Using implementation science to evaluate a population-wide genomic screening program: Findings from the first 20,000 In Our DNA SC participants.

We use the implementation science framework RE-AIM (reach, effectiveness, adoption, implementation, and maintenance) to describe outcomes of In Our DNA SC, a population-wide genomic screening (PWGS) program. In Our DNA SC involves participation through clinical appointments, community events, or at home collection. Participants provide a saliva sample that is sequenced by Helix, and those with a pathogenic variant or likely pathogenic variant for CDC Tier 1 conditions are offered free genetic counseling. We assessed key outcomes among the first cohort of individuals recruited. Over 14 months, 20,478 participants enrolled, and 14,053 samples were collected. The majority selected at-home sample collection followed by clinical sample collection and collection at community events. Participants were predominately female, White (self-identified), non-Hispanic, and between the ages of 40-49. Participants enrolled through community events were the most racially diverse and the youngest. Half of those enrolled completed the program. We identified 137 individuals with pathogenic or likely pathogenic variants for CDC Tier 1 conditions. The majority (77.4%) agreed to genetic counseling, and of those that agreed, 80.2% completed counseling. Twelve clinics participated, and we conducted 108 collection events. Participants enrolled at home were most likely to return their sample for sequencing. Through this evaluation, we identified facilitators and barriers to implementation of our state-wide PWGS program. Standardized reporting using implementation science frameworks can help generalize strategies and improve the impact of PWGS.

Use of a multi-phased approach to identify and address facilitators and barriers to the implementation of a population-wide genomic screening program.

INTRODUCTION: Population-wide genomic screening for CDC Tier-1 conditions offers the ability to identify the 1-2% of the US population at increased risk for Hereditary Breast and Ovarian Cancer, Lynch Syndrome, and Familial Hypercholesterolemia. Implementation of population-wide screening programs is highly complex, requiring engagement of diverse collaborators and implementation teams. Implementation science offers tools to promote integration of these programs through the identification of determinants of success and strategies to address potential barriers. METHODS: Prior to launching the program, we conducted a pre-implementation survey to assess anticipated barriers and facilitators to reach, effectiveness, adoption, implementation, and maintenance (RE-AIM), among 51 work group members (phase 1). During the first year of program implementation, we completed coding of 40 work group meetings guided by the Consolidated Framework for Implementation Research (CFIR) (phase 2). We matched the top barriers to implementation strategies identified during phase 2 using the CFIR-ERIC (Expert Recommendation for Implementing Change) matching tool. RESULTS: Staffing and workload concerns were listed as the top barrier in the pre-implementation phase of the program. Top barriers during implementation included adaptability (n = 8, 20%), complexity (n = 14, 35%), patient needs and resources (n = 9, 22.5%), compatibility (n = 11, 27.5%), and self-efficacy (n = 9, 22.5%). We identified 16 potential implementation strategies across six ERIC clusters to address these barriers and operationalized these strategies for our specific setting and program needs. CONCLUSION: Our findings provide an example of successful use of the CFIR-ERIC tool to guide implementation of a population-wide genomic screening program.

Telehealth Palliative Care in Nursing Homes: A Scoping Review.

OBJECTIVES: Many adults older than 65 spend time in a nursing home (NH) at the end of life where specialist palliative care is limited. However, telehealth may improve access to palliative care services. A review of the literature was conducted to synthesize the evidence for telehealth palliative care in NHs to provide recommendations for practice, research, and policy. DESIGN: Joanna Briggs Institute guidance for scoping reviews, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews frameworks were used to guide this literature review. SETTINGS AND PARTICIPANTS: Reviewed articles focused on residents in NHs with telehealth palliative care interventionists operating remotely. Participants included NH residents, care partner(s), and NH staff/clinicians. METHODS: We searched Medline (Ovid), Embase (Elsevier), Cochrane Library (WileyOnline), Scopus (Elsevier), CINHAL (EBSCOhost), Trip PRO, and Dissertations & Theses Global (ProQuest) in June 2021, with an update in January 2022. We included observational and qualitative studies, clinical trials, quality improvement projects, and case and clinical reports that self-identified as telehealth palliative care for NH residents. RESULTS: The review yielded 11 eligible articles published in the United States and internationally from 2008 to 2020. Articles described live video as the preferred telehealth delivery modality with goals of care and physical aspects of care being most commonly addressed. Findings in the articles focused on 5 patient and family-centered outcomes: symptom management, quality of life, advance care planning, health care use, and evaluation of care. Consistent benefits of telehealth palliative care included increased documentation of goals of care and decrease in acute care use. Disadvantages included technological difficulties and increased NH financial burden. CONCLUSIONS AND IMPLICATIONS: Although limited in scope and quality, the current evidence for telehealth palliative care interventions shows promise for improving quality and outcomes of serious illness care in NHs. Future empirical studies should focus on intervention effectiveness, implementation outcomes (eg, managing technology), stakeholders' experience, and costs.

