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PURPOSE: Radiotherapy is an under-investigated tool for priming the immune system in intact human breast cancers. We sought here to investigate if a preoperative radiotherapy boost delivered was associated with a significant change in tumor infiltrating lymphocytes in the tumor in estrogen receptor positive, HER2Neu non-amplified breast cancers. METHODS AND MATERIALS: 20 patients were enrolled in a phase II clinical trial and received either 7.5Gy x 1 fraction or 2Gy x 5 fractions, completed 6-8 days prior to surgery. Percent stromal tumor infiltrating lymphocytes (TIL) were evaluated on hematoxylin and eosin-stained samples. Short-term safety was assessed based on time to surgery, toxicities, and cosmesis up to 6 months following boost. RESULTS: Stromal TIL increased 6-8 days following completion of boost radiotherapy (median 3.0 (IQR 1.0-6.5) prior to radiotherapy vs. median 5.0 (IQR 1.5-8.0) post radiotherapy, p=0.0037. Zero grade ≥ 3 toxicities up to 6 months following boost were experienced. 94% (16/17) patients with 6 month follow-up cosmetic assessment following breast conservation had good-excellent cosmesis by physician assessment. CONCLUSION: In this phase II trial, preoperative radiotherapy boost resulted in a short-term increase in stromal TIL with minimal toxicities. Preoperative breast radiotherapy appears to be safe and may be a feasible means for priming the tumor microenvironment.
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BACKGROUND: We (1) evaluated the effect of aspiration tubing diameter on intraluminal pressure and (2) compared thrombectomy outcomes in patients treated using small diameter tubing versus those treated using large diameter vacuum tubing. METHODS: Intraluminal negative pressure was measured in a validated benchtop set up where consistency of negative pressure (inHg) was measured between static and dynamic aspiration. Static aspiration refers to activation of vacuum once the catheter is engaged with the clot. Dynamic aspiration refers to activation of vacuum when the catheter is slightly proximal to the clot. Four different sizes of vacuum tubing were trialed. We performed a retrospective analysis of consecutive patients who underwent mechanical thrombectomy. Procedural and functional outcomes were compared. RESULTS: The large diameter aspiration tubing held a consistent high negative pressure in static and dynamic aspiration (p = 0.152). Tubing types I to III were associated with a significant fall off in negative pressure between static and dynamic technique (p < 0.05). Two-hundred and five patients were included in the retrospective analysis; 124 (60%) underwent thrombectomy using small diameter vacuum tubing, and 81 (40%) using the large tubing. Mean thrombectomy time was shorter with the larger tubing [25.9 (17.9) minutes] versus the small tubing [37.5 (28.5) minutes, p = 0.002]. A greater proportion of patients had a thrombolysis in cerebral infarction score ≥2b in the group treated using the large tubing (78, 99%) than those with the small tubing (96, 78%, p < 0.001). CONCLUSION: Vacuum tubing diameter is linearly associated with intraluminal aspiration pressure. These findings have clinical significance as shown by increased recanalization rates and decreased thrombectomy times when large-diameter aspiration tubing is used. Shifting the paradigm toward a flow-based technique using large-bore vacuum tubing ought to be considered.
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Purpose: Emerging research highlights impacts of the COVID-19 pandemic on U.S. families, including changes in eating behavior and increased child body mass index. Aims of the present study were to examine whether child temperament and at-home vs. out-of-home childcare/school predicted families' restaurant-related behaviors during the pandemic. Examining energy balance-related behaviors, like restaurant patronage, during the pandemic can help better understand lasting impacts on child health behaviors and health outcomes. Methods: An online survey was administered to U.S. parents with a 4-to-8-year-old child in October 2020 (n = 1,000). Linear and logistic regression examined whether child temperament and at home vs. out-of-home childcare/school predicted: (1) the frequency the child consumed restaurant meals (take-out, delivery, dine-in), (2) who chose the child's restaurant meal, and (3) parent-reported reasons for the child's meal choice. Income, education, employment, race/ethnicity, and regional COVID-19 restrictions were tested as covariates. Results: Parents with children higher on negative affectivity reported more frequent restaurant use in-person (p < 0.05) and via delivery (p < 0.05) compared to parents of children lower on negativity. Child negativity was also linked with parent-reported reasons for children's restaurant meal choices. Parents of children receiving at-home childcare/schooling used delivery services less frequently than those receiving out-of-home care or schooling (p < 0.01). Conclusion: These findings suggest that individual and family factors may impact restaurant use and the meal selection process for children using restaurants during and beyond the COVID-19 era. Continued examination of individual differences in the impacts of the COVID-19 pandemic can facilitate intervention and policy approaches that fit with different families' needs.
