The impact of inversions across 33,924 families with rare disease from a national genome sequencing project.

Detection of structural variants (SVs) is currently biased toward those that alter copy number. The relative contribution of inversions toward genetic disease is unclear. In this study, we analyzed genome sequencing data for 33,924 families with rare disease from the 100,000 Genomes Project. From a database hosting >500 million SVs, we focused on 351 genes where haploinsufficiency is a confirmed disease mechanism and identified 47 ultra-rare rearrangements that included an inversion (24 bp to 36.4 Mb, 20/47 de novo). Validation utilized a number of orthogonal approaches, including retrospective exome analysis. RNA-seq data supported the respective diagnoses for six participants. Phenotypic blending was apparent in four probands. Diagnostic odysseys were a common theme (>50 years for one individual), and targeted analysis for the specific gene had already been performed for 30% of these individuals but with no findings. We provide formal confirmation of a European founder origin for an intragenic MSH2 inversion. For two individuals with complex SVs involving the MECP2 mutational hotspot, ambiguous SV structures were resolved using long-read sequencing, influencing clinical interpretation. A de novo inversion of HOXD11-13 was uncovered in a family with Kantaputra-type mesomelic dysplasia. Lastly, a complex translocation disrupting APC and involving nine rearranged segments confirmed a clinical diagnosis for three family members and resolved a conundrum for a sibling with a single polyp. Overall, inversions play a small but notable role in rare disease, likely explaining the etiology in around 1/750 families across heterogeneous clinical cohorts.

A human importin-ß-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.

Importin 8, encoded by IPO8, is a ubiquitously expressed member of the importin-ß protein family that translocates cargo molecules such as proteins, RNAs, and ribonucleoprotein complexes into the nucleus in a RanGTP-dependent manner. Current knowledge of the cargoes of importin 8 is limited, but TGF-ß signaling components such as SMAD1-4 have been suggested to be among them. Here, we report that bi-allelic loss-of-function variants in IPO8 cause a syndromic form of thoracic aortic aneurysm (TAA) with clinical overlap with Loeys-Dietz and Shprintzen-Goldberg syndromes. Seven individuals from six unrelated families showed a consistent phenotype with early-onset TAA, motor developmental delay, connective tissue findings, and craniofacial dysmorphic features. A C57BL/6N Ipo8 knockout mouse model recapitulates TAA development from 8-12 weeks onward in both sexes but most prominently shows ascending aorta dilatation with a propensity for dissection in males. Compliance assays suggest augmented passive stiffness of the ascending aorta in male Ipo8-/- mice throughout life. Immunohistological investigation of mutant aortic walls reveals elastic fiber disorganization and fragmentation along with a signature of increased TGF-ß signaling, as evidenced by nuclear pSmad2 accumulation. RT-qPCR assays of the aortic wall in male Ipo8-/- mice demonstrate decreased Smad6/7 and increased Mmp2 and Ccn2 (Ctgf) expression, reinforcing a role for dysregulation of the TGF-ß signaling pathway in TAA development. Because importin 8 is the most downstream TGF-ß-related effector implicated in TAA pathogenesis so far, it offers opportunities for future mechanistic studies and represents a candidate drug target for TAA.

Conclusion of diagnostic odysseys due to inversions disrupting GLI3 and FBN1.

Many genetic testing methodologies are biased towards picking up structural variants (SVs) that alter copy number. Copy-neutral rearrangements such as inversions are therefore likely to suffer from underascertainment. In this study, manual review prompted by a virtual multidisciplinary team meeting and subsequent bioinformatic prioritisation of data from the 100K Genomes Project was performed across 43 genes linked to well-characterised skeletal disorders. Ten individuals from three independent families were found to harbour diagnostic inversions. In two families, inverted segments of 1.2/14.8 Mb unequivocally disrupted GLI3 and segregated with skeletal features consistent with Greig cephalopolysyndactyly syndrome. For one family, phenotypic blending was due to the opposing breakpoint lying ~45 kb from HOXA13 In the third family, long suspected to have Marfan syndrome, a 2.0 Mb inversion disrupting FBN1 was identified. These findings resolved lengthy diagnostic odysseys of 9-20 years and highlight the importance of direct interaction between clinicians and data-analysts. These exemplars of a rare mutational class inform future SV prioritisation strategies within the NHS Genomic Medicine Service and similar genome sequencing initiatives. In over 30 years since these two disease-gene associations were identified, large inversions have yet to be described and so our results extend the mutational spectra linked to these conditions.

