Tiered analysis of whole-exome sequencing for epilepsy diagnosis.

It is thought that despite highly variable phenotypic expression, 70-80% of all epileptic cases are caused by one or more genetic mutations. Next generation sequencing technologies, such as whole exome sequencing (WES), can be used in a diagnostic or research setting to identify genetic mutations which may have significant prognostic implications for patients and their families. In this study, 398 genes associated with epilepsy or recurrent seizures were stratified into tiers based on genotype-phenotype concordance, tissue gene expression, frequency of affected individuals with mutations and evidence from functional and family studies. WES was completed on 14 DNA samples (2 with known mutations in SCN1A and 12 with no known mutations) from individuals diagnosed with epilepsy using an Ion AmpliSeq approach. WES confirmed positive SCN1A mutations in two samples. In n = 5/12 samples (S-3 to -14) we identified potentially causative mutations across five different genes. S-5 was identified to have a novel missense mutation in CCM2; S-6 a novel frameshift mutation identified in ADGRV1; S-10 had a previously reported pathogenic mutation in PCDH19, whilst a novel missense mutation in PCDH19 was shown in S-12; and S-13 identified to have separate missense mutations in KCNA2 and NPRL3. The application of WES followed by a targeted variant prioritization approach allowed for the discovery of potentially causative mutations in our cohort of previously undiagnosed epilepsy patients.

The NRP1 migraine risk variant shows evidence of association with menstrual migraine.

BACKGROUND: In 2016, a large meta-analysis brought the number of susceptibility loci for migraine to 38. While sub-type analysis for migraine without aura (MO) and migraine with aura (MA) found some loci showed specificity to MO, the study did not test the loci with respect to other subtypes of migraine. This study aimed to test the hypothesis that single nucleotide polymorphisms (SNPs) robustly associated with migraine are individually or collectively associated with menstrual migraine (MM). METHODS: Genotyping of migraine susceptibility SNPs was conducted using the Agena MassARRAY platform on DNA samples from 235 women diagnosed with menstrual migraine as per International Classification for Headache Disorders II (ICHD-II) criteria and 140 controls. Alternative genotyping methods including restriction fragment length polymorphism, pyrosequencing and Sanger sequencing were used for validation. Statistical analysis was performed using PLINK and SPSS. RESULTS: Genotypes of 34 SNPs were obtained and investigated for their potential association with menstrual migraine. Of these SNPs, rs2506142 located near the neuropilin 1 gene (NRP1), was found to be significantly associated with menstrual migraine (p = 0.003). Genomic risk scores were calculated for all 34 SNPs as well as a subset of 7 SNPs that were nearing individual significance. Overall, this analysis suggested these SNPs to be weakly predictive of MM, but of no prognostic or diagnostic value. CONCLUSIONS: Our results suggest that NRP1 may be important in the etiology of MM. It also suggests some genetic commonality between common migraine subtypes (MA and MO) and MM. The identification of associated SNPs may be the starting point to a better understanding of how genetic factors may contribute to the menstrual migraine sub-type.

De novo mutations of KIAA2022 in females cause intellectual disability and intractable epilepsy.

BACKGROUND: Mutations in the KIAA2022 gene have been reported in male patients with X-linked intellectual disability, and related female carriers were unaffected. Here, we report 14 female patients who carry a heterozygous de novo KIAA2022 mutation and share a phenotype characterised by intellectual disability and epilepsy. METHODS: Reported females were selected for genetic testing because of substantial developmental problems and/or epilepsy. X-inactivation and expression studies were performed when possible. RESULTS: All mutations were predicted to result in a frameshift or premature stop. 12 out of 14 patients had intractable epilepsy with myoclonic and/or absence seizures, and generalised in 11. Thirteen patients had mild to severe intellectual disability. This female phenotype partially overlaps with the reported male phenotype which consists of more severe intellectual disability, microcephaly, growth retardation, facial dysmorphisms and, less frequently, epilepsy. One female patient showed completely skewed X-inactivation, complete absence of RNA expression in blood and a phenotype similar to male patients. In the six other tested patients, X-inactivation was random, confirmed by a non-significant twofold to threefold decrease of RNA expression in blood, consistent with the expected mosaicism between cells expressing mutant or normal KIAA2022 alleles. CONCLUSIONS: Heterozygous loss of KIAA2022 expression is a cause of intellectual disability in females. Compared with its hemizygous male counterpart, the heterozygous female disease has less severe intellectual disability, but is more often associated with a severe and intractable myoclonic epilepsy.

