Purpose: We conducted a scoping review of studies to examine the implementation of interventions to promote adolescent cancer prevention in rural, primary care settings and identify barriers and facilitators. Methods: We followed the JBI scoping review protocol and used a systematic extraction and coding process. Our search of MEDLINE, PsycInfo, Cochrane, CINAHL, and Scopus identified articles related to implementation of interventions in the following areas: obesity, human papillomavirus (HPV) vaccination, tobacco use, and sun exposure. We used the Consolidated Framework for Implementation Research (CFIR), an implementation framework consisting of 5 domains (outer setting, inner setting, intervention characteristics, individual characteristics, process), each with a sub-set of constructs, to classify barriers and facilitators reported. Results: We identified 3046 references, excluded 2969 during initial screening, assessed 74 for full-text eligibility, and abstracted 24. Of these, 17 addressed obesity, 6 addressed HPV vaccination, 1 addressed skin cancer, and 1 addressed multiple behaviors. 10 studies were either non-randomized experimental designs (n=8) or randomized controlled trials (n=2). The remaining were observational or descriptive research. Barriers in the outer setting (e.g., lack of external funding sources, patients' beliefs) and inner setting (e.g., time available for implementation efforts and clinic infrastructure) were most common, compared to the other CFIR domains. Similarly, facilitators in the outer setting (e.g., partnerships with other organizations and parents' trust in health care providers) and inner setting (e.g., efficiency in practice protocols) were commonly reported. Conclusions: Adolescence is a critical growth window to establish healthy behaviors to prevent future cancers. Rural areas have higher rates of cancer morbidity and mortality than urban ones, putting rural adolescents at heightened risk for cancers. Yet, we found a dearth of studies addressing the implementation of adolescent cancer prevention in rural primary care settings. Further research is needed to understand the implementation challenges and potential strategies to improve implementation efforts to promote cancer prevention among rural adolescents.

Background: The performance of rapid antigen tests for SARS-CoV-2 (Ag-RDT) in temporal relation to symptom onset or exposure is unknown, as is the impact of vaccination on this relationship. Objective: To evaluate the performance of Ag-RDT compared with RT-PCR based on day after symptom onset or exposure in order to decide on 'when to test'. Design setting and participants: The Test Us at Home study was a longitudinal cohort study that enrolled participants over 2 years old across the United States between October 18, 2021 and February 4, 2022. All participants were asked to conduct Ag-RDT and RT-PCR testing every 48 hours over a 15-day period. Participants with one or more symptoms during the study period were included in the Day Post Symptom Onset (DPSO) analyses, while those who reported a COVID-19 exposure were included in the Day Post Exposure (DPE) analysis. Exposure: Participants were asked to self-report any symptoms or known exposures to SARS-CoV-2 every 48-hours, immediately prior to conducting Ag-RDT and RT-PCR testing. The first day a participant reported one or more symptoms was termed DPSO 0, and the day of exposure was DPE 0. Vaccination status was self-reported. Main outcome and measures: Results of Ag-RDT were self-reported (positive, negative, or invalid) and RT-PCR results were analyzed by a central laboratory. Percent positivity of SARS-CoV-2 and sensitivity of Ag-RDT and RT-PCR by DPSO and DPE were stratified by vaccination status and calculated with 95% confidence intervals. Results: A total of 7,361 participants enrolled in the study. Among them, 2,086 (28.3%) and 546 (7.4%) participants were eligible for the DPSO and DPE analyses, respectively. Unvaccinated participants were nearly twice as likely to test positive for SARS-CoV-2 than vaccinated participants in event of symptoms (PCR+: 27.6% vs 10.1%) or exposure (PCR+: 43.8% vs. 22.2%). The highest proportion of vaccinated and unvaccinated individuals tested positive on DPSO 2 and DPE 5-8. Performance of RT-PCR and Ag-RDT did not differ by vaccination status. Ag-RDT detected 78.0% (95% Confidence Interval: 72.56-82.61) of PCR-confirmed infections by DPSO 4. For exposed participants, Ag-RDT detected 84.9% (95% CI: 75.0-91.4) of PCR-confirmed infections by day five post-exposure (DPE 5). Conclusions and relevance: Performance of Ag-RDT and RT-PCR was highest on DPSO 0-2 and DPE 5 and did not differ by vaccination status. These data suggests that serial testing remains integral to enhancing the performance of Ag-RDT.

