Enablers and Barriers for End-of-Life Symptom Management Medications in Long-Term Care Homes: A Qualitative Study.

OBJECTIVES: Long-term care (LTC) homes provide personal and medical care 24/7 to individuals unable to live at home due to illness or disability and are often the final place of care and death for their residents. Therefore, LTC homes are tasked with providing quality end-of-life care, often requiring injectable symptom management medications to relieve distressing symptoms (eg, pain). In this study, we aimed to understand the enablers and barriers to prescribing and administering end-of-life symptom management medications in LTC homes. DESIGN: Qualitative study. SETTING AND PARTICIPANTS: From February 2021 to December 2022, we conducted virtual semi-structured interviews with health care providers (physicians and nurses) who worked in Ontario LTC homes and family caregivers of residents who died in LTC. METHODS: We analyzed interview transcripts using thematic analysis. RESULTS: We identified 4 themes related to factors that may impact the prescribing and administering of medications for end-of-life symptom management: (1) identifying the end-of-life period and symptoms, (2) communication among health care providers and between health care providers and family caregivers, (3) health care provider competency with end-of-life medications, and (4) resources for LTC staff to support medication prescribing and administrating. CONCLUSIONS AND IMPLICATIONS: In LTC, there are distinct challenges in the prescribing and administrating of end-of-life symptom management medications. Our findings can be used to inform interventions aimed at improving end-of-life care for LTC residents. However, these interventions require buy-in and investment from the provincial government and the LTC sector.

Corrigendum: Measuring the Use of End-of-Life Symptom Relief Medications in Long-Term Care Homes-a Qualitative Study.

[This corrects the article DOI: 10.5770/cgj.27.712.].

Daily Positive Alcohol Expectancies and Alcohol Use Outcomes among College Students.

Expectancy theory supports alcohol expectancies, or the expected effects of drinking, as an important factor in alcohol use behaviors. Recent research supports that alcohol expectancies fluctuate daily, but scant research has examined specific types of expectancies and their associations with alcohol use at the daily level. Consequently, the present study examined (1) the daily association between select expectancies (i.e., sociability, tension reduction, liquid courage) and likelihood of drinking, and (2) whether daily expectancies predict alcohol use outcomes (i.e., alcohol-related problems, heavy drinking) on drinking days. Participants (N = 221; 79.2% women) were primarily White (48.4%) and Black (29.7%) university students. Participants completed daily measures of expectancies, alcohol use, and alcohol-related problems each day for 14 days. Results from multilevel models revealed daily sociability as the only expectancy subscale linked with increased odds of drinking. Daily expectancies did not predict heavy drinking or alcohol-related problems on drinking days. At the between-person level, average levels of sociability and tension reduction expectancies were associated with a greater likelihood of engaging in heavy drinking and experiencing a problem. Findings highlight that fluctuations in sociability expectancies may be proximally linked to likelihood of alcohol use, which may inform just-in-time intervention efforts targeting alcohol expectancies.

Changes in End-of-Life Symptom Management Prescribing among Long-Term Care Residents during COVID-19.

OBJECTIVE: To examine changes in the prescribing of end-of-life symptom management medications in long-term care (LTC) homes during the COVID-19 pandemic. DESIGN: Retrospective cohort study using routinely collected health administrative data in Ontario, Canada. SETTING AND PARTICIPANTS: We included all individuals who died in LTC homes between January 1, 2017, and March 31, 2021. We separated the study into 2 periods: before COVID-19 (January 1, 2017, to March 17, 2020) and during COVID-19 (March 18, 2020, to March 31, 2021). METHODS: For each LTC home, we measured the percentage of residents who died before and during COVID-19 who had a subcutaneous symptom management medication prescription in their last 14 days of life. We grouped LTC homes into quintiles based on their mean prescribing rates before COVID-19, and examined changes in prescribing during COVID-19 and COVID-19 outcomes across quintiles. RESULTS: We captured 75,438 LTC residents who died in Ontario's 626 LTC homes during the entire study period, with 19,522 (25.9%) dying during COVID-19. The mean prescribing rate during COVID-19 ranged from 46.9% to 79.4% between the lowest and highest prescribing quintiles. During COVID-19, the mean prescribing rate in the lowest prescribing quintile increased by 9.6% compared to before COVID-19. Compared to LTC homes in the highest prescribing quintile, homes in the lowest prescribing quintile experienced the highest proportion of COVID-19 outbreaks (73.4% vs 50.0%), the largest mean outbreak intensity (0.27 vs 0.09 cases/bed), the highest mean total days with a COVID-19 outbreak (72.7 vs 24.2 days), and the greatest proportion of decedents who were transferred and died outside of LTC (22.1% vs 8.6%). CONCLUSIONS AND IMPLICATIONS: LTC homes in Ontario had wide variations in the prescribing rates of end-of-life symptom management medications before and during COVID-19. Homes in the lower prescribing quintiles had more COVID-19 cases per bed and days spent in an outbreak.

