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The peptidoglycan sensor Nod2 and the autophagy protein ATG16L1 have been linked to Crohn's disease (CD). Although Nod2 and the related sensor, Nod1, direct ATG16L1 to initiate anti-bacterial autophagy, whether ATG16L1 affects Nod-driven inflammation has not been examined. Here, we uncover an unanticipated autophagy-independent role for ATG16L1 in negatively regulating Nod-driven inflammatory responses. Knockdown of ATG16L1 expression, but not that of ATG5 or ATG9a, specifically enhanced Nod-driven cytokine production. In addition, autophagy-incompetent truncated forms of ATG16L1 regulated Nod-driven cytokine responses. Mechanistically, we demonstrated that ATG16L1 interfered with poly-ubiquitination of the Rip2 adaptor and recruitment of Rip2 into large signaling complexes. The CD-associated allele of ATG16L1 was impaired in its ability to regulate Nod-driven inflammatory responses. Overall, these results suggest that ATG16L1 is critical for Nod-dependent regulation of cytokine responses and that disruption of this Nod1- or Nod2-ATG16L1 signaling axis could contribute to the chronic inflammation associated with CD.
Assuntos
Autofagia/fisiologia , Proteínas de Transporte/fisiologia , Citocinas/biossíntese , Proteína Adaptadora de Sinalização NOD1/fisiologia , Proteína Adaptadora de Sinalização NOD2/fisiologia , Animais , Proteína 5 Relacionada à Autofagia , Proteínas Relacionadas à Autofagia , Proteínas de Transporte/química , Proteínas de Transporte/genética , Linhagem Celular , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/patologia , Citocinas/genética , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Células Epiteliais/microbiologia , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Predisposição Genética para Doença , Humanos , Inflamação , Mucosa Intestinal/citologia , Camundongos , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/fisiologia , Processamento de Proteína Pós-Traducional , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Proteína Serina-Treonina Quinase 2 de Interação com Receptor , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Transdução de Sinais , UbiquitinaçãoRESUMO
Breast cancer screening disparities continue to prevail with immigrant women being at the forefront of the under screened population. There is a paucity of knowledge about the role of religious affiliation or cultural orientation on immigrant women's cancer screening uptake. This study examined differences in uptake of breast cancer screening among women from Muslim and non- Muslim majority countries in Ontario, Canada. A cohort of 1,851,834 screening-eligible women living in Ontario during April 1, 2013 to March 31, 2015 was created using linked health and social administrative databases. The study found that being born in a Muslim majority country was associated with lower breast cancer screening uptake after adjusting for region of origin, neighbourhood income, and primary care-related factors. However, screening uptake in Muslim majority countries varied by world region with the greatest differences found in Sub-Saharan Africa and South Asia. Screening uptake was lower for women who had no primary care provider, were in a traditional fee-for service model of primary care, had a male physician, had an internationally trained physician, resided in a low income neighbourhood, and entered Canada under the family class of immigration. Religion may play a role in screening uptake, however, the variation in rates by regions of origin, immigration class, and access to primary care providers alludes to confluence of socio-demographic, cultural beliefs and practices, immigration trajectories and system level factors. Facilitating access for immigrant women to regular primary care providers, particularly female providers and enrollment in primary care models could enhance screening uptake.
Assuntos
Neoplasias da Mama/diagnóstico , Detecção Precoce de Câncer , Emigrantes e Imigrantes/psicologia , Islamismo , Programas de Rastreamento/métodos , Idoso , Neoplasias da Mama/etnologia , Cultura , Feminino , Humanos , Pessoa de Meia-Idade , Ontário , Fatores SocioeconômicosRESUMO
Lung cancer is one of the most commonly diagnosed cancers in Canada and a leading cause of cancer mortality. Lung cancer also affects First Nations, Inuit and Métis peoples significantly in Canada, which deserves further investigation as there is a literature gap on this topic. We sought to develop a deeper understanding of lung cancer diagnosis, incidence, mortality, and survival in First Nations, Inuit, and Métis peoples in Canada. A systematic search was conducted in bibliographic databases to identify relevant studies published between January 2000 and March 2023. Articles were screened and assessed for relevance using the Population/ Concept/ Context (PCC) framework. A total of 22 articles were included in the final analysis, of which 13 were Inuit-specific, 7 were First Nations-specific, and 2 were Métis-specific. The literature suggests that comparative incidence, mortality, and relative risk of lung cancer is higher and survival is poorer in First Nations, Inuit and Métis peoples. Lung cancer also has varying impact on these population depending on sex, age, location and other factors. This review illustrates that more comprehensive quantitative and qualitative lung cancer research is essential to further identify the structural causes for the high incidence of the disease.
