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1.
Curr Biol ; 2024 Jun 26.
Artículo en Inglés | MEDLINE | ID: mdl-38955177

RESUMEN

Organisms experience constant nutritional flux. Mechanisms at the interface of opposing nutritional states-scarcity and surplus-enable organismal energy homeostasis. Contingent on nutritional stores, adipocytes secrete adipokines, such as the fat hormone leptin, to signal nutrient status to the central brain. Increased leptin secretion underlies metabolic dysregulation during common obesity, but the molecular mechanisms regulating leptin secretion from human adipocytes are poorly understood. Here, we report that Atg8/LC3 family proteins, best known for their role in autophagy during nutrient scarcity, play an evolutionarily conserved role during nutrient surplus by promoting adipokine secretion. We show that in a well-fed state, Atg8/LC3 promotes the secretion of the Drosophila functional leptin ortholog unpaired 2 (Upd2) and leptin from human adipocytes. Proteomic analyses reveal that LC3 directs leptin to a secretory pathway in human cells. We identified LC3-dependent extracellular vesicle (EV) loading and secretion (LDELS) as a required step for leptin release, highlighting a unique secretory route adopted by leptin in human adipocytes. In Drosophila, mutations to Upd2's Atg8 interaction motif (AIM) result in constitutive adipokine retention. Atg8-mediated Upd2 retention alters lipid storage and hunger response and rewires the bulk organismal transcriptome in a manner conducive to starvation survival. Thus, Atg8/LC3's bidirectional role in nutrient sensing-conveying nutrient surplus and responding to nutrient deprivation-enables organisms to manage nutrient flux effectively. We posit that decoding how bidirectional molecular switches-such as Atg8/LC3-operate at the nexus of nutritional scarcity and surplus will inform therapeutic strategies to tackle chronic metabolic disorders.

2.
Patterns (N Y) ; 5(5): 100969, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38800361

RESUMEN

Understanding the cellular composition of a disease-related tissue is important in disease diagnosis, prognosis, and downstream treatment. Recent advances in single-cell RNA-sequencing (scRNA-seq) technique have allowed the measurement of gene expression profiles for individual cells. However, scRNA-seq is still too expensive to be used for large-scale population studies, and bulk RNA-seq is still widely used in such situations. An essential challenge is to deconvolve cellular composition for bulk RNA-seq data based on scRNA-seq data. Here, we present DeepDecon, a deep neural network model that leverages single-cell gene expression information to accurately predict the fraction of cancer cells in bulk tissues. It provides a refining strategy in which the cancer cell fraction is iteratively estimated by a set of trained models. When applied to simulated and real cancer data, DeepDecon exhibits superior performance compared to existing decomposition methods in terms of accuracy.

3.
J Am Pharm Assoc (2003) ; 64(3): 102063, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38432480

RESUMEN

BACKGROUND: Literature on pregabalin use in patients with heart failure is largely limited to patient case reports and cohort studies. OBJECTIVE: This study aimed to evaluate the effect of pregabalin initiation on diuretic requirements in patients with heart failure. METHODS: A retrospective analysis of patients with heart failure who were started on pregabalin between January 1, 2014, and September 1, 2021, at the Veterans Affairs North Texas Health Care System was used. The primary objective was to determine the median change in loop diuretic dose, in furosemide dose equivalents, 6 months after pregabalin initiation. RESULTS: Of 58 patients analyzed, there was no statistically significant difference in the primary outcome (P = 0.162). The secondary outcomes were found to be nonstatistically significant, and there was no correlation between pregabalin dose and outcomes. CONCLUSION: This represents the largest analysis of diuretic dose requirements in patients with heart failure after initiation of pregabalin. Although there was no difference in the median change of diuretic dose prescribed, pregabalin should still be used with caution.