Genetic and neurodevelopmental spectrum of SYNGAP1-associated intellectual disability and epilepsy.

OBJECTIVE: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations. METHODS: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed. RESULTS: We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3' and 5' exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15. CONCLUSIONS: SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.

A national stakeholder consensus study of challenges and priorities for clinical learning environments in postgraduate medical education.

BACKGROUND: High quality clinical learning environments (CLE) are critical to postgraduate medical education (PGME). The understaffed and overcrowded environments in which many residents work present a significant challenge to learning. The purpose of this study was to develop a national expert group consensus amongst stakeholders in PGME to; (i) identify important barriers and facilitators of learning in CLEs and (ii) indicate priority areas for improvement. Our objective was to provide information to focus efforts to provide high quality CLEs. METHODS: Group Concept Mapping (GCM) is an integrated mixed methods approach to generating expert group consensus. A multi-disciplinary group of experts were invited to participate in the GCM process via an online platform. Multi-dimensional scaling and hierarchical cluster analysis were used to analyse participant inputs in regard to barriers, facilitators and priorities. RESULTS: Participants identified facilitators and barriers in ten domains within clinical learning environments. Domains rated most important were those which related to residents' connection to and engagement with more senior doctors. Organisation and conditions of work and Time to learn with senior doctors during patient care were rated as the most difficult areas in which to make improvements. CONCLUSIONS: High quality PGME requires that residents engage and connect with senior doctors during patient care, and that they are valued and supported both as learners and service providers. Academic medicine and health service managers must work together to protect these elements of CLEs, which not only shape learning, but impact quality of care and patient safety.

Unique X-linked familial FSGS with co-segregating heart block disorder is associated with a mutation in the NXF5 gene.

Focal segmental glomerulosclerosis (FSGS) is the consequence of a disease process that attacks the kidney's filtering system, causing serious scarring. More than half of FSGS patients develop chronic kidney failure within 10 years, ultimately requiring dialysis or renal transplantation. There are currently several genes known to cause the hereditary forms of FSGS (ACTN4, TRPC6, CD2AP, INF2, MYO1E and NPHS2). This study involves a large, unique, multigenerational Australian pedigree in which FSGS co-segregates with progressive heart block with apparent X-linked recessive inheritance. Through a classical combined approach of linkage and haplotype analysis, we identified a 21.19 cM interval implicated on the X chromosome. We then used a whole exome sequencing approach to identify two mutated genes, NXF5 and ALG13, which are located within this linkage interval. The two mutations NXF5-R113W and ALG13-T141L segregated perfectly with the disease phenotype in the pedigree and were not found in a large healthy control cohort. Analysis using bioinformatics tools predicted the R113W mutation in the NXF5 gene to be deleterious and cellular studies support a role in the stability and localization of the protein suggesting a causative role of this mutation in these co-morbid disorders. Further studies are now required to determine the functional consequence of these novel mutations to development of FSGS and heart block in this pedigree and to determine whether these mutations have implications for more common forms of these diseases in the general population.

Case-control study of ADARB1 and ADARB2 gene variants in migraine.

BACKGROUND: Migraine causes crippling attacks of severe head pain along with associated nausea, vomiting, photophobia and/or phonophobia. The aim of this study was to investigate single nucleotide polymorphisms (SNPs) in the adenosine deaminase, RNA-specific, B1 (ADARB1) and adenosine deaminase, RNA specific, B2 (ADARB2) genes in an Australian case-control Caucasian population for association with migraine. Both candidate genes are highly expressed in the central nervous system and fit criteria for migraine neuropathology. SNPs in the ADARB2 gene were previously found to be positively associated with migraine in a pedigree-based genome wide association study using the genetic isolate of Norfolk Island, Australia. The ADARB1 gene was also chosen for investigation due to its important function in editing neurotransmitter receptor transcripts. METHODS: Four SNPs in ADARB1 and nine in ADARB2 were selected by inspecting blocks of linkage disequilibrium in Haploview for genotyping using either TaqMan or Sequenom assays. These SNPs were genotyped in two-hundred and ninety one patients who satisfied the International Classification of Headache Disorders-II 2004 diagnostic criteria for migraine, and three-hundred and fourteen controls, and PLINK was used for association testing. RESULTS: Chi-square analysis found no significant association between any of the SNPs tested in the ADARB1 and ADARB2 genes in this study and the occurrence of migraine. CONCLUSIONS: In contrast to findings that SNPs in the ADARB2 gene were positively associated with migraine in the Norfolk Island population, we find no evidence to support the involvement of RNA editing genes in migraine susceptibility in an Australian Caucasian population.

