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OBJECTIVE: Dyslipidemia is a co-existing problem in patients with diabetes mellitus (DM) and coronary artery disease (CAD), and apolipoprotein E (APOE) plays an important role in lipid metabolism. However, the relationship between the APOE gene polymorphisms and the risk of developing CAD in type 2 DM (T2DM) patients remains controversial. The aim of this study was to assess this relationship and provide a reference for further risk assessment of CAD in T2DM patients. METHODS: The study included 378 patients with T2DM complicated with CAD (T2DM + CAD) and 431 patients with T2DM alone in the case group, and 351 individuals without DM and CAD were set as controls. The APOE rs429358 and rs7412 polymorphisms were genotyped by polymerase chain reaction (PCR) - microarray. Differences in APOE genotypes and alleles between patients and controls were compared. Multiple logistic regression analysis was performed after adjusting for age, gender, body mass index (BMI), history of smoking, and history of drinking to access the relationship between APOE genotypes and T2DM + CAD risk. RESULTS: The frequencies of the APOE É3/É4 genotype and ε4 allele were higher in the T2DM + CAD patients, and the frequencies of the APOE É3/É3 genotype and ε3 allele were lower than those in the controls (all p < 0.05). The T2DM + CAD patients with É4 allele had higher level in low-density lipoprotein cholesterol (LDL-C) than those in patients with É2 and É3 allele (p < 0.05). The results of logistic regression analysis showed that age ≥ 60 years old, and BMI ≥ 24.0 kg/m2 were independent risk factors for T2DM and T2DM + CAD, and APOE É3/É4 genotype (adjusted odds ratio (OR) = 1.93, 95% confidence interval (CI) = 1.18-3.14, p = 0.008) and É4 allele (adjusted OR = 1.97, 95% CI = 1.23-3.17) were independent risk factors for T2DM + CAD. However, the APOE genotypes and alleles were not found to have relationship with the risk of T2DM. CONCLUSIONS: APOE ε3/ε4 genotype and ε4 allele were independent risk factors for T2DM complicated with CAD, but not for T2DM.
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Enfermedad de la Arteria Coronaria , Diabetes Mellitus Tipo 2 , Humanos , Persona de Mediana Edad , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/genética , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Apolipoproteínas E/genética , Genotipo , Factores de Riesgo , Apolipoproteína E3/genética , AlelosRESUMEN
Visuospatial working memory (vsWM) requires information transfer among multiple cortical regions, from primary visual (V1) to prefrontal (PFC) cortices. This information is conveyed via layer 3 glutamatergic neurons whose activity is regulated by gamma-aminobutyric acid (GABA)ergic interneurons. In layer 3 of adult human neocortex, molecular markers of glutamate neurotransmission were lowest in V1 and highest in PFC, whereas GABA markers had the reverse pattern. Here, we asked if these opposite V1-visual association cortex (V2)-posterior parietal cortex (PPC)-PFC gradients across the vsWM network are present in layer 3 of monkey neocortex, when they are established during postnatal development, and if they are specific to this layer. We quantified transcript levels of glutamate and GABA markers in layers 3 and 6 of four vsWM cortical regions in a postnatal developmental series of 30 macaque monkeys. In adult monkeys, glutamate transcript levels in layer 3 increased across V1-V2-PPC-PFC regions, whereas GABA transcripts showed the opposite V1-V2-PPC-PFC gradient. Glutamate transcripts established adult-like expression patterns earlier during postnatal development than GABA transcripts. These V1-V2-PPC-PFC gradients and developmental patterns were less evident in layer 6. These findings demonstrate that expression of glutamate and GABA transcripts differs across cortical regions and layers during postnatal development, revealing potential molecular substrates for vsWM functional maturation.