Asunto(s)
Insuficiencia Cardíaca , Pregabalina , Humanos , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Pregabalina/administración & dosificación , Pregabalina/uso terapéutico , Estudios Retrospectivos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Furosemida/administración & dosificación , Furosemida/uso terapéutico , Texas , Anciano de 80 o más Años , Enfermedad Crónica/tratamiento farmacológico , Diuréticos/administración & dosificación , Diuréticos/uso terapéutico , Relación Dosis-Respuesta a Droga , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/administración & dosificación , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico/uso terapéutico
4.
Clin Lymphoma Myeloma Leuk ; 24(6): 364-374, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38378362

RESUMEN

BACKGROUND: Therapies for relapsed/refractory acute myeloid leukemia remain limited and outcomes poor, especially amongst patients who are ineligible for cytotoxic chemotherapy or targeted therapies. PATIENTS AND METHODS: This phase 1b trial evaluated venetoclax, a B-cell lymphoma-2 (BCL-2) inhibitor, plus cobimetinib, a MEK1/2 inhibitor, in patients with relapsed/refractory acute myeloid leukemia, ineligible for cytotoxic chemotherapy. Two-dimensional dose-escalation was performed for venetoclax dosed daily, and for cobimetinib dosed on days 1-21 of each 28-day cycle. RESULTS: Thirty patients (median [range] age: 71.5 years [60-84]) received venetoclax-cobimetinib. The most common adverse events (AEs; in ≥40.0% of patients) were diarrhea (80.0%), nausea (60.0%), vomiting (40.0%), febrile neutropenia (40.0%), and fatigue (40.0%). Overall, 66.7% and 23.3% of patients experienced AEs leading to dose modification/interruption or treatment withdrawal, respectively. The composite complete remission (CRc) rate (complete remission [CR] + CR with incomplete blood count recovery + CR with incomplete platelet recovery) was 15.6%; antileukemic response rate (CRc + morphologic leukemia-free state/partial remission) was 18.8%. For the recommended phase 2 dose (venetoclax: 600 mg; cobimetinib: 40 mg), CRc and antileukemic response rates were both 12.5%. Failure to achieve an antileukemic response was associated with elevated baseline phosphorylated ERK and MCL-1 levels, but not BCL-xL. Baseline mutations in ≥1 signaling gene or TP53 were noted in nonresponders and emerged on treatment. Pharmacodynamic biomarkers revealed inconsistent, transient inhibition of the mitogen-activated protein kinase (MAPK) pathway. CONCLUSION: Venetoclax-cobimetinib showed limited preliminary efficacy similar to single-agent venetoclax, but with added toxicity. Our findings will inform future trials of BCL-2/MAPK pathway inhibitor combinations.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Azetidinas , Compuestos Bicíclicos Heterocíclicos con Puentes , Leucemia Mieloide Aguda , Piperidinas , Sulfonamidas , Humanos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/administración & dosificación , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Anciano , Masculino , Femenino , Persona de Mediana Edad , Azetidinas/uso terapéutico , Azetidinas/farmacología , Azetidinas/administración & dosificación , Piperidinas/uso terapéutico , Piperidinas/farmacología , Anciano de 80 o más Años , Leucemia Mieloide Aguda/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del Tratamiento , Resistencia a Antineoplásicos/efectos de los fármacos
5.
IBRO Neurosci Rep ; 16: 291-299, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38374956

RESUMEN

Background and purpose: Traumatic brain injury (TBI) and its consequences remain great challenges for neurology. Consequences of TBI are associated with various alterations in the brain but little is known about long-term changes of epigenetic DNA methylation patterns. Moreover, nothing is known about potential treatments that can alter these epigenetic changes in beneficial ways. Therefore, we have examined myo-inositol (MI), which has positive effects on several pathological conditions. Methods: TBI was induced in mice by controlled cortical impact (CCI). One group of CCI animals received saline injections for two months (TBI+SAL), another CCI group received MI treatment (TBI+MI) for the same period and one group served as a sham-operated control. Mice were sacrificed 4 months after CCI and changes in DNA methylome and transcriptomes were examined. Results: For the first time we: (i) provide comprehensive map of long-term DNA methylation changes after CCI in the hippocampus; (ii) identify differences by methylation sites between the groups; (iii) characterize transcriptome changes; (iv) provide association between DNA methylation sites and gene expression. MI treatment is linked with upregulation of genes covering 33 biological processes, involved in immune response and inflammation. In support of these findings, we have shown that expression of BATF2, a transcription factor involved in immune-regulatory networks, is upregulated in the hippocampus of the TBI+MI group where the BATF2 gene is demethylated. Conclusion: TBI is followed by long-term epigenetic and transcriptomic changes in hippocampus. MI treatment has a significant effect on these processes by modulation of immune response and biological pathways of inflammation.

