How firearm legislation impacts firearm mortality internationally: A scoping review.

Background: The literature on gun violence is broad and variable, describing multiple legislation types and outcomes in observational studies. Our objective was to document the extent and nature of evidence on the impact of firearm legislation on mortality from firearm violence. Methods: A scoping review was conducted under PRISMA-ScR guidance. A comprehensive peer-reviewed search strategy was executed in several electronic databases from inception to March 2024. Grey literature was searched for unpublished sources. Data were extracted on study design, country, population, type of legislation, and overall study conclusions on legislation impact on mortality from suicide, homicide, femicide, and domestic violence. Critical appraisal for a sample of articles with the same study design (ecological studies) was conducted for quality assessment. Findings: 5057 titles and abstracts and 651 full-text articles were reviewed. Following full-text review and grey literature search, 202 articles satisfied our eligibility criteria. Federal legislation was identified from all included countries, while state-specific laws were only reported in studies from the U.S. Numerous legislative approaches were identified including preventative, prohibitive, and more tailored strategies focused on identifying high risk individuals. Law types had various effects on rates of firearm homicide, suicide, and femicide. Lack of robust design, uneven implementation, and poor evaluation of legislation may contribute to these differences. Interpretation: We found that national, restrictive laws reduce population-level firearm mortality. These findings can inform policy makers, public health researchers, and governments when designing and implementing legislation to reduce injury and death from firearms. Funding: Funding is provided by the Strategy for Patient-Oriented Research (SPOR) Evidence Alliance and in part by St. Michael's Hospital, University of Toronto. Scoping review registration: Open Science Framework (OSF): https://osf.io/sf38n.

Disease-specific survival outcomes for patients after locoregional treatment for ductal carcinoma in situ: observational cohort study.

BACKGROUND: Breast-conserving surgery alone, breast-conserving surgery with adjuvant radiation treatment, and mastectomy are guideline-concordant treatments for ductal carcinoma in situ. The aim of this study was to compare survival outcomes between these treatment options. METHODS: A stratified random sample of patients diagnosed with pure ductal carcinoma in situ between 2008 and 2014 was selected from 1330 sites in the USA. Data on diagnosis, treatment, and follow-up were abstracted by local cancer registrars. Population-averaged marginal estimates of disease-specific survival and overall survival for breast-conserving surgery alone, breast-conserving surgery with radiation treatment, and mastectomy were obtained by combining sampling and overlap weights. RESULTS: A total of 18 442 women were included, with a median follow-up of 67.8 (interquartile range 46.1-93.5) months. A total of 35 women died from breast cancer, at a median age of 62 (interquartile range 50-74) years. Population-averaged 8-year rates of disease-specific survival were 99.6% or higher for all treatment groups, with no significant differences between groups (breast-conserving surgery alone versus breast-conserving surgery with radiation treatment, HR 1.19 (95% c.i. 0.29 to 4.85); and mastectomy versus breast-conserving surgery with radiation treatment, HR 1.74 (95% c.i. 0.53 to 5.72). There was no difference in overall survival between the patients who underwent a mastectomy and the patients who underwent breast-conserving surgery with radiation treatment (HR 1.09 (95% c.i. 0.83 to 1.43)). Patients who underwent breast-conserving surgery alone had lower overall survival compared with the patients who underwent breast-conserving surgery with radiation treatment (HR 1.29 (95% c.i. 1.00 to 1.67)). This survival difference vanished for all but one subgroup, namely patients less than 65 years (HR 1.86 (95% c.i. 1.15 to 3.00)). CONCLUSION: There was no statistically significant difference in disease-specific survival between women operated with breast-conserving surgery alone, breast-conserving surgery with radiation treatment, or mastectomy for ductal carcinoma in situ. Given the low absolute risk of disease-specific mortality, these results provide confidence in offering individualized locoregional treatment without fear of compromising survival.

Routinely collected burn clinical data in Canada: Determining the knowledge gap.

Unlike other developed countries that hold national burn registries to monitor burn injury and care, Canada relies on single-centre secondary datasets and administrative databases as surveillance mechanisms. The objective of this study was to determine the knowledge gap faced in Canada for not having a dedicated burn registry. A comprehensive scoping review was conducted to identify the burn literature that has arisen from secondary datasets in Canada. Literature of all study designs was included with the exception of case reports and cases series. Once data extraction was concluded, a thematic framework was constructed based on the information that arose from nations that hold national burn registries. Eighty-eight studies were included. Twelve studies arose from national datasets, and 18 from provincial databases, most of which were from Ontario and British Columbia. Only seven studies were conducted using a combination of Canadian units' single-centre datasets. The majority of included studies (58%) resulted from non-collaborative use of single-centre secondary datasets. Research efforts were predominantly conducted by burn units in Ontario, British Columbia, Manitoba and Alberta. A significant number of the included studies were outdated and several provinces/territories had no published burn data whatsoever. Efforts should be made towards the development of systems to surveil burn injury and care in Canada. This study supports the development of a nation-wide burn registry to bridge this knowledge gap.

