Case-cohort design as an efficient approach to evaluating COVID-19 vaccine effectiveness, waning, heterologous immune effect and optimal dosing interval.

Though widely applied in other epidemiological fields, the case-cohort study design has seen little application in the field of vaccinology. Case-cohort studies use probabilistic sampling and reweighting to draw inferences about effects (in this case vaccine efficacy) at the population level in an efficient manner. The SARS-CoV-2 pandemic was met with high vaccine uptake, and high rates of population testing prior to the emergence of Omicron variants of concern, in Ontario, Canada, providing an ideal environment for application of case-cohort methodology. We combined a population-based case line list and vaccination database for the province of Ontario between December 2020 and October 2021. Risk of infection after vaccination was evaluated in all laboratory-confirmed vaccinated SARS-CoV-2 cases, and a 2 % sample of vaccinated controls, evaluated using survival analytic methods, including construction of Cox proportional hazards models. Vaccination status was treated as a time-varying covariate. First and second doses of SARS-CoV-2 vaccine markedly reduced risk of infection (first dose efficacy 68 %, 95 % CI 67 %-69 %; second dose efficacy 88 %, 95 % CI 87-88 %). In multivariable models, extended dosing intervals were associated with lowest risk of breakthrough infection (HR for redosing 0.64 (95 % CI 0.61-0.67) at 6-8 weeks). Heterologous vaccine schedules that mixed viral vector vaccine first doses with mRNA second doses were significantly more effective than mRNA only vaccines. Risk of infection largely vanished during the time period 4-6 months after the second vaccine dose, but rose markedly thereafter. We conclude that a case-cohort design provided an efficient means to identify strong protective effects associated with SARS-CoV-2 vaccination in real time, and also served to quantify the timing and magnitude of infection breakthrough risk in the same cohort. Heterologous vaccination and extended dosing intervals improved the durability of immune response.

Systematic review of adherence to swallow and trismus exercises during radiation therapy for head and neck cancer.

Understanding the barriers and facilitators for prophylactic swallowing and trismus exercises for patients undergoing radiation to the head and neck may help exercise adherence. The analysis reviews all published reports of exercise adherence with a critical appraisal following PRISMA guidelines. A total of 137 potential papers were identified; 20 studies met the inclusion criteria. The most commonly reported facilitators for swallowing and trismus exercises were regular clinician contact and online resources to reinforce instructions, set goals, and manage radiation toxicities. Social support and perceived benefit from exercises were also reported to be of help. The most common barriers to exercise were radiation toxicities, anxiety, feeling overwhelmed with information, and not understanding the reason for the exercises. Understanding facilitators and barriers to adherence is critical when designing exercise interventions for patients undergoing radiation for head and neck cancer.

TREATMENT OF HIP AND KNEE PERIPROSTHETIC JOINT INFECTION REQUIRES EXTENSIVE ADMINISTRATIVE WORK.

INTRODUCTION: Treatment of periprosthetic joint infections (PJI) typically requires more resource utilization than primary total joint arthroplasty (TJA). This study quantifies the amount of time spent in the electronic medical record (EMR) for patients who have PJI requiring surgical intervention. METHODS: A retrospective analysis of EMR activity for 165 hip and knee PJI was performed to capture work during the preoperative and postoperative time periods. Independent sample t tests were conducted to compare total time based on procedure, age, insurance, health literacy, sex, race, and ethnicity. RESULTS: The EMR work performed by the orthopaedic team was 338.4 minutes (min) (SD [standard deviation] 130.3), with 119.4 minutes (SD 62.8) occurring preoperatively and 219.0 minutes (SD 112.9) postoperatively. Preoperatively, the surgeon's work accounted for 35.7 minutes (SD 25.4), mid-level providers 21.3 minutes (SD 15.9), nurses 38.6 minutes (SD 36.8), and office staff 32.7 minutes (SD 29.9). Infectious Disease (ID) colleagues independently performed 158.9 minutes (SD 108.5) of postoperative work. Overall, PJI of the knees required more postoperative work. Secondary analysis revealed that patients who have hip PJI and a BMI < 30 and patients < 65 years required more work when compared to the PJI of heavier and older individuals. There was no difference in total work based on insurance, health literacy, race, or ethnicity. CONCLUSION: Over 8 hours of administrative work is required for surgical management of PJI. Surgeons alone performed 451% more work for PJI during the preoperative period (7.9 versus 35.7min) compared to primary TJA. In efforts to provide best care for our sickest patients, much work is required perioperatively. This work is necessary to consider when assigning value and physician reimbursement.