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Ácido Glutámico/biosíntesis , Lóbulo Parietal/metabolismo , Corteza Prefrontal/metabolismo , Transcripción Genética/fisiología , Corteza Visual/metabolismo , Ácido gamma-Aminobutírico/biosíntesis , Factores de Edad , Animales , Transportador 2 de Aminoácidos Excitadores/biosíntesis , Transportador 2 de Aminoácidos Excitadores/genética , Femenino , Neuronas GABAérgicas/metabolismo , Expresión Génica , Ácido Glutámico/genética , Macaca mulatta , Lóbulo Parietal/crecimiento & desarrollo , Corteza Prefrontal/crecimiento & desarrollo , Receptores de GABA-A/biosíntesis , Receptores de GABA-A/genética , Corteza Visual/crecimiento & desarrollo , Ácido gamma-Aminobutírico/genéticaRESUMEN
BACKGROUND: Postmortem human brain studies provide the molecular, cellular, and circuitry levels of resolution essential for the development of mechanistically-novel interventions for cognitive deficits in schizophrenia. However, the absence of measures of premortem cognitive aptitude in postmortem subjects has presented a major challenge to interpreting the relationship between the severity of neural alterations and cognitive deficits within the same subjects. METHODS: To begin addressing this challenge, proxy measures of cognitive aptitude were evaluated in postmortem subjects (N = 507) meeting criteria for schizophrenia, major depressive or bipolar disorder, and unaffected comparison subjects. Specifically, highest levels of educational and occupational attainment of the decedent and their parents were obtained during postmortem psychological autopsies. RESULTS: Consistent with prior findings in living subjects, subjects with schizophrenia had the lowest educational and occupational attainment relative to all other subject groups, and they also failed to show the generational improvement in attainment observed in all other subject groups. CONCLUSIONS: Educational and occupational attainment data obtained during postmortem psychological autopsies can be used as proxy measures of premortem cognitive function to interrogate the neural substrate of cognitive dysfunction in schizophrenia.
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Trastornos del Conocimiento/psicología , Cognición , Escolaridad , Ocupaciones , Esquizofrenia/patología , Psicología del Esquizofrénico , Adulto , Anciano , Autopsia , Trastorno Bipolar/psicología , Trastorno Depresivo Mayor/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , PadresRESUMEN
Visuospatial working memory (WM), which is impaired in schizophrenia, depends on a distributed network including visual, posterior parietal, and dorsolateral prefrontal cortical regions. Within each region, information processing is differentially regulated by subsets of γ-aminobutyric acid (GABA) neurons that express parvalbumin (PV), somatostatin (SST), or vasoactive intestinal peptide (VIP). In schizophrenia, WM impairments have been associated with alterations of PV and SST neurons in the dorsolateral prefrontal cortex. Here, we quantified transcripts selectively expressed in GABA neuron subsets across four cortical regions in the WM network from comparison and schizophrenia subjects. In comparison subjects, PV mRNA levels declined and SST mRNA levels increased from posterior to anterior regions, whereas VIP mRNA levels were comparable across regions except for the primary visual cortex (V1). In schizophrenia subjects, each transcript in PV and SST neurons exhibited similar alterations across all regions, whereas transcripts in VIP neurons were unaltered in any region except for V1. These findings suggest that the contribution of each GABA neuron subset to inhibitory regulation of local circuitry normally differs across cortical regions of the visuospatial WM network and that in schizophrenia alterations of PV and SST neurons are a shared feature across these regions, whereas VIP neurons are affected only in V1.
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Encéfalo/metabolismo , Neuronas GABAérgicas/metabolismo , Memoria a Corto Plazo/fisiología , Parvalbúminas/genética , Esquizofrenia/genética , Somatostatina/genética , Péptido Intestinal Vasoactivo/genética , Adulto , Estudios de Casos y Controles , Femenino , Perfilación de la Expresión Génica , Glutamato Descarboxilasa/genética , Humanos , Proteínas con Homeodominio LIM/genética , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Lóbulo Parietal/metabolismo , Canales de Potasio con Entrada de Voltaje/genética , Corteza Prefrontal/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Opioides mu/genética , Esquizofrenia/fisiopatología , Procesamiento Espacial , Factores de Transcripción/genética , Corteza Visual/metabolismoRESUMEN
The aim of this paper is to conduct a systematic and theoretical analysis of estimation and inference for a class of functional mixed effects models (FMEM). Such FMEMs consist of fixed effects that characterize the association between longitudinal functional responses and covariates of interest and random effects that capture the spatial-temporal correlations of longitudinal functional responses. We propose local linear estimates of refined fixed effect functions and establish their weak convergence along with a simultaneous confidence band for each fixed-effect function. We propose a global test for the linear hypotheses of varying coefficient functions and derive the associated asymptotic distribution under the null hypothesis and the asymptotic power under the alternative hypothesis are derived. We also establish the convergence rates of the estimated spatial-temporal covariance operators and their associated eigenvalues and eigenfunctions. We conduct extensive simulations and apply our method to a white-matter fiber data set from a national database for autism research to examine the finite-sample performance of the proposed estimation and inference procedures.
