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BACKGROUND: Obesity and type 2 diabetes mellitus (T2DM) are risk factors for severe COVID-19 infection. Bariatric surgery (BSG) is an effective treatment of obesity through weight loss and may reduce COVID-19 severity. OBJECTIVES: We examined the effect of BSG on COVID-19 outcomes in patients with or at risk of T2DM. SETTING: Electronic health record data from the PaTH Clinical Data Research Network, a partnership of 5 health systems reviewed from March 1, 2020, to December 31, 2020. METHODS: Ambulatory and in-hospital patient encounters with COVID-19 diagnosis and obesity were identified. We constructed 2 patient groups: BSG and non-BSG (NBSG). The BSG group included patients with at least 1 encounter for the BSG procedure code and/or 1 BSG diagnosis code; the NBSG group included patients with no procedure or diagnosis code for BSG with body mass index (BMI) ≥40 or BMI ≥35 and at least 2 obesity-related co-morbidities. We matched 1 patient in the BSG group to 2 patients in the NBSG group based on age, gender (sex defined at birth), race and ethnicity, group (T2DM and at risk of T2DM), and site. The primary outcome was 30-day outcomes of COVID-19 severity. RESULTS: After matching, we found that patients with BSG had lower odds of respiratory failure (41%) and ventilation/intensive care unit (ICU) admission/death (52%). Patients in the BSG group had lower odds of hospitalization, pneumonia, respiratory failure, and the most severe COVID-19 outcomes combined (ventilation/ICU admission/death). T2DM was identified as a risk factor for COVID-19 severity in the BSG group. CONCLUSIONS: This retrospective, matched-cohort analysis found BSG to have a protective effect against severe COVID-19 outcomes.
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BACKGROUND: Despite continuing advancements in treatments for opioid use disorder (OUD), continued high rates of relapse indicate the need for more effective approaches, including novel pharmacological interventions. Glucagon-like peptide 1 receptor agonists (GLP-1RA) provide a promising avenue as a non-opioid medication for the treatment of OUD. Whereas GLP-1RAs have shown promise as a treatment for alcohol and nicotine use disorders, to date, no controlled clinical trials have been conducted to determine if a GLP-1RA can reduce craving in individuals with OUD. The purpose of the current protocol was to evaluate the potential for a GLP-1RA, liraglutide, to safely and effectively reduce craving in an OUD population in residential treatment. METHOD: This preliminary study was a randomized, double-blinded, placebo-controlled clinical trial designed to test the safety and efficacy of the GLP-1RA, liraglutide, in 40 participants in residential treatment for OUD. Along with taking a range of safety measures, efficacy for cue-induced craving was evaluated prior to (Day 1) and following (Day 19) treatment using a Visual Analogue Scale (VAS) in response to a cue reactivity task during functional near-infrared spectroscopy (fNIRS) and for craving. Efficacy of treatment for ambient craving was assessed using Ecological Momentary Assessment (EMA) prior to (Study Day 1), across (Study Days 2-19), and following (Study Days 20-21) residential treatment. DISCUSSION: This manuscript describes a protocol to collect clinical data on the safety and efficacy of a GLP-1RA, liraglutide, during residential treatment of persons with OUD, laying the groundwork for further evaluation in a larger, outpatient OUD population. Improved understanding of innovative, non-opioid based treatments for OUD will have the potential to inform community-based interventions and health policy, assist physicians and health care professionals in the treatment of persons with OUD, and to support individuals with OUD in their effort to live a healthy life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04199728. Registered 16 December 2019, https://clinicaltrials.gov/study/NCT04199728?term=NCT04199728 . PROTOCOL VERSION: 10 May 2023.
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Fissura , Sinais (Psicologia) , Avaliação Momentânea Ecológica , Receptor do Peptídeo Semelhante ao Glucagon 1 , Liraglutida , Transtornos Relacionados ao Uso de Opioides , Humanos , Fissura/efeitos dos fármacos , Método Duplo-Cego , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Liraglutida/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Feminino , Masculino , Adulto , Tratamento Domiciliar/métodos , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
INTRODUCTION: The substantia nigra pars compacta (SNc) is the key pathologic locus in neurodegenerative parkinsonian disorders. Recently, in vivo susceptibility MRI metrics were associated with postmortem glial cell density and tau burden in the SNc of parkinsonism subjects. This study investigated the red nucleus (RN), another iron-rich region adjacent to the SNc and a potential site of higher functionality in parkinsonisms. METHODS: In vivo MRI and postmortem data were obtained from 34 parkinsonism subjects and 3 controls. Neuron density, glial cell density, and percentages of area occupied by α-synuclein and tau were quantified using digitized midbrain slides. R2* and quantitative susceptibility mapping (QSM) metrics in the RN and SNc were derived from multi-gradient echo images. Histopathology data were compared between the RN and SNc using paired t-tests. MRI-histology associations were analyzed using partial Pearson correlations. RESULTS: The RN had greater neuron (t23 = 3.169, P = 0.004) and glial cell densities (t23 = 2.407, P = 0.025) than the SNc, whereas the SNc had greater α-synuclein (t28 = 4.614, P < 0.0001) and tau burden (t24 = 4.513, P = 0.0001). In both the RN (R2*: r = 0.47, P = 0.043; QSM: r = 0.52, P = 0.024) and SNc (R2*: r = 0.57, P = 0.01; QSM: r = 0.58, P = 0.009), MRI values were associated with glial cell density but not neuron density or α-synuclein (Ps > 0.092). QSM associated with tau burden (r = 0.49, P = 0.038) in the SNc, but not the RN. CONCLUSIONS: The RN is resilient to parkinsonian-related pathological processes compared to the SNc, and susceptibility MRI captured glial cell density in both regions. These findings help to further our understanding of the underlying pathophysiological processes in parkinsonisms.
