ABSTRACT
Working memory deficits are linked to irregularities in the dorsolateral prefrontal cortex (DLPFC) and the posterior parietal cortex (PPC) in schizophrenia, effective intervention strategies are lacking. We evaluated the differential efficacy and underlying neuromechanisms of targeting transcranial direct current stimulation (tDCS) at the DLPFC and the PPC with concurrent cognitive performance for working memory in schizophrenia. In a randomized and double-blind clinical trial, sixty clinically stable schizophrenic patients with below-average working memory were randomly assigned to active DLPFC, active PPC, and sham tDCS groups. Two sessions of tDCS during N-back task were delivered daily for five days. The primary outcome was changes in spatial span test scores from baseline to week 1. The secondary outcomes included changes in scores of color delay-estimation task, other cognitive tasks, and mismatch negativity (biomarker of N-methyl-d-aspartate receptor functioning). Compared with the active DLPFC group, the active PPC group demonstrated significantly greater improvement in spatial span test scores (p = 0.008, d = 0.94) and an augmentation in color delay-estimation task capacity at week 1; the latter sustained to week 2. Compared with the sham tDCS group, the active PPC group did not show a significant improvement in spatial span test scores at week 1 and 2; however, significant enhancement was observed in their color delay-estimation task capacity at week 2. Additionally, mismatch negativity amplitude was enhanced, and changes in theta band measures were positively correlated with working memory improvement in the active PPC group, while no such correlations were observed in the active DLPFC group or the sham tDCS group. Our results suggest that tDCS targeting the PPC relative to the DLPFC during concurrent cognitive performance may improve working memory in schizophrenia, meriting further investigation. The improvement in working memory appears to be linked to enhanced N-methyl-d-aspartate receptor functioning.
Subject(s)
Memory, Short-Term , Parietal Lobe , Prefrontal Cortex , Schizophrenia , Transcranial Direct Current Stimulation , Humans , Memory, Short-Term/physiology , Transcranial Direct Current Stimulation/methods , Schizophrenia/therapy , Schizophrenia/physiopathology , Male , Female , Adult , Double-Blind Method , Parietal Lobe/physiopathology , Prefrontal Cortex/physiopathology , Dorsolateral Prefrontal Cortex/physiology , Middle Aged , Treatment Outcome , Cognition/physiology , Young Adult , Neuropsychological TestsABSTRACT
Single-cell RNA-seq (scRNA-seq) is widely used for transcriptome profiling, but most analyses focus on gene-level events, with less attention devoted to alternative splicing. Here, we present scASfind, a novel computational method to allow for quantitative analysis of cell type-specific splicing events using full-length scRNA-seq data. ScASfind utilizes an efficient data structure to store the percent spliced-in value for each splicing event. This makes it possible to exhaustively search for patterns among all differential splicing events, allowing us to identify marker events, mutually exclusive events, and events involving large blocks of exons that are specific to one or more cell types.
Subject(s)
Alternative Splicing , Single-Cell Analysis , Single-Cell Analysis/methods , RNA-Seq/methods , Humans , Software , Sequence Analysis, RNA/methods , Data Mining , Gene Expression Profiling/methods , Exons , Animals , Computational Biology/methods , Single-Cell Gene Expression AnalysisABSTRACT
PURPOSE OF REVIEW: Higher degrees of myopia are currently being treated with refractive surgery. However, there is limited characterization and outcomes data for this cohort. This article aims to review the literature on highly myopic patients who had refractive surgery and present a retrospective analysis of 149 patients (270 eyes) with high to extreme myopia (≤-5.0D SE) who underwent refractive surgery [laser-assisted subepithelial keratomileusis (LASIK), photorefractive keratectomy (PRK), or implantable collamer lense (ICL)] at a single practice. RECENT FINDINGS: There is substantial literature on the efficacy of LASIK, PRK, and phakic intraocular lenses for refractive error correction, but a dearth of studies on patients with high to extreme myopia undergoing different types of refractive surgery. Our study reveals that this cohort of patients has excellent outcomes with minimal complications. SUMMARY: Our study reveals that the average preoperative myopia was highest in ICL patients (-10.03D), followed by PRK (-7.21D), and LASIK (-7.04D) patients. Not surprisingly, eyes with high myopia and thin corneas were offered and elected ICLs for their procedure. Highly myopic patients achieved outcomes consistent with data reported in the literature- average postoperative uncorrected visual acuity was 20/20 for LASIK and ICL eyes and 20/25 for PRK eyes.