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Major vault protein (MVP) is the main component of the vault complex, which is a highly conserved ribonucleoprotein complex found in most eukaryotic organisms. MVP or vaults have previously been found to be overexpressed in multidrug-resistant cancer cells and implicated in various cellular processes such as cell signaling and innate immunity. The precise function of MVP is, however, poorly understood and its expression and probable function in lower eukaryotes are not well characterized. In this study, we report that the Atlantic salmon louse expresses three full-length MVP paralogues (LsMVP1-3). Furthermore, we extended our search and identified MVP orthologues in several other ecdysozoan species. LsMVPs were shown to be expressed in various tissues at both transcript and protein levels. In addition, evidence for LsMVP to assemble into vaults was demonstrated by performing differential centrifugation. LsMVP was found to be highly expressed in cement, an extracellular material produced by a pair of cement glands in the adult female salmon louse. Cement is important for the formation of egg strings that serve as protective coats for developing embryos. Our results imply a possible novel function of LsMVP as a secretory cement protein. LsMVP may play a role in structural or reproductive functions, although this has to be further investigated.
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Copépodes , Partículas de Ribonucleoproteínas em Forma de Abóbada , Animais , Partículas de Ribonucleoproteínas em Forma de Abóbada/metabolismo , Copépodes/metabolismo , Salmo salar/parasitologia , Salmo salar/metabolismo , Feminino , Filogenia , Sequência de AminoácidosRESUMO
In failure modes and effects analysis (FMEA), the components of the risk priority number (RPN) for a failure mode (FM) are often chosen by consensus. We describe an empirical method for estimating the occurrence (O) and detectability (D) components of a RPN. The method requires for a given FM that its associated quality control measure be performed twice as is the case when a FM is checked for in an initial physics check and again during a weekly physics check. If instances of the FM caught by these checks are recorded, O and D can be computed. Incorporation of the remaining RPN component, Severity, is discussed. This method can be used as part of quality management design ahead of an anticipated FMEA or afterwards to validate consensus values.
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Análise do Modo e do Efeito de Falhas na Assistência à Saúde , Garantia da Qualidade dos Cuidados de Saúde , Radioterapia (Especialidade) , Humanos , Radioterapia (Especialidade)/normas , Radioterapia (Especialidade)/métodos , Garantia da Qualidade dos Cuidados de Saúde/normas , Análise do Modo e do Efeito de Falhas na Assistência à Saúde/métodos , Controle de Qualidade , Planejamento da Radioterapia Assistida por Computador/métodos , Planejamento da Radioterapia Assistida por Computador/normas , Neoplasias/radioterapiaRESUMO
BACKGROUND: Hexanucleotide repeat expansion of C9orf72 is a common genetic cause of amyotrophic lateral sclerosis (ALS). No C9orf72-targeted treatments are available. BIIB078 is an investigational antisense oligonucleotide targeting C9orf72 sense RNA. We aimed to assess the safety, tolerability, and pharmacokinetics of BIIB078 in participants with C9orf72-associated ALS. METHODS: This phase 1, randomised controlled trial was done at 22 sites in six countries (Canada, Ireland, Netherlands, Switzerland, UK, and USA). Adults with ALS and a pathogenic repeat expansion in C9orf72 were randomly assigned within six cohorts, via Interactive Response Technology in a 3:1 ratio per cohort, to receive BIIB078 (5 mg, 10 mg, 20 mg, 35 mg, 60 mg, or 90 mg in cohorts 1-6, respectively) or placebo, via an intrathecal bolus injection. The treatment period consisted of three loading doses of study treatment, administered approximately once every 2 weeks, followed by monthly maintenance doses during a treatment period of about 3 months for cohorts 1-3 and about 6 months for cohorts 4-6. Patients and investigators were masked to treatment assignment. The primary endpoint was the incidence of adverse events and serious adverse events. This trial was registered with ClinicalTrials.gov (NCT03626012) and is completed. FINDINGS: Between Sept 10, 2018, and Nov 17, 2021, 124 patients were screened for inclusion in the study. 