Exercise adherence for patients with trismus after head and neck cancer treatment.

BACKGROUND: Head and neck cancer treatment often leads to trismus, a condition characterized by limited mouth opening. Exercise-based therapy is the most common intervention but there are no clear guidelines as to the optimal exercise regimen. Restorabite™ is a portable and force-regulated trismus device designed to enhance exercise adherence. This study explores the adherence to exercises using Restorabite™ in head and neck cancer patients with trismus and identifies facilitators and barriers to exercise therapy. MATERIALS AND METHODS: Mixed-methods, prospective cohort study undertaken at a quaternary oncology hospital, in Sydney Australia involving participants diagnosed with head and neck cancer diagnosed with trismus (maximal incisal opening under 35 mm). Patients underwent a 10-week individualized trismus program using Restorabite™ with weekly speech pathology reviews. Exercise adherence was tracked through categorized descriptors. Data were collected prospectively at baseline, during 10 weeks of therapy with Restorabite™, and at 6- and 12-month post-trismus exercise. Participants described facilitators of trismus therapy, and barriers to completing the prescribed exercises. Clinical documentation of these responses was then analyzed using content analysis. RESULTS: One-hundred and thirty-five participants were recruited. During the intervention 69% (n = 93) exercised as recommended, 24% (n = 32) exercised less, and 7% (n = 10) exercised more than recommended. At 6 months post-intervention, 55.5% (n = 75) exercised as recommended, 38.5% (n = 52) exercised less, and 4% (n = 6) exercised more. At 12 months, 36% (n = 49) exercised as recommended, 48% (n = 62) exercised less, and 11% (n = 15) exercised more. MIO increased from a mean of 18.6 mm at baseline, to 30.1 mm at the end of the 10-week intervention. This was maintained at 6 and 12 months (31.7 and 32.1 mm, respectively). Adherence to the exercise program was associated with greater improvement in maximum interincisal opening (p < 0.001). Facilitators of adherence included intrinsic motivation, device portability, perceived functional change, and external support tools. Barriers included cancer treatment toxicities, competing priorities, and health challenges. Positive outcomes included functional improvements, while negative outcomes included increased pain. CONCLUSIONS: Seventy-six percent of patients prescribed Restorabite™ performed trismus exercises at or more than the recommended frequency. Facilitators and barriers identified provide insights into factors influencing adherence. Future research should involve comparative studies that compare the adherence and effectiveness of different exercise programs.

Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer.

Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.

Examining the effects of voluntary avoidance behaviour and policy-mediated behaviour change on the dynamics of SARS-CoV-2: A mathematical model.

Background: Throughout the SARS-CoV-2 pandemic, policymakers have had to navigate between recommending voluntary behaviour change and policy-driven behaviour change to mitigate the impact of the virus. While individuals will voluntarily engage in self-protective behaviour when there is an increasing infectious disease risk, the extent to which this occurs and its impact on an epidemic is not known. Methods: This paper describes a deterministic disease transmission model exploring the impact of individual avoidance behaviour and policy-mediated avoidance behaviour on epidemic outcomes during the second wave of SARS-CoV-2 infections in Ontario, Canada (September 1, 2020 to February 28, 2021). The model incorporates an information feedback function based on empirically derived behaviour data describing the degree to which avoidance behaviour changed in response to the number of new daily cases COVID-19. Results: Voluntary avoidance behaviour alone was estimated to reduce the final attack rate by 23.1%, the total number of hospitalizations by 26.2%, and cumulative deaths by 27.5% over 6 months compared to a counterfactual scenario in which there were no interventions or avoidance behaviour. A provincial shutdown order issued on December 26, 2020 was estimated to reduce the final attack rate by 66.7%, the total number of hospitalizations by 66.8%, and the total number of deaths by 67.2% compared to the counterfactual scenario. Conclusion: Given the dynamics of SARS-CoV-2 in a pre-vaccine era, individual avoidance behaviour in the absence of government action would have resulted in a moderate reduction in disease however, it would not have been sufficient to entirely mitigate transmission and the associated risk to the population in Ontario. Government action during the second wave of the COVID-19 pandemic in Ontario reduced infections, protected hospital capacity, and saved lives.

Impact of immune evasion, waning and boosting on dynamics of population mixing between a vaccinated majority and unvaccinated minority.

