Formación de la residencia de Urología en Grecia. Resultados de la primera encuesta nacional / Urology residency training in Greece. Results from the first national resident survey

Contexto y objetivos: Esta es la primera encuesta nacional que evalúa los programas de la residencia de Urología en Grecia. El objetivo principal de este estudio es evaluar el nivel de confianza y la percepción de los residentes griegos de Urología respecto a su programa educativo y detectar las áreas susceptibles a ser mejoradas.Material y métodosSe elaboró una encuesta de 51 preguntas a través de una plataforma electrónica y fue respondida por 91 de 104 residentes griegos desde marzo de 2019 hasta mayo de 2019. Se utilizó el test exacto de Fisher, el test de chi-cuadrado y el test de Kruskal-Wallis, con una significación estadística establecida en p=0,05.ResultadosLa satisfacción global de la formación quirúrgica obtuvo una media de 6/10, independientemente de la jornada laboral, de trabajar en un departamento universitario, el año de posgrado (postgraduate year) o el número de residentes en el centro. La mayoría de los residentes no había realizado ninguna ecografía escrotal ni estudios de flujo-presión, pero estaba familiarizado con la ecografía de vías urinarias (KUB). La inserción del catéter doble J y la cistoscopia eran procedimientos conocidos para los residentes. El 70,4% de los residentes señalaron la burocracia como un problema importante. El 80,2% no había realizado ninguna litotricia extracorpórea por ondas de choque, y el 58,2% de los residentes había realizado menos de 10 ureteroscopias. Solo en el último año, los residentes realizaron más de 10 procedimientos de resección transuretral de tumor vesical y de resección transuretral de la próstata. (AU)

Background and objectives: This is the first national survey assessing Greek Urology residency programs. The main objective of this study is to assess the level of confidence and perception of Greek Urology residents regarding their educational program and detect areas of improvement.Material and methodsA 51-question survey was developed via an electronic platform and answered by 91 out of 104 Greek residents from March 2019 until May 2019. Fisher's exact test, chi-squared test and Kruskal–Wallis test were used with statistical significance set at p=.05.ResultsThe median overall satisfaction regarding surgical training was 6/10 regardless of working schedule, working in a University Department, PGY or number of residents in clinic. Most residents have not performed any scrotal ultrasound or pressure-flow-studies; however, they are more familiar with KUB ultrasound. Double-J stent insertion and cystoscopy were common procedures for residents. Bureaucracy was reported as a major issue by 70.4% of residents. ESWL has not been performed by 80.2% of residents, 58.2% residents performed less than 10 ureteroscopies, and only the last year trainees performed more than 10 TURBT and TURP. Most residents mentioned to rarely perform basic steps in many open or laparoscopic urological procedures. Surprisingly, 59.3% of residents have not published any study in peer-reviewed journals. Regarding satisfaction, 44% rarely feel satisfied at work and 59.3% sometimes suffer from burnout. Response rate reached 87.5%. (AU)

Urology residency training in Greece. Results from the first national resident survey.

BACKGROUND AND OBJECTIVES: This is the first national survey assessing Greek Urology residency programs. The main objective of this study is to assess the level of confidence and perception of Greek Urology residents regarding their educational program and detect areas of improvement. MATERIAL AND METHODS: A 51-question survey was developed via an electronic platform and answered by 91 out of 104 Greek residents from March 2019 until May 2019. Fisher's exact test, chi-squared test and Kruskal-Wallis test were used with statistical significance set at p = .05. RESULTS: The median overall satisfaction regarding surgical training was 6/10 regardless of working schedule, working in a University Department, PGY or number of residents in clinic. Most residents have not performed any scrotal ultrasound or pressure-flow-studies; however, they are more familiar with KUB ultrasound. Double-J stent insertion and cystoscopy were common procedures for residents. Bureaucracy was reported as a major issue by 70.4% of residents. ESWL has not been performed by 80.2% of residents, 58.2% residents performed less than 10 ureteroscopies, and only the last year trainees performed more than 10 TURBT and TURP. Most residents mentioned to rarely perform basic steps in many open or laparoscopic urological procedures. Surprisingly, 59.3% of residents have not published any study in peer-reviewed journals. Regarding satisfaction, 44% rarely feel satisfied at work and 59.3% sometimes suffer from burnout. Response rate reached 87.5%. CONCLUSIONS: Considering the results from this survey, regulatory authorities should join forces to establish a structured curriculum of clinical, surgical and research training in Urology across Europe.

Urology residency training in Greece. Results from the first national resident survey. / Formación de la residencia de Urología en Grecia. Resultados de la primera encuesta nacional.