6.
Nat Commun ; 15(1): 1456, 2024 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-38368402

RESUMEN

Capturing fine spatial, spectral, and temporal information of the scene is highly desirable in many applications. However, recording data of such high dimensionality requires significant transmission bandwidth. Current computational imaging methods can partially address this challenge but are still limited in reducing input data throughput. In this paper, we report a video-rate hyperspectral imager based on a single-pixel photodetector which can achieve high-throughput hyperspectral video recording at a low bandwidth. We leverage the insight that 4-dimensional (4D) hyperspectral videos are considerably more compressible than 2D grayscale images. We propose a joint spatial-spectral capturing scheme encoding the scene into highly compressed measurements and obtaining temporal correlation at the same time. Furthermore, we propose a reconstruction method relying on a signal sparsity model in 4D space and a deep learning reconstruction approach greatly accelerating reconstruction. We demonstrate reconstruction of 128 × 128 hyperspectral images with 64 spectral bands at more than 4 frames per second offering a 900× data throughput compared to conventional imaging, which we believe is a first-of-its kind of a single-pixel-based hyperspectral imager.

7.
Artículo en Inglés | MEDLINE | ID: mdl-38028919

RESUMEN

An outpatient parenteral antimicrobial therapy team from a Veterans Affairs facility managed patients discharged from their own facility and neighboring community hospitals. There were no significant differences in adverse outcomes between the groups, but a majority of regimens were modified from those initially proposed by community providers.

8.
Clin Cancer Res ; 29(24): 5087-5103, 2023 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-37812476

RESUMEN

PURPOSE: Our preclinical studies showed that the oncolytic reovirus formulation pelareorep (PELA) has significant immunomodulatory anti-myeloma activity. We conducted an investigator-initiated clinical trial to evaluate PELA in combination with dexamethasone (Dex) and bortezomib (BZ) and define the tumor immune microenvironment (TiME) in patients with multiple myeloma treated with this regimen. PATIENTS AND METHODS: Patients with relapsed/refractory multiple myeloma (n = 14) were enrolled in a phase Ib clinical trial (ClinicalTrials.gov: NCT02514382) of three escalating PELA doses administered on Days 1, 2, 8, 9, 15, and 16. Patients received 40 mg Dex and 1.5 mg/m2 BZ on Days 1, 8, and 15. Cycles were repeated every 28 days. Pre- and posttreatment bone marrow specimens (IHC, n = 9; imaging mass cytometry, n = 6) and peripheral blood samples were collected for analysis (flow cytometry, n = 5; T-cell receptor clonality, n = 7; cytokine assay, n = 7). RESULTS: PELA/BZ/Dex was well-tolerated in all patients. Treatment-emergent toxicities were transient, and no dose-limiting toxicities occurred. Six (55%) of 11 response-evaluable patients showed decreased paraprotein. Treatment increased T and natural killer cell activation, inflammatory cytokine release, and programmed death-ligand 1 expression in bone marrow. Compared with nonresponders, responders had higher reovirus protein levels, increased cytotoxic T-cell infiltration posttreatment, cytotoxic T cells in significantly closer proximity to multiple myeloma cells, and larger populations of a novel immune-primed multiple myeloma phenotype (CD138+ IDO1+HLA-ABCHigh), indicating immunomodulation. CONCLUSIONS: PELA/BZ/Dex is well-tolerated and associated with anti-multiple myeloma activity in a subset of responding patients, characterized by immune reprogramming and TiME changes, warranting further investigation of PELA as an immunomodulator.