BACKGROUND: We previously demonstrated that when vaccines prevent infection, the dynamics of mixing between vaccinated and unvaccinated sub-populations is such that use of imperfect vaccines markedly decreases risk for vaccinated people, and for the population overall. Risks to vaccinated people accrue disproportionately from contact with unvaccinated people. In the context of the emergence of Omicron SARS-CoV-2 and evolving understanding of SARS-CoV-2 epidemiology, we updated our analysis to evaluate whether our earlier conclusions remained valid. METHODS: We modified a previously published Susceptible-Infectious-Recovered (SIR) compartmental model of SARS-CoV-2 with two connected sub-populations: vaccinated and unvaccinated, with non-random mixing between groups. Our expanded model incorporates diminished vaccine efficacy for preventing infection with the emergence of Omicron SARS-CoV-2 variants, waning immunity, the impact of prior immune experience on infectivity, "hybrid" effects of infection in previously vaccinated individuals, and booster vaccination. We evaluated the dynamics of an epidemic within each subgroup and in the overall population over a 10-year time horizon. RESULTS: Even with vaccine efficacy as low as 20%, and in the presence of waning immunity, the incidence of COVID-19 in the vaccinated subpopulation was lower than that among the unvaccinated population across the full 10-year time horizon. The cumulative risk of infection was 3-4 fold higher among unvaccinated people than among vaccinated people, and unvaccinated people contributed to infection risk among vaccinated individuals at twice the rate that would have been expected based on the frequency of contacts. These findings were robust across a range of assumptions around the rate of waning immunity, the impact of "hybrid immunity", frequency of boosting, and the impact of prior infection on infectivity in unvaccinated people. INTERPRETATION: Although the emergence of the Omicron variants of SARS-CoV-2 has diminished the protective effects of vaccination against infection with SARS-CoV-2, updating our earlier model to incorporate loss of immunity, diminished vaccine efficacy and a longer time horizon, does not qualitatively change our earlier conclusions. Vaccination against SARS-CoV-2 continues to diminish the risk of infection among vaccinated people and in the population as a whole. By contrast, the risk of infection among vaccinated people accrues disproportionately from contact with unvaccinated people.

Adeno-associated virus-mediated trastuzumab delivery to the central nervous system for human epidermal growth factor receptor 2+ brain metastasis.

Trastuzumab improves overall survival for HER2+ breast cancer, but its short half-life in the cerebrospinal fluid (~2-4 days) and delivery limitations restrict the ability to target HER2+ central nervous system (CNS) disease. We developed an adeno-associated virus (AAV) vector expressing a codon-optimized, ubiquitin C (UbC)-promoter-driven trastuzumab sequence (AAV9.UbC.trastuzumab) for intrathecal administration. Transgene expression was evaluated in adult Rag1 knockout mice and rhesus nonhuman primates (NHPs) after a single intracerebroventricular (ICV) or intra-cisterna magna (ICM) AAV9.UbC.trastuzumab injection, respectively, using real-time PCR, ELISA, Western blot, in situ hybridization, single-nucleus RNA sequencing, and liquid chromatography-mass spectrometry; antitumor efficacy was evaluated in brain xenografts using HER2+ breast cancer cell lines (BT-474, MDA-MB-453). Transgene expression was detected in brain homogenates of Rag1 knockout mice following a single ICV injection of AAV9.UbC.trastuzumab (1 × 1011 vector genome copies [GC]/mouse) and tumor progression was inhibited in xenograft models of breast-to-brain metastasis. In NHPs, ICM delivery of AAV9.UbC.trastuzumab (3 × 1013 GC/animal) was well tolerated (36-37 days in-life) and resulted in transgene expression in CNS tissues and cerebrospinal fluid at levels sufficient to induce complete tumor remission in MDA-MB-453 brain xenografts. With AAV9's proven clinical safety record, this gene therapy may represent a viable approach for targeting HER2 + CNS malignancies.

Impact of community mask mandates on SARS-CoV-2 transmission in Ontario after adjustment for differential testing by age and sex.