Assuntos
Inuíte , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/mortalidade , Canadá/epidemiologia , Inuíte/estatística & dados numéricos , Incidência , Indígenas Norte-Americanos/estatística & dados numéricos , Regiões Árticas/epidemiologiaRESUMO
INTRODUCTION: Given the prevalence and staggering cost of neurological disorders, there is dire need for effective early detection and intervention tools. Emerging evidence suggests that multidisciplinary lifestyle interventions (MLI) may mitigate the risk and progression of neurological disorders. The objectives of this protocol are (1) to test the impact of MLI on the progression of neurological disorders and (2) to identify multi-omic biomarkers for early stages of neurological disease and the impact of MLIs on these biomarkers. METHODS AND ANALYSIS: We present the Multidisciplinary lifestyle Interventions for Neurological Disorders during the Silent phase (MINDS) protocol, a randomized controlled trial of MLI in neurologically healthy older adults (≥ 50 years old) exhibiting elevated risk for common neurological disorders: stroke, epilepsy, Parkinson's Disease, or Alzheimer's disease and related dementias. Participants will be randomly assigned to intervention (n = 100) or control (n = 100) groups. The intervention group will receive 3 months of weekly 2-hour sessions on diet education, yoga, music therapy, and cognitive skills training. The participants' neurological health and engagement in relevant lifestyle practices will be assessed at regular intervals for 12 months. Neuroimaging and samples for multi-omic analyses will be collected at baseline, and at 3 months and 12 months after enrollment. Primary outcomes will be signs of progression of the neurological disorder risk that qualified them for study enrollment or a clinical diagnosis of the disorder. Secondary and exploratory outcomes will be based on self-reported health and multi-omic data. Data analysis will include between-group and longitudinal within-group analyses. PERSPECTIVES: The MINDS protocol and trial aims to clarify the impact of MLI on the progression of neurological disorder risk or diagnosis in older adults and to identify biomarkers that can be used to confirm MLI efficacy. The ability to validate the impact of MLI on neurological disorder progression based on biomarker data allows the identification of individuals most likely to benefit from such therapies in the early stages of neurological disease. TRIAL REGISTRATION: The trial is registered on the National Institutes of Health (NIH) ClinicalTrials.gov (NCT05984056) site. It was registered on August 2nd, 2023. The trial has full approval of the Cleveland Clinic Internal Review Board.
RESUMO
Stroke patients who underwent continuous EEG (cEEG) monitoring within 7 days of presentation and developed post-stroke epilepsy (PSE; cases, n = 36) were matched (1:2 ratio) by age and follow-up duration with ones who did not (controls, n = 72). Variables significant on univariable analysis [hypertension, smoking, hemorrhagic conversion, pre-cEEG convulsive seizures, and epileptiform abnormalities (EAs)] were included in the multivariable logistic model and only the presence of EAs on EEG remained significant PSE predictor [OR = 11.9 (1.75-491.6)]. With acute EAs independently predicting PSE development, accounting for their presence may help to tailor post-acute symptomatic seizure management and aid anti-epileptogenesis therapy trials.
Assuntos
Epilepsia , Acidente Vascular Cerebral , Estudos de Casos e Controles , Eletroencefalografia , Epilepsia/etiologia , Humanos , Convulsões/diagnóstico , Convulsões/etiologia , Acidente Vascular Cerebral/complicaçõesRESUMO
OBJECTIVE: To investigate the factors associated with the long-term continuation of anti-seizure medications (ASMs) in acute stroke patients. METHODS: We performed a retrospective cohort study of stroke patients with concern for acute symptomatic seizures (ASySs) during hospitalization who subsequently visited the poststroke clinic. All patients had continuous EEG (cEEG) monitoring. We generated a multivariable logistic regression model to analyze the factors associated with the primary outcome of continued ASM use after the first poststroke clinic visit. RESULTS: A total of 507 patients (43.4% ischemic stroke, 35.7% intracerebral hemorrhage, and 20.9% aneurysmal subarachnoid hemorrhage) were included. Among them, 99 (19.5%) suffered from ASySs, 110 (21.7%) had epileptiform abnormalities (EAs) on cEEG, and 339 (66.9%) had neither. Of the 294 (58%) patients started on ASMs, 171 (33.7%) were discharged on them, and 156 (30.3% of the study population; 53.1% of patients started on ASMs) continued ASMs beyond the first poststroke clinic visit [49.7 (±31.7) days after cEEG]. After adjusting for demographical, stroke- and hospitalization-related variables, the only independent factors associated with the primary outcome were admission to the NICU [Odds ratio (OR) 0.37 (95% CI 0.15-0.9)], the presence of ASySs [OR 20.31(95% CI 9.45-48.43)], and EAs on cEEG [OR 2.26 (95% CI 1.14-4.58)]. INTERPRETATION: Almost a third of patients with poststroke ASySs concerns may continue ASMs for the long term, including more than half started on them acutely. Admission to the NICU may lower the odds, and ASySs (convulsive or electrographic) and EAs on cEEG significantly increase the odds of long-term ASM use.
