Differential sensitivity of intraindividual variability dispersion and global cognition in the prediction of functional outcomes and mortality in precariously housed and homeless adults.

OBJECTIVE: To examine cognitive intraindividual variability (IIV) dispersion as a predictor of everyday functioning and mortality in persons who are homeless or precariously housed. METHOD: Participants were 407 community-dwelling adults, followed for up to 13 years. Neurocognition was assessed at baseline and IIV dispersion was derived using a battery of standardized tests. Functional outcomes (social, physical) were obtained at baseline and last follow-up. Mortality was confirmed with Coroner's reports and hospital records (N = 103 deaths). Linear regressions were used to predict current social and physical functioning from IIV dispersion. Repeated measures Analysis of Covariance were used to predict long-term change in functioning. Cox regression models examined the relation between IIV dispersion and mortality. Covariates included global cognition (i.e. mean-level performance), age, education, and physical comorbidities. RESULTS: Higher IIV dispersion predicted poorer current physical functioning (B = -0.46 p = .010), while higher global cognition predicted better current (B = 0.21, p = .015) and change in social functioning over a period of up to 13 years (F = 4.23, p = .040). Global cognition, but not IIV dispersion, predicted mortality in individuals under 55 years old (HR = 0.50, p = .013). CONCLUSIONS: Our findings suggest that indices of neurocognitive functioning (i.e. IIV dispersion and global cognition) may be differentially related to discrete dimensions of functional outcomes in an at-risk population. IIV dispersion may be a complimentary marker of emergent physical health dysfunction in precariously housed adults and may be best used in conjunction with traditional neuropsychological indices.

Relationship between drug-induced movement disorders and psychosis in adults living in precarious housing or homelessness.

BACKGROUND: Studies have reported positive associations between drug-induced movement disorders (DIMDs) and symptoms of psychosis in patients with schizophrenia. However, it is not clear which subtypes of symptoms are related to each other, and whether one symptom precedes another. The current report assessed both concurrent and temporal associations between DIMDs and symptoms of psychosis in a community-based sample of homeless individuals. METHODS: Participants were recruited in Vancouver, Canada. Severity of DIMDs and psychosis was rated annually, allowing for the analysis of concurrent associations between DIMDs and Positive and Negative Syndrome Scale (PANSS) five factors. A brief version of the PANSS was rated monthly using five psychotic symptoms, allowing for the analysis of their temporal associations with DIMDs. Mixed-effects linear and logistic regression models were used to assess the associations. RESULTS: 401 participants were included, mean age of 40.7 years (SD = 11.2) and 77.4% male. DIMDs and symptoms of psychosis were differentially associated with each other, in which the presence of parkinsonism was associated with greater negative symptoms, dyskinesia with disorganized symptoms, and akathisia with excited symptoms. The presence of DIMDs of any type was not associated with depressive symptoms. Regarding temporal associations, preceding delusions and unusual thought content were associated with parkinsonism, whereas dyskinesia was associated with subsequent conceptual disorganization. CONCLUSIONS: The current study found significant associations between DIMDs and symptoms of psychosis in individuals living in precarious housing or homelessness. Moreover, there were temporal associations between parkinsonism and psychotic symptoms (delusions or unusual thought content), and the presence of dyskinesia was temporally associated with higher odds of clinically relevant conceptual disorganization.

Bone resorption around the annular closure device during a postoperative follow-up of 8 years.

