Burnout among public health workers in Canada: a cross-sectional study.

BACKGROUND: This study presents the prevalence of burnout among the Canadian public health workforce after three years of the COVID-19 pandemic and its association with work-related factors. METHODS: Data were collected using an online survey distributed through Canadian public health associations and professional networks between November 2022 and January 2023. Burnout was measured using a modified version of the Oldenburg Burnout Inventory (OLBI). Logistic regressions were used to model the relationship between burnout and work-related factors including years of work experience, redeployment to pandemic response, workplace safety and supports, and harassment. Burnout and the intention to leave or retire as a result of the COVID-19 pandemic was explored using multinomial logistic regressions. RESULTS: In 2,079 participants who completed the OLBI, the prevalence of burnout was 78.7%. Additionally, 49.1% of participants reported being harassed because of their work during the pandemic. Burnout was positively associated with years of work experience, redeployment to the pandemic response, being harassed during the pandemic, feeling unsafe in the workplace and not being offered workplace supports. Furthermore, burnout was associated with greater odds of intending to leave public health or retire earlier than anticipated. CONCLUSION: The high levels of burnout among our large sample of Canadian public health workers and its association with work-related factors suggest that public health organizations should consider interventions that mitigate burnout and promote recovery.

The RNA m5C modification in R-loops as an off switch of Alt-NHEJ.

The roles of R-loops and RNA modifications in homologous recombination (HR) and other DNA double-stranded break (DSB) repair pathways remain poorly understood. Here, we find that DNA damage-induced RNA methyl-5-cytosine (m5C) modification in R-loops plays a crucial role to regulate PARP1-mediated poly ADP-ribosylation (PARylation) and the choice of DSB repair pathways at sites of R-loops. Through bisulfite sequencing, we discover that the methyltransferase TRDMT1 preferentially generates m5C after DNA damage in R-loops across the genome. In the absence of m5C, R-loops activate PARP1-mediated PARylation both in vitro and in cells. Concurrently, m5C promotes transcription-coupled HR (TC-HR) while suppressing PARP1-dependent alternative non-homologous end joining (Alt-NHEJ), favoring TC-HR over Alt-NHEJ in transcribed regions as the preferred repair pathway. Importantly, simultaneous disruption of both TC-HR and Alt-NHEJ with TRDMT1 and PARP or Polymerase θ inhibitors prevents alternative DSB repair and exhibits synergistic cytotoxic effects on cancer cells, suggesting an effective strategy to exploit genomic instability in cancer therapy.

Effect of Wearing a Face Mask on Hand-to-Face Contact by Children in a Simulated School Environment: The Back-to-School COVID-19 Simulation Randomized Clinical Trial.

Importance: Wearing a face mask in school can reduce SARS-CoV-2 transmission but it may also lead to increased hand-to-face contact, which in turn could increase infection risk through self-inoculation. Objective: To evaluate the effect of wearing a face mask on hand-to-face contact by children while at school. Design, Setting, and Participants: This prospective randomized clinical trial randomized students from junior kindergarten to grade 12 at 2 schools in Toronto, Ontario, Canada, during August 2020 in a 1:1 ratio to either a mask or control class during a 2-day school simulation. Classes were video recorded from 4 angles to accurately capture outcomes. Interventions: Participants in the mask arm were instructed to bring their own mask and wear it at all times. Students assigned to control classes were not required to mask at any time (grade 4 and lower) or in the classroom where physical distancing could be maintained (grade 5 and up). Main Outcomes and Measures: The primary outcome was the number of hand-to-face contacts per student per hour on day 2 of the simulation. Secondary outcomes included hand-to-mucosa contacts and hand-to-nonmucosa contacts. A mixed Poisson regression model was used to derive rate ratios (RRs), adjusted for age and sex with a random intercept for class with bootstrapped 95% CIs. Results: A total of 174 students underwent randomization and 171 students (mask group, 50.6% male; control group, 52.4% male) attended school on day 2. The rate of hand-to-face contacts did not differ significantly between the mask and the control groups (88.2 vs 88.7 events per student per hour; RR, 1.00; 95% CI, 0.78-1.28; P = >.99). When compared with the control group, the rate of hand-to-mucosa contacts was significantly lower in the mask group (RR, 0.12; 95% CI, 0.07-0.21), while the rate of hand-to-nonmucosa contacts was higher (RR, 1.40; 95% CI, 1.08-1.82). Conclusions and Relevance: In this clinical trial of simulated school attendance, hand-to-face contacts did not differ among students required to wear face masks vs students not required to wear face masks; however, hand-to-mucosa contracts were lower in the face mask group. This suggests that mask wearing is unlikely to increase infection risk through self-inoculation. Trial Registration: ClinicalTrials.gov Identifier: NCT04531254.