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Anticonvulsivantes/administração & dosagem , Acidente Vascular Cerebral Hemorrágico/complicações , AVC Isquêmico/complicações , Convulsões/etiologia , Convulsões/prevenção & controle , Doença Aguda , Idoso , Hemorragia Cerebral/complicações , Eletroencefalografia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Hemorragia Subaracnóidea/complicações , Fatores de TempoRESUMO
BACKGROUND: Colorectal cancer (CRC) is the second and third highest cause of cancer deaths among Canadian men and women, respectively. Population-based screening through fecal occult blood testing (FOBT) has been proven to be effective in reducing CRC morbidity and mortality. Although participation in Ontario's organized CRC screening program has been increasing steadily since 2008, its uptake remains low among recent immigrant populations despite the known benefits of screening. To promote participation in CRC screening, it is imperative to understand both individual and system level barriers and enablers. Although a number of immigrant and nonimmigrant factors have been associated with low participation, there is a dearth of knowledge related to the religious affiliation in CRC screening uptake. Our study is among the first to examine this issue in Ontario, one of the most ethnically diverse Canadian provinces and preferred settlement destinations for immigrants. METHODS: We conducted a population-based retrospective cohort study using linked health care administrative databases. Our cohort included Ontario residents, age 50-74 who were eligible for FOBT from 1 April 2013 to 31 March 2015. RESULTS: We found that immigrants from the Middle East and North Africa and Eastern Europe and Central Asia had the lowest rates of screening. Furthermore, being born in a Muslim-majority country was associated with lower FOBT screening even after controlling for other confounders including world region and income (ie, overall adjusted relative risk (ARR) of screening 0.92 [95% CI 0.90-0.93]). Moreover, being enrolled in a primary care model, having a female primary care provider and having an internationally trained physician were associated with increased screening among immigrants from Muslim-majority countries. CONCLUSIONS: These findings can inform future efforts to improve screening uptake like: enhancing access to primary care providers and enrollment in primary care models, targeted FOBT education for male providers and providers not in a primary care model, development of culturally sensitive and appropriate educational materials, and use of interactive approaches for communication of cancer screening information.
Assuntos
Neoplasias Colorretais/diagnóstico , Detecção Precoce de Câncer , Idoso , Neoplasias Colorretais/etnologia , Emigrantes e Imigrantes , Feminino , Humanos , Islamismo , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Sangue Oculto , Ontário/etnologia , Participação do Paciente , Atenção Primária à Saúde , Estudos RetrospectivosRESUMO
Background: Immigrant women are less likely to be screened for cervical cancer in Ontario. Religion may play a role for some women. In this population-based retrospective cohort study, we used country of birth as a proxy for religious affiliation and examined screening uptake among foreign-born women from Muslim-majority versus other countries, stratified by region of origin.Methods: We linked provincial databases and identified all women eligible for cervical cancer screening between April 1, 2012, and March 31, 2015. Women were classified into regions based on country of birth. Countries were classified as Muslim-majority or not.Results: Being born in a Muslim-majority country was significantly associated with lower likelihood of being up-to-date on Pap testing, after adjustment for region of origin, neighborhood income, and primary care-related factors [adjusted relative risk (ARR), 0.93; 95% (confidence interval) CI, 0.92-0.93]. Sub-Saharan African women from Muslim-majority countries had the highest prevalence of being overdue (59.6%), and the lowest ARR for screening when compared with women from non-Muslim-majority Sub-Saharan African countries (ARR, 0.77; 95% CI, 0.76-0.79). ARRs were lowest for women with no primary care versus those in a capitation-based model (ARR, 0.28; 95% CI, 0.27-0.29 overall).Conclusions: We have shown that being born in a Muslim-majority country is associated with a decreased likelihood of being up-to-date on cervical screening in Ontario and that access to primary care has a sizeable impact on screening uptake.Impact: Screening efforts need to take into account the background characteristics of population subgroups and to focus on increasing primary care access for all. Cancer Epidemiol Biomarkers Prev; 26(10); 1493-9. ©2017 AACR.