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Imageamento por Ressonância Magnética , Transtornos Parkinsonianos , Parte Compacta da Substância Negra , Núcleo Rubro , Substância Negra , Humanos , Núcleo Rubro/diagnóstico por imagem , Núcleo Rubro/patologia , Núcleo Rubro/metabolismo , Masculino , Idoso , Feminino , Parte Compacta da Substância Negra/diagnóstico por imagem , Parte Compacta da Substância Negra/patologia , Parte Compacta da Substância Negra/metabolismo , Idoso de 80 Anos ou mais , Pessoa de Meia-Idade , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/patologia , Transtornos Parkinsonianos/metabolismo , Substância Negra/diagnóstico por imagem , Substância Negra/patologia , Substância Negra/metabolismo , Proteínas tau/metabolismo , Neuroglia/patologia , Neuroglia/metabolismo , alfa-Sinucleína/metabolismo , Neurônios/patologia , Neurônios/metabolismoRESUMO
OBJECTIVE: Abnormal expression of T-lymphokine-activated killer cell-originated protein kinase (TOPK) was reported to be closely related to the resistance of prostate cancer to radiotherapy and to targeted drug resistance in lung cancer. However, the role of TOPK inhibition in enhancing radiosensitivity of colorectal cancer (CRC) cells is unclear. This study aimed to evaluate the radiosensitization of TOPK knockdown in CRC cells. METHODS: The expression of TOPK was detected in CRC tissues by immunohistochemistry, and the effect of TOPK knockdown was detected in CRC cells by Western blotting. CCK-8 and clonogenic assays were used to detect the growth and clonogenic ability of CRC cells after TOPK knockdown combined with radiotherapy in CRC cells. Furthermore, proteomic analysis showed that the phosphorylation of TOPK downstream proteins changed after radiotherapy. DNA damage was detected by the comet assay. Changes in the DNA damage response signaling pathway were analyzed by Western blotting, and apoptosis was detected by flow cytometry. RESULTS: The expression of TOPK was significantly greater in CRC tissues at grades 2-4 than in those at grade 1. After irradiation, CRC cells with genetically silenced TOPK had shorter comet tails and reduced expression levels of DNA damage response-associated proteins, including phospho-cyclin-dependent kinase 1 (p-CDK1), phospho-ataxia telangiectasia-mutated (p-ATM), poly ADP-ribose polymerase (PARP), and meiotic recombination 11 homolog 1 (MRE11). CONCLUSIONS: TOPK was overexpressed in patients with moderately to poorly differentiated CRC. Moreover, TOPK knockdown significantly enhanced the radiosensitivity of CRC cells by reducing the DNA damage response.
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Apoptose , Neoplasias Colorretais , Dano ao DNA , Tolerância a Radiação , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/radioterapia , Neoplasias Colorretais/patologia , Dano ao DNA/efeitos da radiação , Tolerância a Radiação/genética , Tolerância a Radiação/efeitos dos fármacos , Linhagem Celular Tumoral , Masculino , Técnicas de Silenciamento de Genes , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Transdução de Sinais , Feminino , Fosforilação , Quinases de Proteína Quinase Ativadas por MitógenoRESUMO
PURPOSE: To investigate the incidence of psychiatric diagnoses in relation to strabismus surgery timing among children with an early strabismus diagnosis who underwent surgery in childhood. METHODS: We conducted a retrospective cohort study using TriNetX network data from 2003-2023 on patients diagnosed with strabismus at ≤5 years of age and having strabismus surgery before 18 years of age. Cohort 1 comprised patients who underwent initial strabismus surgery at ≤6 years of age; cohort 2, patients with initial surgical intervention at ≥7 years of age. Incidence of mental health diagnoses from 7 until 18 years of age were compared between cohorts. RESULTS: In cohort 1, 59 of 688 patients (8.6%) of patients were diagnosed with at least 1 mental health disorder versus 123 of 693 patients (17.7%) in cohort 2 (risk ratio [RR] = 2.07; 95% CI, 1.546 to 2.77; P < 0.0001). Gender analysis showed that only males had a statistically significant increased rate of mental health diagnoses in cohort 2 versus cohort 1 (RR = 1.82; 95% CI, 1.284 to 2.577; P = 0.006). An increased risk for specific psychiatric diagnoses was found in cohort 2 versus cohort 1; anxiety disorders (RR = 2.19; 95% CI, 1.225-3.922; P = 0.0065), attention-deficit / hyperactivity disorder (RR = 2.18; 95% CI, 1.499-3.175; P < 0.0001), conduct disorders (RR = 2.81; 95% CI, 1.425-5.556; P = 0.0018), and adjustment disorders (RR = 2.07; 955% CI, 1.103-3.876; P = 0.0204). Depressive disorders showed no statistically significant difference between cohorts (RR = 1.00; 95% CI, 0.419-2.392; P = 0.9974). CONCLUSIONS: Compared with children having early strabismus surgery, those having surgery at a later age after an early strabismus diagnosis at ≤5 years of age may be more likely to experience a mental health disorder during childhood, although it is unclear whether such disorders are a result of delayed surgery or a driver of the decision to opt for surgery rather than continued conservative management.