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Parvalbumin-positive (PV+) neurons control the timing of pyramidal cell output in cortical neuron networks. In the prefrontal cortex (PFC), PV+ neuron activity is involved in cognitive function, suggesting that PV+ neuron maturation is critical for cognitive development. The two major PV+ neuron subtypes found in the PFC, chandelier cells (ChCs) and basket cells (BCs), are thought to play different roles in cortical circuits, but the trajectories of their physiological maturation have not been compared. Using two separate mouse lines, we found that in the mature PFC, both ChCs and BCs are abundant in superficial layer 2, but only BCs are present in deeper laminar locations. This distinctive laminar distribution was observed by postnatal day 12 (P12), when we first identified ChCs by the presence of axon cartridges. Electrophysiology analysis of excitatory synapse development, starting at P12, showed that excitatory drive remains low throughout development in ChCs, but increases rapidly before puberty in BCs, with an earlier time course in deeper-layer BCs. Consistent with a role of excitatory synaptic drive in the maturation of PV+ neuron firing properties, the fast-spiking phenotype showed different maturation trajectories between ChCs and BCs, and between superficial versus deep-layer BCs. ChC and BC maturation was nearly completed, via different trajectories, before the onset of puberty. These findings suggest that ChC and BC maturation may contribute differentially to the emergence of cognitive function, primarily during prepubertal development.SIGNIFICANCE STATEMENT Parvalbumin-positive (PV+) neurons tightly control pyramidal cell output. Thus PV+ neuron maturation in the prefrontal cortex (PFC) is crucial for cognitive development. However, the relative physiological maturation of the two major subtypes of PV+ neurons, chandelier cells (ChCs) and basket cells (BCs), has not been determined. We assessed the maturation of ChCs and BCs in different layers of the mouse PFC, and found that, from early postnatal age, ChCs and BCs differ in laminar location. Excitatory synapses and fast-spiking properties matured before the onset of puberty in both cell types, but following cell type-specific developmental trajectories. Hence, the physiological maturation of ChCs and BCs may contribute to the emergence of cognitive function differentially, and predominantly during prepubertal development.
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Envejecimiento/fisiología , Neurogénesis/fisiología , Neuronas/fisiología , Parvalbúminas/metabolismo , Corteza Prefrontal/fisiología , Envejecimiento/patología , Animales , Animales Recién Nacidos , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Red Nerviosa/citología , Red Nerviosa/fisiología , Neuronas/clasificación , Neuronas/citología , Corteza Prefrontal/citologíaRESUMEN
Human hair has been employed as a biomarker for exposure to persistent organic pollutants (POPs), but information on the source of dichloro-diphenyl-trichloroethane (DDT) and its metabolites in hair is limited. The present study investigated the contamination of DDTs in human hair from a rural area and an urban area of South China and compared with those in human serum and indoor dust. The concentrations of ∑DDTs ranged from 2.30 to 489ng/g, with a median of 21.8ng/g in human hair. The ∑DDT concentrations (median=40.8ng/g) in female hair were significantly higher than those in male hair (median=20.6ng/g). There were significantly positive correlations between the concentrations of DDTs and ages in both the female and male hair, but the age-dependence for DDTs in serum was less significant. The profile of DDT analogues in female hair, differing from that in the male hair, was more similar to that in the indoor dust, suggesting a more important role of exogenous exposure in female hair. We estimated that exogenous source is responsible for approximately 11% and 20% of the burden of DDTs in the male and female hair, respectively. Adjusted multiple linear regression model showed significantly positive association between the p,p'-DDE concentrations in the paired hair and serum samples, indicating that endogenous origins are the primary sources of DDTs in the hair of the residents in the study areas. Our findings demonstrated that human hair is a reliable biomarker for body burden of DDTs and can be used in epidemiology research and retrospective assessment of DDT exposure.
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DDT/análisis , Contaminantes Ambientales/análisis , Cabello/química , Insecticidas/análisis , Adolescente , Adulto , Contaminación del Aire Interior/análisis , Niño , Preescolar , China , DDT/sangre , Polvo/análisis , Monitoreo del Ambiente , Contaminantes Ambientales/sangre , Femenino , Humanos , Lactante , Recién Nacido , Insecticidas/sangre , Masculino , Persona de Mediana Edad , Población Rural , Población Urbana , Adulto JovenRESUMEN
In prevention trials, outcomes of interest frequently include data that are best quantified as proportion scores. In some cases, however, proportion scores may violate the statistical assumptions underlying common analytic methods. In this paper, we provide guidelines for analyzing frequency and proportion data as primary outcomes. We describe standard methods including generalized linear regression models to compare mean proportion scores and examine tools for testing normality and other assumptions for each model. Recommendations are made for instances when the assumptions are not met, including transformations for proportion scores that are non-normal. We also discuss more sophisticated analytical tools to model change in proportion scores over time. The guidelines provide ready-to-use analytical strategies for frequency and proportion data that are commonly encountered in prevention science.