OBJECTIVE: Annular closure device (ACD) implantation is considered to be an effective means of preventing reherniation after microdiscectomy; however, there is an issue: the bone may resorb around the ACD. The causes of vertebral bone resorption remain unexplored; the dynamics of changes in bone resorption around the ACD have not yet been assessed or characterized. METHODS: One hundred thirty-three patients underwent ACD implantation after microdiscectomy, and 107 of them were followed up for 8 years after surgery (Oswestry, VAS). Lumbar CT scans helped characterize the bone resorption area around the ACD. RESULTS: The median of follow-up was 85 [74; 93] months (from 73 to 105 months). The prevalence of bone resorption around the ACD was up to 63.6%, and it was mainly around the polymer mesh of the ACD (70.6%). The resorbed bone volume increased with time and reached its maximum of 5.2 cm3 (12% of the vertebral body volume) once a sclerotic rim developed around the bone resorption area. No differences in VAS pain intensity or in Oswestry Disability Index were found between patients with resorption and patients without it (p > 0.05). The volume of the intervertebral disc before surgery is a predictor of bone resorption (OR = 0.79, p = 0.009): if it is less than 13.2 cm3, the risk of bone resorption increases significantly (p < 0.05). CONCLUSION: The majority of patients (up to 63.6%) with implanted ACDs have vertebral bone resorption around them. The bone resorption area around the ACD mesh increases with time to up to 12% of the vertebral body volume, with no clinical evidence, though. The formation of a sclerotic rim prevents the bone resorption area from further growth. If the volume of the intervertebral disc before surgery is less than 13.2 cm3, the risk of bone resorption increases significantly.

SETD1A variant-associated psychosis: A systematic review of the clinical literature and description of two new cases.

OBJECTIVE: SETD1A encodes a histone methyltransferase involved in various cell cycle regulatory processes. Loss-of-function SETD1A variants have been associated with numerous neurodevelopmental phenotypes, including intellectual disability and schizophrenia. While the association between rare coding variants in SETD1A and schizophrenia has achieved genome-wide significance by rare variant burden testing, only a few studies have described the psychiatric phenomenology of such individuals in detail. This systematic review and case report aims to characterize the neurodevelopmental and psychiatric phenotypes of SETD1A variant-associated schizophrenia. METHODS: A PubMed search was completed in July 2022 and updated in May 2023. Only studies that reported individuals with a SETD1A variant as well as a primary psychotic disorder were ultimately included. Additionally, another two previously unpublished cases of SETD1A variant-associated psychosis from our own sequencing cohort are described. RESULTS: The search yielded 32 articles. While 15 articles met inclusion criteria, only five provided case descriptions. In total, phenotypic information was available for 11 individuals, in addition to our own two unpublished cases. Our findings suggest that although individuals with SETD1A variant-associated schizophrenia may share a number of common features, phenotypic variability nonetheless exists. Moreover, although such individuals may exhibit numerous other neurodevelopmental features suggestive of the syndrome, their psychiatric presentations appear to be similar to those of general schizophrenia populations. CONCLUSIONS: Loss-of-function SETD1A variants may underlie the development of psychosis in a small percentage of individuals with schizophrenia. Identifying such individuals may become increasingly important, given the potential for advances in precision medicine treatment approaches.

Multilayer depressive symptom networks in adults with bodily pain living in precarious housing or homelessness.

Housing insecurity is associated with co-occurring depression and pain interfering with daily activities. Network analysis of depressive symptoms along with associated risk or protective exposures may identify potential targets for intervention in patients with co-occurring bodily pain. In a community-based sample of adults (n = 408) living in precarious housing or homelessness in Vancouver, Canada, depressive symptoms were measured by the Beck Depression Inventory; bodily pain and impact were assessed with the 36-item Short Form Health Survey. Network and bootstrap permutation analyses were used to compare depressive symptoms endorsed by Low versus Moderate-to-Severe (Mod + Pain) groups. Multilayer networks estimated the effects of risk and protective factors. The overall sample was comprised of 78% men, mean age 40.7 years, with 53% opioid use disorder and 14% major depressive disorder. The Mod + Pain group was characterized by multiple types of pain, more persistent pain, more severe depressive symptoms and a higher rate of suicidal ideation. Global network connectivity did not differ between the two pain groups. Suicidal ideation was a network hub only in the Mod + Pain group, with high centrality and a direct association with exposure to lifetime trauma. Antidepressant medications had limited impact on suicidal ideation. Guilt and increased feelings of failure represented symptoms from two other communities of network nodes, and completed the shortest pathway from trauma exposure through suicidal ideation, to the non-prescribed opioid exposure node. Interventions targeting these risk factors and symptoms could affect the progression of depression among precariously housed patients.