Measuring the Use of End-of-Life Symptom Relief Medications in Long-Term Care Homes-a Qualitative Study.

Background: At the end of life, individuals may experience physical symptoms such as pain, and guidelines recommend medications to manage these symptoms. Yet, little is known about the symptom management long-term care (LTC) residents receive at the end of life. Our research team developed a metric-whether residents receive one or more prescriptions for an end-of-life symptom management medication in their last two weeks-to explore end-of-life care for LTC residents. This qualitative study aimed to inform the refinement of the end-of-life prescribing metric, including the acceptability and applicability to assess the quality of a resident's symptom management at end-of-life. Methods: We conducted 14 semi-structured interviews with Ontario health-care providers (physicians and nurses) who work in LTC homes and family caregivers of residents who died in LTC. Interviews were conducted virtually between February 2021 and December 2022, and were analyzed using thematic analysis. Results: We identified three major themes relating to perceptions of the metric: 1) appropriateness, 2) health-care provider applicability, and 3) caregiver applicability. Participants noted that the metric may be appropriate to assess end-of-life care, but noted important nuances. Regarding applicability, health-care providers found value in the metric and that it could inform their practice. Conversely, caregivers found limited value in the metric. Conclusion: The proposed metric captures a very specific aspect of end-of-life care-whether end-of-life medications were prescribed or not. Participants deemed that the metric may reflect whether LTC homes have processes to manage a resident's end-of-life symptoms with medication. However, participants thought the metric could not provide a complete picture of end-of-life care and its quality.

Estimated mortality risk and use of palliative care services among home care clients during the last 6 months of life: a retrospective cohort study.

BACKGROUND: In Canada, only 15% of patients requiring palliative care receive such services in the year before death. We describe health care utilization patterns among home care users in their last 6 months of life to inform care planning for older people with varying mortality risks and evolving care needs as they decline. METHODS: Using population health administrative data from Ontario, we performed a retrospective cohort study involving home care clients aged 50 years and older who received at least 1 interRAI (Resident Assessment Instrument) Home Care assessment between April 2018 and September 2019. We report the proportion of clients who used acute care, long-term care, and palliative home care services within 6 months of their assessment, stratified by their predicted 6-month mortality risk using a prognostic tool called the Risk Evaluation for Support: Predictions for Elder-life in their Communities Tool (RESPECT) and vital status. RESULTS: The cohort included 247 377 adults, 11.9% of whom died within 6 months of an assessment. Among decedents, 50.6% of those with a RESPECT-estimated median survival of fewer than 3 months received at least 1 nonphysician palliative home care visit before death. This proportion declined to 38.7% and 29.5% among decedents with an estimated median survival between 3 and 6 months and between 6 and 12 months, respectively. INTERPRETATION: Many older adults in Ontario do not receive any palliative home care before death. Prognostic tools such as RESPECT may improve recognition of reduced life expectancies and palliative care needs of individuals in their final years of life.

Palliative End-of-Life Medication Prescribing Rates in Long-Term Care: A Retrospective Cohort Study.

BACKGROUND: Medications are often needed to manage distressing end-of-life symptoms (eg, pain, agitation). OBJECTIVES: In this study, we describe the variation in prescribing rates of symptom relief medications at the end of life among long-term care (LTC) decedents. We evaluate the extent these medications are prescribed in LTC homes and whether prescribing rates of end-of-life symptom management can be used as an indicator of quality end-of-life care. DESIGN: Retrospective cohort study using administrative health data. SETTING AND PARTICIPANTS: LTC decedents in all 626 publicly funded LTC homes in Ontario, Canada, between January 1, 2017, and March 17, 2020. METHODS: For each LTC home, we measured the percent of decedents who received 1+ prescription(s) for a subcutaneous end-of-life symptom management medication ("end-of-life medication") in their last 14 days of life. We then ranked LTC homes into quintiles based on prescribing rates. RESULTS: We identified 55,916 LTC residents who died in LTC. On average, two-thirds of decedents (64.7%) in LTC homes were prescribed at least 1 subcutaneous end-of-life medication in the last 2 weeks of life. Opioids were the most common prescribed medication (overall average prescribing rate of 62.7%). LTC homes in the lowest prescribing quintile had a mean of 37.3% of decedents prescribed an end-of-life medication, and the highest quintile mean was 82.5%. In addition, across these quintiles, the lowest prescribing quintile had a high average (30.3%) of LTC residents transferred out of LTC in the 14 days compared with the highest prescribing quintile (12.7%). CONCLUSIONS AND IMPLICATIONS: Across Ontario's LTC homes, there are large differences in prescribing rates for subcutaneous end-of-life symptom relief medications. Although future work may elucidate why the variability exists, this study provides evidence that administrative data can provide valuable insight into the systemic delivery of end-of-life care.