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Ensayos Clínicos como Asunto , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Medicina Preventiva , Humanos , Modelos LinealesRESUMEN
Hair is increasingly used as a biomarker for human exposure to persistent organic pollutants (POPs). However, the internal and external sources of hair POPs remain a controversial issue. This study analyzed polychlorinated biphenyls (PCBs) in human hair and serum from electronic waste recycling workers. The median concentrations were 894 ng/g and 2868 ng/g lipid in hair and serum, respectively. The PCB concentrations in male and female serum were similar, while concentrations in male hair were significantly lower than in female hair. Significant correlations between the hair and serum PCB levels and congener profiles suggest that air is the predominant PCB source in hair and that hair and blood PCB levels are largely dependent on recent accumulation. The PCB95, 132, and 183 chiral signatures in serum were significantly nonracemic, with mean enantiomer fractions (EFs) of 0.440-0.693. Nevertheless, the hair EFs were essentially racemic (mean EFs = 0.495-0.503). Source apportionment using the Chemical Mass Balance model also indicated primary external PCB sources in human hair from the study area. Air, blood, and indoor dust are responsible for, on average, 64.2%, 27.2%, and 8.79% of the hair PCBs, respectively. This study evidenced that hair is a reliable matrix for monitoring human POP exposure.
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Residuos Electrónicos , Exposición Profesional/análisis , Bifenilos Policlorados/sangre , Reciclaje , China , Polvo/análisis , Contaminantes Ambientales/sangre , Femenino , Cabello/química , Humanos , MasculinoRESUMEN
Many longitudinal imaging studies have collected repeated diffusion tensor magnetic resonance imaging data to understand white matter maturation and structural connectivity pattern in normal controls and diseased subjects. There is an urgent demand for the development of statistical methods for the analysis of diffusion properties along fiber tracts and clinical data obtained from longitudinal studies. Jointly analyzing repeated fiber-tract diffusion properties and covariates (e.g., age or gender) raises several major challenges including (i) infinite-dimensional functional response data, (ii) complex spatial-temporal correlation structure, and (iii) complex spatial smoothness. To address these challenges, this article is to develop a functional mixed effects modeling (FMEM) framework to delineate the dynamic changes of diffusion properties along major fiber tracts and their association with a set of covariates of interest and the structure of the variability of these white matter tract properties in various longitudinal studies. Our FMEM consists of a functional mixed effects model for addressing all three challenges, an efficient method for spatially smoothing varying coefficient functions, an estimation method for estimating the spatial-temporal correlation structure, a test procedure with local and global test statistics for testing hypotheses of interest associated with functional response, and a simultaneous confidence band for quantifying the uncertainty in the estimated coefficient functions. Simulated data are used to evaluate the finite sample performance of FMEM and to demonstrate that FMEM significantly outperforms the standard pointwise mixed effects modeling approach. We apply FMEM to study the spatial-temporal dynamics of white-matter fiber tracts in a clinical study of neurodevelopment.
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Encéfalo/crecimiento & desarrollo , Interpretación de Imagen Asistida por Computador/métodos , Modelos Neurológicos , Fibras Nerviosas Mielínicas , Vías Nerviosas/crecimiento & desarrollo , Algoritmos , Encéfalo/anatomía & histología , Preescolar , Imagen de Difusión Tensora , Femenino , Humanos , Lactante , Recién Nacido , MasculinoRESUMEN
Human hair has been widely used as a bioindicator for human persistent organic pollutants (POPs) exposure, but studies on the sources of hair POPs and the relationship between hair and body burden are limited. This study analyzed the possible source apportionment of hair PBDEs and examined the relationship between PBDE concentrations in paired hair and serum from e-waste recycling workers. Using the ratio of BDE 99/47 and BDE 209/207 as indices, we calculated that only 15% of the highly brominated congeners (nona- and deca-BDE congeners) comes from exogenous (external) exposure for both female and male hair, but an average of 64% and 55% of the lower-brominated congeners (tetra- to penta-BDE congeners) come from exogenous exposure for female and male hair, respectively. The higher contribution of exogenous exposure for less-brominated congeners could be related to their relatively lower log KOW and higher volatility than higher-brominated congeners, which make them more readily to evaporate from dust and then to be adsorbed on hair. Higher hair PBDE levels and higher exogenous exposure of less-brominated congeners in females than in males can be attributed to a longer exogenous exposure time for females than males. Significant positive relationships were found in tri- to hepta-BDE congeners (BDE 28, 47, 66, 85, 100, 153, 154, and 183) (R = 0.36-0.55, p < 0.05) between hair and serum, but this relationship was not found for octa- to deca-BDE. Difference in the half-lives between highly brominated congeners and less-brominated congeners could be a reason. This result also implied that we should treat the results of correlation analyses between hair and other organs cautiously.