Early (years) reactions: comparative analysis of early childhood policies and programs during the first wave of the COVID-19 pandemic.

BACKGROUND: During the first wave of COVID-19 there was little evidence to guide appropriate child and family programs and policy supports. METHODS: We compared policies and programs implemented to support early child health and well-being during the first wave of COVID-19 in Australia, Canada, the Netherlands, Singapore, the UK, and the USA. Program and policy themes were focused on prenatal care, well-baby visits and immunization schedules, financial supports, domestic violence and housing, childcare supports, child protective services, and food security. RESULTS: Significant heterogeneity in implementation of OECD-recommended policy responses was found with all of the included countries implementing some of these policies, but no country implementing supports in all of the potential areas. CONCLUSIONS: This analysis gives insight into initial government reactions to support children and families, and opportunities for governments to implement further supportive programs and policies during the current pandemic and future emergencies.

DNA repair defects in cancer and therapeutic opportunities.

DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability. Defects of DNA repair and damage signaling contribute to tumorigenesis, but also render cancer cells vulnerable to DNA damage and reliant on remaining repair and signaling activities. Here, we review the major classes of DNA repair and damage signaling defects in cancer, the genomic instability that they give rise to, and therapeutic strategies to exploit the resulting vulnerabilities. Furthermore, we discuss the impacts of DNA repair defects on both targeted therapy and immunotherapy, and highlight emerging principles for targeting DNA repair defects in cancer therapy.

Comparison of longitudinal trends in self-reported symptoms and COVID-19 case activity in Ontario, Canada.

BACKGROUND: Limitations in laboratory diagnostic capacity impact population surveillance of COVID-19. It is currently unknown whether participatory surveillance tools for COVID-19 correspond to government-reported case trends longitudinally and if it can be used as an adjunct to laboratory testing. The primary objective of this study was to determine whether self-reported COVID-19-like illness reflected laboratory-confirmed COVID-19 case trends in Ontario Canada. METHODS: We retrospectively analyzed longitudinal self-reported symptoms data collected using an online tool-Outbreaks Near Me (ONM)-from April 20th, 2020, to March 7th, 2021 in Ontario, Canada. We measured the correlation between COVID-like illness among respondents and the weekly number of PCR-confirmed COVID-19 cases and provincial test positivity. We explored contemporaneous changes in other respiratory viruses, as well as the demographic characteristics of respondents to provide context for our findings. RESULTS: Between 3,849-11,185 individuals responded to the symptom survey each week. No correlations were seen been self-reported CLI and either cases or test positivity. Strong positive correlations were seen between CLI and both cases and test positivity before a previously documented rise in rhinovirus/enterovirus in fall 2020. Compared to participatory surveillance respondents, a higher proportion of COVID-19 cases in Ontario consistently came from low-income, racialized and immigrant areas of the province- these groups were less well represented among survey respondents. INTERPRETATION: Although digital surveillance systems are low-cost tools that have been useful to signal the onset of viral outbreaks, in this longitudinal comparison of self-reported COVID-like illness to Ontario COVID-19 case data we did not find this to be the case. Seasonal respiratory virus transmission and population coverage may explain this discrepancy.

Impact of coronavirus disease 2019 (COVID-19) pre-test probability on positive predictive value of high cycle threshold severe acute respiratory coronavirus virus 2 (SARS-CoV-2) real-time reverse transcription polymerase chain reaction (RT-PCR) test results.

