders to the WTC disaster are at increased risk for pain and other health complaints. Therefore, there is a significant need to identify vulnerability factors for exacerbated pain experience among this high-risk population. Anxiety sensitivity (AS), defined as fear of anxiety-related sensations, is one such vulnerability factor associated with pain intensity and disability. Yet, no work has tested the predictive effects of AS on pain, limiting conclusions regarding the predictive utility and direction of associations. Therefore, the current study examined the prospective associations of AS, pain intensity, and pain interference among 452 (M age = 55.22, SD = 8.73, 89.4% male) responders to the WTC disaster completing a 2-week daily diary study. Using multi-level modeling, AS total score was positively associated with both pain intensity and pain interference, and that AS cognitive concerns, but not social or physical concerns, were associated with increased pain. These results highlight the importance of AS as a predictor of pain complaints among WTC responders and provide initial empirical evidence to support AS as a clinical target for treating pain complaints among WTC responders., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose  Incidence of early onset neurocognitive dysfunction has been reported in World Trade Center (WTC) responders. Ongoing studies are investigating the underlying etiology, as we are concerned that an underlying risk of neurodegenerative dementia may be occurring because of their stressful and neurotoxic exposures to particulate matter when they responded to the search and rescue efforts on September 11, 2001. The purpose of this study is to report preliminary results from two ongoing positron emission tomography (PET)/magnetic resonance imaging (MRI) imaging studies investigating the presence of Alzheimer's disease (AD) biomarkers, such as β-amyloid, tau, and neurodegeneration, and compare our findings to published norms. Methods  We present findings on 12 WTC responders diagnosed with either cognitive impairment (CI) or mild cognitive impairment (MCI), now at midlife, who underwent PET/MRI brain imaging as part of ongoing studies. Six responders with CI received [ 18 F] florbetaben (FBB) to detect β-amyloidosis and six separate responders with MCI received [ 18 F] flortaucipir (FTP) to detect tauopathy. All 12 responders underwent concomitant MRI scans for gray matter volume analysis of neurodegeneration. Results  PET analysis revealed 50% FBB and 50% of FTP scans were clinically read as positive and that 50% of FTP scans identified as consistent with Braak's stage I or II. Furthermore, one responder identified as centiloid positive for AD. Gray matter volumes from MRI analyses were compared with age/sex-matched norms (Neuroquant), identifying abnormally low cortical volumes in the occipital and temporal lobes, as well as the inferior temporal gyri and the entorhinal cortex. Conclusion  These preliminary results suggest that WTC responders with neurocognitive dysfunction may be at increased risk for a neurodegenerative dementia process as a result of their exposures at September 11, 2001., Competing Interests: Conflict of Interest The authors have no disclosures to report., (World Association of Radiopharmaceutical and Molecular Therapy (WARMTH). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

An elevated risk of myeloma precursor disease, monoclonal gammopathy of undetermined significance (MGUS), was identified among Fire Department of the City of New York (FDNY) World Trade Center (WTC)-exposed firefighters. Further investigation was needed to determine if these findings were reproducible in a more heterogeneous WTC-exposed rescue/recovery workers cohort, the Stony Brook University-General Responder Cohort GRC (SBU-GRC). MGUS risk was compared between the cohorts and to published general population estimates from Olmsted County, MN, USA. In this observational seroprevalence study, odds ratios (OR) and age-standardized risk ratios (RR) of MGUS (M-spike and light-chain-MGUS combined), M-spike, and light-chain-MGUS were estimated using logistic regression. Age-standardized prevalences were calculated for white males aged 50-79; RRs were estimated by comparing risk in the WTC-exposed cohort with the Olmsted County screened cohort. SBU-GRC had elevated odds of MGUS compared with FDNY (OR = 1.38; 95%CI = 1.00-1.89). The age-standardized prevalence of MGUS was 9.0/100 persons (95%CI = 7.5-10.6), over two-fold higher than the general population (RR = 2.08; 95%CI = 1.72-2.51); the age-standardized prevalence of light-chain-MGUS was 3.5-fold higher (RR = 3.54; 95%CI = 2.52-4.97). This study adds to mounting evidence supporting an association between WTC/environmental exposures and MGUS among rescue/recovery workers. Access to MGUS screenings for the entire WTC-exposed cohort could allow for treatment interventions that improve survival., (© 2022. The Author(s).)

