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Introduction: Pilomatrix carcinomas (PMXCs) are uncommon, locally aggressive tumors with high recurrence rates, metastatic potential, and fewer than 130 cases reported in the literature. Typically, they present as an unassuming, firm, dermal swelling and therefore are frequently mistaken for more common, benign masses, leading to undertreatment which can cause local invasion and metastatic spread. Diagnosis relies on excision with pathologic analysis; however once diagnosed, there are no current recommendations to guide treatment or surveillance for recurrence or metastases. Case Presentation: Here, we present a case of one of these rare tumors. Our case describes a 1.5 × 2.5 cm firm, mobile mass at the supraorbital rim in an otherwise healthy, young patient. Prior to removal, we suspected a benign pathology; however, excision proved difficult and pathologic diagnosis was consistent with PMXC. Following discussion with tumor board, decision was made to perform Mohs micrographic surgery and staging via CT scans with regular follow-up and surveillance scans. Conclusion: PMXCs are exceedingly rare diagnoses and present like many benign lesions. Therefore, we elected to document this case to encourage providers to keep these biologically aggressive tumors on their list of differential diagnoses in an unsuspecting mass, as well as to provide our own recommendations for treatment and screening for recurrence and metastatic spread.

BackgroundRural healthcare has unique characteristics that affect the dissemination and implementation of evidence-based interventions. Numerous theories, models, and frameworks have been developed to guide implementation of healthcare interventions, though not specific to rural healthcare. The present scoping review sought to identify the theories, models, and frameworks most frequently applied to rural health and propose an approach to rural health research that harnesses selected constructs from these theories, models, and frameworks. This resulting synthesis can serve as a guide to researchers, policy makers, and clinicians seeking to employ commonly used theories, models, and frameworks to rural health.MethodsWe used the Scopus abstract indexing service to identify peer-reviewed literature citing one or more of theories, models, or frameworks used in dissemination and implementation research and including the word “rural” in the Title, Abstract, or Keywords. We screened the remaining titles and abstracts to ensure articles met additional inclusion criteria. We conducted a full review of the resulting 172 articles to ensure they identified one or more discrete theory, model, or framework applied to research or quality improvement projects. We extracted the theories, models, and frameworks and categorized these as process models, determinant frameworks, classic theories, or evaluation frameworks.ResultsWe retained 61 articles of which 28 used RE-AIM, 11 used Community-Based Participatory Research (CBPR) framework, eight used the Consolidated Framework for Implementation Research (CFIR), and six used the integrated-Promoting Action on Research Implementation in Health Services (iPARIHS). Additional theories, models, and frameworks were cited in three or fewer reports in the literature. The 14 theories, models, and frameworks cited in the literature were categorized as seven process models, four determinant frameworks, one evaluation framework, and one classic theory.ConclusionsThe RE-AIM framework was the most frequently cited framework in the rural health literature, followed by CBPR, CFIR, and iPARIHS. A notable advantage of RE-AIM in rural healthcare settings is the focus on reach as a specified outcome, given the challenges of engaging a geographically diffuse and often isolated population. We present a rationale for combining the strengths of these theories, models, and frameworks to guide a research agenda specific to rural healthcare research.Systematic Review Registrationhttps://osf.io/fn2cd/.

Abstract Background Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy. Findings We performed a genome-wide association analysis in the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age

Background: Two-stage breast reconstruction is a common technique used to restore preoperative appearance in patients undergoing mastectomy. However, capsular contracture may develop and lead to implant failure and significant morbidity. The objective of this study is to build a machine-learning model that can determine the risk of developing contracture formation after two-stage breast reconstruction. Methods: A total of 209 women (406 samples) were included in the study cohort. Patient characteristics that were readily accessible at the preoperative visit and details pertaining to the surgical approach were used as input data for the machine-learning model. Supervised learning models were assessed using 5-fold cross validation. A neural network model is also evaluated using a 0.8/0.1/0.1 train/validate/test split. Results: Among the subjects, 144 (35.47%) developed capsular contracture. Older age, smaller nipple-inframammary fold distance, retropectoral implant placement, synthetic mesh usage, and postoperative radiation increased the odds of capsular contracture (p < 0.05). The neural network achieved the best performance metrics among the models tested, with a test accuracy of 0.82 and area under receiver operative curve of 0.79. Conclusion: To our knowledge, this is the first study that uses a neural network to predict the development of capsular contraction after two-stage implant-based reconstruction. At the preoperative visit, surgeons may counsel high-risk patients on the potential need for further revisions or guide them toward autologous reconstruction.

Introduction The burden of mental health-related visits to emergency departments (EDs) is growing, and agitation episodes are prevalent with such visits. Best practice guidance from experts recommends early assessment of at-risk populations and pre-emptive intervention using de-escalation techniques to prevent agitation. Time pressure, fluctuating work demands, and other systems-related factors pose challenges to efficient decision-making and adoption of best practice recommendations during an unfolding behavioural crisis. As such, we propose to design, develop and evaluate a computerised clinical decision support (CDS) system, Early Detection and Treatment to Reduce Events with Agitation Tool (ED-TREAT). We aim to identify patients at risk of agitation and guide ED clinicians through appropriate risk assessment and timely interventions to prevent agitation with a goal of minimising restraint use and improving patient experience and outcomes.Methods and analysis This study describes the formative evaluation of the health record embedded CDS tool. Under aim 1, the study will collect qualitative data to design and develop ED-TREAT using a contextual design approach and an iterative user-centred design process. Participants will include potential CDS users, that is, ED physicians, nurses, technicians, as well as patients with lived experience of restraint use for behavioural crisis management during an ED visit. We will use purposive sampling to ensure the full spectrum of perspectives until we reach thematic saturation. Next, under aim 2, the study will conduct a pilot, randomised controlled trial of ED-TREAT at two adult ED sites in a regional health system in the Northeast USA to evaluate the feasibility, fidelity and bedside acceptability of ED-TREAT. We aim to recruit a total of at least 26 eligible subjects under the pilot trial.Ethics and dissemination Ethical approval by the Yale University Human Investigation Committee was obtained in 2021 (HIC# 2000030893 and 2000030906). All participants will provide informed verbal consent prior to being enrolled in the study. Results will be disseminated through publications in open-access, peer-reviewed journals, via scientific presentations or through direct email notifications.Trial registration number NCT04959279; Pre-results.