Lessons Learned from the Pilot Phase of a Population-Wide Genomic Screening Program: Building the Base to Reach a Diverse Cohort of 100,000 Participants.

Background and Objectives: Genomic information is increasingly relevant for disease prevention and risk management at the individual and population levels. Screening healthy adults for Tier 1 conditions of hereditary breast and ovarian cancer, Lynch syndrome, and familial hypercholesterolemia using a population-based approach can help identify the 1−2% of the US population at increased risk of developing diseases associated with these conditions and tailor prevention strategies. Our objective is to report findings from an implementation science study that evaluates multi-level facilitators and barriers to implementation of the In Our DNA SC population-wide genomic screening initiative. Methods: We established an IMPACTeam (IMPlementAtion sCience for In Our DNA SC Team) to evaluate the pilot phase using principles of implementation science. We used a parallel convergent mixed methods approach to assess the Reach, Implementation, and Effectiveness outcomes from the RE-AIM implementation science framework during the pilot phase of In Our DNA SC. Quantitative assessment included the examination of frequencies and response rates across demographic categories using chi-square tests. Qualitative data were audio-recorded and transcribed, with codes developed by the study team based on the semi-structured interview guide. Results: The pilot phase (8 November 2021, to 7 March 2022) included recruitment from ten clinics throughout South Carolina. Reach indicators included enrollment rate and representativeness. A total of 23,269 potential participants were contacted via Epic's MyChart patient portal with 1976 (8.49%) enrolled. Black individuals were the least likely to view the program invitation (28.9%) and take study-related action. As a result, there were significantly higher enrollment rates among White (10.5%) participants than Asian (8.71%) and Black (3.46%) individuals (p < 0.0001). Common concerns limiting reach and participation included privacy and security of results and the impact participation would have on health or life insurance. Facilitators included family or personal history of a Tier 1 condition, prior involvement in genetic testing, self-interest, and altruism. Assessment of implementation (i.e., adherence to protocols/fidelity to protocols) included sample collection rate (n = 1104, 55.9%) and proportion of samples needing recollection (n = 19, 1.7%). There were no significant differences in sample collection based on demographic characteristics. Implementation facilitators included efficient collection processes and enthusiastic clinical staff. Finally, we assessed the effectiveness of the program, finding low dropout rates (n = 7, 0.35%), the identification of eight individuals with Tier 1 conditions (0.72% positive), and high rates of follow-up genetic counseling (87.5% completion). Conclusion: Overall, Asian and Black individuals were less engaged, with few taking any study-related actions. Strategies to identify barriers and promoters for the engagement of diverse populations are needed to support participation. Once enrolled, individuals had high rates of completing the study and follow-up engagement with genetic counselors. Findings from the pilot phase of In Our DNA SC offer opportunities for improvement as we expand the program and can provide guidance to organizations seeking to begin efforts to integrate population-wide genomic screening.

Understanding Perceived Appreciation to Create a Culture of Wellness.