Subject(s)
Photorefractive Keratectomy , Visual Acuity , Humans , Visual Acuity/physiology , Treatment Outcome , Photorefractive Keratectomy/methods , Lens Implantation, Intraocular/methods , Keratomileusis, Laser In Situ/methods , Refraction, Ocular/physiology , Retrospective Studies , Myopia, Degenerative/surgery , Myopia, Degenerative/physiopathology , Myopia/surgery , Myopia/physiopathology , Phakic Intraocular Lenses , Adult , Male , FemaleABSTRACT
BACKGROUND: Regulation of transcription is central to the emergence of new cell types during development, and it often involves activation of genes via proximal and distal regulatory regions. The activity of regulatory elements is determined by transcription factors (TFs) and epigenetic marks, but despite extensive mapping of such patterns, the extraction of regulatory principles remains challenging. RESULTS: Here we study differentially and similarly expressed genes along with their associated epigenomic profiles, chromatin accessibility and DNA methylation, during lineage specification at gastrulation in mice. Comparison of the three lineages allows us to identify genomic and epigenomic features that distinguish the two classes of genes. We show that differentially expressed genes are primarily regulated by distal elements, while similarly expressed genes are controlled by proximal housekeeping regulatory programs. Differentially expressed genes are relatively isolated within topologically associated domains, while similarly expressed genes tend to be located in gene clusters. Transcription of differentially expressed genes is associated with differentially open chromatin at distal elements including enhancers, while that of similarly expressed genes is associated with ubiquitously accessible chromatin at promoters. CONCLUSION: Based on these associations of (linearly) distal genes' transcription start sites (TSSs) and putative enhancers for developmental genes, our findings allow us to link putative enhancers to their target promoters and to infer lineage-specific repertoires of putative driver transcription factors, within which we define subgroups of pioneers and co-operators.
Subject(s)
Epigenomics , Genes, Essential , Animals , Mice , Chromatin/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Gene Expression ProfilingABSTRACT
BACKGROUND: Acute neurological manifestation is a common complication of acute Coronavirus Disease 2019 (COVID-19) disease. This retrospective cohort study investigated the 3-year outcomes of patients with and without significant neurological manifestations during initial COVID-19 hospitalization. METHODS AND FINDINGS: Patients hospitalized for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection between 03/01/2020 and 4/16/2020 in the Montefiore Health System in the Bronx, an epicenter of the early pandemic, were included. Follow-up data was captured up to 01/23/2023 (3 years post-COVID-19). This cohort consisted of 414 patients with COVID-19 with significant neurological manifestations and 1,199 propensity-matched patients (for age and COVID-19 severity score) with COVID-19 without neurological manifestations. Neurological involvement during the acute phase included acute stroke, new or recrudescent seizures, anatomic brain lesions, presence of altered mentation with evidence for impaired cognition or arousal, and neuro-COVID-19 complex (headache, anosmia, ageusia, chemesthesis, vertigo, presyncope, paresthesias, cranial nerve abnormalities, ataxia, dysautonomia, and skeletal muscle injury with normal orientation and arousal signs). There were no significant group differences in female sex composition (44.93% versus 48.21%, p = 0.249), ICU and IMV status, white, not Hispanic (6.52% versus 7.84%, p = 0.380), and Hispanic (33.57% versus 38.20%, p = 0.093), except black non-Hispanic (42.51% versus 36.03%, p = 0.019). Primary outcomes were mortality, stroke, heart attack, major adverse cardiovascular events (MACE), reinfection, and hospital readmission post-discharge. Secondary outcomes were neuroimaging findings (hemorrhage, active and prior stroke, mass effect, microhemorrhages, white matter changes, microvascular disease (MVD), and volume loss). More patients in the neurological cohort were discharged to acute rehabilitation (10.39% versus 3.34%, p < 0.001) or skilled nursing facilities (35.75% versus 25.35%, p < 0.001) and fewer to home (50.24% versus 66.64%, p < 0.001) than matched controls. Incidence of readmission for any reason (65.70% versus 60.72%, p = 0.036), stroke (6.28% versus 2.34%, p < 0.001), and MACE (20.53% versus 16.51%, p = 0.032) was higher in the neurological cohort post-discharge. Per Kaplan-Meier univariate survival curve analysis, such patients in the neurological cohort were more likely to die post-discharge compared to controls (hazard ratio: 2.346, (95% confidence interval (CI) [1.586, 3.470]; p < 0.001)). Across both cohorts, the major causes of death post-discharge were heart disease (13.79% neurological, 15.38% control), sepsis (8.63%, 17.58%), influenza and pneumonia (13.79%, 9.89%), COVID-19 (10.34%, 7.69%), and acute respiratory distress syndrome (ARDS) (10.34%, 6.59%). Factors associated with mortality after leaving the hospital involved the neurological cohort (odds ratio (OR): 1.802 (95% CI [1.237, 2.608]; p = 0.002)), discharge disposition (OR: 1.508 (95% CI [1.276, 1.775]; p < 0.001)), congestive heart failure (OR: 2.281 (95% CI [1.429, 3.593]; p < 0.001)), higher COVID-19 severity score (OR: 1.177 (95% CI [1.062, 1.304]; p = 0.002)), and older age (OR: 1.027 (95% CI [1.010, 1.044]; p = 0.002)). There were no group differences in radiological findings, except that the neurological cohort showed significantly more age-adjusted brain volume loss (p = 0.045) than controls. The study's patient cohort was limited to patients infected with COVID-19 during the first wave of the pandemic, when hospitals were overburdened, vaccines were not yet available, and treatments were limited. Patient profiles might differ when interrogating subsequent waves. CONCLUSIONS: Patients with COVID-19 with neurological manifestations had worse long-term outcomes compared to matched controls. These findings raise awareness and the need for closer monitoring and timely interventions for patients with COVID-19 with neurological manifestations, as their disease course involving initial neurological manifestations is associated with enhanced morbidity and mortality.
Subject(s)
COVID-19 , Stroke , Humans , Female , COVID-19/complications , COVID-19/epidemiology , COVID-19/therapy , SARS-CoV-2 , Retrospective Studies , Follow-Up Studies , Aftercare , Patient Discharge , Seizures , Stroke/epidemiologyABSTRACT
Recent innovations in single-cell RNA-sequencing (scRNA-seq) provide the technology to investigate biological questions at cellular resolution. Pooling cells from multiple individuals has become a common strategy, and droplets can subsequently be assigned to a specific individual by leveraging their inherent genetic differences. An implicit challenge with scRNA-seq is the occurrence of doublets-droplets containing two or more cells. We develop Demuxafy, a framework to enhance donor assignment and doublet removal through the consensus intersection of multiple demultiplexing and doublet detecting methods. Demuxafy significantly improves droplet assignment by separating singlets from doublets and classifying the correct individual.