Past psychiatric diagnoses are central to patient case formulation and prognosis. Recently, alternative classification models such as the Hierarchical Taxonomy of Psychopathology (HiTOP) proposed to assess traits to predict clinically-relevant outcomes. The current study directly compared personality traits and past diagnoses as predictors of future mental health and functioning in three independent, prospective samples. Regression analyses found that personality traits significantly predicted future first onsets of psychiatric disorders (ΔR 2 =06-.15), symptom chronicity (ΔR 2 =.03-.06), and functioning (ΔR 2 =.02-.07), beyond past and current psychiatric diagnoses. Conversely, past psychiatric diagnoses did not provide an incremental prediction of outcomes when personality traits and other concurrent predictors were already included in the model. Overall, personality traits predicted a variety of outcomes in diverse settings, beyond diagnoses. Past diagnoses were generally not informative about future outcomes when personality was considered. Together, these findings support the added value of personality traits assessment in case formulation, consistent with HiTOP model.

The individuals who served our country in the aftermath of the attacks on the World Trade Center (WTC) following the attacks of 11 September 2001 have, since then, been diagnosed with a number of conditions as a result of their exposures. In the present study, we sought to determine whether these conditions were risk factors for increased COVID-19 disease severity within a cohort of N = 1280 WTC responders with complete information on health outcomes prior to and following COVID-19 infection. We collected data on responders diagnosed with COVID-19, or had evidence of receiving positive SARS-CoV-2 polymerase chain reaction or antigen testing, or were asymptomatic but had IgG positive antibody testing. The presence of post-acute COVID-19 sequelae was measured using self-reported symptom severity scales. Analyses revealed that COVID-19 severity was associated with age, Black race, obstructive airway disease (OAD), as well as with worse self-reported depressive symptoms. Similarly, post-acute COVID-19 sequelae was associated with initial analysis for COVID-19 severity, upper respiratory disease (URD), gastroesophageal reflux disease (GERD), OAD, heart disease, and higher depressive symptoms. We conclude that increased COVID-19 illness severity and the presence of post-acute COVID-19 sequelae may be more common in WTC responders with chronic diseases than in those responders without chronic disease processes resulting from exposures at the WTC disaster.

Background: Suicidal ideation (SI) is an early risk factor for suicide among disaster responders. To date, however, no known study has examined the prevalence, and pre-, peri-, and post-disaster risk correlates of SI in World Trade Center (WTC) responders, one of the largest disaster response populations in U.S., Methods: The prevalence, and pre-, peri- and post-event correlates of SI were assessed in a population-based health monitoring cohort of 14,314 police responders and 16,389 non-traditional responders (e.g., construction workers) who engaged in response, recovery, and clean-up efforts following the 9/11/2001 terrorist attacks on the WTC. Multivariable analyses were conducted to identify correlates and individual psychiatric symptoms associated with SI in each group., Results: A total 12.5% of non-traditional and 2.2% of police WTC responders reported SI. Depression, functional impairment, alcohol use problems, and lower family support while working at the WTC site were associated with SI in both groups of responders. Symptom-level analyses revealed that three symptoms accounted for approximately half of the variance in SI for both groups-feeling bad about oneself, or that one has let down oneself or family; feeling down, depressed, or hopeless; and sense of foreshortened future (44.7% in non-traditional and 71% in police)., Limitations: Use of self-report measures and potentially limited generalizability., Conclusions: SI is prevalent in WTC disaster responders, particularly non-traditional responders. Post-9/11 psychiatric symptoms reflecting guilt, shame, hopelessness, and associated functional impairment are most strongly linked to SI, suggesting that interventions targeting these factors may help mitigate suicide risk in this population., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Metabolomics has yielded promising insights into the pathophysiology of post-traumatic stress disorder (PTSD). The current study expands understanding of the systems-level effects of metabolites by using global metabolomics and complex lipid profiling in plasma samples from 124 World Trade Center responders (56 PTSD, 68 control) on 1628 metabolites. Differential metabolomics analysis identified hexosylceramide HCER(26:1) associated with PTSD at FDR < 0.1. The multi-metabolite composite score achieved an AUC of 0.839 for PTSD versus unaffected control classification. Independent component analysis identified three metabolomic modules significantly associated with PTSD. These modules were significantly enriched in bile acid metabolism, fatty acid metabolism and pregnenolone steroids, which are involved in innate immunity, inflammatory process and neuronal excitability, respectively. Integrative analysis of metabolomics and our prior proteomics datasets on subsample of 96 responders identified seven proteomic modules significantly correlated with metabolic modules. Overall, our findings shed light on the molecular alterations and identify metabolomic-proteomic signatures associated with PTSD by using machine learning and network approaches to enhance understanding of the pathways implicated in PTSD. If present results are confirmed in follow-up studies, they may inform development of novel treatments., (© 2022. The Author(s).)