Rasch analysis of the beck depression inventory in a homeless and precariously housed sample.

The approach to analysis of and interpretation of findings from the Beck Depression Inventory (BDI), a self-report questionnaire, depends on sample characteristics. To extend work using conventional BDI scoring, the BDI's suitability in assessing symptom severity in a homeless and precariously housed sample was examined using Rasch analysis. Participants (n=478) recruited from an impoverished neighbourhood in Vancouver, Canada, completed the BDI. Rasch analysis using the partial credit model was done, and the structural validity, unidimensionality, and reliability of the BDI were studied. A receiver operating characteristic curve determined a Rasch cut-off score consistent with clinical depression, and Rasch scores were correlated with raw scores. Good fit to the Rasch model was observed after rescoring all items and removing Item 19 (Weight Loss), and unidimensionality and reliability were satisfactory. Item 9 (Suicidal Wishes) represented the most severe symptom. Rasch-based scores detected clinical depression with moderate sensitivity and specificity, and were positively correlated with conventional scores. The BDI in a community-based sample of homeless and precariously housed adults satisfied Rasch model expectations in a 20-item format, and is suitable for assessing symptom severity. Future research on depression in similar samples may reveal more information on using specific symptoms to determine clinical significance.

Movement disorders associated with substance use in adults living in precarious housing or homelessness.

OBJECTIVE: Many individuals living in precarious housing or homelessness have multimorbid illnesses, including substance use, psychiatric, and neurological disorders. Movement disorders (MDs) associated substance use are amongst the poorly studied subtopics of drug-induced MDs. The aim of the present study was, therefore, to determine the proportion affected and severity of different signs of MDs, as well as their associations with substance use in a community-based sample of precariously housed and homeless individuals. METHODS: Participants were recruited from an impoverished urban neighborhood and were assessed for substance dependence and self-reported substance use (alcohol, cannabis, cocaine, methamphetamine, nicotine, and opioids), as well as for the severity of signs of MDs (akathisia, dyskinesia, dystonia, and parkinsonism). Adjusted regression models were used to estimate the associations of the severity of signs with the frequency of substance use over the past 4 weeks and with the baseline diagnosis of substance dependence. RESULTS: The proportion of the sample with clinically relevant signs of MDs in any of the four categories was 18.6% (n = 401), and these participants demonstrated lower levels of functioning than those without signs. Of the different types of substance use, only methamphetamine (its frequency of use and dependence) was significantly associated with greater severity of overall signs of MDs. Frequency of methamphetamine use significantly interacted with age and sex, whereby older female participants exhibited the greatest overall severity with increased methamphetamine use. Of the different signs of MDs, methamphetamine use frequency was positively associated with the severity of trunk/limb dyskinesia and hypokinetic parkinsonism. Relative to no use, concurrent use of antipsychotics demonstrated lower severity of trunk/limb dyskinesia and greater severity of hypokinetic parkinsonism with methamphetamine use, and greater severity of dystonia with cocaine use. CONCLUSIONS: Our study found a high proportion of MDs in a relatively young sample, and their severity was consistently associated with methamphetamine use, moderated by participant demographics and antipsychotic use. These disabling sequelae represent an important and understudied neurological condition that may affect quality of life and will require further study.

Using serial position effects to investigate memory dysfunction in homeless and precariously housed persons.