18 patients were excluded and 106 participants were enrolled and randomly assigned to receive 5 mg (n=6), 10 mg (n=9), 20 mg (n=9), 35 mg (n=19), 60 mg (n=18), or 90 mg (n=18) of BIIB078, or placebo (n=27). 58 (55%) of 106 patients were female. All patients received at least one dose of study treatment and were included in all analyses. All participants had at least one adverse event; most adverse events were mild or moderate in severity and did not lead to treatment discontinuation. The most common adverse events in BIIB078-treated participants were falls, procedural pain, headache, and post lumbar puncture syndrome. 14 (18%) of 79 patients who received any dose of BIIB078 reported serious adverse events, compared with nine (33%) of 27 patients who received placebo. Five participants who received BIIB078 and three participants who received placebo had fatal adverse events: respiratory failure in a participant who received 10 mg BIIB078, ALS worsening in two participants who received 35 mg BIIB078, traumatic intracerebral haemorrhage in one participant who received 35 mg BIIB078, pulmonary embolism in one participant who received 60 mg BIIB078, and respiratory failure in three participants who received placebo. All deaths were assessed as not related to the study treatment by the reporting investigator. INTERPRETATION: On the basis of these phase 1 study results, including secondary and exploratory findings showing no reduction in neurofilament levels and no benefit on clinical outcomes relative to the placebo cohort, BIIB078 clinical development has been discontinued. However, these results will be informative in furthering our understanding of the complex pathobiology of C9orf72-associated ALS. FUNDING: Biogen.
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Esclerose Lateral Amiotrófica , Proteína C9orf72 , Oligonucleotídeos Antissenso , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/genética , Método Duplo-Cego , Proteína C9orf72/genética , Oligonucleotídeos Antissenso/farmacocinética , Oligonucleotídeos Antissenso/administração & dosagem , Oligonucleotídeos Antissenso/efeitos adversos , Oligonucleotídeos Antissenso/farmacologia , Idoso , Adulto , Relação Dose-Resposta a DrogaRESUMO
Herpes zoster (HZ) incidence is much higher in immunocompromised individuals than in immunocompetent individuals. HZ also occurs at a younger age and is often more severe in immunocompromised persons. Preventive strategies center around the recombinant zoster vaccine (RZV), which is approved for immunocompromised adults age 19 and older. Identifying those at greatest risk is critical. For those considering vaccination, evidence gaps regarding vaccine efficacy, toxicity, length of protection, and potential effects on underlying conditions may complicate shared and informed decision-making. Recent data have filled some of these gaps, with several societies issuing recommendations regarding vaccination. Remaining gaps are currently addressed by expert opinion.
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Vacina contra Herpes Zoster , Herpes Zoster , Hospedeiro Imunocomprometido , Humanos , Herpes Zoster/prevenção & controle , Herpes Zoster/epidemiologia , Vacinação/métodosRESUMO
According to conventional views, colon cancer originates from stem cells. However, inflammation, a key risk factor for colon cancer, has been shown to suppress intestinal stemness. Here, we used Paneth cells as a model to assess the capacity of differentiated lineages to trigger tumorigenesis in the context of inflammation in mice. Upon inflammation, Paneth cell-specific Apc mutations led to intestinal tumors reminiscent not only of those arising in patients with inflammatory bowel disease, but also of a larger fraction of human sporadic colon cancers. The latter is possibly because of the inflammatory consequences of western-style dietary habits, a major colon cancer risk factor. Machine learning methods designed to predict the cell-of-origin of cancer from patient-derived tumor samples confirmed that, in a substantial fraction of sporadic cases, the origins of colon cancer reside in secretory lineages and not in stem cells.