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Transtornos Mentais , Procedimentos Cirúrgicos Oftalmológicos , Estrabismo , Humanos , Estudos Retrospectivos , Estrabismo/cirurgia , Masculino , Criança , Feminino , Adolescente , Pré-Escolar , Transtornos Mentais/epidemiologia , Incidência , Músculos Oculomotores/cirurgia , Lactente , Saúde Mental , Fatores de TempoRESUMO
Objective: Studies suggest that people with major depressive disorder (MDD) often receive treatment that is not concordant with practice guidelines. To evaluate this, we (1) developed a guideline concordance algorithm for MDD pharmacotherapy (GCA-8), (2) scored it using clinical data, and (3) compared its explanation of patient-reported symptom severity to a traditional concordance measure.Methods: This study evaluated 1,403 adults (67% female, 85% non-Hispanic/Latino White, mean age 43 years) with non-psychotic MDD (per ICD-10 codes), from the Penn State Psychiatry Clinical Assessment and Rating Evaluation System (PCARES) registry (visits from February 1, 2015, to April 13, 2021). We (1) scored 1-year concordance using the Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines and deviation from 8 pharmacotherapy-related criteria and (2) examined associations between concordance and Patient Health Questionnaire depression module (PHQ-9) scores.Results: The mean GCA-8 score was 6.37 (standard deviation [SD] = 1.30; 8.00 = perfect concordance). Among those who switched drugs (n = 671), 81% (n = 542) did not have their dose increased to the recommended maximum before switching. In our adjusted analyses, we found that a 1 SD increase in the GCA-8 was associated with a 0.78 improvement in the mean PHQ-9 score (P < .001). The comparison concordance measure was not associated with the mean PHQ-9 score (ß = -0.20; P = .20; R2 = 0.53), and adding the GCA-8 score significantly improved the model (R2 = 0.54; Vuong test P = .008).Conclusions: By measuring naturalistic MDD pharmacotherapy guideline concordance with the GCA-8, we revealed potential treatment gaps and an inverse association between guideline concordance and MDD symptom severity.
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Transtorno Depressivo Maior , Adulto , Feminino , Humanos , Masculino , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/tratamento farmacológico , Questionário de Saúde do Paciente , Guias de Prática Clínica como AssuntoRESUMO
OBJECTIVE: Little is known about deployment of SARS-CoV-2-neutralizing monoclonal antibodies (mab) in skilled nursing facilities (SNFs), a high-risk population for COVID-19-related complications. We assessed the utilization of mabs in SNFs and identified facility characteristics associated with effective use. DESIGN: Retrospective cohort study assessing the correlation of SNF characteristics with increasing mab use. SETTING AND PARTICIPANTS: United States SNFs participating in Project ECHO (Extensions for Community Health Outcomes). METHODS: The primary outcome was percentage of total mabs per COVID-19 cases in SNFs. Facilities were divided into 3 groups based on the percentage of the administration of mabs per number of cases: 0%, >0% to 20%, >20%. Ordinal logistic regression was applied to assess whether facility characteristics-study group, state, location, type, size, rating at baseline, weekly average of residents vaccinated, weekly average of staff vaccinated, and total weeks short staffed-correlated with the primary outcome. A multivariable model was used to evaluate the independent effect of predictors. RESULTS: A total of 130 facilities were included. Between the weeks ending on May 30, 2021, and on May 29, 2022, mean mab use when accounting for the number of COVID-19 cases was 12.96% (±26.71%) and >50% of facilities administered 0 doses of mabs. Facility location was associated with mab use (P value .030), with micropolitan facilities having the highest percentage of facilities administering mabs (30.4% in >0% to 20%, and 39.1% in >20%, respectively). There was a nonsignificant trend toward increased mab use in facilities reporting fewer staffing shortages. When the multivariable ordinal logistic regression model was applied, location in a micropolitan vs metropolitan area was associated with higher odds [3.29 (1.30, 8.32), P value .012] of increasing percentage total mabs per cases. CONCLUSIONS AND IMPLICATIONS: COVID-19 mabs were underutilized in a high-risk population for COVID-19 hospitalization and death. Understanding the barriers to effective distribution is critical in shaping pandemic preparedness efforts for the future.