Abstract It is vital to determine how patient characteristics that precede COVID-19 illness relate to COVID-19 mortality. This is a retrospective cohort study of patients hospitalized with COVID-19 across 21 healthcare systems in the US. All patients (N = 145,944) had COVID-19 diagnoses and/or positive PCR tests and completed their hospital stays from February 1, 2020 through January 31, 2022. Machine learning analyses revealed that age, hypertension, insurance status, and healthcare system (hospital site) were especially predictive of mortality across the full sample. However, multiple variables were especially predictive in subgroups of patients. The nested effects of risk factors such as age, hypertension, vaccination, site, and race accounted for large differences in mortality likelihood with rates ranging from about 2–30%. Subgroups of patients are at heightened risk of COVID-19 mortality due to combinations of preadmission risk factors; a finding of potential relevance to outreach and preventive actions.

Introduction: Race-, ethnicity-, and rurality-related disparities in COVID-19 vaccine uptake have been documented in the U.S. We determined whether these disparities existed among patients at the Department of Veterans Affairs, the largest healthcare system in the U.S. Methods: Using Department of Veterans Affairs Corporate Data Warehouse data, we included 5,871,438 patients (9.4% women) with at least 1 primary care visit in 2019 in a retrospective cohort study. Each patient was assigned a single race and ethnicity, which were mutually exclusive, self-reported categories. Rurality was based on the 2019 home address at the ZIP code level. Our primary outcome was time to first COVID-19 vaccination between December 15, 2020 and June 15, 2021. Additional covariates included age (in years), sex, geographic region (North Atlantic, Midwest, Southeast, Pacific, continental), smoking status (current, former, never), Charlson Comorbidity Index (based on ≥1 inpatient or 1 outpatient International Classification of Diseases codes), service connection (any/none, using standardized Department of Veterans Affairs cut offs for disability compensation), and influenza vaccination in 2019–2020 (yes/no). Results: Compared with unvaccinated patients, those vaccinated (n=3,238,532; 55.2%) were older (mean age in years vaccinated=66.3 [SD=14.4] vs unvaccinated=57.7 [18.0], p

Objective: Health behavior is an important determinant of health. Adherence to medication and abstinence from harmful substances are two critical health behaviors. Although conceptually related, both are assessed using disparate measures. The goal of this study was to develop and test a new index, gamma, which models health behavior by quantifying the connectedness of discrete incidents of health behavior. Study design and setting: We derive gamma from first principles and use it to reanalyze data from a published trial of treatment for alcohol use disorders. We model a primary endpoint, changes in binge drinking, using gamma and a traditional measure: change in number of monthly binges. The original trial was conducted in an urban hospital emergency department in the U.S. Results: Incorporating gamma into the model provided additional insights into the relationship between the intervention and long-term changes in drinking. Conclusion: Gamma provides an additional tool to model the effects of interventions on outcomes in trials of substance use interventions or medication adherence. Gamma measures the pattern of behavior and may increase the explanatory power of models assessing differences between various treatments. The gamma index offers the possibility of novel real-time interventions to promote healthy behaviors.

We evaluated whether inhibiting sterile alpha and (Toll/interleukin receptor (TIR)) motif-containing 1 (SARM1) activity protects retinal ganglion cells (RGCs) following ischemic axonopathy (rodent nonarteritic anterior ischemic optic neuropathy: rNAION) by itself and combined with ciliary neurotrophic factor (CNTF). Genetically modified SARM1(−) rats were rNAION-induced in one eye and compared against equivalently induced wild-type animals of the same background. Optic nerve (ON) diameters were quantified using optical coherence tomography (SD-OCT). RGCs were quantified 30 d post-induction using retinal stereology for Brn3a(+) nuclei. ON sections were analyzed by TEM and immunohistochemistry. SARM1(−)(−) and WT animals were then bilaterally sequentially rNAION-induced. One eye received intravitreal vehicle injection following induction; the contralateral side received CNTF and was analyzed 30 d post-induction. Inhibiting SARM1 activity suppressed axonal collapse following ischemic axonopathy. SARM1(−) animals significantly reduced RGC loss, compared with WT animals (49.4 ± 6.8% RGC loss in SARM1(−) vs. 63.6 ± 3.2% sem RGC loss in WT; Mann–Whitney one-tailed U-test, (p = 0.049)). IVT-CNTF treatment vs. IVT-vehicle in SARM1(−) animals further reduced RGC loss by 24% at 30 d post-induction, but CNTF did not, by itself, improve long-term RGC survival in WT animals compared with vehicle (Mann–Whitney one-tailed t-test; p = 0.033). While inhibiting SARM1 activity is itself neuroprotective, combining SARM1 inhibition and CNTF treatment generated a long-term, synergistic neuroprotective effect in ischemic neuropathy. Combinatorial treatments for NAION utilizing independent neuroprotective mechanisms may thus provide a greater effect than individual treatment modalities.

Abstract Breast tissue enhances on contrast MRI and is called background parenchymal enhancement (BPE). Having high BPE has been associated with an increased risk of breast cancer. We examined the relationship between BPE and the amount of fibroglandular tissue on MRI (MRI-FGT) and breast cancer risk factors. This was a cross-sectional study of 415 women without breast cancer undergoing contrast-enhanced breast MRI at Memorial Sloan Kettering Cancer Center. All women completed a questionnaire assessing exposures at the time of MRI. Prevalence ratios (PR) and 95% confidence intervals (CI) describing the relationship between breast cancer risk factors and BPE and MRI-FGT were generated using modified Poisson regression. In multivariable-adjusted models a positive association between body mass index (BMI) and BPE was observed, with a 5-unit increase in BMI associated with a 14% and 44% increase in prevalence of high BPE in pre- and post-menopausal women, respectively. Conversely, a strong inverse relationship between BMI and MRI-FGT was observed in both pre- (PR = 0.66, 95% CI 0.57, 0.76) and post-menopausal (PR = 0.66, 95% CI 0.56, 0.78) women. Use of preventive medication (e.g., tamoxifen) was associated with having low BPE, while no association was observed for MRI-FGT. BPE is an imaging marker available from standard contrast-enhanced MRI, that is influenced by endogenous and exogenous hormonal exposures in both pre- and post-menopausal women.