Investigation of brain-derived neurotrophic factor (BDNF) gene variants in migraine.

OBJECTIVE: A number of observations have suggested that brain-derived neurotrophic factor (BDNF) plays a role in migraine pathophysiology. This study investigates whether variants in the BDNF gene are associated with migraine in an Australian case-control population. BACKGROUND: BDNF has an important role in neural growth, development, and survival in the central nervous system and is an important modulator of central and peripheral pain responses. Variants in BDNF, in particular the functional Val66Met polymorphism (rs6265), have been found to be associated with a number of psychiatric disorders, cognitive function, and obesity. As BDNF has been found to be differentially expressed in a number of aspects related to migraine, we tested for association between single nucleotide polymorphisms (SNPs) in BDNF and migraine. METHODS: Five SNPs in the BDNF locus (rs1519480, rs6265, rs712507, rs2049046, and rs12273363) were genotyped initially in a cohort of 277 migraine cases, including 172 diagnosed with migraine with aura (MA) and 105 with migraine without aura (MO), and 277 age- and sex-matched controls. Three of these SNPs (rs6265, rs2049046, and rs12273363) were subsequently genotyped in a second cohort of 580 migraineurs, including 473 diagnosed with MA and 105 with MO, and 580 matched controls. RESULTS: BDNF SNPs rs1519480, rs6265, rs712507, and rs12273363 were not significantly associated with migraine. However, rs2049046 showed a significant association with migraine, and in particular, MA in the first cohort. In the second cohort, although an increase in the rs2049046 T-allele frequency was observed in migraine cases, and in both MA and MO subgroups, it was not significantly different from controls. Analysis of data combined from both cohorts for rs2049046 showed significant differences in the genotypic and allelic distributions for this marker in both migraine and the MA subgroup. CONCLUSION: This study confirmed previous studies that the functional BDNF SNP rs6265 (Val66Met) is not associated with migraine. However, we found that rs2049046, which resides at the 5' end of one the BDNF transcripts, may be associated with migraine, suggesting that further investigations of this SNP may be warranted.

Association of oestrogen-receptor gene (ESR1) polymorphisms with migraine in the large Norfolk Island pedigree.

BACKGROUND: Oestrogen receptor 1 ( ESR1) is located in region 6q25.1 and encodes a ligand-activated transcription factor composed of several domains important for hormone binding and transcription activation. Progesterone receptor ( PGR) is located in 11q22-23 and mediates the role of progesterone interacting with different transcriptional co-regulators. ESR1 and PGR have previously been implicated in migraine susceptibility. Here, we report the results of an association study of these genes in a migraine pedigree from the genetic isolate of Norfolk Island, a population descended from a small number of Isle of Man "Bounty Mutineer" and Tahitian founders. METHODS: A significant number of molecular markers in the ESR1 (143) and PGR (43) genes were evaluated in a sample of 285 related individuals (135 males; 150 females). A pedigree-based analysis in the GenABEL package was used to analyse the results. RESULTS AND CONCLUSIONS: A total of 10 markers in the ESR1 gene showed association with migraine ( P < 0.05) in the Norfolk Island population. No association was detected with PGR . Three haplotypes in ESR1 were found to be associated with migraine ( P = 0.004, 0.03, 0.005). Future genetic studies in larger populations and expression analysis are required to clarify the role of ESR1 in migraine susceptibility.

Association of a GRIA3 gene polymorphism with migraine in an Australian case-control cohort.