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Residuos Electrónicos/efectos adversos , Cabello/química , Éteres Difenilos Halogenados/análisis , Exposición Profesional/efectos adversos , Adulto , Carga Corporal (Radioterapia) , China , Polvo/análisis , Residuos Electrónicos/análisis , Monitoreo del Ambiente/métodos , Femenino , Éteres Difenilos Halogenados/sangre , Humanos , Masculino , Persona de Mediana Edad , Exposición Profesional/análisis , Bifenilos Polibrominados/análisis , Bifenilos Polibrominados/sangre , ReciclajeRESUMEN
BACKGROUND: Brain metastasis in nasopharyngeal carcinoma is a rare occurrence, and the characteristics of patients in this subgroup remain poorly defined. This study aims to delineate the clinical features, treatment modalities, prognostic factors, and survival of nasopharyngeal carcinoma patients with brain metastasis. METHODOLOGY: A retrospective analysis was conducted on patients diagnosed with nasopharyngeal carcinoma who developed brain metastasis and were treated at the Sun Yat-sen University Cancer Center between July 2000 and July 2023. Clinical data from patients were collected and used to assess their survival after brain metastases and prognostic factors. RESULTS: Among 82,434 nasopharyngeal carcinoma patients, 40 (0.06 %) developed Brain metastasis with a median follow-up of 5.1 years. The predominant histological subtype was non-keratinizing squamous cell carcinoma (85 %). The median post-BM survival was 25 months. The age, the Eastern Cooperative Oncology Group (ECOG), and the procedural treatment of BM were prognostic factors. Notably, patients receiving local treatments had significantly prolonged post-BM survival compared to those receiving systemic therapy alone (median, 47.00 vs. 11.00 months; p = 0.011). CONCLUSIONS: This is the largest cohort of brain metastasis in nasopharyngeal carcinoma to date. Local therapeutic measures after brain metastasis can significantly enhance the prognosis of these patients, particularly when radiotherapy is applied.
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Neoplasias Encefálicas , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/patología , Pronóstico , Estudios Retrospectivos , Neoplasias Encefálicas/secundario , Neoplasias Nasofaríngeas/radioterapiaRESUMEN
Concentrations of heavy metals (Cd, Pb, Cu, Zn, and Ni) were measured in the foodstuffs, house dust, underground/drinking water, and soil from an electronic waste (e-waste) area in South China. Elevated concentrations of these potentially toxic metals were observed in the samples but not in drinking water. The health risks for metal exposure via food consumption, dust ingestion, and drinking water were evaluated for local residents. For the average residents in the e-waste area, the non-carcinogenic risks arise predominantly from rice (hazard index=3.3), vegetables (2.2), and house dust (1.9) for adults, while the risks for young children are dominated by house dust (15). Drinking water may provide a negligible contribution to risk. However, local residents who use groundwater as a water supply source are at high non-carcinogenic risk. The potential cancer risks from oral intake of Pb are 8×10(-5) and 3×10(-4) for average adults and children, and thus groundwater would have a great potential to induce cancer (5×10(-4) and 1×10(-3)) in a highly exposed population. The results also reveal that the risk from oral exposure is much higher than the risk from inhalation and dermal contact with house dust.