Asunto(s)
Mieloma Múltiple , Viroterapia Oncolítica , Humanos , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/etiología , Viroterapia Oncolítica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bortezomib/uso terapéutico , Dexametasona/uso terapéutico , Citocinas/uso terapéutico , Microambiente Tumoral
9.
J Adolesc Health ; 73(5): 801-812, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37610388

RESUMEN

PURPOSE: This review examined whether there is evidence that brief interventions with condom demonstration lessons have impacts on behavioral and nonbehavioral outcomes for youth and young adults. METHODS: We conducted a systematic review using a prespecified search strategy and processes consistent with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We identified a pool of 11 eligible studies that tested the effectiveness of a single-session intervention that was no longer than 60 minutes and included a condom demonstration. We included all outcomes at all time points and organized them into eight domains. RESULTS: Single-session interventions with condom demonstrations showed favorable short-term and long-term impacts for samples of largely sexually active youth. Studies found statistically significant impacts in 29%-50% of the tests for effects on attitudes toward condoms, knowledge of sexual health and condom use, perceptions of condom use and sexuality, and condoms use intentions. DISCUSSION: Our review found evidence that brief interventions with condom demonstrations have potential effects on behavioral and nonbehavioral outcomes for vulnerable and transient sexually active youth warranting future studies to assess condom demonstrations in isolation.


Asunto(s)
Condones , Enfermedades de Transmisión Sexual , Adulto Joven , Humanos , Adolescente , Enfermedades de Transmisión Sexual/prevención & control , Intervención en la Crisis (Psiquiatría) , Conducta Sexual , Sexualidad , Conocimientos, Actitudes y Práctica en Salud
10.
J Clin Oncol ; 41(32): 5015-5024, 2023 Nov 10.
Artículo en Inglés | MEDLINE | ID: mdl-37582240

RESUMEN

PURPOSE: Improving clinical outcomes with novel drug combinations to treat metastatic castration-resistant prostate cancer (mCRPC) is challenging. Preclinical studies showed cabazitaxel had superior antitumor efficacy compared with docetaxel. Gene expression profiling revealed divergent effects of these taxanes in cycling cells. mCRPC are RB deficient rendering them hypersensitive to taxanes. These data suggested that upfront treatment with cabazitaxel with abiraterone may affect therapeutic response. We designed a phase II randomized noncomparative trial of abiraterone acetate/prednisone (AAP) or AAP and cabazitaxel (AAP + C) in men with mCRPC to address this hypothesis. METHODS: This trial of 81 men with mCRPC determined the radiographic progression-free survival (rPFS), prostate-specific antigen (PSA) progression-free survival, overall objective response, and safety of AAP or AAP + C. Equally allocated patients received AAP followed by switching to cabazitaxel upon radiographic progression (arm 1) or upfront with AAP + C (arm 2). Patients were stratified into high-/low-risk groups by the Halabi nomogram. Real-time assessment of RB status and circulating tumor cell (CTC) analysis to correlate with clinical outcomes was exploratory. RESULTS: Both treatment arms were well-tolerated. Median rPFS in AAP was 6.4 months (95% CI, 3.8 to 10.6) and median overall survival (OS) 18.3 months (95% CI, 14.4 to 37.6), respectively. Fifty-six percent of patients showed ≥50% decline in PSA. Median rPFS in AAP + C was 14.8 months (95% CI, 10.6 to 16.4), and median OS 24.5 months (95% CI, 20.4 to 35.0). There was a ≥50% decline in PSA in 92.1% of men. Neither RB expression in pretherapy tumor biopsy, CTC, or tissue explants identified those who may benefit from AAP + C. CONCLUSION: AAP + C was safe with improved rPFS, OS duration, and a higher proportion of PSA declines. This suggests that AAP + C given earlier rather than sequentially may benefit some men. Further work is needed to identify this population.