Subject(s)
Single-Cell Analysis , Humans , Single-Cell Analysis/methods , Sequence Analysis, RNA/methodsABSTRACT
INTRODUCTION: This study examined the psychological wellbeing of Healthcare Workers (HCWs) during COVID-19 in a mental health setting, associations of psychosocial wellbeing with coping style, and ways that organisations can mitigate the psychosocial burden on HCWs. METHODS: Thirty-seven Mental HCWs (MHCWs) from infected and non-infected wards (control group), were recruited and assessed at three timepoints. Psychological wellbeing, perceived cohesion, and coping style (Brief-COPE) were assessed. Reports on individual coping and feedback on the organisation were collected through in-depth interview. Comparison between infected and non-infected wards, as well as comparison of psychosocial measures and perceived cohesion, across the three timepoints were made. As there were no significant changes in coping styles across the timepoints, Timepoint 1 (T1) coping style was used to correlate with the psychosocial measures across all timepoints. Thematic analysis was used for qualitative data. RESULTS: MHCWs from infected wards reported significantly higher levels of stress, χ2(1) = 6.74, p = 0.009, effect size: medium (ε2 = 0.198), and more severe sleep disturbance (PSQI), χ2(1) = 6.20, p = 0.013, effect size: medium (ε2 = 0.182), as compared to the control group at T2. They also engaged in more problem-focused coping (T2 and T3) and emotion-focused coping (T2). As expected, negative coping style was correlated with negative outcomes except problem-focused coping that was correlated with both negative (sleep disturbance and anxiety symptoms) and positive outcomes (wellbeing). Emotion-focused coping was moderately correlated (Tb = 0.348, p<0.017) with higher levels of wellbeing at T2. Thematic analyses revealed MHCWs felt supported by the responsiveness of the institution, emotional and informational support, and the availability from direct leaders, presence of team and hospital leaders on the ground, helped build trust and confidence in the leadership. CONCLUSIONS: MHCWs experienced significantly higher levels of stress and sleep disturbance during COVID-19. The ways that organizations can offset the psychological burden of pandemics on MHCWs are discussed.
Subject(s)
COVID-19 , Humans , COVID-19/epidemiology , Mental Health , Adaptation, Psychological , Psychological Well-Being , Stress, Psychological/psychology , Health Personnel/psychologyABSTRACT
Machine learning approaches using structural magnetic resonance imaging (sMRI) can be informative for disease classification, although their ability to predict psychosis is largely unknown. We created a model with individuals at CHR who developed psychosis later (CHR-PS+) from healthy controls (HCs) that can differentiate each other. We also evaluated whether we could distinguish CHR-PS+ individuals from those who did not develop psychosis later (CHR-PS-) and those with uncertain follow-up status (CHR-UNK). T1-weighted structural brain MRI scans from 1165 individuals at CHR (CHR-PS+, n = 144; CHR-PS-, n = 793; and CHR-UNK, n = 228), and 1029 HCs, were obtained from 21 sites. We used ComBat to harmonize measures of subcortical volume, cortical thickness and surface area data and corrected for non-linear effects of age and sex using a general additive model. CHR-PS+ (n = 120) and HC (n = 799) data from 20 sites served as a training dataset, which we used to build a classifier. The remaining samples were used external validation datasets to evaluate classifier performance (test, independent confirmatory, and independent group [CHR-PS- and CHR-UNK] datasets). The accuracy of the classifier on the training and independent confirmatory datasets was 85% and 73% respectively. Regional cortical surface area measures-including those from the right superior frontal, right superior temporal, and bilateral insular cortices strongly contributed to classifying CHR-PS+ from HC. CHR-PS- and CHR-UNK individuals were more likely to be classified as HC compared to CHR-PS+ (classification rate to HC: CHR-PS+, 30%; CHR-PS-, 73%; CHR-UNK, 80%). We used multisite sMRI to train a classifier to predict psychosis onset in CHR individuals, and it showed promise predicting CHR-PS+ in an independent sample. The results suggest that when considering adolescent brain development, baseline MRI scans for CHR individuals may be helpful to identify their prognosis. Future prospective studies are required about whether the classifier could be actually helpful in the clinical settings.