Background: Homeless and precariously housed persons exhibit significant memory impairment, but the component processes underlying memory dysfunction have not been explored. We examined the serial position profile (i.e., primacy and recency effects) of verbal memory and its neuroanatomical correlates to identify the nature of memory difficulties in a large cohort of homeless and precariously housed adults. Method: The sample included 227 community-dwelling homeless and precariously housed adults. Serial position scores (primacy, middle, recency) were computed using the Hopkins Verbal Learning Test-Revised. Paired sample t-tests were used to compare percent recall from each word list region. Age-adjusted correlations assessed associations between serial position scores and other cognitive domains (attention, processing speed, executive functioning). Regression analyses were conducted to examine regional brain volumes of interest (hippocampus, entorhinal cortex, dorsolateral prefrontal cortex [DLPFC]) and their differential associations with serial position scores. Results: The serial position profile was characterized by a diminished recency effect in relation to the primacy effect. Serial position scores positively correlated with sustained attention and cognitive control. Larger hippocampal volume was associated with better primacy item recall. DLPFC volume was not associated with serial position recall after adjustment for false discovery rate. There were no associations between regional brain volumes and recency item recall. Conclusion: Our results suggest that commonly reported memory difficulties in homeless and precariously housed adults are likely secondary to a core deficit in executive control due to compromised frontal lobe functioning. These findings have implications for cognitive rehabilitation in this complex and vulnerable group.

Differential age-associated brain atrophy and white matter changes among homeless and precariously housed individuals compared with the general population.

Background: Homeless or precariously housed individuals live with poor health and experience premature mortality compared with the general population, yet little is known about age-related brain changes among these individuals. We evaluated whether MRI measures of brain structure are differentially associated with age and selected risk factors among individuals who are homeless or precariously housed compared with a general population sample. Methods: We compared T1-weighted and diffusion tensor imaging measures of brain macrostructure and white matter microstructure in a well-characterised sample of 312 precariously housed participants with a publicly available dataset of 382 participants recruited from the general population. We used piecewise and multiple linear regression to examine differential associations between MRI measures and between the samples, and to explore associations with risk factors in the precariously housed sample. Results: Compared with the general population sample, older age in the precariously housed sample was associated with more whole-brain atrophy (ß=-0.20, p=0.0029), lower whole-brain fractional anisotropy (ß=-0.32, p<0.0001) and higher whole-brain mean diffusivity (ß=0.69, p<0.0001). Several MRI measures had non-linear associations with age, with further adverse changes after age 35-40 in the precariously housed sample. History of traumatic brain injury, stimulant dependence and heroin dependence was associated with more atrophy or alterations in white matter diffusivity in the precariously housed sample. Conclusions: Older age is associated with adverse MRI measures of brain structure among homeless and precariously housed individuals compared with the general population. Education, improvements in care provision and policy may help to reduce the health disparities experienced by these individuals.

Method for the Isolation of "RNA-seq-Quality" RNA from Human Intervertebral Discs after Mortar and Pestle Homogenization.

The problem of isolating high-quality total RNA from intervertebral discs has no recognized solution yet. This is due to the extremely low content of live cells in the samples and the voluminous intercellular matrix. A variety of published protocols focused on isolating RNA from articular cartilage have recommended the use of expensive equipment, enzymatic matrix cleavage, or cell culture. In our study, we used a combination of the traditional QIAzol protocol (Qiagen, Germany) and RNEasy column purification (Qiagen, Germany) to obtain high-quality RNA from post-surgical intervertebral disc fragments. Only a mortar and a pestle were used for grinding, making our method particularly accessible. The isolated RNA with a RIN of ~7 is suitable for studying the expression profile of chondrocytes in situ. RNA-seq analysis of three samples demonstrated cell type ratios to be mostly relevant to intervertebral disc tissues, with over 70% of the chondrocytes of the three subtypes having an admixture of blood-related cells.

Na,K-ATPase Acts as a Beta-Amyloid Receptor Triggering Src Kinase Activation.