BACKGROUND: The excitatory neurotransmitter glutamate has been implicated in both the hyperexcitability required for cortical spreading depression as well as activation of the trigeminovascular system required for the allodynia associated with migraine. Polymorphisms in the glutamate receptor ionotropic amino-3-hydroxy-5-methyl-4-isoxazole-propionin acid 1 (GRIA1) and GRIA3 genes that code for 2 of 4 subunits of the glutamate receptor have been previously associated with migraine in an Italian population. In addition, the GRIA3 gene is coded within a previously identified migraine susceptibility locus at Xq24. This study investigated the previously associated polymorphisms in both genes in an Australian case-control population. METHODS: Variants in GRIA1 and GRIA3 were genotyped in 472 unrelated migraine cases and matched controls, and data were analyzed for association. RESULTS: Analysis showed no association between migraine and the GRIA1 gene. However, association was observed with the GRIA3 single nucleotide polymorphism (SNP) rs3761555 (P=.008). CONCLUSION: The results of this study confirmed the previous report of association at the rs3761555 SNP within the migraine with aura subgroup of migraineurs. However, the study identified association with the inverse allele suggesting that rs3761555 may not be the causative SNP but is more likely in linkage disequilibrium with another causal variant in both populations. This study supports the plethora of evidence suggesting that glutamate dysfunction may contribute to migraine susceptibility, warranting further investigation of the glutamatergic system and particularly of the GRIA3 gene.

Genetic variation in cytokine-related genes and migraine susceptibility.

Migraine is classified by the World Health Organization (WHO) as being one of the top 20 most debilitating diseases. According to the neurovascular hypothesis, neuroinflammation may promote the activation and sensitisation of meningeal nociceptors, inducing the persistent throbbing headache characterized in migraine. The tumor necrosis factor (TNF) gene cluster, made up of TNFα, lymphotoxin α (LTA), and lymphotoxin ß (LTB), has been implicated to influence the intensity and duration of local inflammation. It is thought that sterile inflammation mediated by LTA, LTB, and TNFα contributes to threshold brain excitability, propagation of neuronal hyperexcitability and thus initiation and maintenance of a migraine attack. Previous studies have investigated variants within the TNF gene cluster region in relation to migraine susceptibility, with largely conflicting results. The aim of this study was to expand on previous research and utilize a large case-control cohort and range of variants within the TNF gene cluster to investigate the role of the TNF gene cluster in migraine. Nine single nucleotide polymorphisms (SNPs) were selected for investigation as follows: rs1800683, rs2229094, rs2009658, rs2071590, rs2239704, rs909253, rs1800630, rs1800629, and rs3093664. No significant association with migraine susceptibility was found for any of the SNPs tested, with further testing according to migraine subtype and gender also showing no association for disease risk. Haplotype analysis showed that none of the tested haplotypes were significantly associated with migraine.

Medical school attrition-beyond the statistics a ten year retrospective study.

BACKGROUND: Medical school attrition is important--securing a place in medical school is difficult and a high attrition rate can affect the academic reputation of a medical school and staff morale. More important, however, are the personal consequences of dropout for the student. The aims of our study were to examine factors associated with attrition over a ten-year period (2001-2011) and to study the personal effects of dropout on individual students. METHODS: The study included quantitative analysis of completed cohorts and qualitative analysis of ten-year data. Data were collected from individual student files, examination and admission records, exit interviews and staff interviews. Statistical analysis was carried out on five successive completed cohorts. Qualitative data from student files was transcribed and independently analysed by three authors. Data was coded and categorized and key themes were identified. RESULTS: Overall attrition rate was 5.7% (45/779) in 6 completed cohorts when students who transferred to other medical courses were excluded. Students from Kuwait and United Arab Emirates had the highest dropout rate (RR = 5.70, 95% Confidence Intervals 2.65 to 12.27;p < 0.0001) compared to Irish and EU students combined. North American students had a higher dropout rate than Irish and EU students; RR = 2.68 (1.09 to 6.58;p = 0.027) but this was not significant when transfers were excluded (RR = 1.32(0.38, 4.62);p = 0.75). Male students were more likely to dropout than females (RR 1.70, .93 to 3.11) but this was not significant (p = 0.079).Absenteeism was documented in 30% of students, academic difficulty in 55.7%, social isolation in 20%, and psychological morbidity in 40% (higher than other studies). Qualitative analysis revealed recurrent themes of isolation, failure, and despair. Student Welfare services were only accessed by one-third of dropout students. CONCLUSIONS: While dropout is often multifactorial, certain red flag signals may alert us to risk of dropout including non-EU origin, academic struggling, absenteeism, social isolation, depression and leave of absence. Psychological morbidity amongst dropout students is high and Student Welfare services should be actively promoted. Absenteeism should prompt early intervention. Behind every dropout statistic lies a personal story. All medical schools have a duty of care to support students who leave the medical programme.