Medical students' perception of their 'distance travelled' in medical school applications.

INTRODUCTION: Within medical school's holistic review of applicants includes a review of their distance travelled to get to this point in their education. The AAMC defines distance travelled (DT) as, 'any obstacles or hardships you've overcome to get to this point in your education or any life challenges you've faced and conquered'. What medical students consider as their distance travelled has not been explored. The authors sought to identify the factors medical students perceive are important for medical school admissions to consider when assessing someone's 'distance travelled' by asking current medical students to share their DT experiences along with the barriers and facilitators they encountered on their medical school journey. METHODS: The authors conducted semi-structured interviews with US medical students through purposeful sampling methods. The social-ecological model framework was used to develop questions to elicit participants' experiences that contributed to their distance travelled. Interviews were conducted in 2021 and ranged from 60-75 minutes. Transcribed interviews were qualitatively analysed using interpretive description. RESULTS: A total of 31 medical students from seven medical schools were included in the study. Overall, participants defined distance travelled as an applicant's hardships (e.g. being the primary caregiver for a family member) and privileges (e.g. having physician parents) they experienced. Three major themes were identified: (1) individual-level characteristics and factors, (2) interpersonal relationships and (3) aspects of the participants' community and society. DISCUSSION: Our findings show that medical school applicants considered DT to be a valuable component of a holistic medical school admission process. Participants' experiences of DT were varied and complex. Our research suggests that admissions teams for medical schools should incorporate more comprehensive recruitment practices and inclusive methodological frameworks to accurately capture the diversity of identities and experiences of medical school applicants and to consider the factors that shape their journey to medical schools.

"The Story I Will Never Forget": Critical Incident Narratives in Surgical Residency.

OBJECTIVE: We sought to better understand what defines a critical incident experience for the surgical trainee. SUMMARY BACKGROUND DATA: Critical incidents are formative moments stamped indelibly on one's memory that shape professional identity. The critical incident technique-using participants' narratives to identify patterns and learn from their perceptions-has been explored in some healthcare settings, but there has been no inquiry within surgery. METHODS: Surgical residents at 5 residency programs (1 community, 1 university-affiliated, 3 university) were surveyed using an online questionnaire from November to December 2020. Convenience sampling was used to identify the study population. Participants were invited to write about formative, impactful experiences in training. Interpretive description was the qualitative methodology used to locate information, analyze, and record patterns in the data. Individual responses were categorized and assessed for overlying themes. RESULTS: Overall, 28 narratives were collected from surgery residents in 3 specialties (general surgery, plastic surgery, and urology), with postgraduate year representation of post-graduate years 1 to 6. Respondents were 40% female. Nineteen of the narratives reported a negative experience. Four themes were identified from responses: 1) growth through personal self-reflection, 2) difficult interpersonal interactions, 3) positive team dynamics as a psychological safety net, and 4) supportive program cultures that promote learning. CONCLUSIONS: Critical incident narratives among surgical residents indicate that unforgettable and formative experiences-both positive and negative- occur in 4 domains: within the individual, within a relationship, among a team, and within a program. Further exploring these domains in surgical training will inform optimal educational programming to support trainee development and wellbeing.

POU3F3-related disorder: Defining the phenotype and expanding the molecular spectrum.