Prevalence and patterns of multimorbidity among linguistic groups of patients receiving home care in Ontario: a retrospective cohort study.

BACKGROUND: Prior studies have demonstrated the negative impact of language barriers on access, quality, and safety of healthcare, which can lead to health disparities in linguistic minorities. As the population ages, those with multiple chronic diseases will require increasing levels of home care and long-term services. This study described the levels of multimorbidity among recipients of home care in Ontario, Canada by linguistic group. METHODS: Population-based retrospective cohort of 510,685 adults receiving home care between April 1, 2010, to March 31, 2018, in Ontario, Canada. We estimated and compared prevalence and characteristics of multimorbidity (2 or more chronic diseases) across linguistic groups (Francophones, Anglophones, Allophones). The most common combinations and clustering of chronic diseases were examined. Logistic regression models were used to explore the main predictors of 'severe' multimorbidity (defined as the presence of five or more chronic diseases). RESULTS: The proportion of home care recipients with multimorbidity and severe multimorbidity was 92% and 44%, respectively. The prevalence of multimorbidity was slightly higher among Allophones (93.6%) than among Anglophones (91.8%) and Francophones (92.4%). However, Francophones had higher rates of cardiovascular and respiratory disease (64.9%) when compared to Anglophones (60.2%) and Allophones (61.5%), while Anglophones had higher rates of cancer (34.2%) when compared to Francophones (25.2%) and Allophones (24.3%). Relative to Anglophones, Allophones were more likely to have severe multimorbidity (adjusted OR = 1.04, [95% CI: 1.02-1.06]). CONCLUSIONS: The prevalence of multimorbidity among Ontarians receiving home care services is high; especially for whose primary language is a language other than English or French (i.e., Allophones). Understanding differences in the prevalence and characteristics of multimorbidity across linguistic groups will help tailor healthcare services to the unique needs of patients living in minority linguistic situations.

Association between non-medical cannabis legalization and emergency department visits for cannabis-induced psychosis.

A major public health concern of cannabis legalization is that it may result in an increase in psychotic disorders. We examined changes in emergency department (ED) visits for cannabis-induced psychosis following the legalization and subsequent commercialization (removal of restrictions on retail stores and product types) of non-medical cannabis in Ontario, Canada (population of 14.3 million). We used health administrative data containing the cause of all ED visits to examine changes over three periods; 1) pre-legalization (January 2014-September 2018); 2) legalization with restrictions (October 2018 - February 2020); and 3) commercialization (March 2020 - September 2021). We considered subgroups stratified by age and sex and examined cocaine- and methamphetamine-induced psychosis ED visits as controls. During our study, there were 6300 ED visits for cannabis-induced psychosis. The restricted legalization period was not associated with changes in rates of ED visits for cannabis-induced psychosis relative to pre-legalization. The commercialization period was associated with an immediate increase in rates of ED visits for cannabis-induced psychosis (IRR 1.30, 95% CI 1.02-1.66) and no gradual monthly change; immediate increases were seen only for youth above (IRR 1.63, 1.27-2.08, ages 19-24) but not below (IRR 0.73 95%CI 0.42-1.28 ages, 15-18) the legal age of purchase, and similar for men and women. Commercialization was not associated with changes in rates of ED visits for cocaine- or methamphetamine-induced psychosis. This suggests that legalization with store and product restrictions does not increase ED visits for cannabis-induced psychosis. In contrast, cannabis commercialization may increase cannabis-induced psychosis presentations highlighting the importance of preventive measures in regions considering legalization.

Acute care related to cannabis use during pregnancy after the legalization of nonmedical cannabis in Ontario.