Two zebrafish cacna1s loss-of-function variants provide models of mild and severe CACNA1S-related myopathy.

CACNA1S-related myopathy, due to pathogenic variants in the CACNA1S gene, is a recently described congenital muscle disease. Disease associated variants result in loss of gene expression and/or reduction of Cav1.1 protein stability. There is an incomplete understanding of the underlying disease pathomechanisms and no effective therapies are currently available. A barrier to the study of this myopathy is the lack of a suitable animal model that phenocopies key aspects of the disease. To address this barrier, we generated knockouts of the two zebrafish CACNA1S paralogs, cacna1sa and cacna1sb. Double knockout fish exhibit severe weakness and early death, and are characterized by the absence of Cav1.1 α1 subunit expression, abnormal triad structure, and impaired excitation-contraction coupling, thus mirroring the severe form of human CACNA1S-related myopathy. A double mutant (cacna1sa homozygous, cacna1sb heterozygote) exhibits normal development, but displays reduced body size, abnormal facial structure, and cores on muscle pathologic examination, thus phenocopying the mild form of human CACNA1S-related myopathy. In summary, we generated and characterized the first cacna1s zebrafish loss-of-function mutants, and show them to be faithful models of severe and mild forms of human CACNA1S-related myopathy suitable for future mechanistic studies and therapy development.

Educational Podcasts in Plastic Surgery: A Cross-Sectional Analysis of Content, Metrics, and Target Audiences.

BACKGROUND: Podcasts provide an efficient means for asynchronous learning. However, no study to date has thoroughly assessed the landscape of educational podcasts in plastic surgery. Thus, this study aims to evaluate and characterize current educational plastic surgery podcasts to ultimately inform future efforts. METHODS: Three platforms were queried for educational plastic surgery podcasts: Apple Podcasts, Spotify, and Google Podcasts. Podcast descriptions and episodes were then independently reviewed to determine primary target audiences, performance metrics, and content categories. RESULTS: There were a total of 163 plastic surgery podcasts. 145 of these 163 podcasts were targeted toward a nonmedical audience. The remaining 18 podcasts met inclusion criteria as educational plastic surgery podcasts. Of all educational podcast episodes, 8.8% targeted a medical student audience, 33.8% targeted trainees (residents/fellows), and 57.4% targeted practicing surgeons or emphasized recent research in the field. Episode content categories included breast (14.2%), cosmetic (11.8%), experimental (0.5%), hand/peripheral nerve (8.6%), pediatric/craniofacial (8.2%), reconstructive (15.6%), practice management (14.8%), residency (6.6%), and others (19.6%). CONCLUSIONS: Despite the large number of plastic surgery podcasts available, few podcasts focus on educating a medical audience. Within this small subset, there is a paucity of content targeted towards medical students interested in plastic surgery. While there is a wide breadth of content available, there is significant room for growth and refinement in the podcast sector for plastic surgery education.

Development and Integration of Machine Learning Algorithm to Identify Peripheral Arterial Disease: Multistakeholder Qualitative Study.