POU3F3 variants cause developmental delay, behavioral problems, hypotonia and dysmorphic features. We investigated the phenotypic and genetic landscape, and genotype-phenotype correlations in individuals with POU3F3-related disorders. We recruited unpublished individuals with POU3F3 variants through international collaborations and obtained updated clinical data on previously published individuals. Trio exome sequencing or single exome sequencing followed by segregation analysis were performed in the novel cohort. Functional effects of missense variants were investigated with 3D protein modeling. We included 28 individuals (5 previously published) from 26 families carrying POU3F3 variants; 23 de novo and one inherited from an affected parent. Median age at study inclusion was 7.4 years. All had developmental delay mainly affecting speech, behavioral difficulties, psychiatric comorbidities and dysmorphisms. Additional features included gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Autism, hearing and eye comorbidities, dysmorphisms were more common in individuals with truncating variants, whereas epilepsy was only associated with missense variants. In silico structural modeling predicted that all (likely) pathogenic variants destabilize the DNA-binding region of POU3F3. Our study refined the phenotypic and genetic landscape of POU3F3-related disorders, it reports the functional properties of the identified pathogenic variants, and delineates some genotype-phenotype correlations.

The Demands of Surgery Residency: More Than Just Duty Hours?

INTRODUCTION: Efforts to improve surgical resident well-being could be accelerated with an improved understanding of resident job demands and resources. In this study, we sought to obtain a clearer picture of surgery resident job demands by assessing how residents distribute their time both inside and outside of the hospital. Furthermore, we aimed to elucidate residents' perceptions about current duty hour regulations. METHODS: A cross-sectional survey was sent to 1098 surgical residents at 27 US programs. Responses regarding work hours, demographics, well-being (utilizing the physician well-being index), and perceptions of duty hours in relation to education and rest, were collected. Data were evaluated using descriptive statistics and content analysis. RESULTS: A total of 163 residents (14.8% response rate) were included in the study. Residents reported a median total patient care hours per week of 78.0 h. Trainees spent 12.5 h on other professional activities. Greater than 40% of residents were "at risk" for depression and suicide based on physician well-being index scores. Four major themes associated with education and rest were identified: 1) duty hour definitions and reporting mechanisms do not completely reflect the amount of work residents perform, 2) quality patient care and educational opportunities do not fit neatly within the duty hour framework, 3) resident perceptions of duty hours are impacted the educational environment, and 4) long work hours and lack of adequate rest negatively affect well-being. CONCLUSIONS: The breadth and depth of trainee job demands are not accurately captured by current duty hour reporting mechanisms, and residents do not believe that their current work hours allow for adequate rest or even completion of other clinical or academic tasks outside of the hospital. Many residents are unwell. Duty hour policies and resident well-being may be improved with a more holistic accounting of resident job demands and greater attention to the resources that residents have to offset those demands.

Hardship and Humanity: A Closer Qualitative Look at Surgical Training and Its Effects on Trainees From the Perspectives of Loved Ones.

OBJECTIVE: The aim of this study was to obtain novel perspectives regarding the effects that surgical training has on the well-being of trainees. SUMMARY BACKGROUND DATA: Improving trainee well-being is a national concern given high rates of burnout, depression, and suicide among physicians. Supporters of surgical trainees may offer new perspectives regarding the effects of surgical training and point to strategies to optimize trainee wellness. METHODS: This qualitative study employs semi-structured interviews of 32 support persons of trainees at a single tertiary care center with multiple surgical training programs. Interviews focused on perspectives related to supporting a surgical trainee. Interview transcripts underwent qualitative analysis with semantic and conceptual coding. Themes related to effects of training on trainee wellness are reported. RESULTS: Four themes were identified: Who Can Endure the Most Hardship?-trainee attributes and programmatic factors contribute to trainees feeling the need to constantly endure the most hardship; Consequences of Hardship-constantly enduring hardships has significant negative effects on wellness; Trainees are Humans-trainees are people with basic human needs, especially the need for worth; Research Time as Refuge-dedicated research time is treated as an oasis away from clinical hardships. CONCLUSIONS: Perspectives from support persons can offer valuable insight into the wellness needs of surgical trainees. According to support persons, surgical training profoundly negatively impacts trainee wellness. Unlike during clinical training, dedicated research time is a period during which wellness can be prioritized. Programs should provide greater attention to mitigating the negative ramifications of surgical training and promoting wellness in a longitudinal fashion throughout training.

Not Just Bystanders: A Qualitative Study on the Vicarious Effects of Surgical Training on the Wellness of Support Persons for Trainees.

