Clinical case study meets population cohort: identification of a BRCA1 pathogenic founder variant in Orcadians.

We multiply ascertained the BRCA1 pathogenic missense variant c.5207T > C; p.Val1736Ala (V1736A) in clinical investigation of breast and ovarian cancer families from Orkney in the Northern Isles of Scotland, UK. We sought to investigate the frequency and clinical relevance of this variant in those of Orcadian ancestry as an exemplar of the value of population cohorts in clinical care, especially in isolated populations. Oral history and birth, marriage and death registrations indicated genealogical linkage of the clinical cases to ancestors from the Isle of Westray, Orkney. Further clinical cases were identified through targeted testing for V1736A in women of Orcadian ancestry attending National Health Service (NHS) genetic clinics for breast and ovarian cancer family risk assessments. The variant segregates with female breast and ovarian cancer in clinically ascertained cases. Separately, exome sequence data from 2088 volunteer participants with three or more Orcadian grandparents, in the ORCADES research cohort, was interrogated to estimate the population prevalence of V1736A in Orcadians. The effects of the variant were assessed using Electronic Health Record (EHR) linkage. Twenty out of 2088 ORCADES research volunteers (~1%) carry V1736A, with a common haplotype around the variant. This allele frequency is ~480-fold higher than in UK Biobank participants. Cost-effectiveness of population screening for BRCA1 founder pathogenic variants has been demonstrated at a carrier frequency below the ~1% observed here. Thus we suggest that Orcadian women should be offered testing for the BRCA1 V1736A founder pathogenic variant, starting with those with known Westray ancestry.

Examination of Factors Affecting Therapeutic Attitude and Empowerment of Perianesthesia Nurses Who Care for Patients With Opioid Use Disorder.

PURPOSE: Patients with opioid use disorder (OUD) and associated complexities are presenting to hospitals in increasing numbers. Preparation of perianesthesia nurses caring for this patient population has lagged, with noted deficits in continuing education, resources, and role support. Previous research found education without considering therapeutic attitude (TA), empowerment and factors that influence nursing practice does not translate into feelings of competence in nursing care. The purpose of this study was to identify correlates and predictors that affect TA and empowerment among perianesthesia nurses caring for patients with OUD. DESIGN: A cross-sectional, correlation design was used to identify correlates and predictors of TA and empowerment in a national sample of perianesthesia nurses (N = 215) METHODS: A national survey collected data from perianesthesia nurses. The Perianesthesia Nurse Empowerment and Therapeutic Attitude Model was the guiding framework. Pearson product-moment correlation and hierarchical multiple regression analyses were used to examine relationships between personal factors, the professional practice environment and societal factors of perianesthesia nurses. FINDINGS: The standardized regression coefficients indicated the professional practice environment (ß = -0.28), drug user stigma (ß = 0.27), access to a pain specialist (ß = 0.25), and exposure to drug users (ß = 0.25) were the strongest predictors of TA. Access to a pain specialist (ß = -0.15) and the professional practice environment (ß = 0.72) were the strongest predictors of empowerment. CONCLUSIONS: The professional practice environment directly influenced the degree of empowerment and TA reported by perianesthesia nurses. Exposure to persons with OUD and personal stigmatization of persons who misuse drugs decreased TA but had no association with empowerment. Access to a pain specialist was moderately predictive of empowerment and negatively associated with TA suggesting a lack of role legitimacy and the need for further research into perianesthesia nurses' perceptions of their role when caring for this population.

Translating mentoring interventions research into practice: Evaluation of an evidence-based workshop for research mentors on developing trainees' scientific communication skills.