BACKGROUND: Machine learning (ML)-driven clinical decision support (CDS) continues to draw wide interest and investment as a means of improving care quality and value, despite mixed real-world implementation outcomes. OBJECTIVE: This study aimed to explore the factors that influence the integration of a peripheral arterial disease (PAD) identification algorithm to implement timely guideline-based care. METHODS: A total of 12 semistructured interviews were conducted with individuals from 3 stakeholder groups during the first 4 weeks of integration of an ML-driven CDS. The stakeholder groups included technical, administrative, and clinical members of the team interacting with the ML-driven CDS. The ML-driven CDS identified patients with a high probability of having PAD, and these patients were then reviewed by an interdisciplinary team that developed a recommended action plan and sent recommendations to the patient's primary care provider. Pseudonymized transcripts were coded, and thematic analysis was conducted by a multidisciplinary research team. RESULTS: Three themes were identified: positive factors translating in silico performance to real-world efficacy, organizational factors and data structure factors affecting clinical impact, and potential challenges to advancing equity. Our study found that the factors that led to successful translation of in silico algorithm performance to real-world impact were largely nontechnical, given adequate efficacy in retrospective validation, including strong clinical leadership, trustworthy workflows, early consideration of end-user needs, and ensuring that the CDS addresses an actionable problem. Negative factors of integration included failure to incorporate the on-the-ground context, the lack of feedback loops, and data silos limiting the ML-driven CDS. The success criteria for each stakeholder group were also characterized to better understand how teams work together to integrate ML-driven CDS and to understand the varying needs across stakeholder groups. CONCLUSIONS: Longitudinal and multidisciplinary stakeholder engagement in the development and integration of ML-driven CDS underpins its effective translation into real-world care. Although previous studies have focused on the technical elements of ML-driven CDS, our study demonstrates the importance of including administrative and operational leaders as well as an early consideration of clinicians' needs. Seeing how different stakeholder groups have this more holistic perspective also permits more effective detection of context-driven health care inequities, which are uncovered or exacerbated via ML-driven CDS integration through structural and organizational challenges. Many of the solutions to these inequities lie outside the scope of ML and require coordinated systematic solutions for mitigation to help reduce disparities in the care of patients with PAD.

Clinical utility of multiple secondary combined tests in prostate cancer screening.

INTRODUCTION: The clinical utility of concurrent Prostate Health Index (PHI) and ExosomeDx Prostate Intelliscore (EPI) testing is unclear. We sought to examine the performance of combined PHI and EPI testing on men undergoing elevated PSA work up. MATERIALS AND METHODS: Patients who received both EPI and PHI testing were identified from an institutional database of men referred to urology for an elevated total PSA. Cut points of EPI > 15.6 and PHI ≥ 36 were used to denote a positive test. Patients were placed into one of four groups determined by combination of EPI and PHI results. Demographic variables and biopsy recommendations were compared between groups. The concordance of test positivity between EPI and PHI was compared by Cohen's kappa. Demographic variables and secondary testing results were compared between patients' compliant and non-compliant with prostate biopsy recommendation. Biopsy pathology was compared between groups. RESULTS: A total of 162 patients had both EPI and PHI testing. Median age was 65 years, with a median PSA of 6.64 ng/mL. Age (p = 0.001), PSA (< 0.001) and biopsy recommendation (< 0.001) differed between combined secondary screening test result groups. Seventy-five percent of patients with both a positive EPI and PHI were found to have prostate cancer, with 54.2% being ≥ Gleason 7. Cohen's kappa was 0.19, indicating poor concordance. The AUC of EPI and PHI for clinically significant cancer was 0.563 (95% CI: 0.4331-0.6923) and 0.685 (95% CI: 0.569-0.8) (p = 0.147). CONCLUSIONS: Concurrently positive EPI and PHI indicate increased prostate cancer risk, with combined usage potentially influencing biopsy recommendation and compliance.

Evaluating Disparities in Pathways to Breast Reconstruction.

BACKGROUND: Rates of postmastectomy breast reconstruction have been shown to vary by racial, ethnic, and socioeconomic factors. In this study, we evaluated disparities across pathways toward breast reconstruction. METHODS: All women who underwent mastectomy for breast cancer at a single institution from 2017 to 2018 were reviewed. Rates of discussions about reconstruction with breast surgeons, plastic surgery referrals, plastic surgery consultations, and ultimate decisions to pursue reconstruction were compared by race/ethnicity. RESULTS: A total of 218 patients were included, with the racial/ethnic demographic of 56% white, 28% Black, 1% American Indian/Native Alaskan, 4% Asian, and 4% Hispanic/Latina. The overall incidence of postmastectomy breast reconstruction was 48%, which varied by race (white: 58% vs. Black: 34%; p < 0.001). Plastic surgery was discussed by the breast surgeon with 68% of patients, and referrals were made in 62% of patients. While older age (p < 0.001) and nonprivate insurance (p < 0.05) were associated with lower rates of plastic surgery discussion and referral, it did not vary by race/ethnicity. The need for an interpreter was associated with lower rates of discussion (p < 0.05). After multivariate adjustment, a lower reconstruction rate was associated with the Black race (odds ratio [OR] = 0.33; p = 0.014) and body mass index (BMI) ≥ 35 (OR = 0.14; p < 0.001). Elevated BMI did not disproportionately lower breast reconstruction rates in Black versus white women (p = 0.27). CONCLUSION: Despite statistically equivalent rates of plastic surgery discussions and referrals, black women had lower breast reconstruction rates versus white women. Lower rates of breast reconstruction in Black women likely represent an amalgamation of barriers to care; further exploration within our community is warranted to better understand the racial disparity observed.