Background and aims: Outcomes of breakthrough SARS-CoV-2 infections have not been well characterized in non-veteran vaccinated patients with chronic liver diseases (CLD). We used the National COVID Cohort Collaborative (N3C) to describe these outcomes. Approach and results: We identified all CLD patients with or without cirrhosis who had SARS-CoV-2 testing in the N3C Data Enclave as of January 15, 2022. We used Poisson regression to estimate incidence rates of breakthrough infections and Cox survival analyses to associate vaccination status with all-cause mortality at 30 days among infected CLD patients. We isolated 278,457 total CLD patients: 43,079 (15%) vaccinated and 235,378 (85%) unvaccinated. Of 43,079 vaccinated patients, 32,838 (76%) were without cirrhosis and 10,441 (24%) with cirrhosis. Breakthrough infection incidences were 5.4 and 4.9 per 1000 person-months for fully vaccinated CLD patients without cirrhosis and with cirrhosis, respectively. Of the 68,048 unvaccinated and 10,441 vaccinated CLD patients with cirrhosis, 15% and 3.7%, respectively, developed SARS-CoV-2 infection. The 30-day outcome of mechanical ventilation or death after SARS-CoV-2 infection for unvaccinated and vaccinated CLD patients with cirrhosis were 15.2% and 7.7%, respectively. Compared to unvaccinated patients with cirrhosis, full vaccination was associated with a 0.34-times adjusted hazard of death at 30 days. Conclusions: In this N3C study, breakthrough infection rates were similar among CLD patients with and without cirrhosis. Full vaccination was associated with a 66% reduction in risk of all-cause mortality for breakthrough infection among CLD patients with cirrhosis. These results provide an additional impetus for increasing vaccination uptake in CLD populations.

CRISPR/Cas9-driven cancer modeling studies are based on the disruption of tumor suppressor genes by small insertions or deletions (indels) that lead to frame-shift mutations. In addition, CRISPR/Cas9 is widely used to define the significance of cancer oncogenes and genetic dependencies in loss-of-function studies. However, how CRISPR/Cas9 influences gain-of-function oncogenic mutations is elusive. Here, we demonstrate that single guide RNA targeting exon 3 of Ctnnb1 (encoding β-catenin) results in exon skipping and generates gain-of-function isoforms in vivo. CRISPR/Cas9-mediated exon skipping of Ctnnb1 induces liver tumor formation in synergy with YAPS127A in mice. We define two distinct exon skipping-induced tumor subtypes with different histological and transcriptional features. Notably, ectopic expression of two exon-skipped β-catenin transcript isoforms together with YAPS127A phenocopies the two distinct subtypes of liver cancer. Moreover, we identify similar CTNNB1 exon-skipping events in patients with hepatocellular carcinoma. Collectively, our findings advance our understanding of β-catenin-related tumorigenesis and reveal that CRISPR/Cas9 can be repurposed, in vivo, to study gain-of-function mutations of oncogenes in cancer. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Background and purpose: In the United States, an exponential increase in total hip arthroplasty (THA) and total knee arthroplasty (TKA) demand has occurred over the last 2 decades. Evidence suggesting patients receiving inpatient rehabilitation following a TKA or THA experience similar outcomes as those with rehabilitation in other settings led to dramatic shifts in postsurgical care settings owing to Centers for Medicare & Medicaid Services (CMS) payment reforms. A contemporary synthesis of evidence about the association between patient and facility factors and outcomes from older adults undergoing THA or TKA in the United States is needed. Methods: To identify eligible studies, we searched PubMed, Scopus, and CINAHL. We followed PRISMA guidelines to identify articles evaluating either patient or facility factors associated with outcomes after THA or TKA for older adults who may have been cared for in inpatient settings (ie, inpatient rehabilitation or skilled nursing facility [SNF]). Eligible articles were conducted in the United States and were published between January 1, 2000, and December 31, 2021. Results: We included 8 articles focused on patient factors and 9 focused on facility factors. Most included older adults and the majority were White (in those reporting race/ethnicity). Most studies evaluated outcomes at discharge and showed that patients admitted to inpatient rehabilitation facilities had either similar or better functional outcomes (mobility, self-care, and functional independence measure (FIM) score) and lower length of stay compared with those in SNFs. Few studies focused on home health care. Conclusions: The systematic review focused on older adults showed that findings in these patients are consistent with previous research. Older adults undergoing THA/TKA had acceptable outcomes regardless of postsurgical, inpatient setting of care. Research conducted after CMS payment reforms, in home health care settings, and in more diverse samples is needed. Given the known racial/ethnic disparities in THA/TKA and the shifts to postsurgical home health care with little regulatory oversight of care quality, contemporary research on outcomes of postsurgical THA/TKA outcomes is warranted.