OBJECTIVE: To fully address physician burnout, academic medical centers need cultures that promote well-being. One observed driver of a culture of wellness is perceived appreciation. The authors identified several contributors to perceived appreciation among faculty at a large, metropolitan academic institution through use of a novel survey. METHODS: The authors surveyed clinical faculty in five departments: psychiatry, emergency medicine, internal medicine, thoracic surgery, and radiology. Two open-ended response questions assessed sources of perceived and lack of perceived appreciation in narrative form. The authors also collected data on gender and department identity. Grounded theory methodology was used to analyze the narrative responses and design thinking to brainstorm specific recommendations based on the main themes identified. RESULTS: A total of 179 faculty respondents filled out the survey for an overall response rate of 29%. Major drivers of perceived appreciation were patient and families (42%); physician, trainee and non-physician colleagues (32.7%); chairs (10%); and compensation (3.3%). Major drivers of perceived lack of appreciation were disrespect for time and skill level, including inadequate staffing (30%); devaluation by a physician colleague, chief of one's service or the chair (29%); poor communication and transparency (13%); and patient and family anger (6%). CONCLUSIONS: Opportunities to improve perceived appreciation include structured communication of patient gratitude, community building programs, top of licensure initiatives and accountability for physician wellness, and inclusivity efforts from organizational leaders.

Chemical and microbial characteristics of municipal drinking water supply systems in the Canadian Arctic.

Drinking water in the vast Arctic Canadian territory of Nunavut is sourced from surface water lakes or rivers and transferred to man-made or natural reservoirs. The raw water is at a minimum treated by chlorination and distributed to customers either by trucks delivering to a water storage tank inside buildings or through a piped distribution system. The objective of this study was to characterize the chemical and microbial drinking water quality from source to tap in three hamlets (Coral Harbour, Pond Inlet and Pangnirtung-each has a population of <2000) on trucked service, and in Iqaluit (population ~6700), which uses a combination of trucked and piped water conveyance. Generally, the source and drinking water was of satisfactory microbial quality, containing Escherichia coli levels of <1 MPN/100 mL with a few exceptions, and selected pathogenic bacteria and parasites were below detection limits using quantitative polymerase chain reaction (qPCR) methods. Tap water in households receiving trucked water contained less than the recommended 0.2 mg/L of free chlorine, while piped drinking water in Iqaluit complied with Health Canada guidelines for residual chlorine (i.e. >0.2 mg/L free chlorine). Some buildings in the four communities contained manganese (Mn), copper (Cu), iron (Fe) and/or lead (Pb) concentrations above Health Canada guideline values for the aesthetic (Mn, Cu and Fe) and health (Pb) objectives. Corrosion of components of the drinking water distribution system (household storage tanks, premise plumbing) could be contributing to Pb, Cu and Fe levels, as the source water in three of the four communities had low alkalinity. The results point to the need for robust disinfection, which may include secondary disinfection or point-of-use disinfection, to prevent microbial risks in drinking water tanks in buildings and ultimately at the tap.

The efficacy of a low-fat diet to manage the symptoms of bile acid malabsorption - outcomes in patients previously treated for cancer.

Dietary fat ingestion triggers bile secretion into the gastrointestinal tract. Bile acid malabsorption affects >1% of the population, causing loose stool and other gastrointestinal symptoms. The diagnosis is frequently missed. Treatments are often considered ineffective. We evaluated low-fat diets for managing gastrointestinal symptoms in these patients. All patients reporting type 6 or 7 stool were offered a selenium-75 homocholic acid taurine (SeHCAT) scan. Prospective data in patients with 7-day scan retention <20% were analysed. -Patients requiring a bile acid sequestrant were given this before receiving dietary advice. Patients completed a 7-day food diary before dietetic consultations. Personalised dietary interventions, providing 20% of daily energy from fat, were prescribed. Symptoms were assessed using a modified gastrointestinal symptom rating scale questionnaire before and 4-12 weeks after dietary intervention. A total of 114 patients (49 male, median age 64 years, median body mass index 27 kg/m2) were evaluated. 44% of these patients were taking colesevelam. After dietary intervention, there was statistically significant improvement in abdominal pain and nocturnal defecation (0.2% alpha, p=0.001). Improvement in bowel frequency, urgency, flatulence, belching, borborygmi and stool consistency were seen, but did not reach statistical significance (p≤0.004-0.031). Dietary intervention is an effective treatment option for patients with symptomatic bile acid malabsorption and should be routinely considered.