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Polvo/análisis , Residuos Electrónicos/análisis , Monitoreo del Ambiente , Contaminantes Ambientales/análisis , Contaminación de Alimentos/análisis , Metales Pesados/análisis , Agua/química , Adulto , Niño , China , Humanos , Oryza/química , Reciclaje/normas , Medición de Riesgo , Suelo/química , Verduras/química , Abastecimiento de Agua/análisisRESUMEN
BACKGROUND: There is still a substantial need of more treatment options for patients with limited-stage small cell lung cancer (LS-SCLC). The standard therapy for LS-SCLC is platinum-based doublet chemotherapy administered concurrently with thoracic radiotherapy (cCRT). In China, sequential chemoradiotherapy (sCRT) is also a common practice. However, the disease inevitably progresses in most patients despite the curative intent and initial response. MATERIALS AND METHODS: Sugemalimab is an anti-programmed death ligand-1 (PD-L1) antibody that improved clinical outcomes for patients with stage III non-small cell lung cancer after cCRT or sCRT. The SUPPASS study is a phase II/III, randomized, double-blind, placebo-controlled, multicenter study (NCT05623267) that aims to investigate the efficacy and tolerability of sugemalimab as consolidation therapy in patients with LS-SCLC who have no progression following cCRT or sCRT. Approximately 346 patients will be randomized in a 1:1 ratio to receive sugemalimab 1200 mg or placebo every 3 weeks for up to 12 months. The primary endpoint is progression-free survival (PFS). Key secondary endpoints include overall survival (OS), landmark PFS rate, landmark OS rate, objective response rate and safety. Longitudinal molecular residual disease (MRD) testing will be performed as preplanned exploratory analysis. CONCLUSION: Study results will help demonstrate the efficacy and tolerability of anti-PD-L1 antibody consolidation therapy in LS-SCLC patients who have not progressed following cCRT or sCRT, and help determine the clinical implications of MRD in LS-SCLC.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células Pequeñas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/radioterapia , Quimioradioterapia/métodos , Quimioterapia de Consolidación , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Método Doble CiegoRESUMEN
Importance: The months following inpatient psychiatric hospitalization are a period of high risk for suicidal behavior. Sexual and gender minority (SGM) individuals have elevated risk for suicidal behavior, but no prior research has examined whether SGM inpatients have disproportionate risk for suicidal behavior following discharge from psychiatric hospitalization. Objectives: To evaluate whether SGM patients have elevated risk for suicidal behavior following discharge from psychiatric hospitalization compared with heterosexual and cisgender patients and to examine whether differences in risk across groups were accounted for by demographic characteristics and clinical factors known to be associated with suicidal behavior. Design, Setting, and Participants: This prospective cohort study was conducted from August 2017 to July 2021 among inpatients aged 18 to 30 years who were voluntarily enrolled during psychiatric hospitalization. The study was conducted at an inpatient psychiatric hospital, with prospective data collected via follow-up visits and electronic health records. Main Outcomes and Measures: Onset and/or recurrence of suicidal behavior following discharge from psychiatric hospitalization, assessed at follow-up visits and through electronic health records. Results: A total of 160 patients were included, with 56 sexual minority (SM) and 15 gender minority (GM) patients. The median (IQR) age of the patients was 23.5 (20.4-27.6) years, 77 (48%) reported male sex assigned at birth, and 114 (71%) identified their race as White. During the follow-up period, 33 suicidal behavior events occurred (among 21% of patients). SM (hazard ratio [HR], 2.02; 95% CI, CI, 1.02-4.00; log-rank P = .04) and GM (HR, 4.27; 95% CI, 1.75-10.40; log-rank P < .001) patients had significantly higher risk for suicidal behavior compared with their heterosexual and cisgender counterparts, respectively, in bivariable analyses. Risk between SM and heterosexual patients was not different after controlling for demographic characteristics and clinical factors associated with suicidal behavior. GM patients exhibited elevated risk during the 100 days following discharge even after controlling for demographic and clinical characteristics (HR, 3.80; 95% CI, 1.18-11.19; P = .03). Conclusions and Relevance: Within this cohort study of psychiatric patients, SGM patients had higher risk for suicidal behavior than non-SGM patients following discharge. While SM patients' risk was accounted for by clinical characteristics, GM patients' risk for suicidal behavior was not accounted for by their acute psychiatric state on admission. Future studies with larger subsamples of GM individuals are needed, and inpatient clinicians must attend to the unique needs of SGM individuals to ensure they receive affirming services.