BACKGROUND: Cannabis use during pregnancy is increasing, but the contribution of cannabis legalization to these trends is unclear. We sought to determine whether health service utilization related to cannabis use during pregnancy increased after the legalization of nonmedical cannabis in October 2018 in Ontario, Canada. METHODS: In this population-based, repeated cross-sectional study, we evaluated changes in the number of pregnant people who received acute care (emergency department visit or admission to hospital) between January 2015 and July 2021 among all people eligible for the province's public health coverage. We used segmented regression to compare changes in the quarterly rate of pregnant people with acute care related to cannabis use (primary outcome) with the quarterly rates of acute care for mental health conditions or for noncannabis substance use (control conditions). We identified risk factors associated with acute care for cannabis use and the risk of adverse neonatal outcomes using multivariable logistic regression models. RESULTS: The mean quarterly rate of acute care for cannabis use during pregnancy increased from 11.0 per 100 000 pregnancies before legalization to 20.0 per 100 000 pregnancies after legalization (incidence rate ratio [IRR] 1.82, 95% confidence interval [CI] 1.44-2.31), while acute care for mental health conditions decreased (IRR 0.86, 95% CI 0.78-0.95) and acute care for noncannabis substance use did not change (IRR 1.03, 95% CI 0.91-1.17). Legalization was not associated with an immediate change, but the quarterly change in rates of pregnancies with acute care for cannabis use increased by 1.13 (95% CI 0.46-1.79) per 100 000 pregnancies after legalization. Pregnant people with acute care for cannabis use had greater odds of having received acute care for hyperemesis gravidarum during their pregnancy than those without acute care for cannabis use (30.9% v. 2.5%, adjusted odds ratio [OR] 9.73, 95% CI 8.01-11.82). Pregnancies with acute care for cannabis use had greater odds of newborns being born preterm (16.9% v. 7.2%, adjusted OR 1.93, 95% CI 1.45-2.56) and of requiring care in the neonatal intensive care unit (31.5% v. 13.0%, adjusted OR 1.94 95% CI 1.54-2.44) than those without acute care for cannabis use. INTERPRETATION: The rate of acute care related to cannabis use during pregnancy almost doubled after legalization of nonmedical cannabis, although absolute increases were small. These findings highlight the need to consider interventions to reduce cannabis use during pregnancy in jurisdictions pursuing legalization.

Mental health and addiction health service use by physicians compared to non-physicians before and during the COVID-19 pandemic: A population-based cohort study in Ontario, Canada.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic has exacerbated mental health challenges among physicians and non-physicians. However, it is unclear if the worsening mental health among physicians is due to specific occupational stressors, reflective of general societal stressors during the pandemic, or a combination. We evaluated the difference in mental health and addictions health service use between physicians and non-physicians, before and during the COVID-19 pandemic. METHODS AND FINDINGS: We conducted a population-based cohort study in Ontario, Canada between March 11, 2017 and August 11, 2021 using data collected from Ontario's universal health system. Physicians were identified using registrations with the College of Physicians and Surgeons of Ontario between 1990 and 2020. Participants included 41,814 physicians and 12,054,070 non-physicians. We compared the first 18 months of the COVID-19 pandemic (March 11, 2020 to August 11, 2021) to the period before COVID-19 pandemic (March 11, 2017 to February 11, 2020). The primary outcome was mental health and addiction outpatient visits overall and subdivided into virtual versus in-person, psychiatrists versus family medicine and general practice clinicians. We used generalized estimating equations for the analyses. Pre-pandemic, after adjustment for age and sex, physicians had higher rates of psychiatry visits (aIRR 3.91 95% CI 3.55 to 4.30) and lower rates of family medicine visits (aIRR 0.62 95% CI 0.58 to 0.66) compared to non-physicians. During the first 18 months of the COVID-19 pandemic, the rate of outpatient mental health and addiction (MHA) visits increased by 23.2% in physicians (888.4 pre versus 1,094.7 during per 1,000 person-years, aIRR 1.39 95% CI 1.28 to 1.51) and 9.8% in non-physicians (615.5 pre versus 675.9 during per 1,000 person-years, aIRR 1.12 95% CI 1.09 to 1.14). Outpatient MHA and virtual care visits increased more among physicians than non-physicians during the first 18 months of the pandemic. Limitations include residual confounding between physician and non-physicians and challenges differentiating whether observed increases in MHA visits during the pandemic are due to stressors or changes in health care access. CONCLUSIONS: The first 18 months of the COVID-19 pandemic was associated with a larger increase in outpatient MHA visits in physicians than non-physicians. These findings suggest physicians may have had larger negative mental health during COVID-19 than the general population and highlight the need for increased access to mental health services and system level changes to promote physician wellness.