OBJECTIVE: To obtain insights into the effects of surgical training on the well-being of support persons. SUMMARY BACKGROUND DATA: Surgical trainee wellness is a critical priority among surgical educators and leaders. The impact of surgical training on the wellness of loved ones who support trainees has not been previously studied. METHODS: This qualitative study employs semi-structured interviews of 32 support persons of surgical trainees at a single tertiary care center with multiple surgical specialty training programs. Interviews focused on perceptions about supporting a surgical trainee. Transcripts underwent thematic analysis with semantic and conceptual coding. Key themes regarding the effects that caring for a trainee has on support persons are reported. RESULTS: Three key themes were identified: (1) Sacrifices-support persons report significant tangible and intangible sacrifices, (2) Delaying life-life is placed on hold to prioritize training, and (3) A disconnect-there is a disconnect and a lack of recognition of support person needs that require greater awareness and targeted interventions. CONCLUSIONS: The impact of surgical training can extend beyond trainees and can affect the wellness of their support persons who endure the effects of training alongside trainees. Programs should be aware of these effects and develop meaningful strategies to aid trainees and their support persons.

Comparing cognitive assessment service provision between Aboriginal and Torres Strait Islanders and non-Indigenous Australians at a metropolitan health service.

OBJECTIVE: Aboriginal and Torres Strait Islander populations are at a significantly higher risk of neurological and cognitive impairment from a range of aetiologies. In order to better identify and support Indigenous Australians with cognitive impairment, culturally appropriate screening, management and referral processes are critical. The primary aim of this study was to investigate the frequency of presentations and type of cognitive screening conducted with Indigenous Australians presenting to health services. METHODS: Hospital data for 30 Indigenous Australians presenting with neurological symptoms to Emergency Departments within a large metropolitan health service were compared with a group of 30 non-Indigenous, Australian-born, English-speaking, age-, gender- and diagnosis-matched individuals. RESULTS: Only two individuals, one from each group, received cognitive screening. This was likely related to a surprisingly large proportion of Indigenous Australians presenting to hospital with headache and migraine. Significantly more Indigenous Australians (36.7%) were consulted by a member of the multidisciplinary team compared to 10% of the non-Indigenous group. No differences in follow-up referrals were observed. CONCLUSIONS: Results indicated a lack of cognitive screening practices being undertaken in both groups. It was encouraging to see Indigenous Australians receiving consultations from multidisciplinary team members at a higher rate, with a similar follow-up pathway being observed. This study further highlights the need for adoption of screening practices in primary health care settings and the development and use of culturally appropriate cognitive screening measures. SO WHAT?: This study investigates the cognitive screening practices of a metropolitan health service and highlights the need for culturally appropriate cognitive screening methods to be developed and implemented to facilitate the identification of cognitive impairment in Indigenous Australians presenting for treatment.

Predictors of Respiratory Improvement 1 Week after Ligation of Patent Ductus Arteriosus in Preterm Infants.

OBJECTIVE: To characterize preterm infants that demonstrates respiratory improvement 7 days after ligation of a patent ductus arteriosus (PDA). STUDY DESIGN: We performed a 2-phase study of preterm infants (birthweight <1500 g between 2010 and 2016). We first did a retrospective analysis using regression modeling of ligation population. We then performed a case-control study comparing a ligation group with infants matched by gestational age, postnatal age, and preligation respiratory condition (ventilator mode, mean airway pressure [MAP], and fraction of inspired oxygen [FiO2]). Respiratory improvement was defined as either extubation, downgrading of ventilatory mode, reduction in MAP >25%, or decrease in FiO2 >25%. RESULTS: Forty-five (42%) of 107 preterm infants (gestational age 25.5 ± 1.7 weeks) with ligation showed respiratory improvement at 7 days. Infants on high frequency ventilation (HFV) were more likely to have respiratory improvement (aOR 5.03, 95% CI [1.14-22.18]). In matched-control analysis of 89 pairs, there was no difference in respiratory improvement. Among infants on HFV, the ligation group had an increase in MAP during 3 days prior to ligation. For infants on conventional ventilation, the ligation group had higher MAP and FiO2 than the control group during the first 2-3 postoperative days. CONCLUSIONS: Among infants undergoing PDA ligation, those on HFV were more likely to have respiratory improvement in the first week, possibly because of the prevention of further respiratory deterioration. For infants on conventional ventilation, ligation was associated with higher respiratory support in the immediate postligation period without respiratory benefits at 7 days. As HFV was used as a rescue mode, our findings suggest that those with worse lung disease may achieve greater short term benefit from PDA ligation.

