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1.
Cancer ; 2024 Jul 10.
Article in English | MEDLINE | ID: mdl-38985726

ABSTRACT

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a cutaneous sarcoma with an infiltrative growth pattern that makes it challenging to clear margins. High quality data regarding DFSP natural history, management, and outcomes are limited. METHODS: Data were retrospectively collected for adult DFSP patients who underwent resection at 10 institutions in eight countries. Demographics, tumor characteristics, treatment strategies, and outcomes were analyzed. RESULTS: Analysis included 347 patients consisting of young (median, 42 years), White (76.2%), males (54.2%) with truncal lesions (57.3%). The majority (76.8%) were symptomatic at presentation. Preoperative imaging was used in 55.9% of cases. Diagnosis was established with excisional biopsy in 50.9% versus incisional biopsy in 25.0% of cases. Despite planned margins of >1.0 cm in 67.4% of cases, only 69.0% of patients achieved R0 resection. Twenty-two percent of patients underwent at least one re-excision. R0 resection was achieved at a second procedure in 80.2% and a third procedure in 86.2%. Ultimately, R0 resection was feasible in 89.5% of all patients. Fibrosarcomatous transformation (FST) was observed in 12.6%. In total, 6.6% (N = 23) recurred (17 local, six distant). Of the six distant recurrences, 50.0% had FST. With a median follow-up of 47.0 months, disease-specific survival rate was 98.8%. In multivariable analysis, R0 margins at index resection were associated with wider circumferential margins and non-FST histology. CONCLUSIONS: In this international, multicenter collaborative, DFSP practice patterns were heterogeneous but achieved favorable recurrence rates and survival. Multiple excisions to clear margins remain commonplace and can inform future efforts to optimize margin selection.

3.
J Public Health Manag Pract ; 30: S71-S79, 2024.
Article in English | MEDLINE | ID: mdl-38870363

ABSTRACT

CONTEXT: Self-monitoring blood pressure (SMBP) programs are an evidence-based hypertension management intervention facilitated through telehealth. SMBP programs can provide a continuum of care beyond a clinical setting by facilitating hypertension management at home; however, equitable access to SMBP is a concern. OBJECTIVES: To evaluate the implementation of telehealth SMBP programs using an equity lens in 5 federally qualified health centers (FQHCs) in Massachusetts (MA). DESIGN: A prospective case series study. SETTING: Five FQHCs. PARTICIPANTS: The MA Department of Public Health (MDPH) selected 5 FQHCs to implement SMBP programs using telehealth. FQHCs were selected if their patient population experiences inequities due to social determinants of health and has higher rates of cardiovascular disease. Each of the 5 FQHCs reported data on patients enrolled in their SMBP programs totaling 241 patients examined in this study. INTERVENTION: SMBP programs implemented through telehealth. MAIN OUTCOME MEASURE: Systolic blood pressure and diastolic blood pressure. RESULTS: Approximately 53.5% of SMBP participants experienced a decrease in blood pressure. The average blood pressure decreased from 146/87 to 136/81 mm Hg. Among all patients across the 5 FQHCs, the average blood pressure decreased by 10.06/5.34 mm Hg (P < .001). Blood pressure improved in all racial, ethnic, and language subgroups. CONCLUSIONS: Five MA FQHCs successfully implemented equitable telehealth SMBP programs. SMBP participants enrolled in the programs demonstrated notable improvements in their blood pressure at the conclusion of the program. A flexible, pragmatic study design that was adjusted to meet unique patient needs; engaging nonphysician team members, particularly community health workers; adapting health information technology; and partnerships with community-based organizations were critical facilitators to program success.


Subject(s)
Hypertension , Telemedicine , Humans , Telemedicine/statistics & numerical data , Prospective Studies , Female , Male , Middle Aged , Hypertension/therapy , Massachusetts , Aged , Blood Pressure Monitoring, Ambulatory/methods , Blood Pressure Monitoring, Ambulatory/statistics & numerical data , Adult , Self Care/methods , Blood Pressure/physiology
4.
Am J Surg ; 2024 Apr 27.
Article in English | MEDLINE | ID: mdl-38719681