A key part of keeping doctoral and postdoctoral trainees in STEM research careers is mentoring. Our previous research indicates that mentoring trainees in scientific communication (SC) skill development increases research career intention through two social-cognitive constructs, self-efficacy in and outcome expectations for acquiring SC skills, as well as science identity. While many mentor training interventions exist, no programs focus on developing SC skills specifically. The "Scientific Communication Advances Research Excellence" (SCOARE) program trains mentors to address trainee scientific communication (SC) skill development as an innovative approach to increase trainee research career persistence. The SCOARE training is a half-day workshop for faculty mentors of research trainees at five sites nationally. Informed by previous research, workshop content focuses on practical, effective mentoring strategies to develop trainee speaking and writing skills. Anonymous evaluation data collected after each workshop indicates participant satisfaction and reported positive increases in skills and knowledge in applying new and various techniques when mentoring trainees (skills) and how linguistic bias influences our perception of others (knowledge). This article outlines the research-based development of the SCOARE program, the first two years' of workshop evaluations showing positive increases in skills and knowledge, and lessons learned to increase participant satisfaction with the program.

EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma.

Juvenile open-angle glaucoma (JOAG) is a severe type of glaucoma with onset before age 40 and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with novel EFEMP1 variants (c.238A>T, p.Asn80Tyr; c.1480T>C, p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cys) co-segregating with disease. Affected variant carriers (N = 34) exhibited severe disease with average age of onset of 16 years and with 76% developing blindness. To investigate functional effects, we transfected COS7 cells with vectors expressing the three novel EFEMP1 variants and showed that all three variants found in JOAG patients caused significant intracellular protein aggregation and retention compared to wild type and also compared to EFEMP1 variants associated with other ocular phenotypes including an early-onset form of macular degeneration, Malattia Leventinese/Doyne's Honeycomb retinal dystrophy. These results suggest that rare EFEMP1 coding variants can cause JOAG through a mechanism involving protein aggregation and retention, and that the extent of intracellular retention correlates with disease phenotype. This is the first report of EFEMP1 variants causing JOAG, expanding the EFEMP1 disease spectrum. Our results suggest that EFEMP1 mutations appear to be a relatively common cause of JOAG in Filipino families, an ethnically diverse population.

Elimination of Routine Urinalysis before Elective Orthopaedic Surgery Reduces Antibiotic Utilization without Impacting Catheter-associated Urinary Tract Infection or Surgical Site Infection Rates.

PURPOSE: Routine preoperative urinalysis has been the standard of care for the orthopedic population for decades, regardless of symptoms. Studies have demonstrated antibiotic overuse and low concordance between bacteria cultured from the surgical wound and the urine. Testing and treatment of asymptomatic urinary tract colonization before total joint arthroplasty (TJA) is unnecessary and increases patient risk. We investigated reducing antibiotic use by (1) modifying testing algorithms to target patients at risk, (2) modifying reflex to culture criteria, and (3) providing treatment guidelines. MATERIALS AND METHODS: A pre-post study was conducted to determine identify the impact of eliminating universal urinalysis prior to TJA on surgical site infection (SSI) and catheter-associated urinary tract infection (CAUTI) rates and number of antibiotic prescriptions. Patients who underwent primary hip or knee TJA or spinal fusions from February 2016 to March 2018 were included. Patient data was collected for pre- and post-practice change period (February 2016-October 2016 and August 2017-March 2018). Patient demographics, urinalysis results, cultures, and prescriptions were analyzed retrospectively from every tenth chart in the pre-period and prospectively on all patients in the post-period. RESULTS: A total of 4,663 patients were studied. There was a 96% decrease in urinalyses performed (P<0.0001), and a 93% reduction rate in antibiotic utilization (P<0.001). No significant difference in SSI and CAUTI rates was observed (P>0.05). CONCLUSION: The elimination of routine urinalysis before orthopedic surgery resulted in a reduction in antibiotic utilization with no significant change in the SSI or CAUTI rates. Cost savings resulted from reduced antibiotic usage.

Delivering tertiary tuberculosis care virtually.