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Carcinogênese , Linhagem da Célula , Neoplasias do Colo , Inflamação , Celulas de Paneth , Animais , Camundongos , Linhagem da Célula/genética , Celulas de Paneth/patologia , Humanos , Inflamação/genética , Inflamação/patologia , Carcinogênese/genética , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Mutação , Células-Tronco/patologia , Diferenciação Celular/genética , Transformação Celular Neoplásica/genética , Proteína da Polipose Adenomatosa do Colo/genética , Camundongos Endogâmicos C57BL , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/patologiaRESUMO
BACKGROUND AND OBJECTIVES: Clinical trials in neurodegenerative diseases often encounter selective enrollment and under-representation of certain patient populations. This delays drug development and substantially limits the generalizability of clinical trial results. To inform recruitment and retention strategies, and to better understand the generalizability of clinical trial populations, we investigated which factors drive participation. METHODS: We reviewed the literature systematically to identify barriers to and facilitators of trial participation in 4 major neurodegenerative disease areas: Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease. Inclusion criteria included original research articles published in a peer-reviewed journal and evaluating barriers to and/or facilitators of participation in a clinical trial with a drug therapy (either symptomatic or disease-modifying). The Critical Appraisal Skills Program checklist for qualitative studies was used to assess and ensure the quality of the studies. Qualitative thematic analyses were employed to identify key enablers of trial participation. Subsequently, we pooled quantitative data of each enabler using meta-analytical models. RESULTS: Overall, we identified 36 studies, enrolling a cumulative sample size of 5,269 patients, caregivers, and health care professionals. In total, the thematic analysis resulted in 31 unique enablers of trial participation; the key factors were patient-related (own health benefit and altruism), study-related (treatment and study burden), and health care professional-related (information availability and patient-physician relationship). When meta-analyzed across studies, responders reported that the reason to participate was mainly driven by (1) the relationship with clinical staff (70% of the respondents; 95% CI 53%-83%), (2) the availability of study information (67%, 95% CI 38%-87%), and (3) the use or absence of a placebo or sham-control arm (53% 95% CI 32%-72%). There was, however, significant heterogeneity between studies (all p < 0.001). DISCUSSION: We have provided a comprehensive list of reasons why patients participate in clinical trials for neurodegenerative diseases. These results may help to increase participation rates, better inform patients, and facilitate patient-centric approaches, thereby potentially reducing selection mechanisms and improving generalizability of trial results.
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Ensaios Clínicos como Assunto , Doenças Neurodegenerativas , Participação do Paciente , Humanos , Doenças Neurodegenerativas/tratamento farmacológico , Seleção de PacientesRESUMO
BACKGROUND AND OBJECTIVES: The Patient-Ranked Order of Function (PROOF) is a novel approach to account for patient-reported preferences in the evaluation of treatments of amyotrophic lateral sclerosis (ALS). In this study, we assess the reliability and prognostic value of different sets of patient-reported preferences that can be used for the PROOF end point. METHODS: Data were obtained through online surveys over the course of 12 months using the population-based registry of the Netherlands. Patients were asked to score functional domains of the ALS Functional Rating Scale (ALSFRS-R) and rank the order of importance of each domain. Two weeks after the initial invite, the questionnaire was repeated to evaluate test-retest reliability. Vital status was extracted from the municipal population register. RESULTS: In total, 611 patients with ALS were followed up for survival and 382 patients were included in the test-retest reliability study. All versions of PROOF, using different sets of preferences, resulted in excellent reliability (intraclass correlation coefficients ranged from 0.89 [95% CI 0.87-0.91] to 0.97 [95% CI 0.97-0.98], all p < 0.001), without systematic differences between baseline and week 2 (mean rank difference range -1 to -3 [95% CI range -8 to 2], all p > 0.20). Preferences about future events were more variable than preferences about current symptoms. All versions of PROOF strongly predicted overall survival (hazard ratios per 10th rank percentile ranged from 0.80 to 0.83 [95% CI range 0.76-0.87], all p < 0.001) and had a more even separation of survival curves between rank-stratified subgroups compared with the ALSFRS-R total score. DISCUSSION: In a large cohort of patients, we show how patient-reported preferences can be measured and integrated reliably with the ALSFRS-R without leading to systematic bias. Patient preferences may provide unique prognostic information in addition to what is already measured conventionally. This could provide a more comprehensive understanding of how medical interventions effectively address the patient's concerns and improve what matters most to them.
