RESUMEN
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, which is refractory to all currently available treatments and bears dismal prognosis. About 70% of all PDAC cases harbor mutations in the TP53 tumor suppressor gene. Many of those are missense mutations, resulting in abundant production of mutant p53 (mutp53) protein in the cancer cells. Analysis of human PDAC patient data from The Cancer Genome Atlas (TCGA) revealed a negative association between the presence of missense mutp53 and infiltration of CD8+ T cells into the tumor. Moreover, CD8+ T cell infiltration was negatively correlated with the expression of fibrosis-associated genes. Importantly, silencing of endogenous mutp53 in KPC cells, derived from mouse PDAC tumors driven by mutant Kras and mutp53, down-regulated fibrosis and elevated CD8+ T cell infiltration in the tumors arising upon orthotopic injection of these cells into the pancreas of syngeneic mice. Moreover, the tumors generated by mutp53-silenced KPC cells were markedly smaller than those elicited by mutp53-proficient control KPC cells. Altogether, our findings suggest that missense p53 mutations may contribute to worse PDAC prognosis by promoting a more vigorous fibrotic tumor microenvironment and impeding the ability of the immune system to eliminate the cancer cells.
Asunto(s)
Carcinoma Ductal Pancreático/genética , Fibrosis , Mutación Missense , Neoplasias Pancreáticas/genética , Proteína p53 Supresora de Tumor/genética , Animales , Linfocitos T CD8-positivos , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Línea Celular Tumoral , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Microambiente Tumoral/inmunología , Proteína p53 Supresora de Tumor/metabolismo , Neoplasias PancreáticasRESUMEN
Importance: Physicians, especially surgeons, delay family building, and face age-related complications of pregnancy. Objective: To explore factors that are associated with family building decisions among residents and fellows and to understand their thoughts on accessing family building supports, workplace culture, and attitudes toward family planning. Design, Setting, and Participants: This qualitative study was conducted from May to August 2022 at postgraduate training sites across Ontario, Canada. Participants included 29 postgraduate learners. Purposive sampling from 80 eligible trainees was used to ensure diverse demographics, including sex, specialty, and institution. Semi-structured individual interviews lasting 30 to 90 minutes were conducted over a virtual platform. Participants were asked to share their thoughts and experiences on family planning in a medical career, family building goals, the role of mentorship, and knowledge of current family planning supports. Main Outcomes and Measures: Themes associated with residents' perception of family planning within the context of a medical career. Results: Twenty-nine trainees, ages 25 to 37 years old (22 [75.9%] were female, 26 [89.7%] were heterosexual; median [range] age, 30 [25-37] years) from various institutions took part in this study. The participants included both 24 residents (82.8%) and 5 fellows (17.2%) and 8 (27.6%) were from surgical specialties, 3 (10.3%) from pediatrics and subspecialties, 4 (13.8%) from internal medicine and subspecialties, 2 (6.9%) from obstetrics and gynecology, 3 (10.3%) family medicine, 2 (6.9%) from anesthesia, and 7 (24.1%) other medical specialties. Four themes were identified: (1) tension between role as a physician and role as a parent; (2) impact of role models and mentorship on family planning choices; (3) family building is discouraged during training, especially in surgical specialties; and (4) need for tangible family planning supports in training. Conclusions and Relevance: In this qualitative study of residents' and fellows' perspectives on family building, trainees did not perceive residency and fellowship programs as supportive for individuals who want to family build during training leading to personal and professional dissonance. Trainees identified that more tangible supports, transparent information, and mentorship may improve a trainees' feeling of support.
Asunto(s)
Servicios de Planificación Familiar , Internado y Residencia , Investigación Cualitativa , Humanos , Femenino , Adulto , Masculino , Servicios de Planificación Familiar/educación , Ontario , Actitud del Personal de Salud , Becas , Mentores/psicologíaRESUMEN
Background: Delays in COVID-19 testing may increase the risk of secondary household and community transmission. Little is known about what patient characteristics and symptom profiles are associated with delays in test seeking. Methods: We conducted a retrospective cohort study of all symptomatic patients diagnosed with COVID-19 and assessed in a COVID Expansion to Outpatients (COVIDEO) virtual care program between March 2020 and June 2021. The primary outcome was later test seeking more than 3 days from symptom onset. Multivariable logistic regression was used to examine predictors of later testing including patient characteristics and symptoms (30 individual symptoms or 7 symptom clusters). Results: Of 5,363 COVIDEO patients, 4,607 were eligible and 2,155/4,607 (46.8%) underwent later testing. Older age was associated with increased odds of late testing (adjusted odds ratio [aOR] 1.007/year; 95% CI 1.00 to 1.01), as was history of recent travel (aOR 1.4; 95% CI 1.01 to 1.95). Health care workers had lower odds of late testing (aOR 0.50; 95% CI 0.39 to 0.62). Late testing was associated with symptoms in the cardiorespiratory (aOR 1.2; 95% CI 1.05, 1.36), gastrointestinal (aOR = 1.2; 95% CI 1.04, 1.4), neurological (aOR 1.1; 95% CI 1.003, 1.3) and psychiatric (aOR 1.3; 95% CI 1.1, 1.5) symptom clusters. Among individual symptoms, dyspnea, anosmia, dysgeusia, sputum, and anorexia were associated with late testing; pharyngitis, myalgia, and headache were associated with early testing. Conclusion: Certain patient characteristics and symptoms are associated with later testing, and warrant further efforts to encourage earlier testing to minimize transmission.