Abstract To evaluate whether mammographic texture features were associated with second primary contralateral breast cancer (CBC) risk, we created a “texture risk score” using pre-treatment mammograms in a case–control study of 212 women with CBC and 223 controls with unilateral breast cancer. The texture risk score was associated with CBC (odds per adjusted standard deviation = 1.25, 95% CI 1.01–1.56) after adjustment for mammographic percent density and confounders. These results support the potential of texture features for CBC risk assessment of breast cancer survivors.

Age-related macular degeneration (AMD) has been connected to deficits in autophagy. Here, the authors demonstrate, in mice and dry-AMD patient samples, that calcium and integrin binding protein 2 (CIB2) regulates Rheb-mTORC1 signaling axis, and subsequently autophagy.

Objective: To examined the impact of reproductive factors on the relationship between radiation treatment (RT) for a first breast cancer and risk of contralateral breast cancer (CBC). Methods: The Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study is a multi-center, population-based case-control study where cases are women with asynchronous CBC (N = 1521) and controls are women with unilateral breast cancer (N = 2211). Rate ratios (RR) and 95% confidence intervals (CI) were estimated using conditional logistic regression to assess the independent and joint effects of RT (ever/never and location-specific stray radiation dose to the contralateral breast [0, >0-

Abstract Background Background parenchymal enhancement (BPE) on breast magnetic resonance imaging (MRI) may be associated with breast cancer risk, but previous studies of the association are equivocal and limited by incomplete blinding of BPE assessment. In this study, we evaluated the association between BPE and breast cancer based on fully blinded assessments of BPE in the unaffected breast. Methods The Imaging and Epidemiology (IMAGINE) study is a multicenter breast cancer case-control study of women receiving diagnostic, screening, or follow-up breast MRI, recruited from three comprehensive cancer centers in the USA. Cases had a first diagnosis of unilateral breast cancer and controls had no history of or current breast cancer. A single board-certified breast radiologist with 12 years’ experience, blinded to case-control status and clinical information, assessed the unaffected breast for BPE without view of the affected breast of cases (or the corresponding breast laterality of controls). The association between BPE and breast cancer was estimated by multivariable logistic regression separately for premenopausal and postmenopausal women. Results The analytic dataset included 835 cases and 963 controls. Adjusting for fibroglandular tissue (breast density), age, race/ethnicity, BMI, parity, family history of breast cancer, BRCA1/BRCA2 mutations, and other confounders, moderate/marked BPE (vs minimal/mild BPE) was associated with breast cancer among premenopausal women [odds ratio (OR) 1.49, 95% CI 1.05–2.11; p = 0.02]. Among postmenopausal women, mild/moderate/marked vs minimal BPE had a similar, but statistically non-significant, association with breast cancer (OR 1.45, 95% CI 0.92–2.27; p = 0.1). Conclusions BPE is associated with breast cancer in premenopausal women, and possibly postmenopausal women, after adjustment for breast density and confounders. Our results suggest that BPE should be evaluated alongside breast density for inclusion in models predicting breast cancer risk.

Objectives Agitation, defined as excessive psychomotor activity leading to aggressive or violent behaviour, is prevalent in the emergency department (ED) due to rising behavioural-related visits. Experts recommend use of verbal de-escalation and avoidance of physical restraint to manage agitation. However, bedside applications of these recommendations may be limited by system challenges in emergency care. This qualitative study aims to use a systems-based approach, which considers the larger context and system of healthcare delivery, to identify sociotechnical, structural, and process-related factors leading to agitation events and physical restraint use in the ED.Design Qualitative study using a grounded theory approach to triangulate interviews of patients who have been physically restrained with direct observations of agitation events.Setting Two EDs in the Northeast USA, one at a tertiary care academic centre and the other at a community-based teaching hospital.Participants We recruited 25 individuals who experienced physical restraint during an ED visit. In addition, we performed 95 observations of clinical encounters of agitation events on unique patients. Patients represented both behavioural (psychiatric, alcohol/drug use) and non-behavioural (medical, trauma) chief complaints.Results Three primary themes with implications for systems-based practice of agitation events in the ED emerged: (1) pathways within health and social systems; (2) interpersonal contexts as reflections of systemic stressors on behavioural emergency care and (3) systems-based and patient-oriented strategies and solutions.Conclusions Agitation events represented manifestations of patients’ structural barriers to care from socioeconomic inequities and high burden of emotional and physical trauma as well as staff members’ simultaneous exposure to external stressors from social and healthcare systems. Potential long-term solutions may include care approaches that recognise agitated patients’ exposure to psychological trauma, improved coordination within the mental health emergency care network, and optimisation of physical environment conditions and organisational culture.

Objective: To evaluate the effect of a multi-component intervention including communication training on provider beliefs and recommendation practices around the human papillomavirus (HPV) vaccine using both self-reports and audio-recordings of clinical interactions. Methods: We conducted a mixed method study at five family medicine and pediatric practices. Providers self-reported beliefs and practices about HPV vaccination via surveys and qualitative interviews conducted pre- and post-intervention. We also assessed provider recommendation style using audio-recordings of clinical interactions pre- and post-intervention. Content analysis was used to identify themes in qualitative interviews. Matched pre- and post-intervention surveys were analyzed for changes in provider beliefs and attitudes. Pre- and post-intervention audio recordings of clinical interactions were analyzed for observed differences in recommendation styles. Bivariate analyses of quantitative data used Chi-square and Fisher’s exact tests; t-tests were used for continuous variables. Results: Providers reported in interviews that the intervention led to communication changes by increasing their knowledge, reframing the HPV vaccine as a routine vaccination, and providing tools for engaging with parents. Surveys indicated that the proportion of providers reporting that the HPV vaccine is one of the most important adolescent vaccines increased from 71% pre-intervention to 100% post-intervention (p = .03). Audio-recording analysis demonstrated that use of an indicated (presumptive) recommendation style increased from 62.5% pre-intervention to 79.6% post-intervention (p = .047). Conclusions: Educating providers about HPV vaccination and giving them tools to facilitate communication with parents can reframe HPV as a routine adolescent vaccination and motivate providers to routinely use effective recommendation styles in practice.