From Pre-Service to Professional Teaching: A Longitudinal Study of Two LGBTQ+-identifying First-Year Elementary Teachers' Experiences.

Researchers have documented that being an LGBTQ+-identifying teacher can present particular challenges and marginalizing experiences. This longitudinal, qualitative study is a follow-up to a year-long endeavor documenting the experiences of one gay and one lesbian-identifying preservice teachers as they navigated school and a professional job search. In this study, we followed these same two teachers as they entered their first year of professional teaching in academic year 2015-2016, and we present the experiences, difficulties, challenges, and navigation of these two LGTBQ+-identifying elementary teachers. The two participants also recently (2020) reflected back on their first year of professional teaching some four years prior, and we used their insights to chronicle another layer of reflection on their professional experiences. With these elementary teachers' experiences at the center, this study offers implications for school systems about how to recognize, support, and advocate for LGBTQ+-identifying teachers, particularly those new to the profession.

Identification of molecular genetic factors that influence migraine.

Migraine is a common neurological disorder with a strong genetic basis. However, the complex nature of the disorder has meant that few genes or susceptibility loci have been identified and replicated consistently to confirm their involvement in migraine. Approaches to genetic studies of the disorder have included analysis of the rare migraine subtype, familial hemiplegic migraine with several causal genes identified for this severe subtype. However, the exact genetic contributors to the more common migraine subtypes are still to be deciphered. Genome-wide studies such as genome-wide association studies and linkage analysis as well as candidate genes studies have been employed to investigate genes involved in common migraine. Neurological, hormonal and vascular genes are all considered key factors in the pathophysiology of migraine and are a focus of many of these studies. It is clear that the influence of individual genes on the expression of this disorder will vary. Furthermore, the disorder may be dependent on gene--gene and gene--environment interactions that have not yet been considered. In addition, identifying susceptibility genes may require phenotyping methods outside of the International Classification of Headache Disorders II criteria, such as trait component analysis and latent class analysis to better define the ambit of migraine expression.

On Becoming an LGBTQ+-Identifying Teacher: A Year-Long Study of Two Gay and Lesbian Preservice Elementary Teachers.

LGBTQ+-identifying preservice teachers must navigate several different contexts, including the university and public schools, wherein they must make decisions about being open ("out") regarding their LGBTQ+ identities. However, the small amount of research to date has typically focused on the experiences of LGBTQ+ educators already actively working in public schools. In this year-long, qualitative case study, we present the experiences, perspectives, and challenges of two elementary preservice teachers who identify as gay and lesbian through their year-long student teaching placement. The study offers implications for teacher education programs about often overlooked ways to recruit, support, and advocate for LGBTQ+ preservice teachers.

Larval survival of fuller's rose weevil, Naupactus cervinus, on common groundcover species in orchards of New Zealand kiwifruit.

Fuller's rose weevil, Naupactus cervinus (Boheman) (Curculionidae: Entiminae), is an important quarantine pest of New Zealand kiwifruit exported to Asian markets. Both adults and larvae are considered to be polyphagous. In this study, the survival of larval N. cervinus was estimated on common groundcover species of kiwifruit (Actinidia spp.) in the Bay of Plenty, the main region in New Zealand where kiwifruit is grown. The botanical composition of groundcover in commercial kiwifruit orchards, characterised by survey, was dominated by ryegrass (Lolium perenne), with white clover (Trifolium repens), creeping buttercup (Ranunculus repens), wild strawberry (Duchesnea indica) and broadleaf dock (Rumex obtusifolius) in lower abundance. Survival to mature larvae or adult was relatively low (.11%) for N. cervinus introduced as neonates to field plots or potted ryegrass, white clover and broadleaf dock. White clover was a more favourable host for survival to adults than ryegrass. This study suggests that increased survival of N. cervinus larvae may occur where white clover and large dock plants are abundant, but that survival is likely to be highly variable because of the heterogeneous availability of preferred host plants and host plant quality. These data suggest that larval polyphagy is a strategy that enables N. cervinus to persist at low densities in kiwifruit orchards despite variation in the quality and diversity of groundcover.

Continuing professional development and Irish hospital doctors: a survey of current use and future needs.