OBJECTIVES: Performance characteristics of SARS-CoV-2 nucleic acid detection assays are understudied within contexts of low pre-test probability, including screening asymptomatic persons without epidemiological links to confirmed cases, or asymptomatic surveillance testing. SARS-CoV-2 detection without symptoms may represent presymptomatic or asymptomatic infection, resolved infection with persistent RNA shedding, or a false-positive test. This study assessed the positive predictive value of SARS-CoV-2 real-time reverse transcription polymerase chain reaction (rRT-PCR) assays by retesting positive specimens from 5 pre-test probability groups ranging from high to low with an alternate assay. METHODS: In total, 122 rRT-PCR positive specimens collected from unique patients between March and July 2020 were retested using a laboratory-developed nested RT-PCR assay targeting the RNA-dependent RNA polymerase (RdRp) gene followed by Sanger sequencing. RESULTS: Significantly fewer (15.6%) positive results in the lowest pre-test probability group (facilities with institution-wide screening having ≤3 positive asymptomatic cases) were reproduced with the nested RdRp gene RT-PCR assay than in each of the 4 groups with higher pre-test probability (individual group range, 50.0%-85.0%). CONCLUSIONS: Large-scale SARS-CoV-2 screening testing initiatives among low pre-test probability populations should be evaluated thoroughly prior to implementation given the risk of false-positive results and consequent potential for harm at the individual and population level.

Longitudinal Outcomes of a Smartphone Application to Prevent Drug Use Among Hispanic Youth.

OBJECTIVE: This trial tested the efficacy of a smartphone application (app) designed to prevent drug use among Hispanic youth. METHOD: Participants were recruited through online advertising and youth service agencies. The baseline sample (N = 644) had a mean age of 14.1 years, was primarily female (60%), and resided in 31 U.S. states and Puerto Rico. Youth assented to study participation and received parental permission to participate. Youth were randomly assigned to an intervention arm or a measurement-only control arm. Intervention-arm youth completed 10 prevention program sessions via a smartphone app. Following intervention delivery, all youth completed posttest and 1-, 2-, and 3-year follow-up measures. RESULTS: Analyzed within an Arm by Time interaction model, follow-up data showed that compared with control-arm youth, intervention-arm youth reported (a) less increase in alcohol use from baseline to 2-year follow-up; (b) less increase in marijuana use from baseline to 2- and 3-year follow-ups; and (c) less increase in polydrug use from baseline to 1-, 2-, and 3-year follow-ups. Compared with youth in the control arm, intervention-arm youth reported (a) less depressed mood and improved skills for refusing offers of alcohol and tobacco at posttest; (b) higher self-efficacy and social self-efficacy at 1-, 2-, and 3-year follow-ups; (c) improved skills for refusing offers of marijuana at 2- and 3-year follow-ups; (d) higher media literacy at 2- and 3-year follow-ups; and (e) better coping skills at 3-year follow-up. CONCLUSIONS: These longitudinal findings suggest that Hispanic youth can profit from tailored, skills-based content delivered via a smartphone app to prevent drug use.

Induction of BRCAness in Triple-Negative Breast Cancer by a CDK12/13 Inhibitor Improves Chemotherapy.

In this issue of Cancer Cell, Quereda and colleagues report that a newly developed specific inhibitor of CDK12/13, SR-4835, sensitizes triple-negative breast cancer cells to PARP inhibitors and DNA-damaging chemotherapeutics by reducing expression of the genes in the DNA damage response pathway.

Avoiding initial hypothermia does not improve liver graft quality in a porcine donation after circulatory death (DCD) model of normothermic perfusion.