Abstract Background While stakeholder mapping is common in public policy, social sciences, and business management, this tool has not often been used in healthcare settings. We developed a new method of healthcare stakeholder mapping, which we call Contextual and Organizational Support Mapping of Stakeholders (COSMOS), to identify and assess key stakeholders in an implementation project. Stakeholder mapping allows the implementation team to assess and visually display all relevant stakeholders, their support for the project, and their ability to facilitate—or hinder—project implementation. Methods The COSMOS model was developed to visualize the stakeholders involved in a hospital-based study conducted from 2013–2016. In this study, a new screen prompt and order set were embedded in the electronic health record to facilitate the identification and treatment of adult smokers admitted to the hospital. Physicians were the unit of randomization; physician behavior and tobacco quit rates among patients were followed for 1 year. Qualitative interviews with hospital administration, physicians, and information technology (IT) personnel (n=24) were conducted to identify the components and characteristics of the COSMOS. Results The COSMOS consists of an organizational chart identifying all key stakeholders, with manipulation of colors and borders of the component boxes to indicate stakeholder support for the implementation project, and degree of criticality to its success. The COSMOS visualization informed the team’s subsequent work by identifying potential impediments that might require additional attention to garner and maintain support throughout the project. In addition, the approach has proved to be a useful tool to explain these concepts to trainees in implementation science. Conclusion The COSMOS schematic provides a visually rich means of identifying stakeholders, understanding their relationships to each other, displaying their level of support for the proposed implementation, and noting their criticality to the effort. The COSMOS can support researchers, project teams, administrators, and others engaged with implementation science-related work in healthcare, as well as other fields such as education, government, and industry.

Main objectiveThere is limited information on how patient outcomes have changed during the COVID-19 pandemic. This study characterizes changes in mortality, intubation, and ICU admission rates during the first 20 months of the pandemic.Study design and methodsUniversity of Wisconsin researchers collected and harmonized electronic health record data from 1.1 million COVID-19 patients across 21 United States health systems from February 2020 through September 2021. The analysis comprised data from 104,590 adult hospitalized COVID-19 patients. Inclusion criteria for the analysis were: (1) age 18 years or older; (2) COVID-19 ICD-10 diagnosis during hospitalization and/or a positive COVID-19 PCR test in a 14-day window (+/- 7 days of hospital admission); and (3) health system contact prior to COVID-19 hospitalization. Outcomes assessed were: (1) mortality (primary), (2) endotracheal intubation, and (3) ICU admission.Results and significanceThe 104,590 hospitalized participants had a mean age of 61.7 years and were 50.4% female, 24% Black, and 56.8% White. Overall risk-standardized mortality (adjusted for age, sex, race, ethnicity, body mass index, insurance status and medical comorbidities) declined from 16% of hospitalized COVID-19 patients (95% CI: 16% to 17%) early in the pandemic (February-April 2020) to 9% (CI: 9% to 10%) later (July-September 2021). Among subpopulations, males (vs. females), those on Medicare (vs. those on commercial insurance), the severely obese (vs. normal weight), and those aged 60 and older (vs. younger individuals) had especially high mortality rates both early and late in the pandemic. ICU admission and intubation rates also declined across these 20 months.ConclusionsMortality, intubation, and ICU admission rates improved markedly over the first 20 months of the pandemic among adult hospitalized COVID-19 patients although gains varied by subpopulation. These data provide important information on the course of COVID-19 and identify hospitalized patient groups at heightened risk for negative outcomes.Trial registrationClinicalTrials.gov Identifier: NCT04506528 (https://clinicaltrials.gov/ct2/show/NCT04506528).

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of sudden optic nerve (ON)-related vision loss in humans. Study of this disease has been limited by the lack of available tissue and difficulties in evaluating both treatments and the window of effectiveness after symptom onset. The rodent nonarteritic anterior ischemic optic neuropathy model (rNAION) closely resembles clinical NAION in its pathophysiological changes and physiological responses. The rNAION model enables analysis of the specific responses to sudden ischemic axonopathy and effectiveness of potential treatments. However, there are anatomic and genetic differences between human and rodent ON, and the inducing factors for the disease and the model are different. These variables can result in marked differences in lesion development between the two species, as well as in the possible responses to various treatments. These caveats are discussed in the current article, as well as some of the species-associated differences that may be related to ischemic lesion severity and responses.

Introduction: Point-of-care ultrasound (POCUS) is a powerful clinical tool that has seen widespread adoption, including in Internal Medicine (IM), yet standardized curricula designed by trained faculty are scant. To address the demand for POCUS education at our institution, we created a resident-championed curriculum with support from skilled faculty across multiple specialties. Our objective was to teach postgraduate year (PGY)-3 IM residents the basics of POCUS for evaluation of the pulmonary, cardiac, and abdominal systems through resident-developed workshops. The goal of acquisition of these skills was for resident education and to inform decisions to pursue further patient testing. Methods: Three half-day workshops were created to teach residents how to obtain and interpret ultrasound images of the pulmonary, cardiac, and abdominal systems. Workshops were comprised of didactic teaching and practical ultrasound instruction with expert supervision of clinicians within and outside of IM. Residents were asked to complete a written survey before and after each workshop to assess confidence, knowledge, and likelihood of future POCUS use. Results: Across the three workshops (pulmonary, cardiac, and abdominal), 66 sets of pre- and post-workshop surveys (32 pulmonary, 25 cardiac, and 9 abdominal) were obtained and analyzed. Confidence in and knowledge regarding POCUS use increased significantly across all three workshops. Likelihood of future use increased in the cardiac workshop. Conclusions: We implemented a resident-championed POCUS curriculum that led to improved attitudes and increased knowledge of POCUS for PGY-3 IM residents.

Introduction Continued smoking following a cancer diagnosis has substantial health risks including increased overall and cancer-specific mortality, risk of secondary malignancies, cancer treatment toxicity and risk of surgical complications. These risks can be mitigated by quitting smoking. The preoperative period represents a prime opportunity in which to administer robust smoking cessation treatment to both improve health and support and improve surgical outcomes. We will conduct a randomised clinical trial to evaluate the effectiveness of financial incentives delivered contingent on biochemically verified smoking abstinence (contingency management (CM)) in patients with cancer undergoing surgery.Methods and analysis The study will take place across two study sites, and participants (N=282) who smoke, are diagnosed with or suspected to have any type of operable cancer and have a surgical procedure scheduled in the next 10 days to 5 weeks will be randomised to receive standard care plus Monitoring Only or CM prior to surgery. All patients will receive breath carbon monoxide (CO) tests three times per week, nicotine replacement therapy and counselling. The CM group will also earn payments for self-reported smoking abstinence confirmed by CO breath test ≤4 ppm on an escalating schedule of reinforcement (with a reset if they smoked). Point prevalence abstinence (PPA) outcomes (self-report of 7-day abstinence confirmed by CO≤4 ppm and/or anabasine ≤2 ng/mL) will be assessed on the day of surgery and 6 months after surgery. The effect of CM on 7-day PPA at the time of surgery and 6-month follow-up will be modelled using generalised linear mixed effects models.Ethics and dissemination This study has been reviewed and approved by the Medical University of South Carolina Institutional Review Board. We will disseminate our scientific results through traditional research-oriented outlets such as presentations at scientific meetings and publications in peer-reviewed journals.Trial registration number NCT04605458.