Beta-amyloid (Aß) has a dual role, both as an important factor in the pathology of Alzheimer's disease and as a regulator in brain physiology. The inhibitory effect of Aß42 oligomers on Na,K-ATPase contributes to neuronal dysfunction in Alzheimer's disease. Still, the physiological role of the monomeric form of Aß42 interaction with Na,K-ATPase remains unclear. We report that Na,K-ATPase serves as a receptor for Aß42 monomer, triggering Src kinase activation. The co-localization of Aß42 with α1- and ß1-subunits of Na,K-ATPase, and Na,K-ATPase with Src kinase in SH-SY5Y neuroblastoma cells, was observed. Treatment of cells with 100 nM Aß42 causes Src kinase activation, but does not alter Na,K-ATPase transport activity. The interaction of Aß42 with α1ß1 Na,K-ATPase isozyme leads to activation of Src kinase associated with the enzyme. Notably, prevention of Na,K-ATPase:Src kinase interaction by a specific inhibitor pNaKtide disrupts the Aß-induced Src kinase activation. Stimulatory effect of Aß42 on Src kinase was lost under hypoxic conditions, which was similar to the effect of specific Na,K-ATPase ligands, the cardiotonic steroids. Our findings identify Na,K-ATPase as a Aß42 receptor, thus opening a prospect on exploring the physiological and pathological Src kinase activation caused by Aß42 in the nervous system.

Subjective cognitive functioning, depressive symptoms, and objective cognitive functioning in people with treatment-resistant psychosis.

Introduction: Relationships between subjective cognitive functioning (SCF), objective cognitive functioning (OCF), and depressive symptoms are poorly understood in treatment-resistant psychosis (TRP). This study (a) compares SCF in TRP using positively and negatively worded scales, (b) assess these scales' accuracy, and (c) explores the association between these scales and depressive symptoms. We hypothesised that both SCF scales would be highly correlated, minimally associated with OCF, and similarly associated with depressive symptoms. Methods: Archival clinical data from 52 TRP inpatients was utilised. OCF composite scores were derived from a broad neuropsychological battery. SCF was assessed using the norm-referenced PROMIS 2.0 Cognitive Abilities (positively worded) and Concerns (negatively worded) subscales. A depressive symptom score was derived from the Positive and Negative Syndrome Scale. Results: SCF ratings were higher in patients than OCF. There was a small but significant correlation between PROMIS subscales (r = .30). Neither PROMIS subscale was associated with OCF (r = -.11, r = .01). Depressive symptoms were correlated with the positively (r = -.29) but not negatively worded scale (r = -.13). Conclusion: Individuals with TRP inaccurately rate their cognitive functioning and tend to overestimate their ability. Positively and negatively worded SCF scales associate variably with depressive symptoms, indicating they may not be used interchangeably in TRP.

Risk factors for hippocampal cavities in a marginally housed population.

Cavities in the hippocampus are morphological variants of uncertain significance. Aberrant neurodevelopment along with vascular and inflammatory etiologies have been proposed. We sought to characterize these cavities and their potential risk factors in a marginally housed population, with high rates of viral infection, addiction, and mental illness. (1) The volume of hippocampal cavities (HCavs) is greater in this highly multimorbid population compared to the general population. (2) Conventional vascular risk factors such as greater age and systolic blood pressure are associated with higher HCav volume. (3) Nonprescribed substance-related risk factors such as stimulant use or dependence, and smoking are associated with increased HCav volume independent of vascular risk factors. This is a retrospective analysis of an ongoing prospective study. We analyzed baseline data, including medical history, physical exam, psychiatric diagnosis, and MRI from a total of 375 participants. Hippocampal cavities were defined as spaces isointense to CSF on T1 MRI sequences, bounded on all sides by hippocampal tissue, with a volume of at least 1 mm3 . Risk factors were evaluated using negative binomial multiple regression. Stimulant use was reported by 87.3% of participants, with stimulant dependence diagnosed in 83.3% of participants. Prevalence of cavities was 71.6%, with a mean total bilateral HCav volume of 13.89 mm3 . On average, a 1 mmHg greater systolic blood pressure was associated with a 2.17% greater total HCav volume (95% CI = [0.57%, 3.79%], p = .0076), while each cigarette smoked per day trended toward a 2.69% greater total HCav volume (95% CI = [-0.87%, 5.54%], p = .058). A diagnosis of stimulant dependence was associated with a 95.6% greater total HCav volume (95% CI = [5.39%, 263.19%], p = .0335). Hypertension and diagnosis of stimulant dependence were associated with a greater total volume of HCav.