Prior research has demonstrated high levels of cognitive and physical functional impairments in World Trade Center (WTC) responders. A follow-up neuroimaging study identified changes to white matter connectivity within the cerebellum in responders with cognitive impairment (CI). In the first study to examine cerebellar cortical thickness in WTC responders with CI, we fielded a structural magnetic resonance imaging protocol. WTC responders (N = 99) participated in a structural magnetic resonance imaging (MRI) study, of whom 48 had CI. Participants with CI did not differ demographically or by intracranial volume when compared to cognitively unimpaired participants. MRIs were processed using the CERES imaging pipeline; bilateral cortical thickness in 12 cerebellar lobules was reported. Analyses were completed comparing mean cerebellar cortical thickness across groups. Lobules were examined to determine the location and functional correlates of reduced cerebellar cortical thickness. Multivariable-adjusted analyses accounted for the false discovery rate. Mean cerebellar cortical thickness was reduced by 0.17 mm in responders with CI. Decrements in cerebellar cortical thickness were symmetric and located in the Cerebellar Crus (I and II), and in Lobules IV, VI, VIIb, VIIIa, VIIIb, and IX. Cerebellar cortical thickness was associated with episodic memory, response speed, and tandem balance. WTC responders with CI had evidence of reduced cerebellar cortical thickness that was present across lobules in a pattern unique to this cohort., (© 2022. The Author(s).)

Elevations in body mass index (BMI) among World Trade Center (WTC) responders may be associated with poor mental health outcomes. The current study examined the association of BMI with anxious arousal, depressive, and insomnia symptoms among this group. Participants were 412 WTC responders (89.4% male, M age = 55.3 years, SD = 8.66) who completed health monitoring assessments (self-report and objective) as part of the Long Island site of the WTC Health Program (LI-WTC-HP). Results suggested BMI was statistically significant only in relation to anxious arousal ( sr 2 = .02, p = .008), after accounting for age and sex. The current study suggests that weight management programs may aid in promoting additional benefits for WTC responders by reducing anxious arousal symptoms as a function of reduced BMI.

Background: The World Trade Center (WTC) general responder cohort (GRC) was exposed to environmental toxins possibly associated with increased risk of developing autoimmune conditions., Objectives: Two study designs were used to assess incidence and risks of autoimmune conditions in the GRC., Methods: Three clinically trained professionals established the status of possible GRC cases of autoimmune disorders adhering to diagnostic criteria, supplemented, as needed, by specialists' review of consenting responders' medical records. Nested case-control analyses using conditional logistic regression estimated the risk associated with high WTC exposure (being in the 9/11/2001 dust cloud or ≥median days' response worked) compared with low WTC exposure (all other GRC members'). Four controls were matched to each case on age at case diagnosis (±2 years), sex, race/ethnicity, and year of program enrollment. Sex-specific and sensitivity analyses were performed. GRC age- and sex-adjusted standardized incidence ratios (SIRs) were compared with the Rochester Epidemiology Project (REP). Complete REP inpatient and outpatient medical records were reviewed by specialists. Conditions meeting standardized criteria on ≥2 visits were classified as REP confirmed cases., Results: Six hundred and twenty-eight responders were diagnosed with autoimmune conditions between 2002 and 2017. In the nested case-control analyses, high WTC exposure was not associated with autoimmune domains and conditions (rheumatologic domain odds ratio [OR] = 1.03, 95% confidence interval [CI] = 0.77, 1.37; rheumatoid arthritis OR = 1.12, 95% CI = 0.70, 1.77). GRC members had lower SIR than REP. Women's risks were generally greater than men's., Conclusions: The study found no statistically significant increased risk of autoimmune conditions with WTC exposures., (© 2021 Wiley Periodicals LLC.)