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COVID-19 , Instituições de Cuidados Especializados de Enfermagem , Humanos , Estados Unidos/epidemiologia , SARS-CoV-2 , COVID-19/epidemiologia , Estudos Retrospectivos , HospitalizaçãoRESUMO
Background: Environmental exposure to metal mixtures is common and may be associated with increased risk for neurodegenerative disorders including Alzheimer's disease. Objective: This study examined associations of mixed metal exposures with medial temporal lobe (MTL) MRI structural metrics and neuropsychological performance. Methods: Metal exposure history, whole blood metal, and neuropsychological tests were obtained from subjects with/without a history of mixed metal exposure from welding fumes (42 exposed subjects; 31 controls). MTL structures (hippocampus, entorhinal and parahippocampal cortices) were assessed by morphologic (volume, cortical thickness) and diffusion tensor imaging [mean (MD), axial (AD), radial diffusivity (RD), and fractional anisotropy (FA)] metrics. In exposed subjects, correlation, multiple linear, Bayesian kernel machine regression, and mediation analyses were employed to examine effects of single- or mixed-metal predictor(s) and their interactions on MTL structural and neuropsychological metrics; and on the path from metal exposure to neuropsychological consequences. Results: Compared to controls, exposed subjects had higher blood Cu, Fe, K, Mn, Pb, Se, and Zn levels (p's<0.026) and poorer performance in processing/psychomotor speed, executive, and visuospatial domains (p's<0.046). Exposed subjects displayed higher MD, AD, and RD in all MTL ROIs (p's<0.040) and lower FA in entorhinal and parahippocampal cortices (p's<0.033), but not morphological differences. Long-term mixed-metal exposure history indirectly predicted lower processing speed performance via lower parahippocampal FA (p=0.023). Higher whole blood Mn and Cu predicted higher entorhinal diffusivity (p's<0.043) and lower Delayed Story Recall performance (p=0.007) without overall metal mixture or interaction effects. Discussion: Mixed metal exposure predicted MTL structural and neuropsychological features that are similar to Alzheimer's disease at-risk populations. These data warrant follow-up as they may illuminate the path for environmental exposure to Alzheimer's disease-related health outcomes.
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BACKGROUND: An accurate diagnosis of peripheral lung and pleural lesions using image-guided transthoracic biopsy procedure becomes a good diagnostic performance protocol. PURPOSE: To examine the difference between ultrasonography (USG)-guided versus computed tomography (CT)-guided transthoracic biopsy for pleural and peripheral lung lesions by pooling data from published studies. MATERIAL AND METHODS: PubMed, CENTRAL, Scopus, Web of Science, and Embase were searched for comparative studies up to 20 February 2023 irrespective of the language of publication. The outcomes were adequacy of the sample and complications (pneumothorax and hemothorax). RESULTS: Two randomized controlled trials (RCTs) and eight non-RCTs were eligible. The total sample size was 1618. Meta-analysis showed that there was no difference in the adequacy of the sample obtained by USG- or CT-guided biopsies; however, an analysis of only non-RCTs indicated better adequacy with USG. On pooled analysis of any pneumothorax, there was a lower risk associated with USG-guided biopsies, but the risk of pneumothorax requiring interventional treatment was not different in the two groups. Similarly, the pooled analysis also demonstrated a reduced risk of hemothorax with USG-guided biopsies. CONCLUSION: While there seems to be no difference in the adequacy of the sample obtained with either imaging modality, retrospective data show that USG guidance offers better diagnostic yield compared to CT guidance for peripheral lung and pleural biopsies. The risk of pneumothorax and hemothorax is also significantly lower with USG-guided biopsies. Results should be interpreted with caution owing to selection bias among studies. There is a need for large-scale RCTs to enhance current evidence.