OBJECTIVE: To assess the impact of a virtual multidisciplinary team (MDT) review panel in reducing travel for children with a rare disease (tuberculosis (TB)) without compromising clinical outcomes. DESIGN: Retrospective review of patients discussed in a virtual MDT panel. Independent pre-intervention and post-intervention data from Public Health England. SETTING: Paediatric departments across North West England. PATIENTS: Children aged <16 years with suspected TB infection/disease. INTERVENTION: Weekly, virtual MDT discussion between district paediatricians and a tertiary TB team. MAIN OUTCOME MEASURE: Care closer to home, time from presentation to treatment. RESULTS: 45% (37 of 82) children received care closer to home. Median time from presentation to treatment reduced by 28% (from 18 to 13 days). 21% more children were diagnosed before developing symptoms (76% of children presented with symptoms pre-intervention, 55% post-intervention). 5 children incorrectly labelled with latent TB infection were treated for TB disease. CONCLUSIONS: A clinical network supported by virtual MDT reviews can improve treatment for children with rare diseases while providing care close to home.

Improving Department Climate Through Bias Literacy: One College's Experience.

Many institutions of higher education are investing in "implicit bias training" as a mechanism to improve diversity and inclusion on their campuses. In this study, we describe an effort to implement this training in the form of a 3-hour workshop delivered to faculty members in the College of Engineering at the University of Wisconsin-Madison. Evaluation form data collected immediately post-workshop, and in-person interviews and survey data collected 6-12 months post-workshop, were used to measure the effectiveness of the intervention. These data show that faculty awareness of implicit bias in their workplace environments increased significantly, although individual motivation and self-efficacy to act without bias, and self-reported bias-reduction actions, did not increase. At the same time, we found evidence of improved department climates and bias-reduction actions at the department level, which increase our confidence that the workshops were having a positive impact. Importantly, women and faculty of color in the College did not report increases in negative behavior after the workshop, and reported that their departments were engaging in explicit discussions of potential biases in departmental processes more often. These findings support the continued implementation of the "Breaking the Bias Habit®" workshops along with measurement of their success.

Opioid use disorder education for acute care nurses: An integrative review.

AIMS AND OBJECTIVES: The purpose of this study was to explore opioid use disorder (OUD) education programmes presented to practicing nurses working in medical-surgical settings and identify the methods used to evaluate their effectiveness. BACKGROUND: Health professionals often express negative attitudes towards patients with OUD which can lead to suboptimal care. Education decreases negative attitudes of healthcare workers. Despite this, few educational programmes are offered to promote knowledge among acute care nurses who work in medical-surgical settings and provide care to patients with OUD. DESIGN: An integrative review. METHODS: The framework by Whittemore and Knafl was used to examine empirical literature between 1995-2019 to answer the research questions, (a) What types of education do acute care nurses receive regarding OUD? (b) What methods are used for measuring educational intervention effectiveness? CINAHL, ERIC, PsycINFO and MEDLINE were searched using combinations of search terms and PRISMA guidelines. The initial 394 articles were narrowed to nine from the United States and Australia that met the search criteria and purpose of the review. RESULTS: Educational programmes used to promote knowledge included interactive workshops, case studies, online modules, simulation sessions, real-time coaching and in-service trainings. Methods used to measure effectiveness of educational interventions were self-assessment tools that measured pre/postknowledge, attitude surveys, alcohol and drug scales and individual researcher-developed instruments. CONCLUSIONS: Additional research is needed to determine best teaching strategies for increasing knowledge of OUD and OUD patient care. Valid and reliable methods for measuring effectiveness of OUD educational interventions are inadequate. RELEVANCE TO CLINICAL PRACTICE: Knowledge of OUD has been linked to positive patient outcomes and nurses would benefit from up-to-date educational offerings. Opioid use disorder is a growing global concern. Translation of current OUD nursing science to acute care nurses would promote health equity in practice for individuals with OUD.

Anterior Segment Parameters of Filipino-Americans Compared to Chinese-Americans and Caucasian Americans Using Anterior Segment Optical Coherence Tomography.