Objective: This study evaluated race/ethnic differences in the prevalence and correlates of World Trade Center (WTC) related posttraumatic stress disorder (PTSD) in WTC responders., Method: Data were analyzed from a population-based, health monitoring cohort of 15,440 nontraditional (i.e., construction workers) and 13,403 police WTC responders., Results: Among nontraditional responders, the prevalence of WTC-related PTSD was highest in Latino/a (40.4%) versus Black (27.3%) and White (26.5%) responders; among police responders, Latino/a (10.4%) responders also had higher prevalence of PTSD relative to Black (9.8%) and White (8.7%) responders. However, multivariable analyses revealed that prior psychiatric diagnosis, greater severity of WTC-related exposures, post-9/11 stressful life events, (in police responders only) older age, and (in nontraditional responders only) lower income and education levels accounted for substantially higher prevalence of WTC-related PTSD across ethnic/racial groups. Additionally, among nontraditional responders, subgroups with added risk included responders who were: Latino/a or White had high post-911 stressful events; Latino/a or Black and had pre-9/11 psychiatric history; and Latinas. Among police responders, subgroups with added risk were Latino/a or Black police with a low annual income., Conclusions: Collectively, results of this study underscore the burden of differential vulnerability that can contribute to higher prevalence of PTSD in certain cultural subgroups following large magnitude traumatic events. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

On 11 September 2001 the World Trade Center (WTC) in New York was attacked by terrorists, causing the collapse of multiple buildings including the iconic 110-story 'Twin Towers'. Thousands of people died that day from the collapse of the buildings, fires, falling from the buildings, falling debris, or other related accidents. Survivors of the attacks, those who worked in search and rescue during and after the buildings collapsed, and those working in recovery and clean-up operations were exposed to severe psychological stressors. Concurrently, these 'WTC-affected' individuals breathed and ingested a mixture of organic and particulate neurotoxins and pro-inflammogens generated as a result of the attack and building collapse. Twenty years later, researchers have documented neurocognitive and motor dysfunctions that resemble the typical features of neurodegenerative disease in some WTC responders at midlife. Cortical atrophy, which usually manifests later in life, has also been observed in this population. Evidence indicates that neurocognitive symptoms and corresponding brain atrophy are associated with both physical exposures at the WTC and chronic post-traumatic stress disorder, including regularly re-experiencing traumatic memories of the events while awake or during sleep. Despite these findings, little is understood about the long-term effects of these physical and mental exposures on the brain health of WTC-affected individuals, and the potential for neurocognitive disorders. Here, we review the existing evidence concerning neurological outcomes in WTC-affected individuals, with the aim of contextualizing this research for policymakers, researchers and clinicians and educating WTC-affected individuals and their friends and families. We conclude by providing a rationale and recommendations for monitoring the neurological health of WTC-affected individuals., (© 2021. Springer Nature Limited.)

Personality is linked to important health outcomes, but most prior studies have relied on self-reports, making it possible that shared-method variance explains the associations. The present study examined self- versus informant-reports of personality and multi-method outcomes. World Trade Center (WTC) responders and informants, 283 pairs, completed five-factor model personality measures and multi-method assessments of stressful events, functioning, mental disorders, 9/11-related treatment costs, BMI, and daily activity across three years. Self-reports were uniquely related to stressful events and functioning. Both self-reports and informant-reports showed incremental validity over one another for mental disorder diagnoses and treatment costs. For objective outcomes daily activity and BMI, informant-reports showed incremental validity over self-reports, accounting for all self-report variance and more. The findings suggest that informant-reports of personality provide better validity for objective health outcomes, which has implications for understanding personality and its role in mental and physical health.