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Minorías Sexuales y de Género , Ideación Suicida , Recién Nacido , Masculino , Humanos , Estudios Prospectivos , Estudios de Cohortes , Alta del PacienteRESUMEN
Using linear regression models, we studied the main and 2-way interaction effects of the predictor variables gender, age, BMI, and 64 folate/vitamin B-12/homocysteine (Hcy)/lipid/cholesterol-related single nucleotide polymorphisms (SNP) on log-transformed plasma Hcy normalized by RBC folate measurements (nHcy) in 373 healthy Caucasian adults (50% women). Variable selection was conducted by stepwise Akaike information criterion or least angle regression and both methods led to the same final model. Significant predictors (where P values were adjusted for false discovery rate) included type of blood sample [whole blood (WB) vs. plasma-depleted WB; P < 0.001] used for folate analysis, gender (P < 0.001), and SNP in genes SPTLC1 (rs11790991; P = 0.040), CRBP2 (rs2118981; P < 0.001), BHMT (rs3733890; P = 0.019), and CETP (rs5882; P = 0.017). Significant 2-way interaction effects included gender × MTHFR (rs1801131; P = 0.012), gender × CRBP2 (rs2118981; P = 0.011), and gender × SCARB1 (rs83882; P = 0.003). The relation of nHcy concentrations with the significant SNP (SPTLC1, BHMT, CETP, CRBP2, MTHFR, and SCARB1) is of interest, especially because we surveyed the main and interaction effects in healthy adults, but it is an important area for future study. As discussed, understanding Hcy and genetic regulation is important, because Hcy may be related to inflammation, obesity, cardiovascular disease, and diabetes mellitus. We conclude that gender and SNP significantly affect nHcy.
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Betaína-Homocisteína S-Metiltransferasa/genética , Proteínas de Transferencia de Ésteres de Colesterol/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Proteínas Celulares de Unión al Retinol/genética , Receptores Depuradores de Clase B/genética , Serina C-Palmitoiltransferasa/genética , Adulto , Anciano , Betaína-Homocisteína S-Metiltransferasa/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Eritrocitos/metabolismo , Femenino , Ácido Fólico/metabolismo , Homocisteína/sangre , Humanos , Hiperhomocisteinemia/sangre , Hiperhomocisteinemia/epidemiología , Hiperhomocisteinemia/genética , Masculino , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Valor Predictivo de las Pruebas , Valores de Referencia , Proteínas Celulares de Unión al Retinol/metabolismo , Factores de Riesgo , Receptores Depuradores de Clase B/metabolismo , Serina C-Palmitoiltransferasa/metabolismo , Distribución por SexoRESUMEN
Purpose: Although the knowledge-based dose-volume histogram (DVH) prediction has been largely researched and applied in External Beam Radiation Therapy, it is still less investigated in the domain of brachytherapy. The purpose of this study is to develop a reliable DVH prediction method for high-dose-rate brachytherapy plans. Method: A DVH prediction workflow combining kernel density estimation (KDE), k-nearest neighbor (kNN), and principal component analysis (PCA) was proposed. PCA and kNN were first employed together to select similar patients based on principal component directions. 79 cervical cancer patients with different applicators inserted was included in this study. The KDE model was built based on the relationship between distance-to-target (DTH) and the dose in selected cases, which can be subsequently used to estimate the dose probability distribution in the validation set. Model performance of bladder and rectum was quantified by |ΔD2cc|, |ΔD1cc|, |ΔD0.1cc|, |ΔDmax|, and |ΔDmean| in the form of mean and standard deviation. The model performance between KDE only and the combination of kNN, PCA, and KDE was compared. Result: 20, 30 patients were selected for rectum and bladder based on KNN and PCA, respectively. The absolute residual between the actual plans and the predicted plans were 0.38 ± 0.29, 0.4 ± 0.32, 0.43 ± 0.36, 0.97 ± 0.66, and 0.13 ± 0.99 for |ΔD2cc|, |ΔD1cc|, |ΔD0.1cc|, |ΔDmax|, and |ΔDmean| in the bladder, respectively. For rectum, the corresponding results were 0.34 ± 0.27, 0.38 ± 0.33, 0.63 ± 0.57, 1.41 ± 0.99 and 0.23 ± 0.17, respectively. The combination of kNN, PCA, and KDE showed a significantly better prediction performance than KDE only, with an improvement of 30.3% for the bladder and 33.3% for the rectum. Conclusion: In this study, a knowledge-based machine learning model was proposed and verified to accurately predict the DVH for new patients. This model is proved to be effective in our testing group in the workflow of HDR brachytherapy.