Retrospective natural history of thymidine kinase 2 deficiency.

BACKGROUND: Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. OBJECTIVE: To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. METHODS: The study was conducted by 42 investigators across 31 academic medical centres. RESULTS: We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion. CONCLUSIONS: In TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder.

Investigating the Experiences of Childhood Cancer Patients and Parents Participating in Optional Nontherapeutic Clinical Research Studies in the UK.

BACKGROUND: While the majority of childhood cancer clinical trials are treatment related, additional optional research investigations may be carried out that do not directly impact on treatment. It is essential that these studies are conducted ethically and that the experiences of families participating in these studies are as positive as possible. METHODS: A questionnaire study was carried out to investigate the key factors that influence why families choose to participate in optional nontherapeutic research studies, the level of understanding of the trials involved, and the experiences of participation. RESULTS: A total of 100 participants from six UK centers were studied; 77 parents, 10 patients >16 years, and 13 patients aged 8-15 years. Ninety-seven percent of parents and 90% of patients felt that information provided prior to study consent was of the right length, with 52% of parents and 65% of patients fully understanding the information provided. Seventy-four percent of parents participated in research studies in order to "do something important", while 74% of patients participated "to help medical staff". Encouragingly, <5% of participants felt that their clinical care would be negatively affected if they did not participate. Positive aspects of participation included a perception of increased attention from medical staff. Negative aspects included spending longer periods in hospital and the requirement for additional blood samples. Ninety-six percent of parents and 87% of patients would participate in future studies. CONCLUSIONS: The study provides an insight into the views of childhood cancer patients and their parents participating in nontherapeutic clinical research studies. Overwhelmingly, the findings suggest that participation is seen as a positive experience.

Klippel-Trénaunay Syndrome: Need for Careful Clinical Classification.

Klippel-Trénaunay syndrome (KTS) is a rare congenital malformation characterized by a triad of clinical presentations: (1) capillary malformations manifesting as a "port wine stain"; (2) limb hypertrophy; and (3) venous varicosities. It is distinguished from Parkes-Weber syndrome by the absence of substantial arteriovenous shunting. Due to the clinical implications of an arteriovenous fistula, differentiation between the two syndromes is important, as the prognosis and treatment greatly differ. We present a series of 5 cases of suspected KTS, while emphasizing the difficulties in distinguishing KTS from Parkes-Weber syndrome without diagnostic imaging and underscoring the importance of accurately classifying patients with the appropriate syndrome.

Comparison of time utilization in an academic inpatient versus an outpatient vascular laboratory.

PURPOSE: Efficient, cost-effective services in vascular laboratories (VLs) will be required in tomorrow's health care environment. Inpatient VLs (IPVL) are burdened with complex patients, excessive workload, and a high percentage of bedside tests. Outpatient VLs (OPVL) are therefore presumed to be more productive and efficient. We compared time utilization in OPVLs and IPVL to test this hypothesis. METHODS: Vascular sonographers at an academic IPVL and OPVL were asked to track their daily activities during five consecutive weekdays. Test type, scan time, delays in patient arrival, preparation for the test, computer entry, and administrative time (patient- and non-patient-related) were logged. RESULTS: Delay in patient arrival and non-patient-related administration activities were both significantly greater in the OPVL (p < 0.01 and 0.03, respectively). Actual scan time occupied only 38.8% of the technologist's day, with the rest spent on patient- and non-patient-related activities. CONCLUSIONS: No appreciable differences were noted between IPVL and OPVL in most of the efficiency parameters measured. General administration time and delay in patient arrival were greater in the OPVL. Thus, OPVL were not more efficient than IPVL. In order to maximize efficiency in the OPVL, non-patient-related activities, which occupy over a quarter of the daily workday, must be shifted from technologists to support staff. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound 44:540-544, 2016.