Background: More than 8% of responders who participated in the search and rescue efforts at the World Trade Center (WTC) following 9/11 developed early-onset cognitive impairment (CI). Approximately 23% were also diagnosed with chronic post-traumatic stress disorder (PTSD)., Objective: To shed light on the pathophysiology of these WTC-related conditions, we examined diffusion connectometry to identify altered white matter tracts in WTC responders with CI and/or PTSD compared to unaffected responders., Methods: 99 WTC responders (mean age 56 years) consisting of CI-/PTSD- (n = 27), CI+/PTSD- (n = 25), CI-/PTSD+ (n = 24), and CI+/PTSD+ (n = 23) were matched on age, sex, occupation, race, and education. Cognitive status was determined using the Montreal Cognitive Assessment and PTSD status was determined using the DSM-IV SCID. Diffusion tensor imaging was acquired on a 3T Siemens Biograph mMR scanner. Connectometry analysis was used to examine whole-brain tract-level differences in white matter integrity as reflected by fractional anisotropy (FA) values after adjusting for confounders., Results: Analyses identified that FA was negatively correlated with CI and PTSD status in the fornix, cingulum, forceps minor of the corpus callosum and the right uncinate fasciculus. Furthermore, FA was negatively correlated with PTSD status, regardless of CI status in the superior thalamic radiation and the cerebellum., Conclusion: This is the first connectometry study to examine altered white matter tracts in a sample of WTC responders with CI and/or PTSD. Results from this study suggest that WTC responders with early-onset CI may be experiencing an early neurodegenerative process characterized by decreased FA in white matter tracts.

The goal of the present work was to examine clinical risk factors for mortality in 1375 COVID + patients admitted to a hospital in Suffolk County, NY. Data were collated by the hospital epidemiological service for patients admitted from 3/7/2020 to 9/1/2020. Time until final discharge or death was the outcome. Cox proportional hazards models were used to estimate time until death among admitted patients. In total, all cases had resolved leading to 207 deaths. Length of stay was significantly longer in those who died as compared to those who did not (p = 0.007). Of patients who had been discharged, 54 were readmitted and nine subsequently died. Multivariable-adjusted Cox proportional hazards regression revealed that in addition to older age, male sex, and a history of chronic heart failure, chronic obstructive pulmonary disease, and diabetes, that a history of premorbid depression was a risk factors for COVID-19 mortality (aHR = 2.42 [1.38-4.23] P = 0.002), and that this association remained after adjusting for age and for neuropsychiatric conditions as well as medical comorbidities including cardiovascular disease and pulmonary conditions. Sex-stratified analyses revealed that associations between mortality and depression was strongest in males (aHR = 4.45 [2.04-9.72], P < 0.001), and that the association between heart failure and mortality was strongest in participants aged < 65 years old (aHR = 30.50 [9.17-101.48], P < 0.001). While an increasing number of studies have identified several comorbid medical conditions including chronic heart failure and age of patient as risk factors for mortality in COVID + patients, this study confirmed several prior reports and also noted that a history of depression is an independent risk factor for COVID-19 mortality., (© 2021. The Author(s).)

Approximately 23% of World Trade Center (WTC) responders are experiencing chronic posttraumatic stress disorder (PTSD) associated with their exposures at the WTC following the terrorist attacks of 9/11/2001, which has been demonstrated to be a risk factor for cognitive impairment raising concerns regarding their brain health. Cortical complexity, as measured by analyzing Fractal Dimension (FD) from T 1 MRI brain images, has been reported to be reduced in a variety of psychiatric and neurological conditions. In this report, we hypothesized that FD would be also reduced in a case-control sample of 99 WTC responders as a result of WTC-related PTSD. The results of our surface-based morphometry cluster analysis found alterations in vertex clusters of complexity in WTC responders with PTSD, with marked reductions in regions within the frontal, parietal, and temporal cortices, in addition to whole-brain absolute bilateral and unilateral complexity. Furthermore, region of interest analysis identified that the magnitude of changes in regional FD severity was associated with increased PTSD symptoms (reexperiencing, avoidance, hyperarousal, negative affect) severity. This study confirms prior findings on FD and psychiatric disorders and extends our understanding of FD associations with posttraumatic symptom severity. The complex and traumatic experiences that led to WTC-related PTSD were associated with reductions in cortical complexity. Future work is needed to determine whether reduced cortical complexity arose prior to, or concurrently with, onset of PTSD., (© 2021. The Author(s).)