Asunto(s)
Acetato de Abiraterona , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Acetato de Abiraterona/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/patología , Antígeno Prostático Específico , Resultado del Tratamiento , Taxoides/uso terapéutico , Prednisona , Supervivencia sin Enfermedad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
11.
Acad Psychiatry ; 47(6): 646-652, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37415064

RESUMEN

OBJECTIVE: The purpose of this study was to determine if a brief ethics curriculum embedded in a third-year required clerkship differentially impacted students' self-rated confidence versus competence (determined by a written examination) regarding ethical principles related to psychiatry. METHODS: Using a naturalistic design, 270 medical students at the University of Washington were assigned to one of three groups during their third-year psychiatry clerkship: a control group with no additional ethics content, a group with access to a pre-recorded video ethics curriculum, or a group with live didactic sessions in addition to the video curriculum. All students took a pre- and post-test that assessed their confidence and competence in ethical theory and behavioral health ethics. RESULTS: Confidence and competence were not statistically different across the three groups prior to completing the curriculum (p > 0.1). Post-test scores on confidence in behavioral health ethics were not significantly different between the three groups (p > 0.05). Post-test scores on confidence in ethical theory were significantly higher in the video-only and video + discussion group as compared to the control group (3.74 ± 0.55 and 4.00 ± 0.44 vs. 3.19 ± 0.59 respectively; p < 0.0001). Both the video-only and video + discussion group showed greater improvement in competence in ethical theory and application than the control group (0.68 ± 0.30 and 0.76 ± 0.23 vs. 0.31 ± 0.33, respectively; p < 0.0001) and behavioral health ethics (0.79 ± 0.14 and 0.85 ± 0.14 vs. 0.59 ± 0.15, respectively; p < 0.002). CONCLUSIONS: With the addition of this ethics curriculum, students showed both increased confidence and competence in their ability to analyze ethical situations as well as increased competence regarding behavioral health ethics.


Asunto(s)
Prácticas Clínicas , Estudiantes de Medicina , Humanos , Curriculum , Ética Médica , Estudiantes de Medicina/psicología
12.
IDCases ; 33: e01821, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37415782

RESUMEN

We report a case of a 32-year-old male with a history of type 1 diabetes, inhaled drug use, and alcohol use disorder, who presented with encephalopathy, holocranial headaches, neck pain, confusion, and generalized tonic-clonic seizures. The patient initially presented at a rural community hospital with a fever and was found to be in diabetic ketoacidosis (DKA). He was also hemodynamically stable but stuporous, prompting intubation to protect his airway. Despite initial treatment measures, his neurological condition worsened and he remained ventilator-dependent. Key findings include a high glucose level, presence of ketones, and evidence of drug use. Blood cultures showed no growth, but his febrile state persisted. Cerebrospinal fluid (CSF) analysis revealed mild pleocytosis, hyperglycorrhachia but normal protein, with no growth. Neuroimaging showed right hemispheric slowing on EEG and diffusion restriction in the right frontal lobe on MRI. The patient's neurological status worsened on the second day of admission, manifesting as sluggish pupillary reflexes, right third nerve palsy, and decerebrate posturing. Emergent MRI suggested cerebral edema, leading to initiation of hypertonic saline. This case highlights the diagnostic challenges and critical management considerations in a patient with multiple comorbidities presenting with unexplained neurological deterioration, emphasizing the importance of a comprehensive and timely approach to diagnosis and treatment.

13.
J Pharm Pract ; : 8971900231184965, 2023 Jun 22.
Artículo en Inglés | MEDLINE | ID: mdl-37347841

RESUMEN

Background: Second-generation antipsychotics (SGAs) are commonly prescribed medications used to treat a variety of mental health conditions. Recent data has correlated antipsychotic medications with venous thromboembolism (VTE). SGAs have diverse side effect profiles, which may contribute to differences in incidence of VTE. It is unknown which SGAs confer the most risk, and what the mechanism of increased risk is. Objective: Determine incidence of VTE in Veterans at Veterans Affairs North Texas Health Care System (VA-NTX HCS) between SGAs aripiprazole, olanzapine and risperidone. Methods: Retrospective chart review of adult Veterans at VA-NTX HCS between October 2015 to December 2019 prescribed aripiprazole, olanzapine, or risperidone. Results: Of 823 Veterans, incidence of VTE was lowest in aripiprazole group at .4%, increased to 1.7% in the olanzapine group, and was highest at 2.5% in the risperidone group. However, differences in incidence of VTE between SGAs were not statistically different, indicating no between-group differences. Conclusion: There was no difference in the incidence of VTE between risperidone, olanzapine, or aripiprazole. Given multiple limitations with this study, higher-powered studies should be conducted to investigate the possibility of differences in the incidence of VTE between the SGAs.