Historique: Les retards à effectuer les tests de dépistage de la COVID-19 peuvent accroître le risque de transmission secondaire dans la famille et la communauté. On ne sait pas vraiment quels sont les caractéristiques des patients et leurs profils de symptômes associés aux retards à se faire dépister. Méthodologie: Les chercheurs ont réalisé une étude de cohorte auprès de tous les patients symptomatiques ayant obtenu un diagnostic de COVID-19 évalués dans le cadre du programme de soins virtuels COVID Expansion to Outpatients (COVIDEO, ou expansion de la COVID aux patients ambulatoires) entre mars 2020 et juin 2021. Le résultat primaire était une demande de dépistage plus de trois jours après l'apparition des symptômes. Les chercheurs ont utilisé la régression logistique multivariable pour examiner les prédicteurs d'un dépistage tardif, y compris les caractéristiques et les symptômes des patients (30 symptômes individuels ou sept grappes de symptômes). Résultats: Des 5 363 patients ayant participé au programme COVIDEO, 4 607 étaient admissibles et 2 155 de ces 4 607 (46,8 %) se sont soumis à un dépistage tardif. Une plus grande probabilité de dépistage tardif était liée à un âge avancé (rapport de cotes corrigé [RCc] 1,007/année, IC à 95 %, 1,00 à 1,01), de même qu'à un voyage récent (RCc = 1,4, IC à 95 %, 1,01 à 1,95). Les travailleurs de la santé étaient moins susceptibles de se faire dépister tardivement (RCc = 0,50, IC à 95 %, 0,39 à 0,62). Le dépistage tardif était associé à des symptômes de la grappe cardiorespiratoire (RCc = 1,2, IC à 95 %, [1,05, 1,36]), gastrointestinale (RCc = 1,2, IC à 95 %, [1,04, 1,4]), neurologique (RCc = 1,1, IC à 95 %, [1,003, 1,3]) et psychiatrique (RCc = 1,3, IC à 95 %, [1,1, 1,5]). Parmi les symptômes individuels, la dyspnée, l'anosmie, la dysgueusie, les expectorations et l'anorexie étaient associées à un dépistage tardif, et la pharyngite, les myalgies et les céphalées, à un dépistage précoce. Conclusion: Certaines caractéristiques des patients et certains symptômes étaient associés à un dépistage tardif, ce qui justifie des efforts supplémentaires pour favoriser un dépistage plus rapide afin de limiter la transmission. Summary: This study of more than 4,000 patients with COVID-19 identified predictors of later test seeking, including older age, recent travel, non-health care worker occupation, cardiorespiratory, gastrointestinal, neurologic and psychiatric symptom clusters, and dyspnea, anosmia, dysgeusia, sputum, and anorexia.
RESUMEN
OBJECTIVES: To evaluate the impact of virtual care in preventing unnecessary healthcare visits for patients with SARS-CoV-2. METHODS: We conducted a retrospective matched cohort study, evaluating the COVID-19 Expansion to Outpatients (COVIDEO) programme involving virtual assessments for all positive patients in the Sunnybrook assessment centre from January 2020 to June 2021, followed by risk-stratified routine follow-up, couriering of oxygen saturation devices, and 24 hour/day direct-to-physician pager for urgent questions. We linked COVIDEO data to province-wide datasets, matching each eligible COVIDEO patient to ≤10 other Ontario SARS-CoV-2 patients on age, sex, neighbourhood, and date. The primary outcome was emergency department (ED) visit, hospitalization or death within 30 days. Multivariable regression accounted for comorbidities, vaccination, and pre-pandemic healthcare utilization. RESULTS: Among 6508 eligible COVIDEO patients, 4763 (73.1%) were matched to ≥1 non-COVIDEO patient. COVIDEO care was protective against the primary composite outcome (adjusted odds ratio [aOR] 0.91, 95% CI, 0.82-1.02), with a reduction in ED visits (7.8% vs. 9.6%; aOR 0.79, 95% CI, 0.70-0.89), but increase in hospitalizations (3.8% vs. 2.7%, aOR 1.37, 95% CI, 1.14-1.63) reflecting more direct-to-ward admissions (1.3% vs. 0.2%, p < 0.0001). Results were similar when matched comparators were limited to patients who had not received virtual care elsewhere with a decrease in ED visits (7.8 vs. 8.6%, aOR 0.86, 95% CI, 0.75-0.99) and an increase in hospitalizations (3.7 vs. 2.4%, aOR 1.45, 95% CI, 1.17-1.80). DISCUSSION: An intensive remote care programme can prevent unnecessary ED visits and facilitate direct-to-ward hospitalizations and thereby mitigate the impact of COVID-19 on the healthcare system.