Objective: High levels of psychological distress increase the risk of a wide range of medical diseases. In this study, we investigated the association between posttraumatic stress disorder (PTSD) and kidney disease., Methods: World Trade Center (WTC) responders were included if they had two or more measures of estimated glomerular filtration rate (eGFR). The PTSD Checklist (PCL) was used to define no PTSD (PCL < 40), "mild" PTSD (40 ≤ PCL <50), and "severe" PTSD (PCL ≥50). Subtypes of PTSD by symptom clusters were analyzed. Multinomial logistic regression was used to estimate the association of PTSD with two GFR change outcomes (decline or increase) compared with the stable GFR outcome., Results: In 2266 participants, the mean age was 53.1 years, 8.2% were female, and 89.1% were White. Individuals with PTSD (n = 373; 16.5%) did not differ in mean baseline GFR from individuals without PTSD (89.73 versus 90.56 mL min-1 1.73 m-2; p = .29). During a 2.01-year mean follow-up, a mean GFR decline of -1.51 mL min-1 1.73 m-2 per year was noted. In multivariable-adjusted models, PTSD was associated with GFR decline (adjusted relative risk [aRR] = 1.74 [1.32-2.30], p < .001) compared with stable GFR, with "hyperarousal" symptoms showing the strongest association (aRR =2.11 [1.40-3.19]; p < .001). Dose-response effects were evident when comparing mild with severe PTSD and comparing PTSD with versus without depression. PTSD was also associated with GFR rise (aRR = 1.47 [1.10-1.97], p < .009). The association between PTSD and GFR change was stronger in participants older than 50 years., Conclusions: PTSD may be a novel risk factor for exaggerated longitudinal GFR change in young, healthy adults. These findings need to be validated in other cohorts., (Copyright © 2021 by the American Psychosomatic Society.)

Background: Recent research on artificial intelligence has demonstrated that natural language can be used to provide valid indicators of psychopathology. The present study examined artificial intelligence-based language predictors (ALPs) of seven trauma-related mental and physical health outcomes in responders to the World Trade Center disaster., Methods: The responders (N = 174, M age  = 55.4 years) provided daily voicemail updates over 14 days. Algorithms developed using machine learning in large social media discovery samples were applied to the voicemail transcriptions to derive ALP scores for several risk factors (depressivity, anxiousness, anger proneness, stress, and personality). Responders also completed self-report assessments of these risk factors at baseline and trauma-related mental and physical health outcomes at two-year follow-up (including symptoms of depression, posttraumatic stress disorder, sleep disturbance, respiratory problems, and GERD)., Results: Voicemail ALPs were significantly associated with a majority of the trauma-related outcomes at two-year follow-up, over and above corresponding baseline self-reports. ALPs showed significant convergence with corresponding self-report scales, but also considerable uniqueness from each other and from self-report scales., Limitations: The study has a relatively short follow-up period relative to trauma occurrence and a limited sample size., Conclusions: This study shows evidence that ALPs may provide a novel, objective, and clinically useful approach to forecasting, and may in the future help to identify individuals at risk for negative health outcomes., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: New York City and Long Island, NY were early foci of the COVID-19 epidemic in the US. The effects of COVID-19 on different sub-populations, and its key epidemiologic parameters remain unknown or highly uncertain. We investigated the epidemiology of COVID-19 from January to August of 2020 in an established academic monitoring cohort of N = 9,697 middle-aged World Trade Center responders residing in Long Island, NY., Methods: A seroprevalence survey and a series of cross-sectional surveys were nested in a prospective cohort study. Measures included IgG antibody testing, SARS-CoV-2 polymerase chain reaction (PCR) testing, review of electronic medical records, and surveys of symptoms. Correlates of infection were analyzed with multivariable logistic regression., Results: The cohort was predominantly men in their mid-fifties; 6,597 cohort members were successfully contacted (68%); 1,042 (11%) individuals participated in the seroprevalence survey; and 369 individuals (5.6% of 6,597 study participants) underwent PCR testing. The estimated standardized cumulative incidence was 21.9% (95%CI: 20.1-23.9%), the asymptomatic proportion was 16.4% (36/219; 95%CI: 11.8-22.0%), the case hospitalization ratio was 9.4% (36/385; 95%CI: 6.6-12.7%), the case fatality ratio was 1.8% (7/385; 95%CI: 0.7-3.7%), and the hospitalization fatality ratio was 8.3% (3/36; 95%CI: 1.8-22.5%). Confirmed SARS-CoV-2 infection was associated with younger age, race/ethnicity, and being currently employed., Conclusions: The results of the present study suggest a high cumulative incidence of SARS-CoV-2 among WTC responders in the spring and summer of 2020 and contribute to narrowing the plausible range of the proportion of infections that exhibit no symptoms. An increased risk of infection among younger employed individuals is likely to reflect a higher probability of exposure to the virus, and the racial disparities in the infection risk warrant further investigation., Competing Interests: The authors have declared that no competing interests exist.