ABSTRACT

BACKGROUND: It remains unclear why female general surgery residents perform fewer cases than male peers. This exploratory study investigated possible contributors to gender-based disparities and solutions for improving equity in operative experience. METHODS: Surveys, including Likert scale and free-text questions, were distributed to 21 accredited general surgery residency programs. RESULTS: There were 96 respondents, of whom 69% were female. 22% of females personally experienced barriers to operative experience versus 13% of males (p â€‹= â€‹0.41), while 52% of female residents believed operative training was affected by gender (p â€‹= â€‹0.004). Inductive analysis revealed the most common barrier to operating room participation was floor work/clinical tasks. The most common barrier for female residents was perceived sexism/gender bias, with subthemes of "misidentification," "feeling unwelcome," and "poor trust/autonomy." To improve parity, residents proposed structured program-level review, feedback, and transparent expectations about case assignments. CONCLUSION: Female general surgery residents believe gender bias impacts training. Further mixed-methods research is crucial to determine the cause of gender-based disparities in operative experience.

5.
Phytopathology ; 2024 May 21.
Article in English | MEDLINE | ID: mdl-38772042

ABSTRACT

The breeding of disease-resistant soybeans cultivars to manage Phytophthora root and stem rot caused by the pathogen Phytophthora sojae involves combining quantitative disease resistance (QDR) and Rps gene-mediated resistance. To identify and confirm potential mechanisms of QDR towards P. sojae, we conducted a time course study comparing changes in gene expression among Conrad and M92-220 with high QDR to susceptible genotypes, Sloan and 3 mutants derived from fast neutron (FN) irradiation of M92-220. Differentially expressed genes from Conrad and M92-220 indicated several shared defense-related pathways at the transcriptomic level, but also defense pathways unique to each cultivar such as stilbenoid, diarylheptanoid and gingerol biosynthesis, and monobactam biosynthesis. Gene Ontology pathway analysis showed that the susceptible FN mutants lacked enrichment of three terpenoid related-pathways and two cell wall-related pathways at either one or both timepoints, in contrast to M92-220. The susceptible mutants also lacked enrichment of potentially important KEGG pathways at either one or both timepoints, including sesquiterpenoid and triterpenoid biosynthesis, thiamine metabolism, arachidonic acid, stilbenoid, diarylheptanoid and gingerol biosynthesis, and monobactam biosynthesis. Additionally, thirty-one genes which were differentially expressed in M92-220 following P. sojae infection were not expressed in the mutants. These 31 genes have annotations related to unknown proteins, valine, leucine, and isoleucine biosynthesis and protein and lipid metabolic processes. The results of this study confirm previously proposed mechanisms of QDR, provide evidence for potential novel QDR pathways in M92-220, and furthers our understanding of the complex network associated with QDR mechanisms in soybean towards P. sojae.

6.
BMC Health Serv Res ; 24(1): 670, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38807237

ABSTRACT

BACKGROUND: Despite advances in cancer research and treatment, the burden of cancer is not evenly distributed. People experiencing socioeconomic disadvantage have higher rates of cancer, later stage at diagnoses, and are dying of cancers that are preventable and screen-detectable. However, less is known about barriers to accessing cancer treatment. METHODS: We conducted a scoping review of studies examining barriers to accessing cancer treatment for populations experiencing socioeconomic disadvantage in high-income countries, searched across four biomedical databases. Studies published in English between 2008 and 2021 in high-income countries, as defined by the World Bank, and reporting on barriers to cancer treatment were included. RESULTS: A total of 20 studies were identified. Most (n = 16) reported data from the United States, and the remaining included publications were from Canada (n = 1), Ireland (n = 1), United Kingdom (n = 1), and a scoping review (n = 1). The majority of studies (n = 9) focused on barriers to breast cancer treatment. The most common barriers included: inadequate insurance and financial constraints (n = 16); unstable housing (n = 5); geographical distribution of services and transportation challenges (n = 4); limited resources for social care needs (n = 7); communication challenges (n = 9); system disintegration (n = 5); implicit bias (n = 4); advanced diagnosis and comorbidities (n = 8); psychosocial dimensions and contexts (n = 6); and limited social support networks (n = 3). The compounding effect of multiple barriers exacerbated poor access to cancer treatment, with relevance across many social locations. CONCLUSION: This review highlights barriers to cancer treatment across multiple levels, and underscores the importance of identifying patients at risk for socioeconomic disadvantage to improve access to treatment and cancer outcomes. Findings provide an understanding of barriers that can inform future, equity-oriented policy, practice, and service innovation.