Infection with HIV-1 subtype D among acutely infected Ugandans is associated with higher median concentration of cytokines compared to subtype A.

Objective: The observation that HIV-1 subtype D progresses faster to disease than subtype A prompted us to examine cytokine levels early after infection within the predominant viral subtypes that circulate in Uganda and address the following research questions: (1) Do cytokine levels vary between subtypes A1 and D? (2) Do cytokine profiles correlate with disease outcomes? Methods: To address these questions, HIV-1 subtypes were determined by population sequencing of the HIV-1 pol gene and 37 plasma cytokine concentrations were evaluated using V-Plex kits on Meso Scale Discovery platform in 65 recent sero-converters. Results: HIV-1 subtype D (pol) infections exhibited significantly higher median plasma concentrations of IL-5, IL-16, IL-1α, IL-7, IL-17A, CCL11 (Eotaxin-1), CXCL10 (IP-10), CCL13 (MCP-4) and VEGF-D compared to subtype A1 (pol) infections. We also found that IL-12/23p40 and IL-1α were associated with faster CD4+T cell count decline, while bFGF was associated with maintenance of CD4+ counts above 350 cells/microliter. Conclusion: Our results suggest that increased production of cytokines in early HIV infection may trigger a disruption of the immune environment and contribute to pathogenic mechanisms underlying the accelerated disease progression seen in individuals infected with HIV-1 subtype D in Uganda.

A protocol for recruiting and analyzing the disease-oriented Russian disc degeneration study (RuDDS) biobank for functional omics studies of lumbar disc degeneration.

Lumbar intervertebral disc degeneration (DD) disease is one of the main risk factors for low back pain and a leading cause of population absenteeism and disability worldwide. Despite a variety of biological studies, lumbar DD is not yet fully understood, partially because there are only few studies that use systematic and integrative approaches. This urges the need for studies that integrate different omics (including genomics and transcriptomics) measured on samples within a single cohort. This protocol describes a disease-oriented Russian disc degeneration study (RuDDS) biobank recruitment and analyses aimed to facilitate further omics studies of lumbar DD integrating genomic, transcriptomic and glycomic data. A total of 1,100 participants aged over 18 with available lumbar MRI scans, medical histories and biological material (whole blood, plasma and intervertebral disc tissue samples from surgically treated patients) will be enrolled during the three-year period from two Russian clinical centers. Whole blood, plasma and disc tissue specimens will be used for genotyping with genome-wide SNP-arrays, glycome profiling and RNA sequencing, respectively. Omics data will be further used for a genome-wide association study of lumbar DD with in silico functional annotation, analysis of plasma glycome and lumbar DD disease interactions and transcriptomic data analysis including an investigation of differential expression patterns associated with lumbar DD disease. Statistical tests applied in each of the analyses will meet the standard criteria specific to the attributed study field. In a long term, the results of the study will expand fundamental knowledge about lumbar DD development and contribute to the elaboration of novel personalized approaches for disease prediction and therapy. Additionally to the lumbar disc degeneration study, a RuDDS cohort could be used for other genetic studies, as it will have unique omics data. Trial registration number NCT04600544.

Pain, opioid use, depressive symptoms, and mortality in adults living in precarious housing or homelessness: a longitudinal prospective study.

ABSTRACT: Pain and related consequences could contribute to comorbid illness and premature mortality in homeless and precariously housed persons. We analyzed longitudinal data from an ongoing naturalistic prospective study of a community-based sample (n = 370) to characterize risk factors and consequences of bodily pain. The aims were to describe bodily pain and associations with symptoms and psychosocial function, investigate factors that may increase or ameliorate pain, and examine the consequences of pain for symptoms, functioning, and all-cause mortality. Bodily pain severity and impact were rated with the 36-item Short Form Health Survey Bodily Pain Scale monthly over 5 years. Mixed-effects linear regression models estimated the effects of time-invariant and time-varying risk factors for pain, verified by reverse causality and multiple imputation analysis. Regression models estimated the associations between overall person-mean pain severity and subsequent functioning and suicidal ideation, and Cox proportional hazard models assessed association with all-cause mortality. Bodily pain of at least moderate severity persisted (>3 months) in 64% of participants, exceeding rates expected in the general population. Greater pain severity was associated with depressive symptom severity and month-to-month opioid use, overlaid on enduring risk associated with age, arthritis, and posttraumatic stress disorder. The frequency of prescribed and nonprescribed opioid use had nonlinear relationships with pain: intermittent use was associated with severe pain, without reverse association or change with the overdose epidemic. Greater longitudinal mean pain severity was associated with premature mortality, poorer functioning, and suicidal ideation. Considering the relationships between pain, intermittent opioid use, and depressive symptoms could improve health care for precariously housed patients.