Doctors rate clinical relevance and applicability as the most important determinants of continuing professional development (CPD) course selection. This study examined patterns of current CPD practice and perceived CPD needs among hospital doctors in Ireland across various clinical specialties. A cross-sectional survey was administered to doctors, focusing on the areas of training needs analysis, CPD course content and preferred course format. In total, 547 doctors identified doctor-patient communication as the skill ranked highest for importance and level of current performance. Workload/time organisation and stress management were areas where a skills deficiency was identified. Non-clinical CPD topics, including resilience training, management and communication skills, were preferred areas for future CPD offerings. All respondents favoured interactive, hands-on sessions. CPD course completion and preference patterns differed significantly across clinical specialties. These results highlight the importance of considering the individual needs and preferences of clinicians across clinical specialties to facilitate more effective CPD programmes.

Protocol for a realist review of workplace learning in postgraduate medical education and training.

BACKGROUND: Postgraduate medical education and training (PGMET) is a complex social process which happens predominantly during the delivery of patient care. The clinical learning environment (CLE), the context for PGMET, shapes the development of the doctors who learn and work within it, ultimately impacting the quality and safety of patient care. Clinical workplaces are complex, dynamic systems in which learning emerges from non-linear interactions within a network of related factors and activities. Those tasked with the design and delivery of postgraduate medical education and training need to understand the relationship between the processes of medical workplace learning and these contextual elements in order to optimise conditions for learning. We propose to conduct a realist synthesis of the literature to address the overarching questions; how, why and in what circumstances do doctors learn in clinical environments? This review is part of a funded projected with the overall aim of producing guidelines and recommendations for the design of high quality clinical learning environments for postgraduate medical education and training. METHODS: We have chosen realist synthesis as a methodology because of its suitability for researching complexity and producing answers useful to policymakers and practitioners. This realist synthesis will follow the steps and procedures outlined by Wong et al. in the RAMESES Publication Standards for Realist Synthesis and the Realist Synthesis RAMESES Training Materials. The core research team is a multi-disciplinary group of researchers, clinicians and health professions educators. The wider research group includes experts in organisational behaviour and human resources management as well as the key stakeholders; doctors in training, patient representatives and providers of PGMET. DISCUSSION: This study will draw from the published literature and programme, and substantive, theories of workplace learning, to describe context, mechanism and outcome configurations for PGMET. This information will be useful to policymakers and practitioners in PGMET, who will be able to apply our findings within their own contexts. Improving the quality of clinical learning environments can improve the performance, humanism and wellbeing of learners and improve the quality and safety of patient care. SYSTEMATIC REVIEW REGISTRATION: The review is not registered with the PROSPERO International Prospective Register of Systematic Reviews as the review objectives relate solely to education outcomes.

DNM1 encephalopathy: A new disease of vesicle fission.

OBJECTIVE: To evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling. METHODS: We reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function. RESULTS: We identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function. CONCLUSIONS: The phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention.

Designing Learning Outcomes for Handoff Teaching of Medical Students Using Group Concept Mapping: Findings From a Multicountry European Study.

PURPOSE: To develop, by consultation with an expert group, agreed learning outcomes for the teaching of handoff to medical students using group concept mapping. METHOD: In 2013, the authors used group concept mapping, a structured mixed-methods approach, applying both quantitative and qualitative measures to identify an expert group's common understanding about the learning outcomes for training medical students in handoff. Participants from four European countries generated and sorted ideas, then rated generated themes by importance and difficulty to achieve. The research team applied multidimensional scaling and hierarchical cluster analysis to analyze the themes. RESULTS: Of 127 experts invited, 45 contributed to the brainstorming session. Twenty-two of the 45 (48%) completed pruning, sorting, and rating phases. They identified 10 themes with which to select learning outcomes and operationally define them to form a basis for a curriculum on handoff training. The themes "Being able to perform handoff accurately" and "Demonstrate proficiency in handoff in workplace" were rated as most important. "Demonstrate proficiency in handoff in simulation" and "Engage with colleagues, patients, and carers" were rated most difficult to achieve. CONCLUSIONS: The study identified expert consensus for designing learning outcomes for handoff training for medical students. Those outcomes considered most important were among those considered most difficult to achieve. There is an urgent need to address the preparation of newly qualified doctors to be proficient in handoff at the point of graduation; otherwise, this is a latent error within health care systems. This is a first step in this process.