Characterization of Problematic Alcohol Use Among Physicians: A Systematic Review.

Importance: Problematic alcohol use in physicians poses a serious concern to physicians' health and their ability to provide care. Understanding the extent and characteristics of physicians with problematic alcohol use will help inform interventions. Objective: To estimate the extent of problematic alcohol use in physicians and how it differs by physician sex, age, medical specialty, and career stage (eg, residency vs practicing physician). Evidence Review: Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) 2020-compliant systematic review, searching Medline, Embase, and PsychInfo from January 2006 to March 2020. Search terms included Medical Subject Headings terms and keywords related to physicians as the population and problematic alcohol use as the primary outcome. The quality of studies was assessed using the Newcastle-Ottawa Scale. We included articles where problematic alcohol use was measured by a validated tool (ie, Alcohol Use Disorders Identification Test [AUDIT], AUDIT Version C [AUDIT-C], or CAGE [Cut down, Annoyed, Guilty, and Eye-opener] questionnaire) in practicing physicians (ie, residents, fellows, or staff physicians). Findings: Thirty-one studies involving 51 680 participants in 17 countries published between January 2006 and March 2020 were included. All study designs were cross-sectional, self-reported surveys. Problematic alcohol use varied widely regardless of measurement method (0 to 34% with AUDIT; 9% to 35% with AUDIT-C; 4% to 22% with CAGE). Reported problematic alcohol use increased over time from 16.3% in 2006 to 2010 to 26.8% in 2017 to 2020. The extent of problematic use by sex was examined in 19 studies, by age in 12 studies, by specialty in 7 studies, and by career stage in 5 studies. Seven of 19 studies (37%) identified that problematic alcohol use was more common in males than females. Based on the wide heterogeneity of methods for included studies, limited conclusions can be made on how problematic alcohol use varies based on physician age, sex, specialty, and career stage. Conclusions and Relevance: Studies about problematic alcohol use in physicians demonstrate a high degree of heterogeneity in terms of methods of measurement, definitions for problematic alcohol use, and cohorts assessed. Most studies are primarily self-reported, precluding the ability to determine the true prevalence among the profession. Few studies provide relevant comparisons to aid in identifying key risk groups for targeted interventions.

Changes in Emergency Department Visits for Cannabis Hyperemesis Syndrome Following Recreational Cannabis Legalization and Subsequent Commercialization in Ontario, Canada.

Importance: Prior research suggests that the legalization of recreational cannabis is associated with increases in cannabis hyperemesis syndrome (CHS), but it is unclear how cannabis commercialization (ie, greater retail store access as well as increased variety and potency of cannabis products) may be associated with these changes. Objectives: To examine changes in the number and characteristics of CHS emergency department (ED) visits from before to after legalization of cannabis in Ontario, Canada. Design, Setting, and Participants: This repeated cross-sectional study used interrupted time-series analyses to examine immediate and gradual changes in ED visits for CHS in Ontario, Canada, during 3 time periods: prelegalization (January 2014-September 2018), legalization with product and retail store restrictions (October 2018-February 2020), and commercialization with new products and expanded stores, which coincided with the COVID-19 pandemic (March 2020-June 2021). Data were obtained from routinely collected and linked health administrative databases. All individuals aged at least 15 years and who were eligible for Ontario's Universal Health Coverage were included. Data were analyzed between March and July 2022. Main Outcomes and Measures: Monthly counts of ED visits for CHS per capita. Results: There were 12 866 ED visits for CHS from 8140 individuals during the study. Overall, the mean (SD) age was 27.4 (10.5) years, with 2834 individuals (34.8%) aged 19 to 24 years, 4163 (51.5%) females, and 1353 individuals (16.6%) with a mental health ED visit or hospitalization in the 2 years before their first CHS ED visit. Nearly 10% of visits (1135 visits [8.8%]) led to hospital admissions. Monthly rates of CHS ED visits increased 13-fold during the 7.5-year study period, from 0.26 visits per 100 000 population in January 2014 to 3.43 visits per 100 000 population in June 2021. Legalization was not associated with an immediate or gradual change in rates of ED visits for CHS; however, commercialization during the COVID-19 pandemic period was associated with an immediate increase in rates of CHS ED visits (incidence rate ratio [IRR], 1.49; 95% CI, 1.31-1.70). During commercialization, rates of CHS ED visits increased more in women (IRR, 1.49; 95% CI, 1.16-1.92) and individuals older than the legal age of cannabis purchase (eg, age 19-24 years: IRR, 1.60; 95% CI, 1.19-2.16) than men (IRR, 1.08; 95% CI, 0.85-1.37) and individuals younger than the legal age of purchase (IRR, 0.78; 95% CI, 0.42-1.45). Conclusions and Relevance: This cross-sectional study found large increases in CHS ED visits during the period of time when the market commercialized and the COVID-19 pandemic occurred. Greater awareness of CHS symptoms by ED staff in regions where legal commercialized cannabis markets exist is indicated.