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Pneumotórax , Humanos , Pneumotórax/etiologia , Hemotórax/complicações , Hemotórax/patologia , Ultrassonografia , Pulmão/diagnóstico por imagem , Pulmão/patologia , Biópsia Guiada por Imagem/efeitos adversos , Tomografia Computadorizada por Raios X/métodos , Estudos RetrospectivosRESUMO
Volatile organic compounds (VOCs) are significant precursors to photochemical pollution. However, reactive VOC species are easily oxidized during transportation, resulting in a systematic underestimate of the measured concentrations. To address this, we applied an improved calculation method to correct the measured VOC concentrations into photochemical initial concentrations (PICs) in Chengdu, a megacity in the Sichuan Basin, China, which is highly vulnerable to complex pollution. In this study, 56 VOC species on the Photochemical Assessment Monitor Station (PAMS) target list were quantitatively monitored throughout all four seasons. Comparing to directly measured values, photochemically initialized total mixing ratios of VOCs increased by 18.6 % in general. The photochemical loss percentages of alkenes and aromatics were prominent in summer (68.6 %, 28.7 %) and spring (65.9 %, 24.7 %), respectively. Furthermore, we examined contributions of VOCs to atmospheric oxidation capacity (AOC) depending on PICs and found that maximum daily total AOC showed a surge in spring and summer. Besides hydroxyl radicals, daytime O3 in spring and late-afternoon nitrate radicals in summer were essential for AOC with PICs. As expected, alkenes and aromatics dominated PIC-based ozone formation potentials (OFPs). Furthermore, contribution of alkenes to secondary organic aerosol formation potentials reached 15.5 % and 7.6 % in spring and summer, respectively. Using positive matrix factorization model, we identified five VOC sources including vehicular exhaust, industrial emissions, solvent usage, biogenic sources, and liquefied petroleum gas/natural gas use. Based on PICs, biogenic sources were significantly underestimated in spring and summer. Meanwhile, m,p-xylene from solvent usage and isoprene from biogenic sources were the primary contributors to OFPs. Consequently, these results emphasize the significance of photochemically oxidized VOC concentrations, especially for reactive species in typical seasons.
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Current pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson's disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients. We explored if a D1/5 dopamine agonist would have efficacy in LsPD using a double-blind placebo-controlled crossover phase Ia/b study comparing the D1/5 agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Caregiver assessment was the primary efficacy measure because caregivers were with patients throughout the study, and standard clinical metrics inadequately gauge efficacy in LsPD. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2-3). Clinicians and caregivers completed the clinical impression of change questionnaires, and caregivers participated in a qualitative exit interview. Blinded triangulation of quantitative and qualitative data was used to integrate findings. Neither traditional scales nor clinician impression of change detected consistent differences between treatments in the five participants who completed the study. Conversely, the overall caregiver data strongly favored PF-06412562 over levodopa in four of five patients. The most meaningful improvements converged on motor, alertness, and functional engagement. These data suggest for the first time that there can be useful pharmacological intervention in LsPD patients using D1/5 agonists and also that caregiver perspectives with mixed method analyses may overcome limitations using methods common in early-stage patients. The results encourage future clinical studies and understanding of the most efficacious signaling properties of a D1 agonist for this population.
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Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Levodopa/uso terapêutico , Levodopa/efeitos adversos , Agonistas de Dopamina/uso terapêutico , Antiparkinsonianos/uso terapêutico , DopaminaRESUMO
BACKGROUND: Nursing homes were ill-equipped for the pandemic; though facilities are required to have infection control staff, only 3% have taken a basic infection control course. Little is known about the implementation of effective practices outside of the acute care setting. We proposed an intervention utilizing Project ECHO, to connect Penn State University experts with nursing home staff and administrators to explore how infection control guidelines can be implemented effectively. METHODS: A stratified cluster randomized design was used to assign nursing homes to either AHRQ-funded COVID-19 ECHO or AHRQ-funded COVID-19 ECHO+. RESULTS: 136 nursing homes participated. There were no significant differences in COVID-19 infection rate, hospitalization, deaths, or influenza, between ECHO or ECHO+. DISCUSSION: The ECHO model has significant strengths when compared to traditional training, as it allows for remote learning delivered by a multidisciplinary team of experts and utilizes case discussions that match the context of nursing homes.
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COVID-19 , Humanos , Pandemias , Casas de Saúde , Instituições de Cuidados Especializados de Enfermagem , Assistência Centrada no PacienteRESUMO
BACKGROUND AND PURPOSE: Cerebral small vessel disease biomarkers including white matter hyperintensities (WMH), lacunes, and enlarged perivascular spaces (ePVS) are under investigation to identify those specific to cerebral amyloid angiopathy (CAA). In subjects with Alzheimer's disease (AD), we assessed characteristic features and amounts of WMH, lacunes, and ePVS in four CAA categories (no, mild, moderate and severe CAA) and correlated these with Clinical Dementia Rating sum of boxes (CDRsb) score, ApoE genotype, and neuropathological changes at autopsy. METHODS: The study included patients with a clinical diagnosis of dementia due to AD and neuropathological confirmation of AD and CAA in the National Alzheimer's Coordinating Center (NACC) database. The WMH, lacunes, and ePVS were evaluated using semi-quantitative scales. Statistical analyses compared the WMH, lacunes, and ePVS values in the four CAA groups with vascular risk factors and AD severity treated as covariates, and to correlate the imaging features with CDRsb score, ApoE genotype, and neuropathological findings. RESULTS: The study consisted of 232 patients, of which 222 patients had FLAIR data available and 105 patients had T2-MRI. Occipital predominant WMH were significantly associated with the presence of CAA (p = 0.007). Among the CAA groups, occipital predominant WMH was associated with severe CAA (ß = 1.22, p = 0.0001) compared with no CAA. Occipital predominant WMH were not associated with the CDRsb score performed at baseline (p = 0.68) or at follow-up 2-4 years after the MRI (p = 0.92). There was no significant difference in high grade ePVS in the basal ganglia (p = 0.63) and centrum semiovale (p = 0.95) among the four CAA groups. The WMH and ePVS on imaging did not correlate with the number of ApoE ε4 alleles but the WMH (periventricular and deep) correlated with the presence of infarcts, lacunes and microinfarcts on neuropathology. CONCLUSION: Among patients with AD, occipital predominant WMH is more likely to be found in patients with severe CAA than in those without CAA. The high-grade ePVS in centrum semiovale were common in all AD patients regardless of CAA severity.