14.
Int Arch Occup Environ Health ; 96(6): 919-930, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37225876

RESUMEN

PURPOSE: The Keokuk County Rural Health Study (KCRHS) is a longitudinal population-based study conducted in rural Iowa. A prior analysis of enrollment data identified an association of airflow obstruction with occupational exposures only among cigarette smokers. The current study used spirometry data from all three rounds to investigate whether level of forced expiratory volume in one second (FEV1) and longitudinal change in FEV1 were associated with occupational vapor-gas, dust, and fumes (VGDF) exposures, and whether these associations were modified by smoking. METHODS: This study sample comprised 1071 adult KCRHS participants with longitudinal data. A job-exposure matrix (JEM) was applied to participants' lifetime work histories to assign exposures to occupational VGDF. Mixed regression models of pre-bronchodilator FEV1 (millimeters, ml) were fit to test for associations with occupational exposures while adjusting for potential confounders. RESULTS: Mineral dust had the most consistent association with change in FEV1, including ever/never ( - 6.3 ml/year) and nearly every level of duration, intensity, and cumulative exposure. Because 92% of participants with mineral dust also had organic dust exposure, the results for mineral dust may be due to a combination of the two. An association of FEV1 level with fumes was observed for high intensity ( - 91.4 ml) among all participants, and limited to cigarette smokers with results of - 104.6 ml ever/never exposed, - 170.3 ml high duration, and - 172.4 ml high cumulative. CONCLUSION: The current findings suggest that mineral dust, possibly in combination with organic dust, and fumes exposure, especially among cigarette smokers, were risk factors for adverse FEV1 results.


Asunto(s)
Enfermedades Profesionales , Exposición Profesional , Enfermedad Pulmonar Obstructiva Crónica , Adulto , Humanos , Estudios Longitudinales , Volumen Espiratorio Forzado , Iowa/epidemiología , Población Rural , Exposición Profesional/efectos adversos , Polvo/análisis
15.
J Natl Cancer Inst ; 115(8): 994-997, 2023 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-37202363

RESUMEN

Real-world evidence regarding the value of integrating genomic profiling (GP) in managing cancer of unknown primary (CUP) is limited. We assessed this clinical utility using a prospective trial of 158 patients with CUP (October 2016-September 2019) who underwent GP using next-generation sequencing designed to identify genomic alterations (GAs). Only 61 (38.6%) patients had sufficient tissue for successful profiling. GAs were seen in 55 (90.2%) patients of which GAs with US Food and Drug Administration-approved genomically matched therapy were seen in 25 (40.9%) patients. A change in therapy was recommended and implemented (primary endpoint of the study) in 16 (10.1%) and 4 (2.5%) patients of the entire study cohort, respectively. The most common reason for inability to implement the profiling-guided therapy was worsening of performance status (56.3%). Integrating GP in management of CUP is feasible but challenging because of paucity of tissue and aggressive natural history of the disease and requires innovative precision strategies.