Patient-physician language concordance and quality and safety outcomes among frail home care recipients admitted to hospital in Ontario, Canada.

BACKGROUND: When patients and physicians speak the same language, it may improve the quality and safety of care delivered. We sought to determine whether patient-physician language concordance is associated with in-hospital and postdischarge outcomes among home care recipients who were admitted to hospital. METHODS: We conducted a population-based study of a retrospective cohort of 189 690 home care recipients who were admitted to hospital in Ontario, Canada, between 2010 and 2018. We defined patient language (obtained from home care assessments) as English (Anglophone), French (Francophone) or other (allophone). We obtained physician language from the College of Physicians and Surgeons of Ontario. We defined hospital admissions as language concordant when patients received more than 50% of their care from physicians who spoke the patients' primary language. We identified in-hospital (adverse events, length of stay, death) and post-discharge outcomes (emergency department visits, readmissions, death within 30 days of discharge). We used regression analyses to estimate the adjusted rate of mean and the adjusted odds ratio (OR) of each outcome, stratified by patient language, to assess the impact of language-concordant care within each linguistic group. RESULTS: Allophone patients who received language-concordant care had lower risk of adverse events (adjusted OR 0.25, 95% confidence interval [CI] 0.15-0.43) and in-hospital death (adjusted OR 0.44, 95% CI 0.29-0.66), as well as shorter stays in hospital (adjusted rate of mean 0.74, 95% CI 0.66-0.83) than allophone patients who received language-discordant care. Results were similar for Francophone patients, although the magnitude of the effect was smaller than for allophone patients. Language concordance or discordance of the hospital admission was not associated with significant differences in postdischarge outcomes. INTERPRETATION: Patients who received most of their care from physicians who spoke the patients' primary language had better in-hospital outcomes, suggesting that disparities across linguistic groups could be mitigated by providing patients with language-concordant care.

Alcohol, cannabis, and tobacco polysubstance use: A latent profile analysis of age of onset.

BACKGROUND: Despite understanding the long-term risks associated with early substance use, less is known about the specific patterns of the age of onset (AO) across multiple substances and whether these patterns of early exposure are linked to substance use later in young adulthood. Consequently, the present study sought to (1) identify distinct classes regarding AO for alcohol, cannabis, and tobacco and (2) compare these classes on patterns of individual and simultaneous alcohol, cannabis, and tobacco use, other substance use, and mental health symptoms. METHODS: Participants were 510 emerging adults (Mage = 21.35; 88.6% men) who reported past-year use of alcohol, cannabis, and tobacco. RESULTS: Latent profile analysis was used to identify classes based on three indicators: AO for alcohol, cannabis, and tobacco. Results revealed that four classes best fit the data: Earliest AO for Alcohol (19.8%); Latest AO for Substances (6.5%); Late AO for Substances (67.8%); Earliest AO for Cannabis and Tobacco (5.9%). Classes varied on current patterns of individual substance use, co-use of substances, other illicit drug use, and mental health symptomology. The Latest AO of Substances class reported the lowest alcohol use, cannabis use, other illicit drug use, and mental health symptomology than the other classes. The Earliest AO for Alcohol and the Late AO of Substances reported a lower frequency of tobacco compared to the other classes. The Late AO of Substance class reported the highest past-year frequency of simultaneous alcohol and cannabis use. CONCLUSIONS: The current study contributed to the larger polysubstance literature by identifying profiles that may signify risky patterns of use. Findings may help guide prevention and intervention work with adolescents and young adults.

Differentiating Ductal Adenocarcinoma of the Pancreas from Benign Conditions Using Routine Health Records: A Prospective Case-Control Study.

