Risk-based lung cancer screening performance in a universal healthcare setting.

Globally, lung cancer is the leading cause of cancer death. Previous trials demonstrated that low-dose computed tomography lung cancer screening of high-risk individuals can reduce lung cancer mortality by 20% or more. Lung cancer screening has been approved by major guidelines in the United States, and over 4,000 sites offer screening. Adoption of lung screening outside the United States has, until recently, been slow. Between June 2017 and May 2019, the Ontario Lung Cancer Screening Pilot successfully recruited 7,768 individuals at high risk identified by using the PLCOm2012noRace lung cancer risk prediction model. In total, 4,451 participants were successfully screened, retained and provided with high-quality follow-up, including appropriate treatment. In the Ontario Lung Cancer Screening Pilot, the lung cancer detection rate and the proportion of early-stage cancers were 2.4% and 79.2%, respectively; serious harms were infrequent; and sensitivity to detect lung cancers was 95.3% or more. With abnormal scans defined as ones leading to diagnostic investigation, specificity was 95.5% (positive predictive value, 35.1%), and adherence to annual recall and early surveillance scans and clinical investigations were high (>85%). The Ontario Lung Cancer Screening Pilot provides insights into how a risk-based organized lung screening program can be implemented in a large, diverse, populous geographic area within a universal healthcare system.

Integrating Smoking Cessation Into Low-Dose Computed Tomography Lung Cancer Screening: Results of the Ontario, Canada Pilot.

INTRODUCTION: Low-dose computed tomography screening in high-risk individuals reduces lung cancer mortality. To inform the implementation of a provincial lung cancer screening program, Ontario Health undertook a Pilot study, which integrated smoking cessation (SC). METHODS: The impact of integrating SC into the Pilot was assessed by the following: rate of acceptance of a SC referral; proportion of individuals who were currently smoking cigarettes and attended a SC session; the quit rate at 1 year; change in the number of quit attempts; change in Heaviness of Smoking Index; and relapse rate in those who previously smoked. RESULTS: A total of 7768 individuals were recruited predominantly through primary care physician referral. Of these, 4463 were currently smoking and were risk assessed and referred to SC services, irrespective of screening eligibility: 3114 (69.8%) accepted referral to an in-hospital SC program, 431 (9.7%) to telephone quit lines, and 50 (1.1%) to other programs. In addition, 4.4% reported no intention to quit and 8.5% were not interested in participating in a SC program. Of the 3063 screen-eligible individuals who were smoking at baseline low-dose computed tomography scan, 2736 (89.3%) attended in-hospital SC counseling. The quit rate at 1 year was 15.5% (95% confidence interval: 13.4%-17.7%; range: 10.5%-20.0%). Improvements were also observed in Heaviness of Smoking Index (p < 0.0001), number of cigarettes smoked per day (p < 0.0001), time to first cigarette (p < 0.0001), and number of quit attempts (p < 0.001). Of those who reported having quit within the previous 6 months, 6.3% had resumed smoking at 1 year. Furthermore, 92.7% of the respondents reported satisfaction with the hospital-based SC program. CONCLUSIONS: On the basis of these observations, the Ontario Lung Screening Program continues to recruit through primary care providers, to assess risk for eligibility using trained navigators, and to use an opt-out approach to referral for cessation services. In addition, initial in-hospital SC support and intensive follow-on cessation interventions will be provided to the extent possible.

Psychiatric disorders in adults with cerebral palsy.

BACKGROUND: Cerebral palsy (CP) is one of the most common neurological conditions in childhood. Individuals with CP often experience various secondary conditions, including intellectual disability (ID), medical conditions, and psychiatric issues. A large number of youth with CP have psychiatric disorders; however, few studies have examined the prevalence of psychiatric issues in adults with CP at the population-level. AIMS: To investigate the prevalence and co-occurrence of psychiatric disorders at the population-level in adults with CP only, and adults with CP and ID. METHOD AND PROCEDURES: Using clinical information from seven Canadian data sources, we conducted a retrospective cross-sectional analysis of adults with CP, with and without ID. OUTCOMES AND RESULTS: Adults with CP were more likely than the general population to have a psychiatric diagnosis, independent of ID status. All psychiatric disorders were more common in individuals with CP than the general population, with the exception of addiction related disorders. In most cases, having an ID substantially increased the risk of having a psychiatric disorder. CONCLUSIONS: Adults with CP are at heightened risk for experiencing psychiatric disorders. Current findings highlight the important role health care providers play in screening for psychiatric issues in individuals with CP.