ALS-linked mutations induce aberrant conformations within the SOD1 protein that are thought to underlie the pathogenic mechanism of SOD1-mediated ALS. Although clinical trials are underway for gene silencing of SOD1, these approaches reduce both wild-type and mutated forms of SOD1. Here, we sought to develop anti-SOD1 nanobodies with selectivity for mutant and misfolded forms of human SOD1 over wild-type SOD1. Characterization of two anti-SOD1 nanobodies revealed that these biologics stabilize mutant SOD1 in vitro. Further, SOD1 expression levels were enhanced and the physiological subcellular localization of mutant SOD1 was restored upon co-expression of anti-SOD1 nanobodies in immortalized cells. In human motor neurons harboring the SOD1 A4V mutation, anti-SOD1 nanobody expression promoted neurite outgrowth, demonstrating a protective effect of anti-SOD1 nanobodies in otherwise unhealthy cells. In vitro assays revealed that an anti-SOD1 nanobody exhibited selectivity for human mutant SOD1 over endogenous murine SOD1, thus supporting the preclinical utility of anti-SOD1 nanobodies for testing in animal models of ALS. In sum, the anti-SOD1 nanobodies developed and presented herein represent viable biologics for further preclinical testing in human and mouse models of ALS.

Early in the COVID-19 pandemic, mortality rates were observed to exceed 25% in patients who developed postoperative SARS-CoV-2 infections.1 This prompted numerous perioperative structural and process changes to mitigate this risk.2,3 As the pandemic has progressed, the emergence of novel therapeutic and preventative measures have proven effective in decreasing the overall burden of SARS-CoV-2 infection. These advances likely reduce the risk in surgical patients; however, this has not been reexamined at a population level. This study reports 30-day adverse postoperative event rates in patients who develop postoperative COVID-19 and measures the impact of vaccination on these outcomes.

Background: Rates of COVID-19 vaccinations among youth remain sub-optimal, particularly among racial and ethnic minority populations. The Centers for Disease Control and Prevention-funded UMass Worcester Prevention Research Center partnered with the vaccination equity initiative of Worcester, Massachusetts and youth-serving organizations to develop, implement, and evaluate a youth led public health campaign to promote COVID-19 vaccine confidence and uptake. Methods: Guided by the youth empowerment model to promote behavior change by helping youth reflect, identify, and take action on what is meaningful to them, we created a youth vaccine ambassador public health campaign to promote COVID-19 vaccination. Ambassadors were guided through self-reflection of questions, answers and motivations for COVID-19 vaccination. Youth motivations and narratives became the campaign messaging. Youth collaborated to create and disseminate social media, video, and print content to display in local neighborhoods, using social norming approaches to foster youth and family vaccine confidence and vaccination. Results: We trained nine youth (aged 18- 22 years) as vaccine ambassadors. English/Spanish vaccine messages developed by youth ambassadors were disseminated through social media platforms (n=3), radio (n=2), local TV (n=2), flyers (n=2,086), posters (n=362), billboards (n=7), and local bus ads (n=18). Qualitative youth feedback indicated participation in the campaign was a positive and empowering experience which reinforces the importance of engaging youth in public health messaging. Discussion: Amplifying youth voices by engaging them to develop and share their personal vaccine stories and motivations facilitated youths’ role as public health messengers. Youth empowerment through storytelling and personal narratives holds promise for future public health campaigns.