Subject(s)
Developed Countries , Health Services Accessibility , Neoplasms , Humans , Neoplasms/therapy , Socioeconomic Factors , Healthcare Disparities , Female , Socioeconomic Disparities in Health
7.
Vet Surg ; 53(5): 844-851, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38641961

ABSTRACT

OBJECTIVE: The objective was to describe the successful thoracoscopic treatment of esophageal entrapment resulting from a vascular ring anomaly (VRA) comprising a persistent right aortic arch (PRAA) and left ligamentum arteriosum (LA) in a Babydoll sheep wether. STUDY DESIGN: Case report. ANIMAL: Eight month old Babydoll sheep wether, 13 kg. METHODS: The patient presented with a weight half that of its sibling, persistent regurgitation following eating, and delayed growth noted from the age of approximately 2 months, coinciding with the introduction of solid feed into the diet. Plain thoracic radiographs were within normal limits but computed tomography angiography (CTA) confirmed multiple congenital vascular anomalies. The primary finding was esophageal and tracheal entrapment by a PRAA and left LA. Thoracoscopic transection of the LA was performed with a bipolar vessel sealing device with the aid of transesophageal endoscopy. RESULTS: Immediate improvement in attitude and absence of regurgitation were observed. The patient was discharged and subsequently reintroduced to grazing and long-stem hay, which were previously not tolerated. By 6 months post discharge, the patient's weight was 36 kg, comparable to an age-matched sibling and considered appropriate for the stage of growth. CONCLUSION: Thoracoscopic transection of the LA in sheep is a feasible treatment for esophageal compression resulting from a VRA. Surgical intervention resolved the clinical signs and allowed normal digestive rumination, restoring bidirectional esophageal function in a ruminant.


Subject(s)
Thoracoscopy , Animals , Thoracoscopy/veterinary , Thoracoscopy/methods , Sheep , Vascular Ring/veterinary , Vascular Ring/surgery , Sheep Diseases/surgery , Male , Female , Aorta, Thoracic/surgery , Aorta, Thoracic/abnormalities
8.
NPJ Parkinsons Dis ; 10(1): 76, 2024 Apr 03.
Article in English | MEDLINE | ID: mdl-38570511

ABSTRACT

Dementia with Lewy bodies (DLB) is a neurodegenerative condition often co-occurring with Alzheimer's disease (AD) pathology. Characterizing white matter tissue microstructure using Neurite Orientation Dispersion and Density Imaging (NODDI) may help elucidate the biological underpinnings of white matter injury in individuals with DLB. In this study, diffusion tensor imaging (DTI) and NODDI metrics were compared in 45 patients within the dementia with Lewy bodies spectrum (mild cognitive impairment with Lewy bodies (n = 13) and probable dementia with Lewy bodies (n = 32)) against 45 matched controls using conditional logistic models. We evaluated the associations of tau and amyloid-ß with DTI and NODDI parameters and examined the correlations of AD-related white matter injury with Clinical Dementia Rating (CDR). Structural equation models (SEM) explored relationships among age, APOE ε4, amyloid-ß, tau, and white matter injury. The DLB spectrum group exhibited widespread white matter abnormalities, including reduced fractional anisotropy, increased mean diffusivity, and decreased neurite density index. Tau was significantly associated with limbic and temporal white matter injury, which was, in turn, associated with worse CDR. SEM revealed that amyloid-ß exerted indirect effects on white matter injury through tau. We observed widespread disruptions in white matter tracts in DLB that were not attributed to AD pathologies, likely due to α-synuclein-related injury. However, a fraction of the white matter injury could be attributed to AD pathology. Our findings underscore the impact of AD pathology on white matter integrity in DLB and highlight the utility of NODDI in elucidating the biological basis of white matter injury in DLB.