Mapping Patient Encounters in Breast Cancer Care: An Analysis of 8800 Clinical Encounters Among Patients Undergoing Mastectomy.

BACKGROUND: Transitions toward value-based systems require a comprehensive definition of the complexity and duration of provider effort required for a given diagnosis. This study modeled the numbers of clinical encounters involved in various treatment pathways among breast cancer patients undergoing mastectomy. METHODS: Clinical encounters with medical oncologists, radiation oncologists, breast surgeons, or plastic surgeons ≤4 years after diagnosis among all patients undergoing mastectomy from 2017 to 2018 were reviewed. Relative encounter volumes were modeled each 90-day period after diagnosis. RESULTS: A total of 8807 breast cancer-related encounters from 221 patients were analyzed, with mean (SD) encounter volume 39.9 (27.2) encounters per patient. Most encounters occurred in the first year after diagnosis (70.0%), with years 2, 3, and 4 representing 15.8%, 9.1%, and 3.5% of encounters, respectively. Overall stage was associated with encounter volume, with higher encounter volume with increasing stage (stages 0: 27.4 vs I: 28.5 vs II: 48.4 vs III: 61.1 vs IV: 80.8 mean encounters). Body mass index (odds ratio [OR], 0.22), adjuvant radiation (OR, 6.8), and receipt of breast reconstruction (OR, 3.5) were also associated with higher encounter volume (all P 's < 0.01). Duration of encounter volume varied by treatment phases, with medical oncology and plastic surgery sustaining high clinical encounter volume 3 years after diagnosis. CONCLUSIONS: Encounter utilization in breast cancer care persists 3 years after index diagnosis and is influenced by overall stage and treatment characteristics, including receipt of breast reconstruction. These results may inform the design of episode durations within value-based models and institutional resource allocation for breast cancer care.

Community collaboration to improve access and outcomes in breast cancer reconstruction: protocol for a mixed-methods qualitative research study.

INTRODUCTION: Breast reconstruction plays an important role for many in restoring form and function of the breast after mastectomy. However, rates of breast reconstruction in the USA vary significantly by race, ethnicity and socioeconomic status. The lower rates of breast reconstruction in non-white women and in women of lower socioeconomic status may reflect a complex interplay between patient and physician factors and access to care. It remains unknown what community-specific barriers may be impacting receipt of breast reconstruction. METHODS AND ANALYSIS: This is a mixed-methods study combining qualitative patient interview data with quantitative practice patterns to develop an actionable plan to address disparities in breast reconstruction in the local community. The primary aims are to (1) capture barriers to breast reconstruction for patients in the local community, (2) quantitatively evaluate practice patterns at the host institution and (3) identify issues and prioritise interventions for change using community-based engagement. ETHICS AND DISSEMINATION: Ethics approval was obtained at the investigators' institution. Results from both the quantitative and qualitative portions of the study will be circulated via peer-review publication. These findings will also serve as pilot data for extramural funding to implement and evaluate these proposed solutions.

Ubiquitin phosphorylated at Ser57 hyper-activates parkin.

Malfunction of the ubiquitin (Ub) E3 ligase, parkin, leads to defects in mitophagy and protein quality control linked to Parkinson's disease. Parkin activity is stimulated by phosphorylation of Ub at Ser65 (pUbS65). Since the upstream kinase is only known for Ser65 (PINK1), the biochemical function of other phosphorylation sites on Ub remain largely unknown. We used fluorescently labelled and site-specifically phosphorylated Ub substrates to quantitatively relate the position and stoichiometry of Ub phosphorylation to parkin activation. Fluorescence measurements show that pUbS65-stimulated parkin is 5-fold more active than auto-inhibited and un-stimulated parkin, which catalyzes a basal level of auto-ubiquitination. We consistently observed a low but detectable level of parkin activity with pUbS12. Strikingly, pUbS57 hyper-activates parkin, and our data demonstrate that parkin is able to selectively synthesize poly-pUbS57 chains, even when 90% of the Ub in the reaction is un-phosphorylated. We further found that parkin ubiquitinates its physiological substrate Miro-1 with chains solely composed of pUbS65 and more efficiently with pUbS57 chains. Parkin hyper-activation by pUbS57 demonstrates the first PINK1-independent route to active parkin, revealing the roles of multiple ubiquitin phosphorylation sites in governing parkin stimulation and catalytic activity. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O'Donoghue.