PURPOSE: We compare anterior segment characteristics of Filipino- versus Chinese- and Caucasian-Americans to describe the differences in risk factors among each ethnic group. METHODS: A cross-sectional study was conducted among Filipino, Chinese, and Caucasian subjects without glaucoma who underwent a standardized set of ocular examinations and anterior segment optical coherence tomography (Visante ASOCT) imaging. Zhongshan Angle Assessment Program (ZAAP) 4 was used for ASOCT image analysis. The following quantitative parameters wereobtained from ZAAP: (1) angle opening distance (AOD500, AOD750), angle recess area at 750 µm (ARA), and trabecular-iris space area at 500 and 750 µm (TISA500, TISA750); (2) iris parameters, including iris thickness at 750 µm from the scleral spur (IT750), iris area (IArea), iris curvature or convexity (ICurv), and pupil diameter; 3) anterior chamber parameters; and (4) lens vault. RESULTS: The Filipino (122 eyes), Chinese (121 eyes), and Caucasian (111 eyes) subject groups were similar in terms of demographic and clinical characteristics. We reported pairwise comparisons of Filipino parameter values to Chinese or Caucasian values, represented as B-coefficients and P values. In multivariate analysis, Filipinos had narrower angles than Caucasians (AOD750, TISA 500, TISA 750, ARA, P < 0.001). Filipinos had thicker and more convex irises than Caucasians (IT750, IT 2000, ICurv P < 0.003). Angle and iris parameters were similar overall for Filipino and Chinese. CONCLUSIONS: Filipinos appear to have more convex and thicker irises, smaller lens vault and narrower angles compared to Caucasians. Filipino eyes closely resembled Chinese eyes with similar iris and angle parameters. TRANSLATIONAL RELEVANCE: The anatomic angle parameters of Filipinos may contribute to angle closure risk among this population, thus ASOCT and thorough angle analysis is recommended in this population.

Discrepancies Between US Food and Drug Administration Vaccine Licensure Indications and Advisory Committee on Immunization Practices Recommendations: Provider Knowledge and Attitudes.

PURPOSE: In the United States, the Center for Biologics Evaluation and Research at the US Food and Drug Administration (FDA) is responsible for licensure of vaccines. The Advisory Committee on Immunization Practices (ACIP) is a federal advisory committee that provides guidance to the Centers for Disease Control and Prevention (CDC) on use of vaccines. Discrepancies between FDA licensure indications and ACIP/CDC vaccine recommendations exist, challenging health care providers. The objectives of this study were: (1) to categorize differences between FDA vaccine licensure indications and ACIP/CDC vaccine recommendations for vaccines; and (2) to assess knowledge, attitudes, and practices of pediatricians, family physicians, and obstetrician-gynecologists regarding their understanding of differences. METHODS: Information was extracted from FDAvaccine package inserts, and corresponding information was collected for ACIP/CDC vaccine recommendations (2000-2014) for vaccines in the childhood and adult immunization schedules. Surveys regarding knowledge of discrepancies were distributed electronically to members of the Georgia chapters of the American Academy of Pediatrics (GA-AAP) and the American Academy of Family Physicians (GA-AAFP), and the national American College of Obstetricians and Gynecologists (ACOG) in 2014. FINDINGS: Differences were identified in 20 instances: differences in age group indications were identified in 6, in dosing administration schedules in 4, and in immunocompromised hosts and pregnant women in 10. We received 145 (8.5%) responses from GA-AAP, 237 (9.5%) from GA-AAFP, and 869 (1.5%) from national ACOG members. A total of 105 (72%) GA-AAP respondents reported that they follow AAP recommendations and 168 (71%) GA-AAFP respondents follow ACIP recommendations. GA-AAP and GA-AAFP respondents generally were not aware of data the FDA considers for vaccine licensure or data that pharmaceutical company representatives are permitted to discuss. Respondents remain current with vaccine recommendations through review of materials from professional organizations, the CDC, and package inserts; Continuing Medical Education; and information from pharmaceutical representatives. A total of 780 (90%) ACOG respondents had no concerns regarding routinely recommended reduced diphtheria toxoid and acellular pertussis vaccines (n = 730 [84%]) and influenza during pregnancy vaccines (n = 852 [98%]) to pregnant patients. However, these findings must be interpreted within the context of a low overall ACOG survey response rate. IMPLICATIONS: Education regarding existence of and reasons for discrepancies between FDA licensure of and ACIP/CDC recommendations for vaccines and reasons for these differences could optimize immunization delivery.

Comparison of Anterior Segment Optical Coherence Tomography Parameters Among Vietnamese, Chinese, and Whites.