Mask use for prevention of respiratory infectious disease transmission is not new but has proven controversial during the SARS-CoV-2 pandemic. In Ontario, Canada, irregular regional introduction of community mask mandates in 2020 created a quasi-experiment useful for evaluating the impact of such mandates; however, Ontario SARS-CoV-2 case counts were likely biased by testing focused on long-term care facilities and healthcare workers. We developed a regression-based method that allowed us to adjust cases for under-testing by age and gender. We evaluated mask mandate effects using count-based regression models with either unadjusted cases, or testing-adjusted case counts, as dependent variables. Models were used to estimate mask mandate effectiveness, and the fraction of SARS-CoV-2 cases, severe outcomes, and costs, averted by mask mandates. Models using unadjusted cases as dependent variables identified modest protective effects of mask mandates (range 31-42%), with variable statistical significance. Mask mandate effectiveness in models predicting test-adjusted case counts was higher, ranging from 49% (95% CI 44-53%) to 76% (95% CI 57-86%). The prevented fraction associated with mask mandates was 46% (95% CI 41-51%), with 290,000 clinical cases, 3,008 deaths, and loss of 29,038 quality-adjusted life years averted from 2020 June to December, representing $CDN 610 million in economic wealth. Under-testing in younger individuals biases estimates of SARS-CoV-2 infection risk and obscures the impact of public health preventive measures. After adjustment for under-testing, mask mandates emerged as highly effective. Community masking saved substantial numbers of lives, and prevented economic costs, during the SARS-CoV-2 pandemic in Ontario, Canada.

Lung cancer screening program factors that influence psychosocial outcomes: A systematic review.

OBJECTIVES: Lung cancer screening (LCS) programs are being designed and implemented globally. Early data suggests that the psychosocial impacts of LCS are influenced by program factors, but evidence synthesis is needed. This systematic review aimed to elucidate the impact of service-level factors on psychosocial outcomes to inform optimal LCS program design and future implementation. METHODS: Four databases were searched from inception to July 2023. Inclusion criteria were full-text articles published in English that reported an association between any program factors and psychosocial outcomes experienced during LCS. Study quality was appraised, and findings were synthesised narratively. RESULTS: Thirty-two articles were included; 29 studies were assessed at high or moderate risk of bias. Study designs were RCT (n = 3), pre-post (n = 6), cross-sectional (n = 12), mixed-methods (n = 1), and qualitative (n = 10) studies, and conducted primarily in the USA (n = 25). Findings suggested that targeted interventions can improve smoking-related or decisional psychosocial outcomes (e.g., smoking cessation interventions increase readiness/motivation to quit) but impacts of interventions on other psychological outcomes were varied. There was limited evidence reporting association between service delivery components and psychological outcomes, and results suggested moderation by individual aspects (e.g., expectation of results, baseline anxiety). Opportunities for discussion were key in reducing psychological harm. CONCLUSIONS: Certain program factors are reportedly associated with psychosocial impacts of LCS, but study heterogeneity and quality necessitate more real-world studies. Future work should examine (a) implementation of targeted interventions and high-value discussion during LCS, and (b) optimal methods and timing of risk and result communication, to improve psychosocial outcomes while reducing time burden for clinicians.

Mechanisms of cellular crosstalk in the gastric tumor microenvironment are mediated by YAP1 and STAT3.

Deregulation of the Hippo pathway is a driver for cancer progression and treatment resistance. In the context of gastric cancer, YAP1 is a biomarker for poor patient prognosis. Although genomic tumor profiling provides information of Hippo pathway activation, the present study demonstrates that inhibition of Yap1 activity has anti-tumor effects in gastric tumors driven by oncogenic mutations and inflammatory cytokines. We show that Yap1 is a key regulator of cell metabolism, proliferation, and immune responses in normal and neoplastic gastric epithelium. We propose that the Hippo pathway is targetable across gastric cancer subtypes and its therapeutic benefits are likely to be mediated by both cancer cell-intrinsic and -extrinsic mechanisms.

Genomic surveillance reveals dynamic shifts in the connectivity of COVID-19 epidemics.

The maturation of genomic surveillance in the past decade has enabled tracking of the emergence and spread of epidemics at an unprecedented level. During the COVID-19 pandemic, for example, genomic data revealed that local epidemics varied considerably in the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage importation and persistence, likely due to a combination of COVID-19 restrictions and changing connectivity. Here, we show that local COVID-19 epidemics are driven by regional transmission, including across international boundaries, but can become increasingly connected to distant locations following the relaxation of public health interventions. By integrating genomic, mobility, and epidemiological data, we find abundant transmission occurring between both adjacent and distant locations, supported by dynamic mobility patterns. We find that changing connectivity significantly influences local COVID-19 incidence. Our findings demonstrate a complex meaning of "local" when investigating connected epidemics and emphasize the importance of collaborative interventions for pandemic prevention and mitigation.

Tumor macrophage functional heterogeneity can inform the development of novel cancer therapies.