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Doença de Alzheimer , Angiopatia Amiloide Cerebral , Doenças de Pequenos Vasos Cerebrais , Humanos , Doença de Alzheimer/genética , Angiopatia Amiloide Cerebral/complicações , Angiopatia Amiloide Cerebral/diagnóstico por imagem , Imageamento por Ressonância Magnética , Apolipoproteínas E/genética , Gânglios da Base/patologia , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagemRESUMO
INTRODUCTION: Chronic excessive welding exposure may be related to higher metal accumulation and structural differences in different subcortical structures. We examined how welding affected brain structures and their associations with metal exposure and neurobehavioral consequences. METHODS: Study includes 42 welders and 31 controls without a welding history. Welding-related structural differences were assessed by volume and diffusion tensor imaging (DTI) metrics in basal ganglia, red nucleus (RN), and hippocampus. Metal exposure was estimated by both exposure questionnaires and whole blood metal levels. Brain metal accumulations were estimated by R1 (for Mn) and R2* (for Fe). Neurobehavioral status was assessed by standard neuropsychological tests. RESULTS: Compared to controls, welders displayed higher hippocampal mean (MD), axial (AD), and radial diffusivity (RD) (p's < 0.036), but similar DTI or volume in other ROIs (p's > 0.117). Welders had higher blood metal levels (p's < 0.004), higher caudate and RN R2* (p's < 0.014), and lower performance on processing/psychomotor speed, executive function, and visuospatial processing tasks (p's < 0.046). Higher caudate and RN R2* were associated with higher blood Fe and Pb (p's < 0.043), respectively. RN R2* was a significant predictor of all hippocampal diffusivity metrics (p's < 0.006). Higher hippocampal MD and RD values were associated with lower Trail Making Test-A scores (p's < 0.025). A mediation analysis of both groups revealed blood Pb indirectly affected hippocampal diffusivity via RN R2* (p's < 0.041). DISCUSSION: Welding-related higher hippocampal diffusivity metrics may be associated with higher RN R2* and lower psychomotor speed performance. Future studies are warranted to test the role of Pb exposure in these findings.
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Exposição Ocupacional , Soldagem , Humanos , Imagem de Tensor de Difusão/métodos , Desempenho Psicomotor , Ferreiros , Chumbo/análise , Núcleo Rubro/química , Exposição Ocupacional/efeitos adversos , Exposição Ocupacional/análise , Hipocampo/diagnóstico por imagemRESUMO
BACKGROUND: Evidence of associations between daily variation in air pollution and blood pressure (BP) is varied and few prior longitudinal studies adjusted for calendar time. METHODS: We studied 143,658 postmenopausal women 50 to 79 years of age from the Women's Health Initiative (1993-2005). We estimated daily atmospheric particulate matter (PM) (in three size fractions: PM2.5, PM2.5-10, and PM10) and nitrogen dioxide (NO2) concentrations at participants' residential addresses using validated lognormal kriging models. We used linear mixed-effects models to estimate the association between air pollution concentrations and repeated measures of systolic and diastolic BP (SBP, DBP) adjusting for confounders and calendar time. RESULTS: Short-term PM2.5 and NO2 were each positively associated with DBP {0.10 mmHg [95% confidence interval (CI): 0.04, 0.15]; 0.13 mmHg (95% CI: 0.09, 0.18), respectively} for interquartile range changes in lag 3-5 day PM2.5 and NO2. Short-term NO2 was negatively associated with SBP [-0.21 mmHg (95%CI: -0.30, -0.13)]. In two-pollutant models, the NO2-DBP association was slightly stronger, but for PM2.5 was attenuated to null, compared with single-pollutant models. Associations between short-term NO2 and DBP were more pronounced among those with higher body mass index, lower neighborhood socioeconomic position, and diabetes. When long-term (annual) and lag 3-5 day PM2.5 were in the same model, associations with long-term PM2.5 were stronger than for lag 3-5 day. CONCLUSIONS: We observed that short-term PM2.5 and NO2 levels were associated with increased DBP, although two-pollutant model results suggest NO2 was more likely responsible for observed associations. Long-term PM2.5 effects were larger than short-term.