PURPOSE: To evaluate the difference in anterior segment optical coherence tomography (AS-OCT) parameters among ethnic Vietnamese, Chinese, and whites. DESIGN: Cross-sectional study. METHODS: We prospectively recruited phakic nonglaucomatous participants (based on intraocular pressure < 21 mm Hg, normal optic nerve head and retinal nerve fiber, and cup-to-disc ratio < 0.6) of 3 ethnic groups-Vietnamese, Chinese, and white. AS-OCT parameters including angle (angle opening distance, trabecular-iris space area, and angle recess area), iris (iris thickness, iris area, and iris curvature [Icurv]), and anterior chamber parameters (anterior chamber depth, width [ACW], area, and lens vault [LV]) were obtained. A linear regression model with adjustment for age, sex, axial length, and pupillary diameter was used for analysis. Subgroup analysis was performed in closed- and open-angle subgroups, which were defined in eyes with gonioscopically visible posterior trabecular meshwork for less than 2 quadrants (closed) and equal to or more than 2 quadrants (open). RESULTS: Data were obtained from 126 Vietnamese, 124 Chinese, and 112 white participants. Mean (standard deviation) age of participants was 60.2 (11.8) years. Among overall subjects, Vietnamese had significantly smaller values in all angle and anterior chamber parameters than Chinese and white subjects (all P ≤ .001) except LV. Vietnamese had significantly higher Icurv than Chinese (B -0.065, P < .001) and white subjects (B -0.073, P < .001). In the open-angle subgroup, Vietnamese had significantly smaller angle and anterior chamber dimensions (P ≤ .001) and thicker iris (P < .001) than whites, whereas there was no significant difference in all parameters compared to Chinese except for smaller ACW in Vietnamese (P < .001). In the closed-angle subgroup, Vietnamese possessed smaller angle, smaller anterior chamber dimensions, and higher Icurv than Chinese and white subjects (P < .001). Vietnamese had significantly greater LV compared to Chinese (B -204.8, P = .001). CONCLUSION: Vietnamese subjects had more of the anatomic characteristics associated with risk for angle closure, including small anterior chamber dimension, high iris curvature, and high lens vault, compared to the other 2 ethnicities.

Assessing the effectiveness of NICE criteria for stratifying breast cancer risk in a UK cohort.

Breast cancer risk is a common indication for referral to clinical genetics services. UK National Institute of Health and Care Excellence (NICE) guidelines use family history (FH) to stratify by 10-year risk of breast cancer from age 40. Patients are stratified into population risk (PR, 10-year risk <3%), moderate (MR, 3-8%) and high risk (HR, >8%). Women at increased risk are offered screening at or prior to age 40. To assess the clinical effectiveness of current risk stratification, FH data were obtained for all unaffected women with a FH of breast cancer aged <50, referred to cancer genetics from 2000-2010. Patients were risk stratified by NICE criteria, identifying patients who subsequently developed breast cancer. A total of 1409 women had 15,414 patient years of follow-up. Thirty invasive breast cancers developed, 13 in MR and 13 in HR women. Kaplan-Meier analysis demonstrated no significant difference in the rate of breast cancer development between PR and MR women from ages 40 to 49 (Log rank p = 0.431). There was a significant difference between ages 40 and 49 years between PR and HR women (p = 0.036), but not on exclusion of BRCA mutation carriers (p = 0.136). NICE absolute 10-year risk thresholds between ages 40 and 49 were not met in any risk group, when risk was estimated using the guidelines (PR = 0.82%, MR = 1.68%, HR = 3.56%). Our data suggest that improved criteria are required for risk assessment prior to age 50 and screening resources may be best focussed on those with highly penetrant mutations in cancer risk genes.

Development of Glatopa® (Glatiramer Acetate): The First FDA-Approved Generic Disease-Modifying Therapy for Relapsing Forms of Multiple Sclerosis.