Abstract Background Dexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose doxorubicin is unknown. Methods We evaluated children with osteosarcoma (OS) on two Children’s Oncology Group trials with higher dose doxorubicin (375–600 mg/m2) preceded by dexrazoxane (10:1 dexrazoxane:doxorubicin dosing). They were evaluated after the minimum expected treatment time (METT), defined as 28 weeks. Cardiotoxicity was identified by echocardiography and serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Second malignant neoplasm (SMN) data was collected. Results All children had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. The end-diastolic septal thickness Z-scores (P

Abstract Tobacco use is a chronic relapsing disease, and remains the leading cause of preventable death in much of the world. Increasingly, tobacco use, chiefly cigarette smoking, is being framed as a chronic disease, with periods of use and periods of abstinence. An implicit component of this conceptualization is that treatment—both counseling and pharmacotherapy—may be needed at various intervals for extended periods of time, perhaps over an individual’s lifetime. This would mirror the treatment of other chronic conditions, such as diabetes, hypertension, or hyperlipidemia. Yet, clinical trials of tobacco dependence treatment still generally model outcome measures in terms of cessation, abstinence, or quitting, measured at discrete time points. This reinforces the notion that smoking, or tobacco dependence, is a dichotomous condition, and that one is either “cured,” or not. Although the goal of treating tobacco dependence is to ensure long-term abstinence (i.e. “quitting”), this model is discordant with clinical reality, in which of periods of tobacco use are interspersed with periods of abstinence. Hence, the goal of treatment is to lengthen the duration of the latter, while shortening the duration of the former. In the clinical arena, this dichotomous model of tobacco use is reflected in electronic health records, where smoking is generally categorized as current, former, or never. We propose that clinicians move away from the dichotomous categorization of tobacco use, and adopt methods used to categorize the status of other chronic conditions. Specifically, biomarkers such as carbon monoxide, cotinine, and anabasine, measured at regular intervals, can provide clinicians with much clearer, clinically relevant and actionable assessments of current tobacco use by their patients. This can be done without making reference to dichotomous states such as current or former use of tobacco. In psychological terms, one can frame tobacco use in terms of states, attributes in specific situations at discrete moments in time, rather than the more durable traits.

Abstract Background Smokers usually abstain from tobacco while hospitalized but relapse after discharge. Inpatient interventions may encourage sustained quitting. We previously demonstrated that a decision support tool embedded in an electronic health record (EHR) improved physicians’ treatment of hospitalized smokers. This report describes the effect on quit rates of this decision support tool and order set for hospitalized smokers. Methods In a single hospital system, 254 physicians were randomized 1:1 to receive a decision support tool and order set, embedded in the EHR. When an adult patient was admitted to a medical service, an electronic alert appeared if current smoking was recorded in the EHR. For physicians receiving the intervention, the alert linked to an order set for tobacco treatment medications and electronic referral to the state tobacco quitline. Additionally, “Tobacco Use Disorder” was added to the patient’s problem list, and a secure message was sent to the patient’s primary care provider (PCP). In the control arm, no alert appeared. Patients were contacted by phone at 1, 6, and 12 months; those reporting tobacco abstinence at 12 months were asked to return to measure exhaled carbon monoxide. Generalized estimating equations were used to model the data. Results From 2013 to 2016, the alert fired for 10,939 patients (5391 intervention, 5548 control). Compared to control physicians, intervention physicians were more likely to order tobacco treatment medication, populate the problem list with tobacco use disorder, refer to the quitline, and notify the patient’s PCP. In a subset of 1044 patients recruited for intensive follow-up, one-year quit rates for intervention and control patients were, respectively, 11.5% and 11.6%, (p = 0.94), after controlling for age, sex, race, ethnicity, and insurance. Similarly, there were no differences in 1- and 6-month quit rates. Conclusions Although we were able to improve processes of care, long-term tobacco quit rates were unchanged. This likely reflects, in part, the need for sustained quitting interventions, and higher-than-expected quit rates in controls. Future enhancements should improve prescription of medications for smoking cessation at discharge, engagement of primary care providers, and perhaps direct engagement of patients in a more longitudinal approach. Trial registration ClinicalTrials.gov, NCT01691105. Registered on September 12, 2012

Abstract Background Tobacco smoking is the leading cause of cancer, preventable death, and disability. Smoking cessation can increase life expectancy by nearly a decade if achieved in the third or fourth decades of life. Various stop smoking interventions are available including pharmacotherapies, electronic cigarettes, behavioural support, and alternative therapies. This protocol outlines an evidence review which will evaluate the benefits and harms of stop smoking interventions in adults. Methods The evidence review will consist of two stages. First, an overview of systematic reviews evaluating the benefits and harms of various stop smoking interventions delivered in or referred from the primary care setting will be conducted. The second stage will involve updating a systematic review on electronic cigarettes identified in the overview; randomized controlled trials will be considered for outcomes relating to benefits while randomized controlled trials, non-randomized controlled trials, and comparative observational studies will be considered for evaluating harms. Search strategies will be developed and peer-reviewed by medical information specialists. The search strategy for the updated review on e-cigarettes will be developed using that of the candidate systematic review. The MEDLINE®, PsycINFO, Embase, and the Cochrane Library electronic databases will be searched as of 2008 for the overview of reviews and from the last search date of the selected review for the updated review. Organizational websites and trial registries will be searched for unpublished or ongoing reviews/studies. Two reviewers will independently screen the title and abstracts of citations using the liberal accelerated method. Full-text screening will be performed independently by two reviewers. Extracted data will be verified by a second reviewer. Disagreements regarding full-text screening and data extraction will be resolved by consensus or third-party adjudication. The methodological quality of systematic reviews, risk of bias of randomized and non-randomized trials, and methodological quality of cohort studies will be evaluated using AMSTAR 2, the Cochrane risk of bias tool, and a modified version of the Scottish Intercollegiate Guidelines Network critical appraisal tool, respectively. The GRADE framework will be used to assess the quality of the evidence for outcomes. Discussion The evidence review will evaluate the benefits and harms of various stop smoking interventions for adults. Findings will be used to inform a national tobacco cessation guideline by the Canadian Task Force on Preventive Health Care. Systematic review registration PROSPERO (CRD42018099691, CRD42018099692)