Long-term tumour control in sacral chordoma following high-dose palliative image-guided intensity-modulated radiotherapy (IG-IMRT).

Chordomas can present a challenge to the radiation oncologist and surgeon owing to the proximity to neurological structures. We describe a case of long-term tumour control in a chordoma of the lumbar spine following high-dose palliative radiotherapy. Image-guided intensity-modulated radiotherapy with photons provided a good solution to deliver 65 Gy to the tumour in a technically challenging case, and local control has been sustained over a period of years.

Pharmacological inhibition of cyclin dependent kinases causes p53 dependent apoptosis in renal cell carcinoma.

PURPOSE: We evaluated the effect of roscovitine (Sigma-Aldrich®), a pharmacological inhibitor of cyclin dependent kinase, on renal cell carcinoma cell lines in vitro. MATERIALS AND METHODS: We exposed several renal cell carcinoma cell lines to roscovitine and examined apoptotic signaling pathways using immunoblotting and immunohistochemistry. RESULTS: As expected, roscovitine caused dose and time dependent inhibition of cyclin dependent kinase 2 autophosphorylation, and of cyclin dependent kinase mediated Pol II phosphorylation in the ACHN (p53-wt) and 786-O (p53 inactive) renal cell carcinoma cell lines (ATCC®). Roscovitine also induced apoptosis in each cell line within a narrow concentration range (about 10 µg/ml). Apoptosis induction was more efficient in ACHN than in 786-O cells and at least partly due to p53 activity. In ACHN cells roscovitine induced apoptosis was associated with p21 induction, and decreased Akt1, XIAP and phospho-Rb expression. These changes also depended on p53 and were not present (p21) or showed a different dose pattern (Akt1, XIAP and phospho-Rb) in 786-O cells. Partial restoration of roscovitine induced apoptosis in 786-O cells by the Mdm-2 inhibitor nutlin-3 (Sigma-Aldrich) suggests that the inactivating mutation of VHL in these cells and its destabilizing effect on p53 are responsible for the decreased sensitivity to apoptosis. CONCLUSIONS: Our data extend previous studies documenting the pro-apoptotic effect of roscovitine and to our knowledge show for the first time that this activity is restricted to a narrow dose range in renal cell carcinoma cells and partly depends on p53. Thus, roscovitine is a novel potential chemotherapy in a subset of patients with renal cell carcinoma if a narrow therapeutic window is used. These data also provide insight into the role of VHL mutation and p53 in the renal cell carcinoma response to therapeutic cyclin dependent kinase manipulation.

Evaluation of methodology for administration of porcine FSH for use in estrus induction and for increasing ovulation rate in prepubertal gilts.

Ovulation rate influences production efficiency of oocytes and embryos and depends upon the amount of gonadotropin administered and the ratio of FSH:LH activity. In Experiment 1, gilts (n=135) were assigned to receive 10 or 15 Armour units (AU) of porcine FSH containing 6%, 10%, or 15% LH, whereas controls received PG600. Gilts received 1/6th the FSH dose in six sc administrations at 8-h intervals. There was no treatment effect on incidence of estrus (66%) or cysts (23.9%), or number of corpora lutea (CL, 29.6). However, treatment did affect the percentage of gilts ovulating (P<0.05) with fewer 10 AU FSH with 15% LH-treated gilts ovulating (15%) compared to controls (72%), whereas the other treatments did not differ (range, 44-65%). Experiment 2 tested whether FSH in polyvinlypyrrolidinone (PVP) could induce estrus and ovulation with reduced administration frequency. Gilts (n=105) were assigned to receive 15 AU FSH with 10% LH in one (1P) or two sc administrations (2P) whereas controls received PG600. There was no treatment effect on incidence of estrus (64%) or cysts (22%). However, the percentage of gilts ovulating was lower for 1P (56%), but did not differ (P<0.05) between 2P (83%) and controls (85%). Treatment influenced ovulation rate (P<0.05) with 2P having more CL (24) than controls (12) and 1P (19). Results indicated that 10 and 15 AU FSH induced estrus and ovulation, although high LH content proved detrimental. Further, 15 AU FSH with 10% LH in PVP allowed for reduced administration frequency without compromising ovulation.