Characterizing Traumatic Brain Injury and Its Association with Losing Stable Housing in a Community-based Sample.

OBJECTIVE: Traumatic brain injury (TBI) is increasingly recognized as a common and impactful health determinant in homeless and precariously housed populations. We sought to describe the history of TBI in a precariously housed sample and evaluate how TBI was associated with the initial loss and lifetime duration of homelessness and precarious housing. METHOD: We characterized the prevalence, mechanisms, and sex difference of lifetime TBI in a precariously housed sample. We also examined the impact of TBI severity and timing on becoming and staying homeless or precariously housed; 285 precariously housed participants completed the Brain Injury Screening Questionnaire in addition to other health assessments. RESULTS: A history of TBI was reported in 82.1% of the sample, with 64.6% reporting > 1 TBI, and 21.4% reporting a moderate or severe TBI. Assault was the most common mechanism of injury overall, and females reported significantly more traumatic brain injuries due to physical abuse than males (adjusted OR = 1.26, 95% CI = 1.14 to 1.39, P < 0.0001). The first moderate or severe TBI was significantly closer to the first experience of homelessness (b = 2.79, P = 0.003) and precarious housing (b = 2.69, P < 0.0001) than was the first mild TBI. In participants who received their first TBI prior to becoming homeless or precariously housed, traumatic brain injuries more proximal to the initial loss of stable housing were associated with a longer lifetime duration of homelessness (RR = 1.04, 95% CI = 1.02 to 1.06, P < 0.0001) and precarious housing (RR = 1.03, 95% CI = 1.01 to 1.04, P < 0.0001). CONCLUSIONS: These findings demonstrate the high prevalence of TBI in this vulnerable population, and that aspects of TBI severity and timing are associated with the loss and lifetime duration of stable housing.

Prenatal development of sympathetic innervation of the human pancreas.

BACKGROUND: The sympathetic nervous system plays an important role in the regulation of pancreatic exocrine and endocrine secretion. The results of experimental studies also demonstrate the involvement of the sympathetic nervous system in the regulation of endocrine cell differentiation and islet formation during the development of the pancreas. However, the prenatal development of sympathetic innervation of the human pancreas has not yet been studied. MATERIAL AND METHODS: Pancreatic autopsy samples from 24 human fetuses were examined using immunohistochemistry with antibodies to tyrosine hydroxylase (TH). The density, concentration, and size (width, length, perimeter and area) of the TH-positive sympathetic nerves were compared in four developmental periods: pre-fetal (8-11 weeks post conception (w.p.c.), n = 6), early fetal (13-20 gestational weeks (g.w.), n = 7), middle fetal (21-28 g.w., n = 6) and late fetal (29-40 g.w., n = 5) using morphometric methods and statistical analysis (Multiple Comparisons p values). Double immunofluorescence with antibodies to TH and either insulin or glucagon and confocal microscopy were applied to analyze the interaction between the sympathetic nerves and endocrine cells, and the co-localization of TH with hormones. RESULTS: TH-positive sympathetic nerves were detected in the fetal pancreas starting from the early stages (8 w.p.c.). The developmental dynamics of sympathetic nerves was follows: from the pre-fetal period, the amount of TH-positive nerves gradually increased and their branching occurred reaching the highest density and concentration in the middle fetal period, followed by a decrease in these parameters in the late fetal period. From the 14th g.w. onwards, thin TH-positive nerve fibers were mainly distributed in the vicinity of blood vessels and around the neurons of intrapancreatic ganglia, which is similar in adults. There were only rare TH-positive nerve fibers adjacent to acini or located at the periphery of some islets. The close interactions between the TH-positive nerve fibers and endocrine cells were observed in the neuro-insular complexes. Additionally, non-neuronal TH-containing cells were found in the pancreas of fetuses from the pre-fetal and early fetal periods. Some of these cells simultaneously contained glucagon. CONCLUSIONS: The results demonstrate that sympathetic innervation of the human pancreas, including the formation of perivascular and intraganglionic nerve plexuses, extensively develops during prenatal period, while some processes, such as the formation of sympathetic innervation of islet capillaries, may occur postnatally. Non-neuronal TH-containing cells, as well as the interactions between the sympathetic terminals and endocrine cells observed in the fetal pancreas may be necessary for endocrine pancreas development in humans.