Asunto(s)
Perfilación de la Expresión Génica , Neoplasias Primarias Desconocidas , Humanos , Estudios de Factibilidad , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias Primarias Desconocidas/tratamiento farmacológico , Neoplasias Primarias Desconocidas/genética , Estudios Prospectivos
16.
Artículo en Inglés | MEDLINE | ID: mdl-37048011

RESUMEN

Arsenic and atrazine are two water contaminants of high public health concern in Iowa. The occurrence of arsenic and atrazine in drinking water from Iowa's private wells and public water systems was investigated over several decades. In this study, the percentages of detection and violation of regulations were compared over region, season, and water source, and factors affecting the detection and concentration of arsenic and atrazine were analyzed using a mixed-effects model. Atrazine contamination in drinking water was found to vary by region, depending on agricultural usage patterns and hydrogeological features. The annual median atrazine levels of all public water systems were below the drinking water standard of 3 ppb in 2001-2014. Around 40% of public water systems contained arsenic at levels > 1 ppb in 2014, with 13.8% containing arsenic at levels of 5-10 ppb and 2.6% exceeding 10 ppb. This unexpected result highlights the ongoing public health threat posed by arsenic in drinking water in Iowa, emphasizing the need for continued monitoring and mitigation efforts to reduce exposure and associated health risks. Additionally, an atrazine metabolite, desethylatrazine, should be monitored to obtain a complete account of atrazine exposure and possible health effects.


Asunto(s)
Arsénico , Atrazina , Agua Potable , Contaminantes Químicos del Agua , Atrazina/análisis , Agua Potable/análisis , Arsénico/análisis , Iowa/epidemiología , Salud Pública , Contaminantes Químicos del Agua/análisis , Abastecimiento de Agua
17.
Acta Neurochir (Wien) ; 165(5): 1323-1331, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36920663

RESUMEN

BACKGROUND: Meningiomas are the most common intracranial tumors. Recent advancements in the genetic profiling of tumors have allowed information including DNA copy number analysis, mutational analysis, and RNA sequencing to be more frequently reported, in turn allowing better characterization of meningiomas. In recent years, analysis of tumor methylomes that reflects both cell-origin methylation signatures and somatically acquired DNA methylation changes has been utilized to better classify meningiomas with great success. METHOD: We report DNA methylation profiling on meningiomas from 17 patients. Formalin-fixed paraffin-embedded (FFPE) meningioma tumor samples were processed, loaded onto the Infinium Methylation EPIC array, and scanned using the Illumina IScan system. Raw IDAT files were processed through the the CNS tumor classifier developed by the Molecular Neuropathology group at the German Cancer Research Center (DKFZ). Corresponding genomics were captured using targeted sequencing panels. RESULT: Among the meningioma samples, 13 samples were classified as "benign," two samples as "intermediate," and the remaining three samples (from two patients) as "malignant," based on previously validated classification algorithms. In addition to tumor methylation profiling, we also present information that includes patient demographics, clinical presentations, tumor characteristics (including size and location), surgical approaches, and mutational analysis. The two patients who provided the samples with "malignant" methylation classifications had tumor recurrence, reflecting a more aggressive disease course. CONCLUSION: In accordance with prior reports, our case series provides support that tumor DNA methylation profiling adds meaningful classification information and may be beneficial to incorporate in clinical practice. Our report also reveals that DNA methylation combined with WHO histology classification can more accurately predict tumor behavior than WHO classification alone.


Asunto(s)
Neoplasias del Sistema Nervioso Central , Neoplasias Meníngeas , Meningioma , Humanos , Meningioma/diagnóstico , Meningioma/genética , Metilación de ADN/genética , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/genética , Neoplasias Meníngeas/diagnóstico , Neoplasias Meníngeas/genética
18.
Dermatitis ; 34(2): 135-144, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-36917518

RESUMEN

Background: Atopic dermatitis (AD) affects 2%-10% of adults worldwide. Occurrence and severity of symptoms and treatment success vary among patients. Objective: To determine disease severity, burden, and treatment use and satisfaction in adults with AD. Methods: An international internet-based survey was conducted (October 5-November 1, 2021) in participants with AD from Canada, France, Germany, Italy, Japan, Spain, the United Kingdom, and the United States. Results: Of 2005 AD patients surveyed, 92% had body surface area (BSA) involvement <10%. Itch was the most bothersome symptom; 48.5% of participants reported severe itch in the past week (Itch Numerical Rating Scale [NRS] 7-10; 45.9% for BSA <10%, 75.0% for BSA ≥10%). Most participants reported moderate or severe sleep disturbance in the past week (Sleep NRS 4-10; 67.1% for BSA <10%, 92.3% for BSA ≥10%). Itch was the top reason for participants' most recent health care provider visit; reducing itching was their top treatment goal. Topical therapies, which were most commonly used, resulted in low treatment satisfaction. Conclusions: Itch was the most bothersome AD symptom. Although clinical development has focused on improving skin lesions, improving itch is patients' top treatment goal. This survey highlights the need for systemic antipruritic therapies that could reduce itch in nonlesional and lesional skin.