9.
Neurol Clin Pract ; 14(3): e200292, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38617555

ABSTRACT

Background and Objectives: Dementia with Lewy bodies (DLB) is a common degenerative dementia, but research on caregiver experiences in late stages is lacking. This study aimed to investigate the caregiving experience in moderate-advanced DLB to identify opportunities for improving care and support. Methods: Dyads of individuals with moderate-advanced DLB and their primary informal caregivers were recruited from specialty clinics, advocacy organizations, and research registries. The study collected demographics, disease-related measures, and measures of the caregiver experience relating to caregiver support, burden, grief, self-efficacy, depression, quality of life, and coping. Spearman correlation coefficients and Wilcoxon rank-sum tests evaluated the relationships of caregiver measures with patient and caregiver variables with adjustments for multiple testing. Results: Caregivers (n = 143) were mostly women (83.5%) and spouses (84.7%) (mean age 68 years; range 37-85). Almost 40% reported high burden and/or depression. Caregiver measures correlated with fluctuation and behavioral symptom severity, sleepiness, and autonomic symptoms of the person with DLB. Higher burden correlated with worse caregiver quality of life, higher depression, and grief. Greater self-efficacy, social support, and resilience correlated with lower caregiver burden. The most frequently reported caregiver concerns were being unable to plan for the future, having to put the needs of the person with DLB ahead of the caregiver's own needs, and worry that the person with DLB would become too dependent on the caregiver, but many additional concerns were endorsed. Caregivers were generally satisfied with medical team support. The lowest reported satisfaction related to information regarding disease progression and how well medical teams shared information with each other. Discussion: Various patient-related and caregiver-related factors influence caregiver experiences in moderate-advanced DLB. Clinicians can target caregiver needs by providing support resources and DLB education and treating bothersome patient symptoms. Future research should investigate what interventions can modify and improve caregiver experiences in advanced DLB and identify therapeutics for patient symptoms currently without adequate treatments (e.g., fluctuations, daytime sleepiness). Trial Registration Information: NCT04829656.

10.
bioRxiv ; 2024 Mar 11.
Article in English | MEDLINE | ID: mdl-38559000

ABSTRACT

The evolution of SARS-CoV-2 variants and their respective phenotypes represents an important set of tools to understand basic coronavirus biology as well as the public health implications of individual mutations in variants of concern. While mutations outside of Spike are not well studied, the entire viral genome is undergoing evolutionary selection, particularly the central disordered linker region of the nucleocapsid (N) protein. Here, we identify a mutation (G215C), characteristic of the Delta variant, that introduces a novel cysteine into this linker domain, which results in the formation of a disulfide bond and a stable N-N dimer. Using reverse genetics, we determined that this cysteine residue is necessary and sufficient for stable dimer formation in a WA1 SARS-CoV-2 background, where it results in significantly increased viral growth both in vitro and in vivo. Finally, we demonstrate that the N:G215C virus packages more nucleocapsid per virion and that individual virions are larger, with elongated morphologies.

12.
Res Child Adolesc Psychopathol ; 52(7): 1105-1117, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38478358

ABSTRACT

Irritability is a common presenting problem in youth mental health settings that is thought to include two components: tonic (e.g., irritable, touchy mood) and phasic (e.g., temper outbursts), each with unique correlates and outcomes, including later internalizing and externalizing problems, respectively. However, we are unaware of any studies of early predictors of tonic and phasic irritability. We utilized data from a longitudinal study of a community sample of 3-year-old children followed to age 15 (n = 444). We conducted confirmatory factor analysis (CFA) of items from several self-report irritability measures at age 15, including the Affective Reactivity Index, the International Personality Item Pool, the Schedule for Non-Adaptive and Adaptive Personality Youth Version, and the Child Depression Inventory, and examined their early childhood predictors. The CFA identified dimensions consistent with tonic and phasic irritability. Tonic irritability at age 15 was uniquely associated with concurrent internalizing disorders and suicidal behavior while phasic irritability was uniquely associated with concurrent externalizing disorders. When adolescent tonic and phasic irritability were examined together, female sex and parental depressive and substance use disorders at age 3 uniquely predicted adolescent tonic irritability. Additionally, male sex, less parental education, greater laboratory-observed anger and impulsivity, ODD symptoms, higher irritability, and no parental substance use history at age 3 uniquely predicted adolescent phasic irritability. Youth-reported tonic and phasic irritability at age 15 appear to be distinguishable constructs with distinct concurrent correlates and early antecedents. Findings have important implications for research on the etiology of irritability and developing effective treatments.