Macrophages represent a key component of the tumor microenvironment (TME) and are largely associated with poor prognosis. Therapeutic targeting of macrophages has historically focused on inhibiting their recruitment or reprogramming their phenotype from a protumor (M2-like) to an antitumor (M1-like) one. Unfortunately, this approach has not provided clinical breakthroughs that have changed practice. Emerging studies utilizing single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics have improved our understanding of the ontogeny, phenotype, and functional plasticity of macrophages. Overlaying the wealth of current information regarding macrophage molecular subtypes and functions has also identified novel therapeutic vulnerabilities that might drive better control of tumor-associated macrophages (TAMs). Here, we discuss the functional profiling of macrophages and provide an update of novel macrophage-targeted therapies in development.

A tuft cell - ILC2 signaling circuit provides therapeutic targets to inhibit gastric metaplasia and tumor development.

Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here, we report the pro-tumorigenic properties of the crosstalk between intestinal tuft cells and type 2 innate lymphoid cells (ILC2) that is evolutionarily optimized for epithelial remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) drives ILC2 activation, inducing the release of IL13 and promoting epithelial tuft cell hyperplasia. While the resulting tuft cell - ILC2 feed-forward circuit promotes gastric metaplasia and tumor formation, genetic depletion of tuft cells or ILC2s, or therapeutic targeting of IL13 or IL25 alleviates these pathologies in mice. In gastric cancer patients, tuft cell and ILC2 gene signatures predict worsening survival in intestinal-type gastric cancer where ~40% of the corresponding cancers show enriched co-existence of tuft cells and ILC2s. Our findings suggest a role for ILC2 and tuft cells, along with their associated cytokine IL13 and IL25 as gatekeepers and enablers of metaplastic transformation and gastric tumorigenesis, thereby providing an opportunity to therapeutically inhibit early-stage gastric cancer through repurposing antibody-mediated therapies.

Patient-reported experiences and satisfaction with head and neck surgery outreach clinics in regional New South Wales, Australia: A cross-sectional survey.

RATIONALE: Head and neck surgery services are increasingly being centralised in Australia. Outreach models can overcome burdens of travel that patients in regional and rural areas experience when attending routine appointments, by providing services closer to home. AIM: To explore patient-reported experiences and satisfaction with regional outreach services for head and neck surgery in Australia. METHODS: Patients who attended two regional outreach clinics in New South Wales (NSW), Australia, were surveyed over a 6-month period. Patients completed the Outpatient Cancer Clinics Survey (2020 version) that explored perceptions and experiences of the clinic. Patients with cancer were asked to complete the Edmonton Symptom Assessment System and the Communication and Attitudinal Self-Efficacy scale. Descriptive statistics and analysis of data was performed, and results were compared to the NSW statewide Outpatient Cancer Clinics Survey (2020). Content analysis of free text responses was performed. RESULTS: Some 128 patients responded (56% response rate; mean age 67.2 years, 46.1% female). Compared to the 2020 NSW survey, a higher proportion of patients in our cohort responded positively to 14 of the 26 questions, with the greatest differences observed for questions regarding waiting area comfort (+12.1%, p = 0.008), being informed about different treatment options (+9.5%, p = 0.04), and issues relating to parking (+9.5%, p = 0.03). A lower proportion of our sample responded positively to the question about whether health professionals knew enough about their medical history (-19.3%, p < 0.001). Respondents appreciated having a local clinic that helped them avoid travel to major cities and associated expenses and highlighted benefits of expert consultation and timeliness of investigations. However, cost of appointments and level of reimbursements remain barriers for some patients. CONCLUSIONS: Patients had a high level of satisfaction with regional outreach clinics for head and neck surgery across most domains, indicating patients highly value this service.

"What do I think about implementing lung cancer screening? It all depends on how." Acceptability and feasibility of lung cancer screening in Australia: The view of key stakeholders about health system factors.