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Poluição do Ar , Poluentes Ambientais , Feminino , Humanos , Idoso , Pressão Sanguínea , Dióxido de Nitrogênio , Poluição do Ar/efeitos adversos , Material ParticuladoRESUMO
Intensive behavioral therapy (IBT) is an important component of obesity treatment and can reduce the risk of type 2 diabetes (T2DM). Objective was to compare the effectiveness of IBT to usual care in achieving weight loss in two study cohorts within PaTH Network: T2DM and At-Risk of T2DM. The TD2M cohort was defined as age 18 years and older with an indication of T2DM in the EHR based on a validated algorithm and at least 2 outpatient primary care visits. The At-Risk of T2DM cohort was defined by a BMI ≥ 25 kg/m2. The primary outcome was weight change within 1-year of index date. Mixed-effects models assessed the effectiveness of IBT by comparing the changes between study groups. Between 2009 and 2020, a total of 567,908 patients were identified in the T2DM cohort and2,054,256 patients in the At-Risk of T2DM cohort. Both IBT patients and matched non-IBT patients in the T2DM cohort had decreased mean weight (primary outcome) (-1.56 lbs, 95 %CI: -1.88, -1.24 vs -1.70 lbs, 95 %CI: -1.95, -1.44) in 1-year after index date. In the At-Risk of T2DM cohort, both IBT and non-IBT patients experienced weight gain and resultant increased BMI. Patients with more than one IBT visit gained less weight than those with only one visit (1.22 lbs, 95 %CI: 0.82, 1.62 vs 6.72 lbs, 95 %CI: 6.48, 6.97; p < 0.001). IBT was unlikely to result in clinically significant weight loss. Barriers to utilizing IBT require further research to ensure broader adoption of obesity management in primary care.
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BACKGROUND: Susceptibility magnetic resonance imaging (MRI) is sensitive to iron-related changes in the substantia nigra pars compacta (SNc), the key pathologic locus of parkinsonisms. It is unclear, however, if iron deposition in the SNc is associated with its neurodegeneration. OBJECTIVE: The objective of this study was to test whether susceptibility MRI metrics in parkinsonisms are associated with SNc neuropathologic features of dopaminergic neuron loss, gliosis, and α-synuclein and tau burden. METHODS: This retrospective study included 27 subjects with both in vivo MRI and postmortem data. Multigradient echo imaging was used to derive the apparent transverse relaxation rate (R2*) and quantitative susceptibility mapping (QSM) in the SNc. Archived midbrain slides that were stained with hematoxylin and eosin, anti-α-synuclein, and anti-tau were digitized to quantify neuromelanin-positive neuron density, glial density, and the percentages of area occupied by positive α-synuclein and tau staining. MRI-histology associations were examined using Pearson correlations and regression. RESULTS: Twenty-four subjects had postmortem parkinsonism diagnoses (Lewy body disorder, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration), two had only Alzheimer's neuropathology, and one exhibited only mild atrophy. Among all subjects, both R2* and QSM were associated with glial density (r ≥ 0.67; P < 0.001) and log-transformed tau burden (r ≥ 0.53; P ≤ 0.007). Multiple linear regression identified glial density and log-transformed tau as determinants for both MRI metrics (R2 ≥ 0.580; P < 0.0001). Neither MRI metric was associated with neuron density or α-synuclein burden. CONCLUSIONS: R2* and QSM are associated with both glial density and tau burden, key neuropathologic features in the parkinsonism SNc. © 2023 International Parkinson and Movement Disorder Society.
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Doença de Parkinson , Transtornos Parkinsonianos , Humanos , Parte Compacta da Substância Negra , Doença de Parkinson/diagnóstico por imagem , Doença de Parkinson/patologia , Substância Negra/diagnóstico por imagem , Substância Negra/patologia , Estudos Retrospectivos , Transtornos Parkinsonianos/patologia , Imageamento por Ressonância Magnética/métodos , FerroRESUMO
BACKGROUND AND PURPOSE: The circuitry underlying heterogenous cognitive profiles in Parkinson's disease (PD) remains unclear. The purpose of this study is to investigate whether structural changes in frontostriatal and limbic pathways contribute to different cognitive trajectories in PD. METHODS: We obtained clinical and multimodal MRI data from 120 control and 122 PD subjects without dementia or severe motor disability. T1/T2-weighted images estimated volume, and diffusion imaging evaluated fractional anisotropy (FA) of frontostriatal (striatum and frontostriatal white matter [FSWM]) and limbic (hippocampus and fornix) structures. Montreal Cognitive Assessment (MoCA) gauged total and domain-specific (attention/executive and memory) cognitive function. Linear mixed-effects models were used to compare MRI and cognitive progression over 4.5 years between controls and PD and evaluate associations between baseline MRI and cognitive changes in PD. RESULTS: At baseline, control and PD groups were comparable, except PD participants had smaller striatal volume (p < 0.001). Longitudinally, PD showed faster decline in hippocampal volume, FSWM FA, and fornix FA (ps < .016), but not striatal volume (p = .218). Total and domain-specific MoCA scores declined faster in PD (ps < .030). In PD, lower baseline hippocampal volume (p = .005) and fornix FA (p = .032), but not striatal volume (p = .662) or FSWM FA (p = .143), were associated with faster total MoCA decline. Baseline frontostriatal metrics of striatal volume and FSWM FA were associated with faster attention/executive decline (p < .038), whereas lower baseline hippocampal volume was associated with faster memory decline (p = .005). CONCLUSION: In PD, frontostriatal structural metrics are associated with attention/executive tasks, whereas limbic changes correlated with faster global cognitive decline, particularly in memory tasks.