Subject(s)
Irritable Mood , Humans , Irritable Mood/physiology , Male , Female , Adolescent , Child, Preschool , Longitudinal Studies , Risk Factors , Sex Factors , Substance-Related Disorders/psychology , Factor Analysis, Statistical , Child
13.
J Clin Invest ; 134(8)2024 Mar 05.
Article in English | MEDLINE | ID: mdl-38441967

ABSTRACT

Antitumor responses of CD8+ T cells are tightly regulated by distinct metabolic fitness. High levels of glutathione (GSH) are observed in the majority of tumors, contributing to cancer progression and treatment resistance in part by preventing glutathione peroxidase 4-dependent (GPX4-dependent) ferroptosis. Here, we show the necessity of adenosine A2A receptor (A2AR) signaling and the GSH/GPX4 axis in orchestrating metabolic fitness and survival of functionally competent CD8+ T cells. Activated CD8+ T cells treated ex vivo with simultaneous inhibition of A2AR and lipid peroxidation acquire a superior capacity to proliferate and persist in vivo, demonstrating a translatable means to prevent ferroptosis in adoptive cell therapy. Additionally, we identify a particular cluster of intratumoral CD8+ T cells expressing a putative gene signature of GSH metabolism (GMGS) in association with clinical response and survival across several human cancers. Our study addresses a key role of GSH/GPX4 and adenosinergic pathways in fine-tuning the metabolic fitness of antitumor CD8+ T cells.


Subject(s)
Neoplasms , Receptor, Adenosine A2A , Humans , Phospholipid Hydroperoxide Glutathione Peroxidase/metabolism , Receptor, Adenosine A2A/genetics , Receptor, Adenosine A2A/metabolism , Neoplasms/genetics , Neoplasms/therapy , Neoplasms/metabolism , CD8-Positive T-Lymphocytes/metabolism , Glutathione/metabolism
14.
Nat Commun ; 15(1): 1987, 2024 Mar 05.
Article in English | MEDLINE | ID: mdl-38443336

ABSTRACT

Abundant macrophage infiltration and altered tumor metabolism are two key hallmarks of glioblastoma. By screening a cluster of metabolic small-molecule compounds, we show that inhibiting glioblastoma cell glycolysis impairs macrophage migration and lactate dehydrogenase inhibitor stiripentol emerges as the top hit. Combined profiling and functional studies demonstrate that lactate dehydrogenase A (LDHA)-directed extracellular signal-regulated kinase (ERK) pathway activates yes-associated protein 1 (YAP1)/ signal transducer and activator of transcription 3 (STAT3) transcriptional co-activators in glioblastoma cells to upregulate C-C motif chemokine ligand 2 (CCL2) and CCL7, which recruit macrophages into the tumor microenvironment. Reciprocally, infiltrating macrophages produce LDHA-containing extracellular vesicles to promote glioblastoma cell glycolysis, proliferation, and survival. Genetic and pharmacological inhibition of LDHA-mediated tumor-macrophage symbiosis markedly suppresses tumor progression and macrophage infiltration in glioblastoma mouse models. Analysis of tumor and plasma samples of glioblastoma patients confirms that LDHA and its downstream signals are potential biomarkers correlating positively with macrophage density. Thus, LDHA-mediated tumor-macrophage symbiosis provides therapeutic targets for glioblastoma.


Subject(s)
Glioblastoma , Animals , Humans , Mice , Glioblastoma/genetics , L-Lactate Dehydrogenase/genetics , Lactate Dehydrogenase 5 , Lactic Acid , Symbiosis , Tumor Microenvironment
15.
Alzheimers Dement ; 20(4): 2485-2496, 2024 04.
Article in English | MEDLINE | ID: mdl-38329197

ABSTRACT

INTRODUCTION: Patients with dementia with Lewy bodies (DLB) may have Alzheimers disease (AD) pathology that can be detected by plasma biomarkers. Our objective was to evaluate plasma biomarkers of AD and their association with positron emission tomography (PET) biomarkers of amyloid and tau deposition in the continuum of DLB, starting from prodromal stages of the disease. METHODS: The cohort included patients with isolated rapid eye movement (REM) sleep behavior disorder (iRBD), mild cognitive impairment with Lewy bodies (MCI-LB), or DLB, with a concurrent blood draw and PET scans. RESULTS: Abnormal levels of plasma glial fibrillary acidic protein (GFAP) were found at the prodromal stage of MCI-LB in association with increased amyloid PET. Abnormal levels of plasma phosphorylated tau (p-tau)-181 and neurofilament light (NfL) were found at the DLB stage. Plasma p-tau-181 showed the highest accuracy in detecting abnormal amyloid and tau PET in patients with DLB. DISCUSSION: The range of AD co-pathology can be detected with plasma biomarkers in the DLB continuum, particularly with plasma p-tau-181 and GFAP.


Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Lewy Body Disease , REM Sleep Behavior Disorder , Humans , Alzheimer Disease/diagnosis , Lewy Body Disease/diagnosis , Amyloid beta-Peptides , tau Proteins , Biomarkers/metabolism , Cognitive Dysfunction/diagnosis
16.
J Child Health Care ; : 13674935241231346, 2024 Feb 06.
Article in English | MEDLINE | ID: mdl-38319137

ABSTRACT

Research partnerships between researchers and knowledge users (KUs) in child health are understudied. This study examined the scope of KU engagement reported in published child health research, inclusive of health research partnership approaches and KU groups. Search strategies were developed by a health research librarian. Studies had to be in English, published since 2007, and were not excluded based on design. A two-step, multiple-person hybrid screening approach was used for study inclusion. Data on study and engagement characteristics, barriers and facilitators, and effects were extracted by one reviewer, with 10% verified by a second reviewer. Three hundred fifteen articles were included, with 243 (77.1%) published between 2019 and 2021. Community-based participatory research was the most common approach used (n = 122, 38.3%). Most studies (n = 235, 74.6%) engaged multiple KU groups (range 1-11), with children/youth, healthcare professionals, and parents/families being most frequently engaged. Reporting of barriers and facilitators and effects were variable, reported in 170 (53.8%) and 197 (62.5%) studies, respectively. Publications have increased exponentially over time. There is ongoing need to optimize evaluation and reporting consistency to facilitate growth in the field. Additional studies are needed to further our understanding of research partnerships in child health.

17.
Sleep ; 47(6)2024 Jun 13.
Article in English | MEDLINE | ID: mdl-38181205

ABSTRACT

STUDY OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g. Parkinson's disease (PD), Lewy body dementia, and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD)-henceforth "neurotrauma" (NT)-increase the odds of RBD by ~2.5-fold and are associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD. METHODS: Participants ≥18 years with overnight polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal Synucleinopathy Consortium. Standardized assessments for RBD, TBI, and PTSD history, as well as cognitive, motor, sensory, and autonomic function, were completed. This cross-sectional analysis compared cases (n = 24; RBD + NT) to controls (n = 96; RBD), matched for age (~60 years), sex (15% female), and years of education (~15 years). RESULTS: RBD + NT reported earlier RBD symptom onset (37.5 ±â€…11.9 vs. 52.2 ±â€…15.1 years of age) and a more severe RBD phenotype. Similarly, RBD + NT reported more severe anxiety and depression, greater frequency of hypertension, and significantly worse cognitive, motor, and autonomic function compared to RBD. No differences in olfaction or color vision were observed. CONCLUSIONS: This cross-sectional, matched case:control study shows individuals with RBD + NT have significantly worse neurological measures related to common features of an overt synucleinopathy. Confirmatory longitudinal studies are ongoing; however, these results suggest RBD + NT may be associated with more advanced neurological symptoms related to an evolving neurodegenerative process.


Subject(s)
REM Sleep Behavior Disorder , Humans , REM Sleep Behavior Disorder/epidemiology , REM Sleep Behavior Disorder/physiopathology , Male , Female , Middle Aged , Cross-Sectional Studies , Aged , Brain Injuries, Traumatic/complications , Brain Injuries, Traumatic/physiopathology , Synucleinopathies/physiopathology , Synucleinopathies/epidemiology , Synucleinopathies/complications , Stress Disorders, Post-Traumatic/epidemiology , Stress Disorders, Post-Traumatic/physiopathology , Prodromal Symptoms , Polysomnography , Comorbidity , Autonomic Nervous System Diseases/epidemiology , Autonomic Nervous System Diseases/physiopathology , Cognitive Dysfunction/epidemiology , Cognitive Dysfunction/physiopathology , Cognitive Dysfunction/etiology , Parkinson Disease/complications , Parkinson Disease/physiopathology , Parkinson Disease/epidemiology
18.
EMBO Rep ; 25(2): 902-926, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38177924

ABSTRACT

Viruses interact with numerous host factors to facilitate viral replication and to dampen antiviral defense mechanisms. We currently have a limited mechanistic understanding of how SARS-CoV-2 binds host factors and the functional role of these interactions. Here, we uncover a novel interaction between the viral NSP3 protein and the fragile X mental retardation proteins (FMRPs: FMR1, FXR1-2). SARS-CoV-2 NSP3 mutant viruses preventing FMRP binding have attenuated replication in vitro and reduced levels of viral antigen in lungs during the early stages of infection. We show that a unique peptide motif in NSP3 binds directly to the two central KH domains of FMRPs and that this interaction is disrupted by the I304N mutation found in a patient with fragile X syndrome. NSP3 binding to FMRPs disrupts their interaction with the stress granule component UBAP2L through direct competition with a peptide motif in UBAP2L to prevent FMRP incorporation into stress granules. Collectively, our results provide novel insight into how SARS-CoV-2 hijacks host cell proteins and provides molecular insight into the possible underlying molecular defects in fragile X syndrome.