Little is known about the characteristics and causes of early-onset cognitive impairment. Responders to the 2001 New York World Trade Center disaster represent an ageing population that was recently shown to have an excess prevalence of cognitive impairment. Neuroimaging and molecular data demonstrate that a subgroup of affected responders may have a unique form of parietal-dominant Alzheimer's Disease. Recent neuropsychological testing and artificial intelligence approaches have emerged as methods that can be used to identify and monitor subtypes of cognitive impairment. We utilized data from World Trade Center responders participating in a health monitoring program and applied a deep learning approach to evaluate neuropsychological and neuroimaging data to generate a cortical atrophy risk score. We examined risk factors associated with the prevalence and incidence of high risk for brain atrophy in responders who are now at midlife. Training was conducted in a randomly selected two-thirds sample ( N  = 99) enrolled using of the results of a structural neuroimaging study. Testing accuracy was estimated for each training cycle in the remaining third subsample. After training was completed, the scoring methodology that was generated was applied to longitudinal data from 1441 World Trade Center responders. The artificial neural network provided accurate classifications of these responders in both the testing (Area Under the Receiver Operating Curve, 0.91) and validation samples (Area Under the Receiver Operating Curve, 0.87). At baseline and follow-up, responders identified as having a high risk of atrophy ( n  =   378) showed poorer cognitive functioning, most notably in domains that included memory, throughput, and variability as compared to their counterparts at low risk for atrophy ( n  =   1063). Factors associated with atrophy risk included older age [adjusted hazard ratio, 1.045 (95% confidence interval = 1.027-1.065)], increased duration of exposure at the WTC site [adjusted hazard ratio, 2.815 (1.781-4.449)], and a higher prevalence of post-traumatic stress disorder [aHR, 2.072 (1.408-3.050)]. High atrophy risk was associated with an increased risk of all-cause mortality [adjusted risk ratio, 3.19 (1.13-9.00)]. In sum, the high atrophy risk group displayed higher levels of previously identified risk factors and characteristics of cognitive impairment, including advanced age, symptoms of post-traumatic stress disorder, and prolonged duration of exposure to particulate matter. Thus, this study suggests that a high risk of brain atrophy may be accurately monitored using cognitive data., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Neuroinflammation has long been theorized to arise from exposures to fine particulate matter and to be modulated when individuals experience chronic stress, both of which are also though to cause cognitive decline in part as a result of neuroinflammation., Objectives: Hypothesizing that neuroinflammation might be linked to experiences at the World Trade Center (WTC) events, this study explored associations between glial activation and neuropsychological measures including post-traumatic stress disorder (PTSD) symptom severity and WTC exposure duration., Methods: Translocator protein 18-kDa (TSPO) is overexpressed by activated glial cells, predominantly microglia and astrocytes, making TSPO distribution a putative biomarker for neuroinflammation. Twenty WTC responders completed neuropsychological assessments and in vivo PET brain scan with [ 18 F]-FEPPA. Generalized linear modeling was used to test associations between PTSD, and WTC exposure duratiioni as the predictor and both global and regional [ 18 F]-FEPPA total distribution volumes as the outcomes., Result: Responders were 56.0 ​± ​4.7 years-old, and 75% were police officers on 9/11/2001, and all had at least a high school education. Higher PTSD symptom severity was associated with global and regional elevations in [ 18 F]-FEPPA binding predominantly in the hippocampus ( d  ​= ​0.72, P  ​= ​0.001) and frontal cortex ( d  ​= ​0.64, P  ​= ​0.004). Longer exposure duration to WTC sites was associated with higher [ 18 F]-FEPPA binding in the parietal cortex., Conclusion: Findings from this study of WTC responders at midlife suggest that glial activation is associated with PTSD symptoms, and WTC exposure duration. Future investigation is needed to understand the important role of neuroinflammation in highly exposed WTC responders., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Posttraumatic stress disorder (PTSD) has been linked to increased prevalence and incidence of cognitive and physical impairment. When comorbid, these conditions may be associated with poor long-term outcomes. We examined associations between chronic PTSD and symptom domains with cognitive and physical functioning in World Trade Center (WTC) responders nearly 20 years after the September 11, 2001, terrorist attacks. Participants included a cross-sectional sample of 4,815 responders who attended a monitoring program in 2015-2018. Montreal Cognitive Assessment scores less than 23 indicated cognitive impairment (CogI); Short Physical Performance Battery scores 9 or lower on a hand-grip test indicated physical impairment (PhysI). Comorbid cognitive/physical impairment (Cog/PhysI) was defined as having cognitive impairment with at least one objective PhysI indicator. Clinical chart review provided PTSD diagnoses; symptom domains were assessed using the PTSD Checklist. Participants were on average 53.05 years (SD = 8.01); 13.44% had PTSD, 7.8% had CogI, 24.8% had PhysI, and 5.92% had comorbid Cog/PhysI. Multivariable-adjusted multinomial logistic regression demonstrated that Responders with PTSD have more than three times the risk of Cog/PhysI (adjusted RR = 3.29, 95% CI 2.44- 4.44). Domain-specific analyses revealed that emotional numbing symptoms predicted an increased risk of PhysI (adjusted RR = 1.57, 95% CI 1.08-2.28), whereas reexperiencing symptoms were associated with comorbid Cog/PhysI (adjusted RR = 3.96, 95% CI, 2.33-6.74). These results suggest that responders with chronic PTSD may have increased risk of deficits beyond age-expected impairment characterized by the emergence of comorbid Cog/PhysI at midlife., (© 2020 The Authors. Journal of Traumatic Stress published by Wiley Periodicals LLC on behalf of International Society for Traumatic Stress Studies.)