Abstract Background Tamoxifen treatment greatly reduces a woman’s risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown. Methods Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5–0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS. Results Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20–55% reduced RR of CBC (AS = 2, RR = – 0.81, 95% CI 0.62–1.06; AS = 1.5, RR = 0.45, 95% CI 0.30–0.68; and AS = 1, RR = 0.55, 95% CI 0.40–0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59–1.96; and AS = 0, RR = 1.17, 95% CI 0.58–2.35) (p for homogeneity = – 0.02). Conclusion This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC.

BackgroundThe functions of most glioma risk alleles are unknown. Very few studies had evaluated expression quantitative trait loci (eQTL), and insights of susceptibility genes were limited due to scarcity of available brain tissues. Moreover, no prior study had examined the effect of glioma risk alleles on alternative RNA splicing.ObjectiveThis study explored splicing quantitative trait loci (sQTL) as molecular QTL and improved the power of QTL mapping through meta-analyses of both cis eQTL and sQTL.MethodsWe first evaluated eQTLs and sQTLs of the CommonMind Consortium (CMC) and Genotype-Tissue Expression Project (GTEx) using genotyping, or whole-genome sequencing and RNA-seq data. Alternative splicing events were characterized using an annotation-free method that detected intron excision events. Then, we conducted meta-analyses by pooling the eQTL and sQTL results of CMC and GTEx using the inverse variance-weighted model. Afterward, we integrated QTL meta-analysis results (Q < 0.05) with the Glioma International Case Control Study (GICC) GWAS meta-analysis (case:12,496, control:18,190), using a summary statistics-based mendelian randomization (SMR) method.ResultsBetween CMC and GTEx, we combined the QTL data of 354 unique individuals of European ancestry. SMR analyses revealed 15 eQTLs in 11 loci and 32 sQTLs in 9 loci relevant to glioma risk. Two loci only harbored sQTLs (1q44 and 16p13.3). In seven loci, both eQTL and sQTL coexisted (2q33.3, 7p11.2, 11q23.3 15q24.2, 16p12.1, 20q13.33, and 22q13.1), but the target genes were different for five of these seven loci. Three eQTL loci (9p21.3, 20q13.33, and 22q13.1) and 4 sQTL loci (11q23.3, 16p13.3, 16q12.1, and 20q13.33) harbored multiple target genes. Eight target genes of sQTLs (C2orf80, SEC61G, TMEM25, PHLDB1, RP11-161M6.2, HEATR3, RTEL1-TNFRSF6B, and LIME1) had multiple alternatively spliced transcripts.ConclusionOur study revealed that the regulation of transcriptome by glioma risk alleles is complex, with the potential for eQTL and sQTL jointly affecting gliomagenesis in risk loci. QTLs of many loci involved multiple target genes, some of which were specific to alternative splicing. Therefore, quantitative trait loci that evaluate only total gene expression will miss many important target genes.

The rodent model of nonarteritic anterior ischemic optic neuropathy (rNAION) is similar in many of its pathophysiological responses to clinical NAION. Like human NAION, there is significant variability in the severity of the lesion produced, and little is known of the parameters associated with rNAION induction severity or if pre- or early post-induction biomarkers can be identified that enable prediction of lesion severity and ultimate loss of retinal ganglion cells (RGCs). Adult male Sprague-Dawley outbred rats were evaluated for various parameters including physiological characteristics (heart rate, respiratory rate, temperature, hematocrit [Hct]), optic nerve head (ONH) appearance, pre- and post-induction mean diameter, and intravenous fluorescein and indocyanine green angiographic patterns of vascular leakage at 5 hours post-induction, performed using a spectral domain-optical coherence tomography (SD-OCT) instrument. Early changes were correlated with ultimate RGC loss by Brn3a (+) immunohistology. RGC loss also was correlated with the relative level of laser exposure. The severity of ONH edema 2d, but not 5hr, post induction was most closely associated with the degree of RGC loss, revealing a threshold effect, and consistent with a compartment syndrome where a minimum level of capillary compression within a tight space is responsible for damage. RGC loss increased dramatically as the degree of laser exposure increased. Neither physiological parameters nor the degree of capillary leakage 5hr post induction were informative as to the ultimate degree of RGC loss. Similar to human NAION, the rNAION model exhibits marked variability in lesion severity. Unlike clinical NAION, pre-induction ONH diameter likely does not contribute to ultimate lesion severity; however, cross-sectional ONH edema can be used as a biomarker 2d post-induction to determine randomization of subjects prior to inclusion in specific neuroprotection or neuroregeneration studies.

Stroke is a debilitating illness facing healthcare today, affecting over 800,000 people and causing over 140,000 deaths each year in the United States. Despite being the third-leading cause of death, very few treatments currently exist for stroke. Often, during an ischemic attack, the blood-brain barrier (BBB) is significantly damaged, which can lead to altered interactions with the immune system, and greatly worsen the damage from a stroke. The impaired, BBB promotes the infiltration of peripheral inflammatory cells into the brain, secreting deleterious mediators (cytokines/chemokines) and resulting in permanent barrier injury. let-7 microRNAs (miRs) are critical for regulating immune responses within the BBB, particularly after ischemic stroke. We have previously shown how transient stroke decreases expression of multiple let-7 miRs, and that restoration of expression confers significant neuroprotection, reduction in brain infiltration by neutrophils, monocytes and T cells. However, the specific mechanisms of action of let-7 miRs remain unexplored, though emerging evidence implicates a range of impacts on cytokines. In the current study, we evaluate the impacts of miR-98 and let-7g* on targeting of cytokine mRNAs, cytokine release following ischemic stroke, and cell-specific changes to the neurovascular space. We determined that miR-98 specifically targets IP-10, while let-7g* specifically aims IL-8, and attenuates their levels. Both produce strong impacts on CCL2 and CCL5. Further, let-7g* strongly improves neurovascular perfusion following ischemic stroke. Together, the results of the study indicate that let-7 miRs are critical for mediating endothelial-immune reactions and improving recovery following ischemic stroke.