Subject(s)
Brain , Machine Learning , Magnetic Resonance Imaging , Neuroimaging , Psychotic Disorders , Humans , Psychotic Disorders/pathology , Psychotic Disorders/diagnostic imaging , Magnetic Resonance Imaging/methods , Male , Female , Brain/pathology , Brain/diagnostic imaging , Neuroimaging/methods , Adult , Young Adult , Adolescent , Prodromal SymptomsABSTRACT
OBJECTIVE: Lower white matter integrity of frontal-subcortical circuitry has been associated with late-life depression in normally aging older adults and with the presence of multiple sclerosis (MS). Frontal-striatal white matter tracts involved in executive, cognitive, emotion, and motor function may underlie depression in older adults with MS. The present study examined the association between depression score and frontal-striatal white matter integrity in older adults with MS and controls. METHODS: Older adults with MS (OAMS) (n = 67, mean age = 64.55 ± 3.89) and controls (n = 74, mean age = 69.04 ± 6.32) underwent brain MRI, cognitive assessment, psychological, and motoric testing. Depression was assessed through the 30-item Geriatric Depression Scale. Fractional anisotropy (FA) was extracted from two bilateral tracts: dorsolateral prefrontal cortex to putamen nucleus (DLPFC-pn) and dorsolateral prefrontal cortex to caudate nucleus (DLPFC-cn). RESULTS: OAMS reported significantly worse (i.e., higher) depression symptoms (ß = .357, p < .001) compared to healthy controls. Adjusted moderation analyses revealed, via group by FA interactions, significantly stronger associations between FA of the left DLPFC-pn tract and total depression (B = - 61.70, p = .011) among OAMS compared to controls. Conditional effects revealed that lower FA of the left DLPFC-pn was significantly associated with worse (i.e., higher) depression symptoms (b = - 38.0, p = .028) only among OAMS. The other three tracts were not significant in moderation models. CONCLUSIONS: We provided first evidence that lower white matter integrity of the left DLPFC-pn tract was related to worse depression in older adults with MS.
Subject(s)
Depression , Multiple Sclerosis , White Matter , Humans , Male , Aged , Female , Depression/diagnostic imaging , Depression/pathology , Middle Aged , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/pathology , Multiple Sclerosis/complications , White Matter/diagnostic imaging , White Matter/pathology , Diffusion Tensor Imaging , Corpus Striatum/diagnostic imaging , Corpus Striatum/pathology , Neural Pathways/diagnostic imaging , Neural Pathways/pathology , Magnetic Resonance ImagingABSTRACT
BACKGROUND: Outpatient plastic surgery at office-based surgery facilities (OBSFs) and ambulatory surgery centers (ASCs) has become increasingly prevalent over the past 30 years. Importantly, historical data are inconsistent regarding the safety outcomes of these venues, with advocates for both citing supporting studies. This investigation's purpose is to provide a more definitive comparative evaluation of outcomes and safety for outpatient surgery performed in these facilities. METHODS: The most common outpatient procedures were identified using the Tracking Operations and Outcomes for Plastic Surgeons database between 2008 and 2016. Outcomes were analyzed for OBSFs and ASCs. Patient and perioperative information was also analyzed using regression analysis to identify risk factors for complications. RESULTS: A total of 286,826 procedures were evaluated, of which 43.8% were performed at ASCs and 56.2% at OBSFs. Most patients were healthy, middle-aged women categorized as American Society of Anesthesiologists class I. The incidence of adverse events was 5.7%, and most commonly included antibiotic requirement (1.4%), dehiscence (1.3%), or seroma requiring drainage (1.1%). Overall, there was no significant difference in adverse events between ASCs and OBSFs. Age, American Society of Anesthesiologists class, body mass index, diabetes, smoking history, general anesthesia, certified registered nurse anesthetist involvement, operative duration, noncosmetic indications, and body region were associated with adverse events. CONCLUSIONS: This study provides an extensive analysis of common plastic surgery procedures performed in an outpatient setting in a representative population. With appropriate patient selection, procedures are safely performed by board-certified plastic surgeons in ambulatory surgery centers and office-based settings, as evidenced by the low incidence of complications in both environments. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.