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Esclerose Lateral Amiotrófica , Preferência do Paciente , Humanos , Esclerose Lateral Amiotrófica/terapia , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/fisiopatologia , Masculino , Feminino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Prognóstico , Idoso , Países Baixos , Ensaios Clínicos como Assunto , Inquéritos e Questionários , Sistema de RegistrosRESUMO
BACKGROUND AND OBJECTIVES: Dysfunction of energy metabolism, cognition, and behavior are important nonmotor symptoms of amyotrophic lateral sclerosis (ALS), negatively affecting survival and quality of life, but poorly understood. Neuroimaging is ideally suited to studying nonmotor neurodegeneration in ALS, but few studies have focused on the hypothalamus, a key region for regulating energy homeostasis, cognition, and behavior. We evaluated, therefore, hypothalamic neurodegeneration in ALS and explored the relationship between hypothalamic volumes and dysregulation of energy metabolism, cognitive and behavioral changes, disease progression, and survival. METHODS: Patients with ALS and population-based controls were included for this cross-sectional and longitudinal MRI study. The hypothalamus was segmented into 5 subregions and their volumes were calculated. Linear (mixed) models, adjusted for age, sex, and total intracranial volume, were used to compare hypothalamic volumes between groups and to analyze associations with metabolism, cognition, behavior, and disease progression. Cox proportional hazard models were used to investigate the relationship of hypothalamic volumes with survival. Permutation-based corrections for multiple hypothesis testing were applied to all analyses to control the family-wise error rate. RESULTS: Data were available for 564 patients with ALS and 356 controls. The volume of the anterior superior subregion of the hypothalamus was smaller in patients with ALS than in controls (ß = -0.70 [-1.15 to -0.25], p = 0.013). Weight loss, memory impairments, and behavioral disinhibition were associated with a smaller posterior hypothalamus (ß = -4.79 [-8.39 to -2.49], p = 0.001, ß = -10.14 [-15.88 to -4.39], p = 0.004, and ß = -12.09 [-18.83 to -5.35], p = 0.003, respectively). Furthermore, the volume of this subregion decreased faster over time in patients than in controls (ß = -0.25 [0.42 to -0.09], p = 0.013), and a smaller volume of this structure was correlated with shorter survival (hazard ratio = 0.36 [0.21-0.61], p = 0.029). DISCUSSION: We obtained evidence for hypothalamic involvement in ALS, specifically marked by atrophy of the anterior superior subregion. Moreover, we found that atrophy of the posterior hypothalamus was associated with weight loss, memory dysfunction, behavioral disinhibition, and survival, and that this subregion deteriorated faster in patients with ALS than in controls. These findings improve our understanding of nonmotor involvement in ALS and could contribute to the identification of new treatment targets for this devastating disease.
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Esclerose Lateral Amiotrófica , Hipotálamo , Imageamento por Ressonância Magnética , Humanos , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Hipotálamo/diagnóstico por imagem , Hipotálamo/metabolismo , Hipotálamo/patologia , Idoso , Estudos Transversais , Estudos Longitudinais , Progressão da Doença , Cognição/fisiologia , Adulto , Metabolismo Energético/fisiologiaRESUMO
OBJECTIVES: Spirometry is the primary lung function test utilised for medical surveillance and disability examination for coal mine dust lung disease. However, spirometry likely underestimates physiologic impairment. We sought to characterise abnormalities of single-breath diffusing capacity for carbon monoxide (DLCO) among a population of former coal miners. METHODS: Data from 3115 former coal miners evaluated at a West Virginia black lung clinic between 2006 and 2015 were retrospectively analysed to study the association between diffusion impairment (abnormally low DLCO), resting spirometry and the presence and severity of coal workers' pneumoconiosis on chest radiography. We developed ordinary least squares linear regression models to evaluate factors associated with per cent predicted DLCO (DLCOpp). RESULTS: Diffusion impairment was identified in 20.2% of subjects. Ten per cent of all miners with normal spirometry had diffusion impairment including 7.4% of never smokers. The prevalence of diffusion impairment increased with worsening radiographic category of pneumoconiosis. Mean DLCOpp decreased with increasing small opacity profusion subcategory in miners without progressive massive fibrosis. Linear regression analysis also showed significant decreases in DLCOpp with increasing small opacity profusion and presence of large opacities. CONCLUSIONS: Diffusion impairment is common among former coal miners, including among never smokers, miners without radiographic pneumoconiosis and miners with normal spirometry. These findings demonstrate the value of including DLCO testing in disability examinations of former coal miners and an important role for its use in medical surveillance of working miners to detect early chronic lung disease.