Background: The safety, reactogenicity, immunogenicity, and efficacy of the mRNA-1273 coronavirus disease 2019 (Covid-19) vaccine in young children are unknown. Methods: Part 1 of this ongoing phase 2-3 trial was open label for dose selection; part 2 was an observer-blinded, placebo-controlled evaluation of the selected dose. In part 2, we randomly assigned young children (6 months to 5 years of age) in a 3:1 ratio to receive two 25-μg injections of mRNA-1273 or placebo, administered 28 days apart. The primary objectives were to evaluate the safety and reactogenicity of the vaccine and to determine whether the immune response in these children was noninferior to that in young adults (18 to 25 years of age) in a related phase 3 trial. Secondary objectives were to determine the incidences of Covid-19 and severe acute respiratory syndrome coronavirus 2 infection after administration of mRNA-1273 or placebo. Results: On the basis of safety and immunogenicity results in part 1 of the trial, the 25-μg dose was evaluated in part 2. In part 2, 3040 children 2 to 5 years of age and 1762 children 6 to 23 months of age were randomly assigned to receive two 25-μg injections of mRNA-1273; 1008 children 2 to 5 years of age and 593 children 6 to 23 months of age were randomly assigned to receive placebo. The median duration of follow-up after the second injection was 71 days in the 2-to-5-year-old cohort and 68 days in the 6-to-23-month-old cohort. Adverse events were mainly low-grade and transient, and no new safety concerns were identified. At day 57, neutralizing antibody geometric mean concentrations were 1410 (95% confidence interval [CI], 1272 to 1563) among 2-to-5-year-olds and 1781 (95% CI, 1616 to 1962) among 6-to-23-month-olds, as compared with 1391 (95% CI, 1263 to 1531) among young adults, who had received 100-μg injections of mRNA-1273, findings that met the noninferiority criteria for immune responses for both age cohorts. The estimated vaccine efficacy against Covid-19 was 36.8% (95% CI, 12.5 to 54.0) among 2-to-5-year-olds and 50.6% (95% CI, 21.4 to 68.6) among 6-to-23-month-olds, at a time when B.1.1.529 (omicron) was the predominant circulating variant. Conclusions: Two 25-μg doses of the mRNA-1273 vaccine were found to be safe in children 6 months to 5 years of age and elicited immune responses that were noninferior to those in young adults. (Funded by the Biomedical Advanced Research and Development Authority and National Institute of Allergy and Infectious Diseases; KidCOVE ClinicalTrials.gov number, NCT04796896.).

Published studies report inconsistent associations of polyunsaturated fatty acid (PUFA) intake with non-Hodgkin lymphoma (NHL) risk. We conducted a nested case-control study in Nurses' Health Study and Health Professionals Follow-Up Study participants to evaluate a hypothesis of inverse association of pre-diagnosis red blood cell (RBC) membrane PUFA levels with risk of NHL endpoints. We confirmed 583 NHL cases and matched 583 controls by cohort/sex, age, race and blood draw date/time. We estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL endpoints using logistic regression. RBC PUFA levels were not associated with all NHL risk; cis 20:2n-6 was associated with follicular lymphoma risk (OR [95% CI] per one standard deviation increase: 1.35 [1.03-1.77]), and the omega-6/omega-3 PUFA ratio was associated with diffuse large B-cell lymphoma risk (2.33 [1.23-4.43]). Overall, PUFA did not demonstrate a role in NHL etiology; the two unexpected positive associations lack clear biologic explanations.