Subject(s)
COVID-19 , Fragile X Syndrome , Humans , Fragile X Mental Retardation Protein/genetics , Fragile X Mental Retardation Protein/metabolism , Fragile X Syndrome/genetics , Fragile X Syndrome/metabolism , Peptides/metabolism , RNA-Binding Proteins/genetics , SARS-CoV-2
19.
J Am Vet Med Assoc ; 262(4): 1-3, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38266389

ABSTRACT

OBJECTIVE: Synovial extramedullary hematopoiesis is a rarely reported condition in humans and, to date, has never been reported in canines. This case report describes the clinical presentation, diagnostic work-up, treatment, and outcome of a canine case confirmed to have hematopoietic tissue within multiple joints. ANIMAL: A client-owned canine. CLINICAL PRESENTATION, PROGRESSION, AND PROCEDURES: The clinical presentation was most consistent with immune-mediated polyarthritis, and arthrocentesis was performed in multiple joints for cytological evaluation and culture. Cytology revealed evidence of extramedullary hematopoiesis, and shortly thereafter the dog was diagnosed with immune-mediated hemolytic anemia and thrombocytopenia. TREATMENT AND OUTCOME: Pregabalin, prednisolone, clopidogrel, and cyclosporine were started, and after several recheck appointments and dose adjustments, the dog's clinical signs resolved for all conditions. CLINICAL RELEVANCE: Unusual sites of extramedullary hematopoietic tissue may result in a clinical presentation for which more traditional etiologies and differentials are not applicable.


Subject(s)
Anemia , Dog Diseases , Hematopoiesis, Extramedullary , Humans , Dogs , Animals , Bone Marrow , Anemia/veterinary , Dog Diseases/diagnosis
20.
Child Abuse Negl ; 150: 106353, 2024 04.
Article in English | MEDLINE | ID: mdl-37482505

ABSTRACT

BACKGROUND: Adverse Childhood Experiences are traumatic events early in life and have been associated with significant negative health outcomes. OBJECTIVE: To estimate the prevalence of ACEs in five low- and middle-income sub-Saharan African countries. PARTICIPANTS AND SETTING: Nationally representative data from the Cote d'Ivoire (2018), Kenya (2019), Lesotho (2018), Mozambique (2019), and Namibia (2019) Violence Against Children and Youth Surveys (VACS) were used. Analyses were restricted to youth ages 18-24 years (n = 8766 females and 2732 males). METHODS: VACS data were analyzed to generate sex-stratified weighted prevalence of individual ACEs (including sexual, physical, and emotional violence; witnessing interparental violence and violence in the community; and orphanhood) and aggregate ACEs (total ACEs; 0, 1-2, and 3 or more), for each country and combined. RESULTS: The most common type of ACEs among both females and males was witnessing physical violence (males: 55.0 % [95 % CI: 51.1-58.8] and females: 37.2 % [95 % CI = 34.3-40.1]) followed by experiencing physical violence (males: 49.7 % [95 % CI = 45.5-53.9] and in females: 36.5 % [95 % CI = 33.8-39.2]). Prevalence of sexual violence was significantly higher in females than in males (16.0 % [95 % CI = 13.9-18.2] vs 8.3 % [95 % CI = 7.0-9.8]; p < 0.001). About 72 % of females and 82 % of males have experienced at least one form of ACE with 20 % of females and 24.2 % of males experiencing 3 or more ACEs. CONCLUSION: This study demonstrated that majority of the children in countries in sub-Saharan Africa have experienced multiple ACEs in their lifetime. Understanding the extent of the problem will help design early interventions to reduce childhood exposure to ACEs or mitigate against the harmful impact of ACEs.


Subject(s)
Adverse Childhood Experiences , Sex Offenses , Male , Child , Female , Humans , Adolescent , Prevalence , Violence , Sex Offenses/psychology , Kenya
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