BACKGROUND: Normothermic machine perfusion (NMP) of liver grafts donated after circulatory death (DCD) has shown promise in large animal and clinical trials. Following procurement, initial flush with a cold preservation solution is the standard of care. There is concern that initial cooling followed by warming may exacerbate liver injury, and the optimal initial flush temperature has yet to be identified. We hypothesize that avoidance of the initial cold flush will yield better quality liver grafts. METHODS: Twenty-four anaesthetized pigs were withdrawn from mechanical ventilation and allowed to arrest. After 60-minutes of warm ischemia to simulate a DCD procurement, livers were flushed with histidine-tryptophan-ketoglutarate (HTK) at 4°C, 25°C or 35°C (n = 4 per group). For comparison, an adenosine-lidocaine crystalloid solution (AD), shown to have benefit at warm temperatures in heart perfusions, was also used (n = 4 per group). During 12-hours of NMP, adenosine triphosphate (ATP), lactate, transaminase levels, and histological injury were determined. Bile production and hemodynamics were monitored continuously. RESULTS: ATP levels recovered substantially following 1-hour of NMP reaching pre-ischemic levels by the end of NMP with no difference between groups. There was no difference in peak aspartate aminotransferase (AST) or in lactate dehydrogenase (LDH). Portal vein resistance was lowest in the 4°C group reaching significance after 2 hours (0.13 CI -0.01,0.277, p = 0.025). Lactate levels recovered promptly with no difference between groups. Comparison to AD groups showed no statistical difference in the abovementioned parameters. On electron microscopy the HTK4°C group had the least edema with mean cell thickness of 2.92µm (p = 0.41) while also having the least sinusoidal dilatation with a mean diameter of 5.36µm (p = 0.04). For AD, the 25°C group had the lowest mean cell thickness at 3.14µm (p = 0.09). CONCLUSIONS: Avoidance of the initial cold flush failed to demonstrate added benefit over standard 4°C HTK in this DCD model of liver perfusion.

Change in Skeletal Muscle Following Resection of Stage I-III Colorectal Cancer is Predictive of Poor Survival: A Cohort Study.

BACKGROUND: Sarcopenia at time of diagnosis predicts worse survival outcomes. It is currently unknown how changes in muscle mass over time interact with sarcopenia in colorectal patients treated with curative intent. Objectives of this study were to quantify sarcopenia and skeletal muscle loss from time of diagnosis to end of surveillance and determine its effect on survival outcomes after completion of 2 years of surveillance. METHODS: Retrospective cohort study of stage I-III colorectal cancer patients from 2007-2009, who underwent resection and had preoperative and 2-year surveillance computed tomography scans, without recurrence during that time. Body composition analysis was done at both time points to determine lumbar skeletal muscle index, radiodensity and adiposity. Change over time was standardized as a percentage per year. Cox proportional hazard regression modeling was used for survival analysis. RESULTS: Of 667 patients included, median survival from surgery was 7.96 years, with 75 recurrences occurring after 2 years. On average patients lost muscle mass (-0.415%/year; CI -0.789, -0.042) and radiodensity (-5.76 HU/year; CI -6.74, -4.80), but gained total adipose tissue (7.06%/year; CI 4.34, 9.79). Patients with sarcopenia at diagnosis (HR 1.80; CI 1.13, 2.85) or muscle loss over time (HR 1.55; CI 1.01, 2.37) had worse overall survival, with significantly worse joint effect (HR 2.73; CI 1.32, 5.65). CONCLUSIONS: Sarcopenia at diagnosis combined with ongoing skeletal muscle loss over time resulted in significantly worse survival. Patients with these features who are recurrence-free at 2 years are more likely to have a non-colorectal cancer cause of death.

The Impact of Muscle and Adipose Tissue on Long-term Survival in Patients With Stage I to III Colorectal Cancer.

BACKGROUND: Computed tomography-derived body composition parameters are emerging prognostic factors in colorectal cancer. OBJECTIVE: This study aimed to determine the roles of sarcopenia, myosteatosis, and obesity as independent and overlapping parameters in stage I to III colorectal cancer. DESIGN: This is a retrospective cohort study from a prospectively collected database. Multivariate Cox proportional hazards models were performed to assess the associations between body composition parameters and survival. SETTINGS: All patients were seen in a tertiary care cancer center. PATIENTS: Adult patients with stage I to III colorectal cancer, undergoing curative resection from 2007 to 2009, were included. INTERVENTION: Computed tomography-derived quantification of skeletal muscle and adipose tissues was used to determine population-specific cutoffs for sarcopenia, myosteatosis, and total adiposity. MAIN OUTCOME MEASURES: Primary outcome measures were overall, recurrence-free, and cancer-specific survival. RESULTS: In the 968 patients included, there were a total of 254 disease recurrences and 350 deaths. Body mass index and CT-derived measures of adiposity did not result in worse survival outcomes. Sarcopenia was independently predictive of worse overall (HR, 1.45; 95% CI, 1.16-1.84), recurrence-free (HR, 1.32; 95% CI, 1.00-1.75), and cancer-specific survival (HR, 1.46; 95% CI, 1.09-1.94) in a multivariate model. Myosteatosis was also independently predictive of overall survival (HR, 1.53; 95% CI, 1.19-1.97). In a model considering joint effects of sarcopenia and myosteatosis, the presence of both predicted the worst overall (HR, 2.23; 95% CI, 1.62-3.06), recurrence-free (HR, 1.53; 95% CI, 1.06-2.21), and cancer-specific survival (HR, 2.40; 95% CI, 1.69-3.42) in a multivariate model. LIMITATIONS: The limitations of this study are inherent in retrospective observational studies. CONCLUSIONS: Sarcopenia and myosteatosis are independent predictors of worse survival in stage I to III colorectal cancer, and their joint effect is highly predictive of reduced overall, recurrence-free, and cancer-specific survival. See Video Abstract at http://links.lww.com/DCR/A923.