Introduction Emergency department (ED) visits for behavioural conditions are rising, with 1.7 million associated episodes of patient agitation occurring annually in acute care settings. When de-escalation techniques fail during agitation management, patients are subject to use of physical restraints and sedatives, which are associated with up to 37% risk of hypotension, apnoea and physical injuries. At the same time, ED staff report workplace violence due to physical assaults during agitation events. We recently developed a theoretical framework to characterise ED agitation, which identified teamwork as a critical component to reduce harm. Currently, no structured team response protocol for ED agitation addressing both patient and staff safety exists.Methods and analysis Our proposed study aims to develop and implement the agitation code team (ACT) response intervention, which will consist of a standardised, structured process with defined health worker roles/responsibilities, work processes and clinical protocols. First, we will develop the ACT response intervention in a two-step design loop; conceptual design will engage users in the creation of the prototype, and iterative refinement will occur through in situ simulated agitated patient encounters in the ED to assess and improve the design. Next, we will pilot the intervention in the clinical environment and use a controlled interrupted time series design to evaluate its effect on our primary outcome of patient restraint use. The intervention will be considered efficacious if we effectively lower the rate of restraint use over a 6-month period.Ethics and dissemination Ethical approval by the Yale University Human Investigation Committee was obtained in 2019 (HIC #2000025113). Results will be disseminated through peer-reviewed publications and presentations at scientific meetings for each phase of the study. If this pilot is successful, we plan to formally integrate the ACT response intervention into clinical workflows at all EDs within our entire health system.

Tobacco cessation after cancer diagnosis leads to better patient outcomes. However, tobacco treatment services are frequently unavailable in cancer care settings, and multilevel implementation challenges can impede uptake of new programs. The National Cancer Institute (NCI) dedicated Cancer Moonshot funding through the Cancer Center Cessation Initiative (C3I) for NCI-Designated Cancer Centers to implement or enhance the implementation of tobacco treatment services. We examined a pragmatic application of the RE-AIM framework (reach, effectiveness, adoption, implementation, and maintenance) to evaluate tobacco treatment programs implemented within Cancer Centers funded through C3I. Using three C3I-funded Centers as examples, we describe how each RE-AIM construct was operationalized to evaluate the implementation of a wide range of cessation services (e.g., tobacco use screening, counseling, Quitline referral, pharmacotherapy) in this heterogeneous group of cancer care settings. We discuss the practical challenges encountered in assessing RE-AIM constructs in real world situations, including using the electronic health record (EHR) to aid in assessment. Reach and effectiveness evaluation required that Centers define the setting(s) where cessation services were implemented (to determine the “denominator”), enumerate the patient population, report current patient tobacco use, patient engagement in tobacco treatment, and 6-month cessation outcomes. To reduce site heterogeneity, increase data accuracy, and reduce burden, reach was frequently captured via standardized EHR enhancements that improved the identification of current smokers and tobacco treatment referrals. Effectiveness was determined by cessation outcomes (30-day point prevalence abstinence at 6-months post-engagement) assessed through a variety of data collection approaches. Adoption was measured by the characteristics and proportion of targeted cancer care settings and clinicians engaged in cessation service delivery. Implementation was assessed by examining the delivery of tobacco screening assessments and intervention components across sites, and provider-level implementation consistency. Maintenance assessments identified whether tobacco treatment services continued in the setting after implementation and documented the sustainability plan and organizational commitment to continued delivery. In sum, this paper demonstrates a pragmatic approach to using RE-AIM as an evaluation framework that yields relevant outcomes on common implementation metrics across widely differing tobacco treatment approaches and settings.

The purpose of this study was to identify germline single nucleotide polymorphisms (SNPs) that optimally predict radiation-associated contralateral breast cancer (RCBC) and to provide new biological insights into the carcinogenic process. Fifty-two women with contralateral breast cancer and 153 women with unilateral breast cancer were identified within the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study who were at increased risk of RCBC because they were ≤ 40 years of age at first diagnosis of breast cancer and received a scatter radiation dose > 1 Gy to the contralateral breast. A previously reported algorithm, preconditioned random forest regression, was applied to predict the risk of developing RCBC. The resulting model produced an area under the curve (AUC) of 0.62 (p = 0.04) on hold-out validation data. The biological analysis identified the cyclic AMP-mediated signaling and Ephrin-A as significant biological correlates, which were previously shown to influence cell survival after radiation in an ATM-dependent manner. The key connected genes and proteins that are identified in this analysis were previously identified as relevant to breast cancer, radiation response, or both. In summary, machine learning/bioinformatics methods applied to genome-wide genotyping data have great potential to reveal plausible biological correlates associated with the risk of RCBC.

A broad consensus exists that the use of appropriate methods are important in the Scholarship of Teaching and Learning. However, methodological controversies arise around what constitutes acceptable evidence, if one needs a control group, how generalizable results must be, and other similar issues. Much SoTL work, I argue, asks questions about how much a particular treatment (innovation) caused an effect (student learning), and how the results found in one particular context can be extended outside that context (generalizability). These concepts, known as internal validity and external validity, respectively, provide a common point of departure for much scholarship on teaching and learning. This paper addresses these concepts and demonstrates how they can unite much of what divides us within the methodological realm of SoTL.

Abstract Incidence of glioma is approximately 50% higher in males. Previous analyses have examined exposures related to sex hormones in women as potential protective factors for these tumors, with inconsistent results. Previous glioma genome-wide association studies (GWAS) have not stratified by sex. Potential sex-specific genetic effects were assessed in autosomal SNPs and sex chromosome variants for all glioma, GBM and non-GBM patients using data from four previous glioma GWAS. Datasets were analyzed using sex-stratified logistic regression models and combined using meta-analysis. There were 4,831 male cases, 5,216 male controls, 3,206 female cases and 5,470 female controls. A significant association was detected at rs11979158 (7p11.2) in males only. Association at rs55705857 (8q24.21) was stronger in females than in males. A large region on 3p21.31 was identified with significant association in females only. The identified differences in effect of risk variants do not fully explain the observed incidence difference in glioma by sex.