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Antracose , Minas de Carvão , Capacidade de Difusão Pulmonar , Espirometria , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Antracose/fisiopatologia , Antracose/epidemiologia , Idoso , Avaliação da Deficiência , West Virginia/epidemiologia , Feminino , Adulto , Pulmão/fisiopatologia , Pulmão/diagnóstico por imagem , Exposição Ocupacional/efeitos adversos , Modelos LinearesRESUMO
OBJECTIVES: Previous radiologic and histopathologic studies suggest respirable crystalline silica (RCS) overexposure has been driving the resurgence of pneumoconiosis among contemporary US coal miners, with a higher prevalence of severe disease in Central Appalachia. We sought to better understand RCS exposure among US underground coal miners. METHODS: We analysed RCS levels, as measured by respirable quartz, from coal mine dust compliance data from 1982 to 2021. RESULTS: We analysed 322 919 respirable quartz samples from 5064 US underground coal mines. Mean mine-level respirable quartz percentage and mass concentrations were consistently higher for Central Appalachian mines than the rest of the USA. Mean mine-level respirable quartz mass concentrations decreased significantly over time, from 0.116 mg/m3 in 1982 to as low as 0.017 mg/m3 for Central Appalachian mines, and from 0.089 mg/m3 in 1983 to 0.015 mg/m3 in 2020 for the rest of the USA. Smaller mine size, location in Central Appalachia, lack of mine safety committee and thinner coal seams were predictive of higher respirable quartz mass concentrations. CONCLUSIONS: These data substantially support the association between RCS overexposure and the resurgence of coal workers' pneumoconiosis in the USA, particularly in smaller mines in Central Appalachia.
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Minas de Carvão , Poeira , Exposição Ocupacional , Quartzo , Dióxido de Silício , Humanos , Exposição Ocupacional/análise , Exposição Ocupacional/efeitos adversos , Dióxido de Silício/análise , Dióxido de Silício/efeitos adversos , Estados Unidos , Poeira/análise , Quartzo/análise , Região dos Apalaches/epidemiologia , Exposição por Inalação/análise , Exposição por Inalação/efeitos adversos , Poluentes Ocupacionais do Ar/análiseRESUMO
BACKGROUND: The US Department of Labor (DOL) does not fund diffusing capacity (DLCO) or metabolic measurements from cardiopulmonary exercise testing (CPET) for coal miners' disability evaluations. Although exercise arterial blood gas testing is covered, many miners are unable to perform maximal tests, and sampling at peak exercise can be challenging. We explored the relationship between resting DLCO, radiographic disease severity, and CPET abnormalities in former US coal miners. METHODS: We analyzed data from miners evaluated between 2005 and 2015. Multivariable linear and logistic regression analyses were used to examine relationships between percent predicted (pp) forced expiratory volume in 1 s (FEV1pp), DLCOpp, VO2maxpp, A-a oxygen gradient (A-a)pp, dead space fraction (Vd/Vt), disabling oxygen tension (PO2), and radiographic findings of pneumoconiosis. RESULTS: Data from 2015 male coal miners was analyzed. Mean tenure was 28 years (SD 8.6). Thirty-twopercent had an abnormal A-a gradient (>150 pp), 20% had elevated Vd/Vt (>0.33), and 34% a VO2max < 60 pp. DLCOpp strongly predicted a disabling PO2, with an odds ratio (OR) of 2.33 [2.09-2.60], compared to 1.18 [1.08-1.29] for FEV1. Each increase in subcategory of small opacity (simple) pneumoconiosis increased the odds of a disabling PO2 by 42% [1.29-1.57], controlling for age, body mass index, pack-years of tobacco smoke exposure, and years of coal mine employment. CONCLUSIONS: DLCO is the best resting pulmonary function test predictor of CPET abnormalities. Radiographic severity of pneumoconiosis was also associated with CPET abnormalities. These findings support funding DLCO testing for impairment and suggest the term "small opacity" should replace "simple" pneumoconiosis to reflect significant associations with impairment.