Background: Posttraumatic stress disorder (PTSD) symptoms are common in the immediate aftermath of a trauma, but it is their persistence over time that leads to a diagnosis. This pattern highlights the critical role of symptom maintenance to understanding and treating the disorder. Relatively few studies have explored whether PTSD symptoms may be interacting or triggering one another to worsen and maintain the disorder, a dynamic we refer to as "symptom cascades." Additionally, little work has tested in real-time how other maintenance factors, such as stress, contribute to such events in daily life., Methods: The present study in a group (N = 202) of World Trade Center (WTC) responders oversampled for PTSD tested day-to-day temporal associations among PTSD symptom dimensions (i.e., intrusions, avoidance, numbing, and hyperarousal) and stress across one week., Results: Longitudinal models found hyperarousal on a given day predicted increased PTSD symptoms the next day, with the effect sizes almost double compared to other symptom dimensions or daily stress. Intrusions, in contrast, showed little prospective predictive effects, but instead were most susceptible to the effects from other symptoms the day before. Avoidance and numbing showed weaker bidirectional effects., Limitations: Findings are from a unique population and based on naturalistic observation., Conclusions: Results are consistent with the idea of symptom cascades, they underscore hyperarousal's strong role in forecasting short-term increases in PTSD (even more than stress per se) and they raise the prospect of highly specific ecological momentary interventions to potentially disrupt PTSD maintenance in daily life., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Posttraumatic stress disorder (PTSD) is associated with shortened lifespan and healthspan, which suggests accelerated aging. Emerging evidence suggests that methylation age may be accelerated in PTSD. It is important to examine whether transcriptional age is also accelerated because transcriptome is highly dynamic, associated with age-related outcomes, and may offer greater insight into the premature aging in PTSD. This study is the first reported investigation of the relationship between transcriptional age and PTSD. Using RNA-Seq data from our previous study on 324 World Trade Center responders (201 never had PTSD, 81 with current PTSD, and 42 with past PTSD), as well as a transcriptional age calculator (RNAAgeCalc) recently developed by our group, we found that responders with current PTSD, compared with responders without a PTSD diagnosis, showed accelerated transcriptional aging (p = 0.0077) after adjustment for chronological age and race. We compared our results to the epigenetic aging results computed from several epigenetic clock calculators on matching DNA methylation data. GrimAge methylation age acceleration was also associated with PTSD diagnosis (p = 0.0097), and the results remained significant after adjustment for the proportions of immune cell types. PhenoAge, Hannum, and Horvath methylation age acceleration were not reliably related to PTSD. Both epigenetic and transcriptional aging may provide biological insights into the mechanisms underpinning aging in PTSD.