Organized Lung Cancer Screening Pilot: Informing a Province-Wide Program in Ontario, Canada.

BACKGROUND: Lung cancer is the leading cause of cancer deaths in Ontario. The National Lung Screening Trial demonstrated that screening with low-dose computed tomography (LDCT) reduces lung cancer mortality. METHODS: In June 2017, Ontario Health (Cancer Care Ontario) initiated a pilot for lung cancer screening to inform implementation of a province-wide initiative. The screening pathway includes targeted recruitment strategies, the Tammemägi risk prediction model (PLCOm2012) to determine eligibility, opt-out smoking cessation services for all current smokers, use of the Lung-RADS scoring system to guide abnormal results management, and screening navigators providing end-to-end support. Referral criteria include being 55 years of age to 74 years of age and a current or former daily cigarette smoker for greater than or equal to 20 years, while the screening eligibility criterion is a PLCOm2012 risk greater than or equal to 2% in 6 years. Selected results of the interim pilot evaluation are presented. Four hospitals contributed data in the first year of the pilot. RESULTS: During 2017 to 2018, 4205 Ontarians were recruited, 3234 risk assessments were conducted, and 2151 (66.5%) individuals were eligible for screening. Baseline LDCT scans were performed in 1624 (50.2%) individuals. Diagnostic evaluation in 120 (7.4%) individuals identified 28 (1.7%) with lung cancer, and proportions of stage I to II and stage III to IV were 71% and 29%, respectively. Of those recruited, 1443 (34.3%) individuals were smokers and 1326 (91.9%) accepted smoking cessation services. CONCLUSIONS: The pilot is the largest in Canada and aligns with International Agency for Research on Cancer standards for population-based, organized cancer screening. Recruitment of high-risk individuals, high rates of smoking cessation program acceptance, and detection of early-stage cancers are demonstrated.

Health Concerns and Health Service Utilization in a Population Cohort of Young Adults with Autism Spectrum Disorder.

Individuals with autism spectrum disorder (ASD) have many health needs that place demands on the health service sector. This study used administrative data to compare health profiles in young adults 18-24 years of age with ASD to peers with and without other developmental disability. Young adults with ASD were more likely to have almost all the examined clinical health issues and health service use indicators compared to peers without developmental disability. They were more likely to have at least one psychiatric diagnosis, and visit the family physician, pediatrician, psychiatrist, and emergency department for psychiatric reasons, compared to peers with other developmental disability. Planning for the mental health care of transition age adults with ASD is an important priority for health policy.

Substance-related and addictive disorders among adults with intellectual and developmental disabilities (IDD): an Ontario population cohort study.

OBJECTIVES: Describe the prevalence of substance-related and addictive disorders (SRAD) in adults with intellectual and developmental disabilities (IDD) and compare the sociodemographic and clinical characteristics of adults with IDD and SRAD to those with IDD or SRAD only. DESIGN: Population-based cohort study (the Health Care Access Research and Development Disabilities (H-CARDD) cohort). SETTING: All legal residents of Ontario, Canada. PARTICIPANTS: 66 484 adults, aged 18-64, with IDD identified through linked provincial health and disability income benefits administrative data from fiscal year 2009. 96 589 adults, aged 18-64, with SRAD but without IDD drawn from the provincial health administrative data. MAIN OUTCOME MEASURES: Sociodemographic (age group, sex, neighbourhood income quintile, rurality) and clinical (psychiatric and chronic disease diagnoses, morbidity) characteristics. RESULTS: The prevalence of SRAD among adults with IDD was 6.4%, considerably higher than many previous reports and also higher than found for adults without IDD in Ontario (3.5%). Among those with both IDD and SRAD, the rate of psychiatric comorbidity was 78.8%, and the proportion with high or very high overall morbidity was 59.5%. The most common psychiatric comorbidities were anxiety disorders (67.6%), followed by affective (44.6%), psychotic (35.8%) and personality disorders (23.5%). These adults also tended to be younger and more likely to live in the poorest neighbourhoods compared with adults with IDD but no SRAD and adults with SRAD but no IDD. CONCLUSIONS: SRAD is a significant concern for adults with IDD. It is associated with high rates of psychiatric and other comorbidities, indicating that care coordination and system navigation may be important concerns. Attention should be paid to increasing the recognition of SRAD among individuals with IDD by both healthcare and social service providers and to improving staff skills in successfully engaging those with both IDD and SRAD.