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Disfunção Cognitiva , Pessoas com Deficiência , Transtornos Motores , Doença de Parkinson , Humanos , Doença de Parkinson/complicações , Doença de Parkinson/diagnóstico por imagem , Transtornos Motores/complicações , Cognição , Testes NeuropsicológicosRESUMO
PURPOSE: Under-desk pedaling devices could help reduce health risks associated with the global decline in work-related energy expenditure. However, the optimal pedaling work rate to facilitate concurrent work performance among physically inactive adults is unclear. We examined the effects of two light-intensity pedaling work rates on physically inactive adults' work performance. METHODS: We recruited equal numbers of older (45-65 yr) versus younger (20-44 yr), male versus female, and overweight/obese (body mass index [BMI], 25-35 kg·m -2 ) versus normal weight (BMI, 18.5-24.9 kg·m -2 ) participants. Using a Graeco-Latin square design, participants ( n = 96) completed a laboratory experiment to evaluate the effects of using an under-desk pedaling device at two seated light-intensity work rates (17 and 25 W), relative to a seated nonpedaling condition on objectively measured typing, reading, logical reasoning, and phone task performance. Ergonomic comfort under each pedaling work rate was also assessed. Equivalence tests were used to compare work performance under the pedaling versus nonpedaling conditions. RESULTS: Treatment fidelity to the 17- and 25-W pedaling work rates exceeded 95%. Mean work performance scores for each pedaling and nonpedaling condition were equivalent under alpha = 0.025. Age, sex, and BMI did not significantly moderate the effect of pedaling on work performance. Participants reported greater ergonomic comfort while completing work tasks at the 17-W relative to the 25-W work rate. CONCLUSIONS: Physically inactive adults obtained similar work performance scores under the 17- and 25-W pedaling and the nonpedaling conditions, suggesting that either pedaling work rate could help reduce health risks of sedentary work time. The 17-W work rate yielded greater ergonomic comfort and may be an appropriate starting point for introducing diverse inactive workers to under-desk pedaling.
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Comportamento Sedentário , Desempenho Profissional , Adulto , Feminino , Humanos , Masculino , Metabolismo Energético , Sobrepeso , Postura Sentada , Adulto Jovem , Pessoa de Meia-Idade , IdosoRESUMO
Crop reproductive development is vulnerable to heat stress, and the genetic modulation of thermotolerance during the reproductive phase, especially the early stage, remains poorly understood. We isolated a Poaceae-specific FAR-RED ELONGATED HYPOCOTYLS3 (FHY3)/FAR-RED IMPAIRED RESPONSE1 (FAR1)family transcription factor, Thermo-sensitive Spikelet Defects 1 (TSD1), derived from transposase in rice (Oryza sativa) TSD1 was highly expressed in spikelets, induced by heat, and specifically enhanced the thermotolerance of spikelet morphogenesis. Disrupting TSD1 did not affect vegetative growth but markedly retarded spikelet initiation and development, as well as caused varying degrees of spikelet degeneration, depending on the temperature. Most tsd1 spikelets were normal at low temperature but gradually degenerated as temperature increased, and all disappeared at high temperature, leading to naked branches. TSD1 directly promoted the transcription of YABBY1 and YABBY3 and could physically interact with YABBY1 and three TOB proteins, YABBY5, YABBY4, and YABBY3. These YABBY proteins can form either homodimers or heterodimers and play an important role in spikelet morphogenesis, similar to TSD1. Notably, the knockout mutant yab5-ko and double mutant tsd1 yab5-ko resembled tsd1 in spikelet appearance and response to temperature, indicating that these genes likely participate in spikelet development through the cooperative TSD1-YABBY module. These findings reveal a distinctive function of FHY3/FAR1 family genes and a unique TSD1-YABBY complex to acclimate spikelet development to high temperature in rice, providing insight into the regulating pathway of enhancing thermotolerance in plant reproductive development.