Barriers to shared decisions in the most serious of cancers: a qualitative study of patients with pancreatic cancer treated in the UK.

BACKGROUND: Less than 20% of patients with pancreatic cancer present with localized, potentially curable tumours. Even when potentially curative surgery is possible, mortality is high. Only 20-25% of patients who have had resected ductal adenocarcinoma of the pancreatic head survive 5 years. Other treatments include chemotherapy, radiotherapy and palliative care. AIM: To explore patients' perceptions of barriers to shared decision making in a condition in which shared decision making might be difficult. METHOD: Thematic analysis of narrative interviews with 32 people diagnosed with pancreatic cancer in the UK; interviews with a social scientist, usually in people's homes. RESULTS: We found that barriers to shared decisions include the idea that investigations are conducted to determine whether the patient qualifies for surgery, rather than to establish whether surgery is an option to consider; a sense of being pressured to accept treatment, a sense that in a life-threatening situation, there are no 'real options'; and the confusion that can be caused when clinical opinions differ. CONCLUSION: We need to ask how patients can be expected to engage in an informed, shared decision if they are made to feel that they are one of the 'winners' if they qualify for surgery. When each treatment decision might have serious consequences for a patient's remaining months, we suggest that there is a particularly strong imperative to make sure that the patient is not subject to other people's assumptions about what is best for them and that patients are offered the opportunity to share in decisions.

Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model.

Many neurological conditions are caused by immensely heterogeneous gene mutations. The diagnostic process is often long and complex with most patients undergoing multiple invasive and costly investigations without ever reaching a conclusive molecular diagnosis. The advent of massively parallel, next-generation sequencing promises to revolutionize genetic testing and shorten the 'diagnostic odyssey' for many of these patients. We performed a pilot study using heterogeneous ataxias as a model neurogenetic disorder to assess the introduction of next-generation sequencing into clinical practice. We captured 58 known human ataxia genes followed by Illumina Next-Generation Sequencing in 50 highly heterogeneous patients with ataxia who had been extensively investigated and were refractory to diagnosis. All cases had been tested for spinocerebellar ataxia 1-3, 6, 7 and Friedrich's ataxia and had multiple other biochemical, genetic and invasive tests. In those cases where we identified the genetic mutation, we determined the time to diagnosis. Pathogenicity was assessed using a bioinformatics pipeline and novel variants were validated using functional experiments. The overall detection rate in our heterogeneous cohort was 18% and varied from 8.3% in those with an adult onset progressive disorder to 40% in those with a childhood or adolescent onset progressive disorder. The highest detection rate was in those with an adolescent onset and a family history (75%). The majority of cases with detectable mutations had a childhood onset but most are now adults, reflecting the long delay in diagnosis. The delays were primarily related to lack of easily available clinical testing, but other factors included the presence of atypical phenotypes and the use of indirect testing. In the cases where we made an eventual diagnosis, the delay was 3-35 years (mean 18.1 years). Alignment and coverage metrics indicated that the capture and sequencing was highly efficient and the consumable cost was ∼£400 (€460 or US$620). Our pathogenicity interpretation pathway predicted 13 different mutations in eight different genes: PRKCG, TTBK2, SETX, SPTBN2, SACS, MRE11, KCNC3 and DARS2 of which nine were novel including one causing a newly described recessive ataxia syndrome. Genetic testing using targeted capture followed by next-generation sequencing was efficient, cost-effective, and enabled a molecular diagnosis in many refractory cases. A specific challenge of next-generation sequencing data is pathogenicity interpretation, but functional analysis confirmed the pathogenicity of novel variants showing that the pipeline was robust. Our results have broad implications for clinical neurology practice and the approach to diagnostic testing.

Engaging men with penile cancer in qualitative research: reflections from an interview-based study.