The diaphragms of fenestrated endothelia: gatekeepers of vascular permeability and blood composition.

Fenestral and stomatal diaphragms are endothelial subcellular structures of unknown function that form on organelles implicated in vascular permeability: fenestrae, transendothelial channels, and caveolae. PV1 protein is required for diaphragm formation in vitro. Here, we report that deletion of the PV1-encoding Plvap gene in mice results in the absence of diaphragms and decreased survival. Loss of diaphragms did not affect the fenestrae and transendothelial channels formation but disrupted the barrier function of fenestrated capillaries, causing a major leak of plasma proteins. This disruption results in early death of animals due to severe noninflammatory protein-losing enteropathy. Deletion of PV1 in endothelium, but not in the hematopoietic compartment, recapitulates the phenotype of global PV1 deletion, whereas endothelial reconstitution of PV1 rescues the phenotype. Taken together, these data provide genetic evidence for the critical role of the diaphragms in fenestrated capillaries in the maintenance of blood composition.

PV1 down-regulation via shRNA inhibits the growth of pancreatic adenocarcinoma xenografts.

PV1 is an endothelial-specific protein with structural roles in the formation of diaphragms in endothelial cells of normal vessels. PV1 is also highly expressed on endothelial cells of many solid tumours. On the basis of in vitro data, PV1 is thought to actively participate in angiogenesis. To test whether or not PV1 has a function in tumour angiogenesis and in tumour growth in vivo, we have treated pancreatic tumour-bearing mice by single-dose intratumoural delivery of lentiviruses encoding for two different shRNAs targeting murine PV1. We find that PV1 down-regulation by shRNAs inhibits the growth of established tumours derived from two different human pancreatic adenocarcinoma cell lines (AsPC-1 and BxPC-3). The effect observed is because of down-regulation of PV1 in the tumour endothelial cells of host origin, PV1 being specifically expressed in tumour vascular endothelial cells and not in cancer or other stromal cells. There are no differences in vascular density of tumours treated or not with PV1 shRNA, and gain and loss of function of PV1 in endothelial cells does not modify either their proliferation or migration, suggesting that tumour angiogenesis is not impaired. Together, our data argue that down-regulation of PV1 in tumour endothelial cells results in the inhibition of tumour growth via a mechanism different from inhibiting angiogenesis.

Caveolae, fenestrae and transendothelial channels retain PV1 on the surface of endothelial cells.

PV1 protein is an essential component of stomatal and fenestral diaphragms, which are formed at the plasma membrane of endothelial cells (ECs), on structures such as caveolae, fenestrae and transendothelial channels. Knockout of PV1 in mice results in in utero and perinatal mortality. To be able to interpret the complex PV1 knockout phenotype, it is critical to determine whether the formation of diaphragms is the only cellular role of PV1. We addressed this question by measuring the effect of complete and partial removal of structures capable of forming diaphragms on PV1 protein level. Removal of caveolae in mice by knocking out caveolin-1 or cavin-1 resulted in a dramatic reduction of PV1 protein level in lungs but not kidneys. The magnitude of PV1 reduction correlated with the abundance of structures capable of forming diaphragms in the microvasculature of these organs. The absence of caveolae in the lung ECs did not affect the transcription or translation of PV1, but it caused a sharp increase in PV1 protein internalization rate via a clathrin- and dynamin-independent pathway followed by degradation in lysosomes. Thus, PV1 is retained on the cell surface of ECs by structures capable of forming diaphragms, but undergoes rapid internalization and degradation in the absence of these structures, suggesting that formation of diaphragms is the only role of PV1.