The study aimed to develop a prediction model for differentiating suspected PDAC from benign conditions. We used a prospective cohort of patients with pancreatic disease (n = 762) enrolled at the Barts Pancreas Tissue Bank (2008-2021) and performed a case-control study examining the association of PDAC (n = 340) with predictor variables including demographics, comorbidities, lifestyle factors, presenting symptoms and commonly performed blood tests. Age (over 55), weight loss in hypertensive patients, recent symptoms of jaundice, high serum bilirubin, low serum creatinine, high serum alkaline phosphatase, low red blood cell count and low serum sodium were identified as the most important features. These predictors were then used for training several machine-learning-based risk-prediction models on 75% of the cohort. Models were assessed on the remaining 25%. A logistic regression-based model had the best overall performance in the validation cohort (area-under-the-curve = 0.90; Spiegelhalter's z = -1·82, p = 0.07). Setting a probability threshold of 0.15 guided by the maximum F2-score of 0.855, 96.8% sensitivity was reached in the full cohort, which could lead to earlier detection of 84.7% of the PDAC patients. The prediction model has the potential to be applied in primary, secondary and emergency care settings for the early distinction of suspected PDAC patients and expedited referral to specialist hepato-pancreatico-biliary services.

Validation of a Novel, Flash-Freezing Method: Aluminum Platform.

Stored biological materials should have minimal pre-analytical variations in order to provide researchers with high-quality samples that will give reliable and reproducible results, yet methods of storage should be easy to implement, with minimal cost and health hazard. Frozen tissue samples are a valuable biological resource. Here we compare different methods, such as liquid nitrogen (LN) or dry ice (DI), to a cheap and safe alternative using an aluminum platform (AP). Murine fresh liver and pancreas tissues were used with varying lengths of warm ischemia time. Quality assessment was based on histological evaluation, DNA and RNA extraction and quantification, and RNA degradation analysis, as well preservation of antigens for immunofluorescence, in a blinded manner. Both in superficial and deep tissue sections, based on histological assessment, AP is superior to DI, or as good as LN techniques in terms of presence of ice crystals, cutting artifacts, and overall quality/structural preservation. DNA and RNA were successfully extracted in reasonable quantities from all freezing techniques, but RNA degradation was seen for pancreas samples across all techniques. Immunofluorescence with cytokeratin8 (CK-8), alpha smooth muscle actin (αSMA), CD3, and B220 shows equally good outcomes for AP and LN, which are better than DI. The aluminum platform is a cheap, yet reliable method to freeze samples, rapidly preserving histological, antigenic, and DNA/RNA quality. Wider testing is required across different sample types. © 2020 The Authors. Basic Protocol: Flash-freezing fresh tissue with aluminum platform Alternate Protocol 1: Freezing fresh tissue with liquid nitrogen Alternate Protocol 2: Freezing fresh tissue with dry ice.

A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case-control study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with around 9% of patients surviving >5 years. Asymptomatic in its initial stages, PDAC is mostly diagnosed late, when already a locally advanced or metastatic disease, as there are no useful biomarkers for detection in its early stages, when surgery can be curative. We have previously described a promising biomarker panel (LYVE1, REG1A, and TFF1) for earlier detection of PDAC in urine. Here, we aimed to establish the accuracy of an improved panel, including REG1B instead of REG1A, and an algorithm for data interpretation, the PancRISK score, in additional retrospectively collected urine specimens. We also assessed the complementarity of this panel with CA19-9 and explored the daily variation and stability of the biomarkers and their performance in common urinary tract cancers. METHODS AND FINDINGS: Clinical specimens were obtained from multiple centres: Barts Pancreas Tissue Bank, University College London, University of Liverpool, Spanish National Cancer Research Center, Cambridge University Hospital, and University of Belgrade. The biomarker panel was assayed on 590 urine specimens: 183 control samples, 208 benign hepatobiliary disease samples (of which 119 were chronic pancreatitis), and 199 PDAC samples (102 stage I-II and 97 stage III-IV); 50.7% were from female individuals. PDAC samples were collected from patients before treatment. The samples were assayed using commercially available ELISAs. Statistical analyses were performed using non-parametric Kruskal-Wallis tests adjusted for multiple comparisons, and multiple logistic regression. Training and validation datasets for controls and PDAC samples were obtained after random division of the whole available dataset in a 1:1 ratio. The substitution of REG1A with REG1B enhanced the performance of the panel to detect resectable PDAC. In a comparison of controls and PDAC stage I-II samples, the areas under the receiver operating characteristic curve (AUCs) increased from 0.900 (95% CI 0.843-0.957) and 0.926 (95% CI 0.843-1.000) in the training (50% of the dataset) and validation sets, respectively, to 0.936 in both the training (95% CI 0.903-0.969) and the validation (95% CI 0.888-0.984) datasets for the new panel including REG1B. This improved panel showed both sensitivity (SN) and specificity (SP) to be >85%. Plasma CA19-9 enhanced the performance of this panel in discriminating PDAC I-II patients from controls, with AUC = 0.992 (95% CI 0.983-1.000), SN = 0.963 (95% CI 0.913-1.000), and SP = 0.967 (95% CI 0.924-1.000). We demonstrate that the biomarkers do not show significant daily variation, and that they are stable for up to 5 days at room temperature. The main limitation of our study is the low number of stage I-IIA PDAC samples (n = 27) and lack of samples from individuals with hereditary predisposition to PDAC, for which specimens collected from control individuals were used as a proxy. CONCLUSIONS: We have successfully validated our urinary biomarker panel, which was improved by substituting REG1A with REG1B. At a pre-selected cutoff of >80% SN and SP for the affiliated PancRISK score, we demonstrate a clinically applicable risk stratification tool with a binary output for risk of developing PDAC ('elevated' or 'normal'). PancRISK provides a step towards precision surveillance for PDAC patients, which we will test in a prospective clinical study, UroPanc.