Two- and three-year follow-up from a gender-specific, web-based drug abuse prevention program for adolescent girls.

INTRODUCTION: Rates of drug use among early adolescent girls meet or exceed rates of their male counterparts. Girls are also vulnerable to differential risk factors for drug use. Yet, expressly designed prevention programs targeting this population are absent. The present study reports 2- and 3-year findings on a web-based drug abuse prevention program for adolescent girls. METHODS: A sample of adolescent girls (N = 788) were recruited via Facebook. Online, all girls completed pretests; girls were randomly assigned to a 9-session intervention arm or to a measurement-only control arm and all girls completed posttests. All girls also completed 1-, 2-, and 3-year follow-up measurements. RESULTS: At 2-year follow-up and compared to girls in the control arm, intervention-arm girls reported less past-month cigarette, marijuana, and "other" drug use (club drugs, cocaine, ecstasy, hallucinogens, heroin, inhalants, methamphetamines, steroids, prescription drugs), lower rates of peer drug use, and increased scores on drug refusal skills, coping skills, self-esteem, media literacy, and self-efficacy. At 3-year follow-up, and compared to girls in the control arm, intervention-arm girls reported less past-month cigarette and e-cigarette use, lower rates of peer drug use, lower reported anxiety and stress, and increased scores on drug refusal skills, self-esteem, media literacy, self-efficacy, and body image. CONCLUSIONS: Longitudinal outcome data lend support to the efficacy of a gender-specific, web-based drug abuse prevention program to reduce adolescent girls' drug use rates and associated risk factors.

Low prioritization of latent tuberculosis infection-A systemic barrier to tuberculosis control: A qualitative study in Ontario, Canada.

BACKGROUND: Eliminating tuberculosis (TB) in low-incidence countries is an important global health priority, and Canada has committed to achieve this goal. The elimination of TB in low-incidence countries requires effective management and treatment of latent tuberculosis infection (LTBI). This study aimed to understand and describe the system-level barriers to LTBI treatment for immigrant populations in the Greater Toronto and Hamilton Area, Ontario, Canada. METHODS: A qualitative study that used purposive sampling to recruit and interview health system advisors and planners (n = 10), providers (n = 13), and clients of LTBI health services (n = 9). Data were recorded, transcribed verbatim, and analyzed using content analysis. RESULTS: Low prioritization of LTBI was an overarching theme that impacted four dimensions of LTBI care: management, service delivery, health literacy, and health care access. These factors explained, in part, inequities in the system that were linked to variations in health care quality and health care access. While some planners and providers at the local level were attempting to prioritize LTBI care, there was no clear pathway for information sharing. CONCLUSIONS: This multiperspective study identified barriers beyond the typical socioeconomic determinants and highlighted important upstream factors that hinder treatment initiation and adherence. Addressing these factors is critical if Canada is to meet the WHO's global call to eradicate TB in all low incidence settings.

Assessment of Computed Tomography (CT)-Defined Muscle and Adipose Tissue Features in Relation to Short-Term Outcomes After Elective Surgery for Colorectal Cancer: A Multicenter Approach.