AIM: To explore the challenges of engaging men with penile cancer in qualitative interview research. BACKGROUND: Qualitative interviewing offers an ideal tool for exploring men's experiences of illness, complementing and providing context to gendered health inequalities identified in epidemiological research on men. But conducting interviews with men can be challenging and embarking on a qualitative interview study with males can feel like a daunting task, given the limited amount of practical, gender-sensitive guidance for researchers. Reflecting on a researcher's experience of conducting qualitative research on men with penile cancer, this paper explores the potential challenges of interviewing this group, but also documents how engagement and data collection were achieved. REVIEW METHODS: This is a reflective paper, informed by the experiences of a male researcher (KW) with no nurse training, who conducted 28 interviews with men who had been treated for penile cancer. The researcher's experiences are reported in chronological order, from the methodological challenges of recruitment to those of conducting the interview. IMPLICATIONS FOR PRACTICE/RESEARCH: The paper offers a resource for the novice researcher, highlighting some advantages and disadvantages of conducting qualitative interview research as a nurse researcher, as well as recommendations on how to overcome challenges. CONCLUSION: Engaging men with penile cancer in qualitative interview raises practical, methodological, ethical and emotional challenges for the researcher. However, when these challenges are met, men will talk about their health. Methodological procedures must enable an open and ongoing dialogue with clinical gatekeepers and potential participants to promote engagement. Support from colleagues is essential for any interviewer, no matter how experienced the researcher is.

Faculty perception of resident promotion and prevention associated behaviors in the operating room to facilitate intra-operative learning.

BACKGROUND: Previous work has demonstrated that residents are able to accurately perceive the intraoperative motivational style of faculty. Additionally, alignment of motivational style between residents and faculty has been demonstrated to enhance resident intraoperative autonomy. This study evaluated if faculty perception of resident behaviors aligned with resident self-perception in order to identify ways of enhancing intraoperative learning. METHODS: General surgery residents were asked to complete a self-assessment evaluating their own intraoperative behaviors. Conversely, faculty rated how strongly the residents exhibited these behaviors in the operating room. RESULTS: Of the 10 intraoperative behaviors that were evaluated, eight demonstrated no correlation between resident self-perception and faculty perception of resident behavior. Similarly, inconsistent correlations emerged when behaviors were assessed according to the self-reported gender and race of the resident. CONCLUSION: Faculty are not able to accurately perceive the motivational style of residents. Strategies to improve faculty perception of resident motivational style may enhance intraoperative learning.

From Athlete to Surgeon: Examining Sports and Grit Among General Surgery Residents.

OBJECTIVE: The transition of Step 1 to pass/fail has generated concerns over selecting promising candidates. Holistic reviews integrate other proficiencies, including extracurriculars such as sports. Grit - defined as perseverance and passion for long-term goals - has been positively associated with competitive activities and is predictive of academic success. The prevalence and impact of sports participation and its relationship to grit in the general surgery resident population has not been described and was investigated in this study. DESIGN: Surveys measuring sports participation and grit were distributed after the 2021 ABSITE. Grit was assessed through the short grit scale. Inferential statistics were performed. SETTING/PARTICIPANTS: General surgery residents in all US training programs who completed the 2021 ABSITE. RESULTS: Of 5468 respondents (response rate 59.6%), 2,548 (46.7%) were female, 917 (17.4%) URiM, 2171 (39.8%) married, and 1,069 (19.6%) parents. About 4284 (83.8%) residents reported being involved in competitive sports. Grit was higher in residents with a competitive sports history (3.67 ± 0.58 versus 3.60 ± 0.61, p = 0.0022). Greater time commitment and being part of a team was positively correlated to grit (both p < 0.0001). Individuals that self-identified as underrepresented in medicine (URiM) had higher grit (3.71 ± 0.59 versus 3.65 ± 0.58 for non-URiM, p < 0.0001) as did female (p = 0.0016), married residents (p < 0.0001), and parents (p < 0.0001). Being an athlete was associated with significantly higher grit for nearly all demographic subgroups, including URiM (p = 0.0068), married (p = 0.0175), and parents (p = 0.0487). CONCLUSIONS: Higher grit was found in athletes and marginalized groups including females, URiM, and residents that were married or parents. Our data suggests that recruiting applicants of diverse backgrounds and experiences will result in a grittier cohort; a group potentially equipped to weather the arduous surgical residency training path. Recruiting residents with characteristics associated with higher grit can potentially impact diversity of the surgical workforce.