The multiple sclerosis (MS) treatment landscape in the United States has changed dramatically over the past decade. While many disease-modifying therapies (DMTs) have been approved by the US Food and Drug Administration (FDA) for the treatment of relapsing forms of MS, DMT costs continue to rise. The availability of generics and biosimilars in the MS-treatment landscape is unlikely to have a major impact on clinical benefit. However, their availability will provide alternative treatment options and potentially lower costs through competition, thus increasing the affordability of and access to these drugs. In April 2015, the first generic version of the complex drug glatiramer acetate (Glatopa® 20 mg/mL) injection was approved in the United States as a fully substitutable generic for all approved indications of the 20 mg/mL branded glatiramer acetate (Copaxone®) dosage form. Despite glatiramer acetate's complex nature-being a chemically synthesized (ie, nonbiologic) mixture of peptides-the approval occurred without conducting any clinical trials. Rather, extensive structural and functional characterization was performed to demonstrate therapeutic equivalence to the innovator drug. The approval of Glatopa signifies an important milestone in the US MS-treatment landscape, with the hope that the introduction of generic DMTs and eventually biosimilar DMTs will lead to future improvements in the affordability and access of these much-needed treatments for MS.

Ocular Gossypiboma: Ultrasound B-Scan Assessment of Retained Surgical Sponge After Ahmed Valve Surgery: A Case Report.

PURPOSE OF THE STUDY: To present the first documented case of an ocular gossypiboma (retained foreign body) of a mitomycin-C-soaked sponge confirmed echographically using diagnostic ultrasound B-scan after Ahmed valve surgery. PATIENTS AND METHODS: A patient who underwent phacoemulsification with Ahmed valve implantation surgery had a retained Weck-Cels sponge soaked with mitomycin-C. With the use of ocular ultrasound B-scan, the retained sponge was localized and a second procedure was performed to explant it. CONCLUSION: In cases of ocular gossypiboma the use of ultrasound modalities can be a valuable tool especially because B-scan access is common and can be cost-effective.

Demonstration of equivalence of a generic glatiramer acetate (Glatopa™).

Glatiramer acetate (GA) has been available under the brand name Copaxone® for nearly two decades. Recently, the US Food and Drug Administration (FDA) approved the first generic GA, Glatopa™, as fully substitutable for all indications for which Copaxone 20mg is approved; Glatopa also represents the first FDA-approved "AP-rated," substitutable generic for treating patients with MS. Glatiramer acetate is a complex mixture of polypeptides and, consequently, its characterization presented challenges not generally encountered in drug development. Despite its complexity, and without requiring any clinical data, approval was accomplished through an Abbreviated New Drug Application in which equivalence to Copaxone was evaluated across four criteria: starting materials and basic chemistry; structural signatures for polymerization, depolymerization, and purification; physicochemical properties; and biological and immunological properties. This article describes the rigorous overall scientific approach used to successfully establish equivalence between Glatopa and Copaxone, and presents key representative data from several of the comprehensive sets of physicochemical (structural) and biological (functional) assays that were conducted.

LDLR gene synonymous mutation c.1813C>T results in mRNA splicing variation in a kindred with familial hypercholesterolaemia.

Familial hypercholesterolaemia, one of the most common inherited diseases in the general population, is associated with mutations in at least three different genes including the low density lipoprotein receptor (LDLR), apolipoprotein B (APOB) and protein convertase subtilisin/kexin type 9 (PCSK9) genes. In this report, we describe an unclassified DNA variant (c.1813C>T; p.Leu605Leu) within exon 12 of the LDLR gene in a kindred in which familial hypercholesterolaemia is associated with c.1813C>T heterozygosity. In silico analysis suggested that c.1813C>T might affect splicing of the LDLR gene by creating a cryptic donor splice site, which was confirmed by RT-PCR coupled with cDNA sequencing, to result in the loss of 34 base pairs in the coding sequence. The latter truncated mRNA is predicted to generate a frameshift leading to a premature stop at codon 652 and early termination of the low density lipoprotein receptor polypeptide chain, and thus provides a molecular basis for the hypercholesterolaemic phenotype. This case report highlights the emerging utility of RNA studies for the molecular diagnosis of familial hypercholesterolaemia in patients with potential mRNA splicing variants.