BACKGROUND: Sarcopenia, visceral obesity (VO), and reduced muscle radiodensity (myosteatosis) are suggested risk factors for postoperative morbidity in colorectal cancer (CRC), but usually are not concurrently assessed. Published thresholds used to define these features are not CRC-specific and are defined in relation to mortality, not postoperative outcomes. This study aimed to evaluate body composition in relation to length of hospital stay (LOS) and postoperative outcomes. METHODS: Pre-surgical computed tomography (CT) images were assessed for total area and radiodensity of skeletal muscle and visceral adipose tissue in a pooled Canadian and UK cohort (n = 2100). Sex- and age-specific values for these features were calculated. For 1139 of 2100 patients, LOS data were available, and sex- and age-specific thresholds for sarcopenia, myosteatosis, and VO were defined on the basis of LOS. Association of CT-defined features with LOS and readmissions was explored using negative binomial and logistic regression models, respectively. RESULTS: In the multivariable analysis, the predictors of LOS (P < 0.001) were age, surgical approach, major complications (incidence rate ratio [IRR] 2.42; 95% confidence interval [CI] 2.18-2.68), study cohort, and three body composition profiles characterized by myosteatosis combined with either sarcopenia (IRR, 1.27; 95% CI 1.12-1.43) or VO (IRR, 1.25; 95% CI 1.10-1.42), and myosteatosis combined with both sarcopenia and VO (IRR, 1.58; 95% CI 1.29-1.93). In the multivariable analysis, risk of readmission was associated with VO alone (odds ratio [OR] 2.66; 95% CI 1.18-6.00); P = 0.018), VO combined with myosteatosis (OR, 2.72; 95% CI 1.36-5.46; P = 0.005), or VO combined with myosteatosis and sarcopenia (OR, 2.98; 95% CI 1.06-5.46; P = 0.038). Importantly, the effect of body composition profiles on LOS and readmission was independent of major complications. CONCLUSION: The findings showed that CT-defined multidimensional body habitus is independently associated with LOS and hospital readmission.

Interactions of lean soft-tissue and chemotherapy toxicities in patients receiving anti-cancer treatments.

Use of cross-sectional imaging to identify whole-body lean soft-tissue mass has recently emerged as an attractive prognostic factor for chemotherapy toxicities. Beyond that, there is increasing interest in use of lean soft-tissue mass as a more accurate method for dosing chemotherapy, as compared to body surface area. In this review, we summarize the current evidence that supports interactions between skeletal muscle and chemotherapy, the role of lean soft tissue in predicting chemotherapy toxicities and potential use of an alternate method of chemotherapeutic dosing, all based on quantification of skeletal muscle mass by computed tomography.

Chromatin Spread Preparations for the Analysis of Mouse Oocyte Progression from Prophase to Metaphase II.

Chromatin spread techniques have been widely used to assess the dynamic localization of various proteins during gametogenesis, particularly for spermatogenesis. These techniques allow for visualization of protein and DNA localization patterns during meiotic events such as homologous chromosome pairing, synapsis and DNA repair. While a few protocols have been described in the literature, general chromatin spread techniques using mammalian prophase oocytes are limited and difficult due to the timing of meiosis initiation in fetal ovaries. In comparison, prophase spermatocytes can be collected from juvenile male mice with higher yields without the need for microdissection. However, it is difficult to obtain a pure synchronized population of cells at specific stages due to the heterogeneity of meiotic and post-meiotic germ cell populations in the juvenile and adult testis. For later stages of meiosis, it is advantageous to assess oocytes undergoing meiosis I (MI) or meiosis II (MII), because groups of mature oocytes can be collected from adult female mice and stimulated to resume meiosis in culture. Here, methods for meiotic chromatin spread preparations using oocytes dissected from fetal, neonatal and adult ovaries are described with accompanying video demonstrations. Chromosome missegregation events in mammalian oocytes are frequent, particularly during MI. These techniques can be used to assess and characterize the effects of different mutations or environmental exposures during various stages of oogenesis. As there are distinct differences between oogenesis and spermatogenesis, the techniques described within are invaluable to increase our understanding of mammalian oogenesis and the sexually dimorphic features of chromosome and protein dynamics during meiosis.