Subject(s)
Plastic Surgery Procedures , Surgery, Plastic , Middle Aged , Humans , Female , Ambulatory Surgical Procedures/adverse effects , Ambulatory Surgical Procedures/methods , Outpatients , Retrospective StudiesABSTRACT
Importance: The lack of robust neuroanatomical markers of psychosis risk has been traditionally attributed to heterogeneity. A complementary hypothesis is that variation in neuroanatomical measures in individuals at psychosis risk may be nested within the range observed in healthy individuals. Objective: To quantify deviations from the normative range of neuroanatomical variation in individuals at clinical high risk for psychosis (CHR-P) and evaluate their overlap with healthy variation and their association with positive symptoms, cognition, and conversion to a psychotic disorder. Design, Setting, and Participants: This case-control study used clinical-, IQ-, and neuroimaging software (FreeSurfer)-derived regional measures of cortical thickness (CT), cortical surface area (SA), and subcortical volume (SV) from 1340 individuals with CHR-P and 1237 healthy individuals pooled from 29 international sites participating in the Enhancing Neuroimaging Genetics Through Meta-analysis (ENIGMA) Clinical High Risk for Psychosis Working Group. Healthy individuals and individuals with CHR-P were matched on age and sex within each recruitment site. Data were analyzed between September 1, 2021, and November 30, 2022. Main Outcomes and Measures: For each regional morphometric measure, deviation scores were computed as z scores indexing the degree of deviation from their normative means from a healthy reference population. Average deviation scores (ADS) were also calculated for regional CT, SA, and SV measures and globally across all measures. Regression analyses quantified the association of deviation scores with clinical severity and cognition, and 2-proportion z tests identified case-control differences in the proportion of individuals with infranormal (z < -1.96) or supranormal (z > 1.96) scores. Results: Among 1340 individuals with CHR-P, 709 (52.91%) were male, and the mean (SD) age was 20.75 (4.74) years. Among 1237 healthy individuals, 684 (55.30%) were male, and the mean (SD) age was 22.32 (4.95) years. Individuals with CHR-P and healthy individuals overlapped in the distributions of the observed values, regional z scores, and all ADS values. For any given region, the proportion of individuals with CHR-P who had infranormal or supranormal values was low (up to 153 individuals [<11.42%]) and similar to that of healthy individuals (<115 individuals [<9.30%]). Individuals with CHR-P who converted to a psychotic disorder had a higher percentage of infranormal values in temporal regions compared with those who did not convert (7.01% vs 1.38%) and healthy individuals (5.10% vs 0.89%). In the CHR-P group, only the ADS SA was associated with positive symptoms (ß = -0.08; 95% CI, -0.13 to -0.02; P = .02 for false discovery rate) and IQ (ß = 0.09; 95% CI, 0.02-0.15; P = .02 for false discovery rate). Conclusions and Relevance: In this case-control study, findings suggest that macroscale neuromorphometric measures may not provide an adequate explanation of psychosis risk.
Subject(s)
Psychotic Disorders , Humans , Male , Young Adult , Adult , Female , Case-Control Studies , Psychotic Disorders/diagnostic imaging , Brain/diagnostic imaging , Neuroimaging , Cognition , Prodromal SymptomsABSTRACT
OBJECTIVE: Stroke has a major impact on a person's life. While much research exists on stroke prevention and treatment, explorations into psychosocial recovery needs are lacking. This review critically consolidates the challenges and needs of stroke survivors and develops a trajectory that encapsulates their journey from illness to recovery. DATA SOURCES: Six major databases were searched, including Academic Search Premier, CINAHL, Global Health, Medline, PsycArticles, and PsycINFO. METHODS: This review adhered to the PRISMA guidelines and employed the PICo (population, phenomena of interest, context) framework to screen for relevant qualitative reviews published between 1 January 2010 and 31 August 2023. Following full-text screening and the assessment of methodological quality using a modified version of the Assessment of Multiple Systematic Reviews scale, a total of 17 reviews were included for thematic synthesis. RESULTS: Included reviews referenced 400 qualitative primary studies involving more than 5623 stroke survivors. Data synthesis revealed 18 themes that were further organized into six conceptual categories: (1) The unfamiliar body, (2) compassionate healthcare system, (3) holistic rehabilitation, (4) intrapersonal strength, (5) interpersonal relations, and (6) thriving forward to form the psychosocial rehabilitation trajectory of stroke survivor (PReTS) model. The model recognizes the losses that can occur after a stroke and emphasizes the essentiality of addressing psycho-socio-emotional and spiritual needs alongside physical impairments. CONCLUSION: The PReTS model is the first to highlight stroke survivors' losses, recovery journeys, and psychosocial needs. The conceptualization serves to inform and advance stroke rehabilitation practices with holistic and wellness recovery research.