Asunto(s)
Dermatitis Atópica , Adulto , Humanos , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/epidemiología , Índice de Severidad de la Enfermedad , Prurito/etiología , Prurito/terapia , Prurito/diagnóstico , Encuestas y Cuestionarios , Costo de Enfermedad , Calidad de Vida
19.
J Psychiatr Res ; 160: 163-170, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-36804111

RESUMEN

Military service members are at increased risk for suicide, but there are few strategies for detecting those who are at highest risk after a deployment. Using all available data collected from 4119 Military service members before and after their deployment to Iraq for Operation Iraqi Freedom, we tested whether predeployment characteristics clustered together to predict postdeployment suicidal risk. Latent class analysis showed that three classes best characterized the sample at predeployment. Class 1 had significantly higher scores on PTSD severity pre- and postdeployment than Classes 2 and 3 (Ps < .001). At postdeployment, Class 1 also had a greater proportion of endorsement of lifetime and past year suicidal ideation than Classes 2 and 3 (Ps < .05) and a greater proportion of lifetime suicide attempts than Class 3 (P < .001). Class 1 also had a greater proportion of endorsement of past-30-days intention to act on suicidal thoughts than Classes 2 and 3 (Ps < .05) and past-30-days specific plan for suicide than Classes 2 and 3 (Ps < .05). The study showed that based only on predeployment data, it is possible to determine which service members might be at highest risk for suicidal ideation and behavior at postdeployment.


Asunto(s)
Personal Militar , Trastornos por Estrés Postraumático , Humanos , Intento de Suicidio , Ideación Suicida , Irak , Guerra de Irak 2003-2011 , Factores de Riesgo
20.
Arthritis Care Res (Hoboken) ; 75(3): 667-673, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-34606694

RESUMEN

OBJECTIVE: Previous research with civilian populations has found strong associations between fibromyalgia (FM) and posttraumatic stress disorder (PTSD). We undertook this study to investigate the prevalence of FM in military service members with and without PTSD. METHODS: Participants were active duty military personnel recruited into either an epidemiologic cohort study of service members before a military deployment or 1 of 3 PTSD treatment trials. Instruments used to document FM and PTSD included the PTSD Checklist-Stressor-Specific Version, the PTSD Symptom Scale-Interview, and the 2012 American College of Rheumatology FM questionnaire. RESULTS: Across the 4 studies, 4,376 subjects completed surveys. The prevalence of FM was 2.9% in the predeployment cohort, and the prevalence was significantly higher in individuals with PTSD (10.8%) compared with those without PTSD (0.8%). In the treatment trials, all of the participants met criteria for PTSD before starting treatment, and the prevalence of FM was 39.7%. CONCLUSION: The prevalence of FM in active duty service members preparing to deploy is similar to that reported for the general population of the US but is higher than expected for a predominantly male cohort. Furthermore, the prevalence of FM was significantly higher in service members with comorbid PTSD and was highest among those seeking treatment for PTSD. Further investigation is needed to determine the factors linking PTSD and FM.


Asunto(s)
Fibromialgia , Personal Militar , Trastornos por Estrés Postraumático , Humanos , Masculino , Femenino , Fibromialgia/diagnóstico , Fibromialgia/epidemiología , Estudios de Cohortes , Prevalencia , Trastornos por Estrés Postraumático/diagnóstico , Trastornos por Estrés Postraumático/epidemiología , Trastornos por Estrés Postraumático/terapia
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