Dynamic networks of psychotic symptoms in adults living in precarious housing or homelessness.

BACKGROUND: People living in precarious housing or homelessness have higher than expected rates of psychotic disorders, persistent psychotic symptoms, and premature mortality. Psychotic symptoms can be modeled as a complex dynamic system, allowing assessment of roles for risk factors in symptom development, persistence, and contribution to premature mortality. METHOD: The severity of delusions, conceptual disorganization, hallucinations, suspiciousness, and unusual thought content was rated monthly over 5 years in a community sample of precariously housed/homeless adults (n = 375) in Vancouver, Canada. Multilevel vector auto-regression analysis was used to construct temporal, contemporaneous, and between-person symptom networks. Network measures were compared between participants with (n = 219) or without (n = 156) history of psychotic disorder using bootstrap and permutation analyses. Relationships between network connectivity and risk factors including homelessness, trauma, and substance dependence were estimated by multiple linear regression. The contribution of network measures to premature mortality was estimated by Cox proportional hazard models. RESULTS: Delusions and unusual thought content were central symptoms in the multilevel network. Each psychotic symptom was positively reinforcing over time, an effect most pronounced in participants with a history of psychotic disorder. Global connectivity was similar between those with and without such a history. Greater connectivity between symptoms was associated with methamphetamine dependence and past trauma exposure. Auto-regressive connectivity was associated with premature mortality in participants under age 55. CONCLUSIONS: Past and current experiences contribute to the severity and dynamic relationships between psychotic symptoms. Interrupting the self-perpetuating severity of psychotic symptoms in a vulnerable group of people could contribute to reducing premature mortality.

Selective Inhibition of HDAC Class I Sensitizes Leukemia and Neuroblastoma Cells to Anticancer Drugs.

The acquired resistance of neuroblastoma (NB) and leukemia cells to anticancer therapy remains the major challenge in the treatment of patients with these diseases. Although targeted therapy, such as receptor tyrosine kinase (RTK) inhibitors, has been introduced into clinical practice, its efficacy is limited to patients harboring mutant kinases. Through the analysis of transcriptomic data of 701 leukemia and NB patient samples and cell lines, we revealed that the expression of RTK, such as KIT, FLT3, AXL, FGFR3, and NTRK1, is linked with HDAC class I. Although HDAC inhibitors have antitumor activity, they also have high whole-body toxicity. We developed a novel belinostat derivative named hydrazostat, which targets HDAC class I with limited off-target effects. We compared the toxicity of these drugs within the panel of leukemia and NB cell lines. Next, we revealed that HDAC inhibition with hydrazostat reactivates NTRK1, FGFR3, ROR2, KIT, and FLT3 expression. Based on this finding, we tested the efficacy of hydrazostat in combination with RTK inhibitor imatinib. Additionally, we show the ability of hydrazostat to enhance venetoclax-induced apoptosis. Thus, we reveal the connection between HDACs and RTK and describe a useful strategy to overcome the complications of single-agent therapies.