EPIC3, a novel Ca2+ indicator located at the cell cortex and in microridges, detects high Ca2+ subdomains during Ca2+ influx and phagocytosis.

The construction of a low affinity Ca2+-probe that locates to the cell cortex and cell surface wrinkles, is described called. EPIC3 (ezrin-protein indicator of Ca2+). The novel probe is a fusion of CEPIA3 with ezrin, and is used in combination with a Ca2+-insensitive probe, ezrin-mCherry, both of which locate at the cell cortex. EPIC3 was used to monitor the effect of Ca2+ influx on intra-wrinkle Ca2+ in the macrophage cell line, RAW 264.7. During experimentally-induced Ca2+influx, EPIC3 reported Ca2+ concentrations at the cell cortex in the region of 30-50 µM, with peak locations towards the tips of wrinkles reaching 80 µM. These concentrations were associated with cleavage of ezrin (a substrate for the Ca2+ activated protease calpain-1) and released the C-terminal fluors. The cortical Ca2+ levels, restricted to near the site of phagocytic cup formation and pseudopodia extension during phagocytosis also reached high levels (50-80 µM) during phagocytosis. As phagocytosis was completed, hotspots of Ca2+ near the phagosome were also observed.

Phase I clinical trial repurposing all-trans retinoic acid as a stromal targeting agent for pancreatic cancer.

Pre-clinical models have shown that targeting pancreatic stellate cells with all-trans-retinoic-acid (ATRA) reprograms pancreatic stroma to suppress pancreatic ductal adenocarcinoma (PDAC) growth. Here, in a phase Ib, dose escalation and expansion, trial for patients with advanced, unresectable PDAC (n = 27), ATRA is re-purposed as a stromal-targeting agent in combination with gemcitabine-nab-paclitaxel chemotherapy using a two-step adaptive continual re-assessment method trial design. The maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D, primary outcome) is the FDA/EMEA approved dose of gemcitabine-nab-paclitaxel along-with ATRA (45 mg/m2 orally, days 1-15/cycle). Dose limiting toxicity (DLT) is grade 4 thrombocytopenia (n = 2). Secondary outcomes show no detriment to ATRA pharmacokinetics.. Median overall survival for RP2D treated evaluable population, is 11.7 months (95%CI 8.6-15.7 m, n = 15, locally advanced (2) and metastatic (13)). Exploratory pharmacodynamics studies including changes in diffusion-weighted (DW)-MRI measured apparent diffusion coefficient after one cycle, and, modulation of cycle-specific serum pentraxin 3 levels over various cycles indicate stromal modulation. Baseline stromal-specific retinoid transport protein (FABP5, CRABP2) expression may be predicitve of response. Re-purposing ATRA as a stromal-targeting agent with gemcitabine-nab-paclitaxel is safe and tolerable. This combination will be evaluated in a phase II randomized controlled trial for locally advanced PDAC. Clinical trial numbers: EudraCT: 2015-002662-23; NCT03307148. Trial acronym: STARPAC.