Abstract Background Mammographic density (MD) is an established predictor of risk of a first breast cancer, but the relationship of MD to contralateral breast cancer (CBC) risk is not clear, including the roles of age, mammogram timing, and change with treatment. Multivariable prediction models for CBC risk are needed and MD could contribute to these. Methods We conducted a case-control study of MD and CBC risk in phase II of the WECARE study where cases had a CBC diagnosed ≥ 2 years after first diagnosis at age

Abstract Background An inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. Methods Two-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis. Results Under IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93–1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94–0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91–1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92–1.02, P = 0.194). Conclusions Our investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions.

Abstract Background In fructose 1,6 bisphosphatase (FBPase) deficiency, management aims to prevent hypoglycaemia and lactic acidosis by avoiding prolonged fasting, particularly during febrile illness. Although the need for an emergency regimen to avoid metabolic decompensation is well established at times of illness, there is uncertainty about the need for other dietary management strategies such as sucrose or fructose restriction. We assessed international differences in the dietary management of FBPase deficiency. Methods A cross-sectional questionnaire (13 questions) was emailed to all members of the Society for the Study of Inborn Errors of Metabolism (SSIEM) and a wide database of inherited metabolic disorder dietitians. Results Thirty-six centres reported the dietary prescriptions of 126 patients with FBPase deficiency. Patients’ age at questionnaire completion was: 1-10y, 46% (n = 58), 11-16y, 21% (n = 27), and >16y, 33% (n = 41). Diagnostic age was: 16y, 2% (n = 2). Seventy-five per cent of centres advocated dietary restrictions. This included restriction of: high sucrose foods only (n = 7 centres, 19%); fruit and sugary foods (n = 4, 11%); fruit, vegetables and sugary foods (n = 13, 36%). Twenty-five per cent of centres (n = 9), advised no dietary restrictions when patients were well. A higher percentage of patients aged >16y rather than ≤16y were prescribed dietary restrictions: patients aged 1-10y, 67% (n = 39/58), 11-16y, 63% (n = 17/27) and >16y, 85% (n = 35/41). Patients classified as having a normal fasting tolerance increased with age from 30% in 1-10y, to 36% in 11-16y, and 58% in >16y, but it was unclear if fasting tolerance was biochemically proven. Twenty centres (56%) routinely prescribed uncooked cornstarch (UCCS) to limit overnight fasting in 47 patients regardless of their actual fasting tolerance (37%). All centres advocated an emergency regimen mainly based on glucose polymer for illness management. Conclusions Although all patients were prescribed an emergency regimen for illness, use of sucrose and fructose restricted diets with UCCS supplementation varied widely. Restrictions did not relax with age. International guidelines are necessary to help direct future dietary management of FBPase deficiency.

Background/Aims: Epigenetic regulation is considered the main molecular mechanism underlying the developmental origin of health and disease’s (DOHAD) hypothesis. Previous studies that have investigated the role of paternal exercise on the metabolic health of the offspring did not control for the amount and intensity of the training or possible effects of adaptation to exercise and produced conflicting results regarding the benefits of parental exercise to the next generation. We employed a precisely regulated exercise regimen to study the transgenerational inheritance of improved metabolic health. Methods: We subjected male mice to a well-controlled exercise -training program to investigate the effects of paternal exercise on glucose tolerance and insulin sensitivity in their adult progeny. To investigate the molecular mechanisms of epigenetic inheritance, we determined chromatin markers in the skeletal muscle of the offspring and the paternal sperm. Results: Offspring of trained male mice exhibited improved glucose homeostasis and insulin sensitivity. Paternal exercise modulated the DNA methylation profile of PI3Kca and the imprinted H19/Igf2 locus at specific differentially methylated regions (DMRs) in the skeletal muscle of the offspring, which affected their gene expression. Remarkably, a similar DNA methylation profile at the PI3Kca, H19, and Igf2 genes was present in the progenitor sperm indicating that exercise-induced epigenetic changes that occurred during germ cell development contributed to transgenerational transmission. Conclusion: Paternal exercise might be considered as a strategy that could promote metabolic health in the offspring as the benefits can be inherited transgenerationally.

ABSTRACT IMPACT: Within three EDs in a regional health system in Connecticut, African American race, male gender, non-Hispanic ethnicity, lack of private insurance, and homelessness were associated with significant odds of being physically restrained during a visit. OBJECTIVES/GOALS: Agitated patient encounters in the Emergency Department (ED) are on the rise, and physical restraints are used to protect staff and prevent self-harm. However, these are associated with safety risks and potential stigmatization of vulnerable individuals. We aim to determine factors that are associated with odds of being restrained in the ED. METHODS/STUDY POPULATION: We conducted a retrospective cohort analysis of all patients (≥18 yo) placed in restraints during an ED visit to three hospitals within a large tertiary health system from Jan 2013-Aug 2018. We undertook descriptive analysis of the data and created a generalized linear mixed model with a binary logistic identity link to model restraint use and determine odds ratios for various clinically significant demographic factors. These include gender, race, ethnicity, insurance status, alcohol use, illicit drug use, and homelessness. Our model accounted for patients nested across the three EDs and also accounted for multiple patient visits. RESULTS/ANTICIPATED RESULTS: In 726,417 total ED visits, 7,090 (1%) had associated restraint orders. Restrained patients had an average age of 45, with 64% male, 54% Caucasian and 29% African American. 17% had private insurance, 36% endorsed illicit substances, 51.4% endorsed alcohol use and 2.3% were homeless. African Americans had statistically significant odds of being restrained compared to Caucasians with adjusted odds ratio (AOR) of 1.14 (1.08,1.21). Females (AOR 0.75 [0.71, 0.79] had lower odds of being restrained compared to males while patients with Medicaid (AOR 1.57 [1.46, 1.68]) and Medicare (AOR 1.70 [1.57, 1.85]) had increased odds compared to the privately insured. Illicit substance use (AOR 1.55 [1.46, 1.64]), alcohol use (AOR 1.13 [1.07, 1.20] and homelessness (AOR 1.35 [1.14, 1.16]) had increased odds of restraint use. DISCUSSION/SIGNIFICANCE OF FINDINGS: We showed statistically significant effects of patient demographics on odds of restraint use in the ED. The increased odds based on race, insurance status, and substance use highlight the potential effects of implicit bias on the decision to physically restrain patients and underscores the importance of objective assessments of these patients.