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Minas de Carvão , Capacidade de Difusão Pulmonar , Humanos , Masculino , Pessoa de Meia-Idade , Estados Unidos/epidemiologia , Índice de Gravidade de Doença , Adulto , Teste de Esforço , Troca Gasosa Pulmonar , Volume Expiratório Forçado , Antracose/fisiopatologia , Antracose/diagnóstico por imagem , Modelos LogísticosRESUMO
In their recent Viewpoint article, Beidas et al. (2023) argue that researchers should test psychosocial interventions in the contexts in which they are meant to be delivered and that they can accelerate the deployment of these interventions by advancing directly from pilot trials to effectiveness and implementation studies without conducting efficacy trials. In this commentary, we argue that this is a well-intended but problematic approach and that there is a more productive strategy for translational behavioral intervention research. The commentary discusses issues concerning intervention development, refinement, and optimization; pilot and efficacy testing of interventions; the contexts in which interventions are delivered; clinical practice guidelines; and quick versus programmatic answers to significant clinical research questions. Testing psychosocial interventions in the contexts in which they are meant to be delivered is a complex task for interventions that are designed to be used in a wide variety of contexts. Nevertheless, interventions can be tested in the contexts in which they are meant to be delivered without sacrificing programmatic intervention development or safety and efficacy testing. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Intervenção Psicossocial , Humanos , Intervenção Psicossocial/métodosRESUMO
PURPOSE: This study aimed to validate qPCR assays for specific microbiota, for use on dental plaque samples stored on Whatman FTA cards to compare relative oral health risk in Rett syndrome. METHODS: Supragingival dental plaque samples were collected, using a sterile swab, (COPAN FLOQswab™) swabbed onto Whatman FTA™ cards. DNA extraction was performed using a modified Powersoil™ protocol. Where published assays were unsuitable, species-specific qPCR assays for caries-associated, gingivitis-associated and oral-health-associated bacteria were designed using multiple sequence alignment, Primer3Plus and PrimerQuest. Assays were run using absolute quantification. Limit of detection (LOD) and limit of quantification (LOQ) were calculated, and PCR products verified by Sanger sequencing. RESULTS: Most assays allowed detection using real-time qPCR with high specificity on samples collected on FTA cards. Several assays showed low or even single gene copy numbers on the test samples. CONCLUSION: Assays were optimised for detection and evaluation of oral health risk in dental plaque samples stored on FTA cards when cold storage is not feasible, except for F. nucleatum. Several assays showed gene copy numbers less than the LOQ or outside the range of the standard curve, so there is merit in optimising these assays using digital droplet PCR.
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Placa Dentária , Saúde Bucal , Reação em Cadeia da Polimerase em Tempo Real , Síndrome de Rett , Humanos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Placa Dentária/microbiologia , Síndrome de Rett/genética , Síndrome de Rett/complicações , Cárie Dentária/microbiologia , Criança , Microbiota/genética , DNA Bacteriano/análise , Feminino , Gengivite/microbiologiaRESUMO
OBJECTIVE: To systematically assess decline in respiratory measures in amyotrophic lateral sclerosis (ALS) and to examine the impact of sex, disease onset type and baseline morbidity on progression. METHODS: The REVEALS study (Registry of Endpoints and Validated Experiences in ALS) was conducted between April 2018 and February 2021 in six European ALS centers. Slow and forced vital capacity (S/FVC), sniff nasal inspiratory pressure (SNIP), peak cough flow, amyotrophic lateral sclerosis functional rating scale-revised (ALSFRS-R), and respiratory morbidity were collected. Data were analyzed using a Bayesian multiple outcomes random effects model. RESULTS: Two hundred and eighty participants had a median of three assessments (IQR 2.0, 5.0) over a median of 8 months (IQR 2.3, 14.1). There were 974 data collection timepoints. Differences in respiratory measures and rates of decline between disease-onset and sex subgroups were identified. Females had lower scores in all respiratory measures and females with bulbar onset ALS had faster decline compared with other sub-groups. These differences were not detected by the ALSFRS-r respiratory subscale. Dyspnea, orthopnea, and a higher King's stage at baseline were associated with lower respiratory scores throughout follow-up, while having a regular productive cough at baseline was associated with lower peak cough flow scores. CONCLUSION: Respiratory function declines more quickly in females with ALS compared with males when measured by FVC, SVC, SNIP, or PCF, but not the ALSFRS-R respiratory sub-score. Higher baseline King's staging and the presence of clinical respiratory symptoms at baseline were associated with worse respiratory function. The ALSFRS-R respiratory sub-score is poorly correlated with objective respiratory measurements.