RESUMEN
Visuospatial working memory (vsWM), which is impaired in schizophrenia (SZ), is mediated by a distributed cortical network. In one node of this network, the dorsolateral prefrontal cortex (DLPFC), altered expression of transcripts for actin assembly and mitochondrial oxidative phosphorylation (OXPHOS) have been reported in SZ. To understand the relationship between these processes, and the extent to which similar alterations are present in other regions of vsWM network in SZ, a subset of actin- (CDC42, BAIAP2, ARPC3, and ARPC4) and OXPHOS-related (ATP5H, COX4I1, COX7B, and NDUFB3) transcripts were quantified in DLPFC by RNA sequencing in 139 SZ and unaffected comparison (UC) subjects, and in DLPFC and three other regions of the cortical vsWM network by qPCR in 20 pairs of SZ and UC subjects. By RNA sequencing, levels of actin- and OXPHOS-related transcripts were significantly altered in SZ, and robustly correlated in both UC and SZ subject groups. By qPCR, cross-regional expression patterns of these transcripts in UC subjects were consistent with greater actin assembly in DLPFC and higher OXPHOS activity in primary visual cortex (V1). In SZ, CDC42 and ARPC4 levels were lower in all regions, BAIAP2 levels higher only in V1, and ARPC3 levels unaltered across regions. All OXPHOS-related transcript levels were lower in SZ, with the disease effect decreasing from posterior to anterior regions. The differential alterations in markers of actin assembly and energy production across regions of the cortical vsWM network in SZ suggest that each region may make specific contributions to vsWM impairments in the illness.
Asunto(s)
Esquizofrenia , Actinas/genética , Actinas/metabolismo , Humanos , Memoria a Corto Plazo , Fosforilación Oxidativa , Corteza Prefrontal/metabolismo , Esquizofrenia/genética , Esquizofrenia/metabolismoRESUMEN
BACKGROUND: Suicide is a leading cause of death in the young adult population, with few biological markers identified thus far to be associated with suicidality. Cytokines (including IL-6 and TNFα) may contribute to increased risk for depression and suicidality. Few studies have examined the associations of cytokine mRNA expression with depression and suicidal ideation and behavior. This study examines these associations and whether cytokine signaling networks differentiate suicide attempters (SA), suicide ideators (SI), and healthy controls (HC). METHODS: Cytokine pathway marker (CPM; e.g. cytokines and proteins in cytokine signaling pathways) mRNA gene expression in whole blood was examined in suicide attempters (n = 38), suicide ideators (n = 38), and healthy controls (n = 36). Between-group differences in CPM gene expression were examined. We also examined association of the mRNA of these genes with the severity of depression and suicidal ideation. Novel Gaussian Graphical Model (GGM) techniques were utilized to examine between-network partial correlation differences in cytokine signaling networks relevant to IL-6 and TNFα signaling pathways. RESULTS: The severity of depression symptoms was positively associated with TNFα mRNA levels and negatively associated with IL-10 mRNA levels, but CPM expression was not associated with suicidal ideation severity. There were no between-group differences in CPM markers among healthy controls, SI and SA groups after correcting for multiple comparisons. In network analyses, we found suggestive results of between-group network differences between SI and control groups in gene pairs with IL-6R and STAT3 as common nodes. DISCUSSION: In a cohort of suicide attempters and ideators, TNFα and IL-10 mRNA levels appear to be associated with depressive symptomology, consistent with elevation of pro-inflammatory cytokine production and reduction of anti-inflammatory cytokine production. Additionally, cytokine signaling networks may differentiate suicide ideators from healthy controls based on between-network differences, with differences possibly related to relationships of IL6R or STAT3 with other components of cytokine signaling networks.
RESUMEN
BACKGROUND: Schizophrenia (SZ) is associated with cognitive impairment that contributes to disability, but the cognitive dysfunction is relatively refractory to pharmacologic intervention. Though Valproate augmentation is reported to improve psychopathology among patients with SZ, its effects on cognitive functions have not been investigated systematically. METHODS: Using a randomized double blind placebo controlled design, the effects of Valproate or placebo as adjuncts to risperidone (RISP) treatment were evaluated among patients with early course SZ (Nâ¯=â¯109). Domains of cognitive function, estimated using the Arabic version of the Penn Computerized Neurocognitive Battery, were the prime outcomes. Clinical severity and social function were secondary outcomes. We also explored the effects of valproate treatment on serological responses to Toxoplama Gondii (TOXO), a putative risk factor for cognitive dysfunction in SZ. RESULTS: There were no significant differences between Valproate and placebo (PLA) treated groups with respect to changes in cognitive functions, positive or negative symptom scores or daily function scores at the beginning and end of the study. No significant Valproate/PLA differences were noted on TOXO serostatus or TOXO-related cognitive dysfunction. CONCLUSION: Valproate treatment may not be beneficial for cognitive dysfunction in SZ or for TOXO infection.