Subject(s)
Psychiatric Rehabilitation , Stroke Rehabilitation , Stroke , Humans , Systematic Reviews as Topic , Stroke/diagnosis , Stroke/psychology , Qualitative Research , Survivors/psychologyABSTRACT
The quality of carbohydrates has metabolic consequences in people with prediabetes. However, the causality of short-chain fermentable carbohydrate intakes and metabolic parameters has not been explored in the prediabetic or diabetic population. We investigated associations between different types of carbohydrates, including fermentable oligosaccharides, disaccharides, monosaccharides, polyols (FODMAPs), and polysaccharides (dietary fibre), and body composition and glucose/insulin responses in subjects with prediabetes. In this prospective cross-sectional study, 177 subjects with impaired glucose tolerance (IGT) (mean age: 60 (54-62) years, 41% men) underwent an assessment of body composition and completed six-point oral glucose tolerance tests (OGTT), Homeostatic Model Assessment of Insulin Resistance (HOMA2-IR), insulin sensitivity, detailed 3-day food records, and physical activity questionnaire. Daily habitual FODMAP intake decreased progressively with increasing BMI, ranging from 7.9 (6.2-12.7) g/d in subjects with normal BMI and 6.6 (4.6-9.9) g/d in subjects with overweight to 5.8 (3.8-9.0) g/d in subjects with obesity (p = 0.038). After adjustment for age and gender, galactooligosaccharides (GOSs) were negatively correlated with body fat (Standardised Beta coefficient ß = -0.156, p = 0.006) and positively associated with insulin sensitivity (ß = 0.243, p = 0.001). This remained significant after adjustment for macronutrients, fibre, and physical activity (p = 0.035 and p = 0.010, respectively). In individuals with IGT, higher dietary GOS intake was associated with lower body fat and higher insulin sensitivity independent of macronutrients and fibre intake, calling for interventional studies to evaluate the effect of FODMAP intake in prediabetes.
Subject(s)
Glucose Intolerance , Insulin Resistance , Prediabetic State , Male , Humans , Middle Aged , Female , Prospective Studies , Cross-Sectional Studies , Oligosaccharides , Adipose Tissue , HexosesABSTRACT
Malignant peritoneal mesothelioma (MPeM) is a rare malignancy with historically poor prognosis. Recent research has started to reveal increasingly prevalent genetic mutations seen in this malignancy. Here, we report a case of complete clinical remission of unresectable, metastatic MPeM with systemic chemotherapy. Immunohistochemistry of our patient's malignant cytology sample showed loss of Breast Cancer Gene 1-associated protein-1 expression (BAP1). The patient had synchronous diagnoses of primary squamous cell carcinoma of the anus, benign schwannoma and meningioma. Following the completion of 18 cycles of pemetrexed and bevacizumab, the patient has remained in clinical remission for 8 months. We examine the unusual susceptibility of unresectable MPeM to systemic chemotherapy and attribute susceptibility to the molecular milieu created by mutations in multiple DNA repair pathways. We encourage increased testing for and analysis of mutations in DNA repair pathways to improve future treatment outcomes in this rare malignancy.
Subject(s)
Lung Neoplasms , Mesothelioma, Malignant , Mesothelioma , Peritoneal Neoplasms , Humans , Bevacizumab/therapeutic use , Pemetrexed/therapeutic use , Lung Neoplasms/pathology , Mesothelioma, Malignant/drug therapy , Mesothelioma/drug therapy , Mesothelioma/genetics , Mesothelioma/diagnosis , Peritoneal Neoplasms/drug therapy , Peritoneal Neoplasms/genetics , Peritoneal Neoplasms/pathology , Mutation , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/therapeutic use , Tumor Suppressor Proteins/geneticsABSTRACT
BACKGROUND: Obsessive-compulsive symptoms (OCS) and obsessive-compulsive disorder (OCD) are commonly reported in patients with schizophrenia. Furthermore, the use of clozapine in treatment-resistant schizophrenia has been thought to induce or aggravate these disorders. To date, there is a paucity of research regarding the prevalence and associated factors. Hence, this study aims to report the prevalence of OCS and OCD, and examine potential risk factors, in clozapine-treated schizophrenia. METHODS: This is a cross-sectional study conducted in the only tertiary hospital for psychiatric patients in Singapore. In total, 162 patients on a stable dose of clozapine were recruited for this study; 159 patients with a diagnosis of schizophrenia or schizoaffective disorder were included in the current analysis. Sociodemographic, clinical and treatment factors were analysed to identify factors associated with OCS and OCD. RESULTS: The prevalence of OCS and OCD is 21.4% and 12.6% respectively. Factors associated with OCS include younger age (OR:0.96, p=0.033) and younger age of onset of psychosis (OR:0.92, p=0.017). There were no significant factors associated with OCD. However, in an analysis of both OCS and/or OCD, factors associated include younger age (OR:0.96, p=0.027) and younger age of onset of psychosis (OR:0.91, p=0.016). Severity of psychotic illness and Clozapine dose were not associated with OCS or OCD in clozapine-treated schizophrenia. DISCUSSION & CONCLUSIONS: Our results suggest a high prevalence of OCS and OCD in clozapine-treated schizophrenia which clinicians should routinely screen for. Further research is warranted to establish the link between the factors identified in this study and OCS/OCD in clozapine-treated schizophrenia.