BACKGROUND: Lung cancer is the number one cause of cancer death worldwide. Although international trials demonstrate that targeted screening using low dose computed tomography (LDCT) significantly reduces lung cancer mortality, implementation of screening in the high-risk population presents complex health system challenges that need to be thoroughly understood to support policy change. AIM: To elicit health care providers' and policymakers' views about the acceptability and feasibility of lung cancer screening (LCS) and barriers and enablers to implementation in the Australian setting. METHODS: We conducted 24 focus groups and three interviews (22 focus groups and all interviews online) in 2021 with 84 health professionals, researchers, and current cancer screening program managers and policy makers across all Australian states and territories. Focus groups included a structured presentation about lung cancer and screening and lasted approximately one hour each. A qualitative approach to analysis was used to map topics to the Consolidated Framework for Implementation Research. RESULTS: Nearly all participants considered LCS to be acceptable and feasible but identified a wide range of implementation challenges. Topics (five specific to health systems and five cross-cutting with participant factors) identified were mapped to CFIR constructs, of which 'readiness for implementation', 'planning' and 'executing' were most salient. Health system factor topics included delivery of the LCS program, cost, workforce considerations, quality assurance and complexity of health systems. Participants strongly advocated for streamlined referral processes. Practical strategies to address equity and access, such as using mobile screening vans, were emphasised. CONCLUSIONS: Key stakeholders readily identified the complex challenges associated with the acceptability and feasibility of LCS in Australia. The barriers and facilitators across health system and cross-cutting topics were clearly elicited. These findings are highly relevant to the scoping of a national LCS program by the Australian Government and a subsequent recommendation for implementation.

Functional roles of SRC signaling in pancreatic cancer: Recent insights provide novel therapeutic opportunities.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of <10%. Aberrant activation or elevated expression of the tyrosine kinase c-SRC (SRC) is frequently observed in PDAC and is associated with a poor prognosis. Preclinical studies have revealed a multifaceted role for SRC activation in PDAC, including promoting chronic inflammation, tumor cell proliferation and survival, cancer cell stemness, desmoplasia, hypoxia, angiogenesis, invasion, metastasis, and drug resistance. Strategies to inhibit SRC signaling include suppressing its catalytic activity, inhibiting protein stability, or by interfering with signaling components of the SRC signaling pathway including suppressing protein interactions of SRC. In this review, we discuss the molecular and immunological mechanisms by which aberrant SRC activity promotes PDAC tumorigenesis. We also provide a comprehensive update of SRC inhibitors in the clinic, and discuss the clinical challenges associated with targeting SRC in pancreatic cancer.

Vaccine effectiveness against hospitalization among adolescent and pediatric SARS-CoV-2 cases between May 2021 and January 2022 in Ontario, Canada: A retrospective cohort study.

BACKGROUND: Vaccines against SARS-CoV-2 have been shown to reduce risk of infection as well as severe disease among those with breakthrough infection in adults. The latter effect is particularly important as immune evasion by Omicron variants appears to have made vaccines less effective at preventing infection. Therefore, we aimed to quantify the protection conferred by mRNA vaccination against hospitalization due to SARS-CoV-2 in adolescent and pediatric populations. METHODS: We retrospectively created a cohort of reported SARS-CoV-2 case records from Ontario's Public Health Case and Contact Management Solution among those aged 4 to 17 linked to vaccination records from the COVaxON database on January 19, 2022. We used multivariable logistic regression to estimate the association between vaccination and hospitalization among SARS-CoV-2 cases prior to and during the emergence of Omicron. RESULTS: We included 62 hospitalized and 27,674 non-hospitalized SARS-CoV-2 cases, with disease onset from May 28, 2021 to December 4, 2021 (Pre-Omicron) and from December 23, 2021 to January 9, 2022 (Omicron). Among adolescents, two mRNA vaccine doses were associated with an 85% (aOR = 0.15; 95% CI: [0.04, 0.53]; p<0.01) lower likelihood of hospitalization among SARS-CoV-2 cases caused by Omicron. Among children, one mRNA vaccine dose was associated with a 79% (aOR = 0.21; 95% CI: [0.03, 0.77]; p<0.05) lower likelihood of hospitalization among SARS-CoV-2 cases caused by Omicron. The calculation of E-values, which quantifies how strong an unmeasured confounder would need to be to nullify our findings, suggest that these effects are unlikely to be explained by unmeasured confounding. CONCLUSIONS: Despite immune evasion by SARS-CoV-2 variants, vaccination continues to be associated with a lower likelihood of hospitalization among adolescent and pediatric Omicron (B.1.1.529) SARS-CoV-2 cases, even when the vaccines do not prevent infection. Continued efforts are needed to increase vaccine uptake among adolescent and pediatric populations.

Longitudinal quantification of mouse gastric tumor organoid viability and growth using luminescence and microscopy.

Tumor-derived organoids are valuable for testing anti-cancer drugs in vitro, but existing lysis-based protocols for viability measurement are laborious and restricted at a single time point. Here, we provide a lysis-free protocol for longitudinal and rapid assessment of mouse gastric tumor organoid viability and growth. We describe organoid plating, viability assessment via luminescence measurement, quantification of organoid growth by microscopy imaging, and treatment of organoids with test compounds to evaluate the effects on viability and growth at various time points.