ABSTRACT
BACKGROUND: Treatment-resistant schizophrenia (TRS) affects a substantial proportion of patients who do not respond adequately to antipsychotic medications, yet the underlying biological mechanism remains poorly understood. This study investigates the link between the genetic predisposition to schizophrenia and TRS. METHODS: 857 individuals diagnosed with schizophrenia were divided into TRS (n = 142) and non-TRS (n = 715) based on well-defined TRS criteria. Polygenic risk scores (PRS) were calculated using schizophrenia genome-wide association summary statistics from East-Asian and European ancestry populations. PRS was estimated using both P-value thresholding and Bayesian framework methods. Logistic regression analyses were performed to differentiate between TRS and non-TRS individuals. RESULTS: The schizophrenia PRS derived from the East-Asian training dataset effectively distinguished between TRS and non-TRS individuals (R2 = 0.029, p = 4.86 ×10-5, pT = 0.1, OR = 1.52, 95% CI = 1.242-1.861), with higher PRS values observed in the TRS group. Similar PRS analysis was conducted based on the European ancestry GWAS summary statistics, but we found superior prediction based on the East-Asian ancestry discovery data. CONCLUSION: This study reveals an association between common risk variants for schizophrenia and TRS status, suggesting that the genetic burden of schizophrenia may partly contribute to treatment resistance in individuals with schizophrenia. These findings propose the potential use of genetic risk factors for early TRS identification and timely access to clozapine. However, the ancestral background of the discovery sample is crucial for successfully implementing PRS in clinical settings.
Subject(s)
Schizophrenia, Treatment-Resistant , Humans , Bayes Theorem , East Asian People , Genetic Predisposition to Disease , Genome-Wide Association Study , Schizophrenia, Treatment-Resistant/diagnosis , Schizophrenia, Treatment-Resistant/drug therapy , Schizophrenia, Treatment-Resistant/geneticsABSTRACT
Selecting informative features, such as accurate biomarkers for disease diagnosis, prognosis and response to treatment, is an essential task in the field of bioinformatics. Medical data often contain thousands of features and identifying potential biomarkers is challenging due to small number of samples in the data, method dependence and non-reproducibility. This paper proposes a novel ensemble feature selection method, named Filter and Wrapper Stacking Ensemble (FWSE), to identify reproducible biomarkers from high-dimensional omics data. In FWSE, filter feature selection methods are run on numerous subsets of the data to eliminate irrelevant features, and then wrapper feature selection methods are applied to rank the top features. The method was validated on four high-dimensional medical datasets related to mental illnesses and cancer. The results indicate that the features selected by FWSE are stable and statistically more significant than the ones obtained by existing methods while also demonstrating biological relevance. Furthermore, FWSE is a generic method, applicable to various high-dimensional datasets in the fields of machine intelligence and bioinformatics.
Subject(s)
Mental Disorders , Neoplasms , Humans , Algorithms , Artificial Intelligence , Biomarkers , Neoplasms/diagnosis , Neoplasms/geneticsABSTRACT
SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.