BACKGROUND AND OBJECTIVES: This is the first national survey assessing Greek Urology residency programs. The main objective of this study is to assess the level of confidence and perception of Greek Urology residents regarding their educational program and detect areas of improvement. MATERIAL AND METHODS: A 51-question survey was developed via an electronic platform and answered by 91 out of 104 Greek residents from March 2019 until May 2019. Fisher's exact test, chi-squared test and Kruskal-Wallis test were used with statistical significance set at p=.05. RESULTS: The median overall satisfaction regarding surgical training was 6/10 regardless of working schedule, working in a University Department, PGY or number of residents in clinic. Most residents have not performed any scrotal ultrasound or pressure-flow-studies; however, they are more familiar with KUB ultrasound. Double-J stent insertion and cystoscopy were common procedures for residents. Bureaucracy was reported as a major issue by 70.4% of residents. ESWL has not been performed by 80.2% of residents, 58.2% residents performed less than 10 ureteroscopies, and only the last year trainees performed more than 10 TURBT and TURP. Most residents mentioned to rarely perform basic steps in many open or laparoscopic urological procedures. Surprisingly, 59.3% of residents have not published any study in peer-reviewed journals. Regarding satisfaction, 44% rarely feel satisfied at work and 59.3% sometimes suffer from burnout. Response rate reached 87.5%. CONCLUSIONS: Considering the results from this survey, regulatory authorities should join forces to establish a structured curriculum of clinical, surgical and research training in Urology across Europe.

The laboratory mouse and wild immunology.

The laboratory mouse, Mus musculus domesticus, has been the workhorse of the very successful laboratory study of mammalian immunology. These studies--discovering how the mammalian immune system can work--have allowed the development of the field of wild immunology that is seeking to understand how the immune responses of wild animals contributes to animals' fitness. Remarkably, there have hardly been any studies of the immunology of wild M. musculus domesticus (or of rats, another common laboratory model), but the general finding is that these wild animals are more immunologically responsive, compared with their laboratory domesticated comparators. This difference probably reflects the comparatively greater previous exposure to antigens of these wild-caught animals. There are now excellent prospects for laboratory mouse immunology to make major advances in the field of wild immunology.

High frequency of genomic deletions--and a duplication--in the LIS1 gene in lissencephaly: implications for molecular diagnosis.

BACKGROUND: LIS1 is the main gene causing classical (isolated) lissencephaly predominating in the posterior brain regions (p>a). However, about 40% of patients with this malformation pattern show no abnormality after fluorescence in situ hybridisation (FISH) analysis of the 17p13.3 region and LIS1 sequencing. To investigate whether alternative gene(s) or genomic deletions/duplications of LIS1 may account for the high percentage of individuals who show no abnormalities on FISH and sequencing, we performed multiplex ligation dependent probe amplification assay (MLPA) in a series of patients. METHODS: We initially performed DNA sequencing in 45 patients with isolated lissencephaly with a p>a gradient, in whom FISH had revealed normal results. We subsequently performed MLPA in those who were mutation negative, and long range polymerase chain reaction (PCR) to characterise the breakpoint regions in patients in whom the deletions were small enough. RESULTS: We found LIS1 mutations in 44% of patients (20/45) of the whole sample and small genomic deletions/duplications in 76% of the remaining (19/25). Deletions were much more frequent than duplications (18 vs 1). Overall, small genomic deletions/duplications represented 49% (19/39) of all LIS1 alterations and brought to 87% (39/45) the number of patients in whom any involvement of LIS1 could be demonstrated. Breakpoint characterisation, performed in 5 patients, suggests that Alu mediated recombination is a major molecular mechanism underlying LIS1 deletions. CONCLUSIONS: LIS1 is highly specific for isolated p>a lissencephaly. The high frequency of genomic deletions/duplications of LIS1 is in keeping with the over representation of Alu elements in the 17p13.3 region. MLPA has a high diagnostic yield and should be used as first line molecular diagnosis for p>a lissencephaly.

Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients.

MECP2 mutations are identifiable in approximately 80% of classic Rett syndrome (RTT), but less frequently in atypical RTT. We recruited 110 patients who fulfilled the diagnostic criteria for Rett syndrome and were referred to Cardiff for molecular analysis, but in whom an MECP2 mutation was not identifiable. Dosage analysis of MECP2 was carried out using multiplex ligation dependent probe amplification or quantitative fluorescent PCR. Large deletions were identified in 37.8% (14/37) of classic and 7.5% (4/53) of atypical RTT patients. Most large deletions contained a breakpoint in the deletion prone region of exon 4. The clinical phenotype was ascertained in all 18 of the deleted cases and in four further cases with large deletions identified in Goettingen. Five patients with large deletions had additional congenital anomalies, which was significantly more than in RTT patients with other MECP2 mutations (2/193; p<0.0001). Quantitative analysis should be included in molecular diagnostic strategies in both classic and atypical RTT.

Co-occurrence of autosomal dominant polycystic kidney disease and Marfan syndrome in a kindred.

Several reports exist of the co-occurrence of autosomal dominant polycystic kidney disease (ADPKD) and Marfan syndrome, including a report of ADPKD and "overlap" connective tissue disorder in a family with linkage to the PKD1 locus. We report the results of clinical and linkage investigations of an ADPKD family in whom several affected subjects also had aortic vascular complications as well as features of Marfan syndrome. Detailed clinical assessment and linkage analysis were performed with polymorphic microsatellite markers closely linked to the PKD1 and FBN1 loci. Survival data were compared with 10 geographically matched PKD1 families. Although several subjects had features of both ADPKD and Marfan syndrome, detailed clinical examination of the extended family indicated that the two conditions had converged within the kindred. For those with ADPKD, linkage was established to the PKD1 locus (lod score, 6.04). Among those with features of Marfan syndrome, linkage was confirmed to the FBN1 locus (lod score, 1.87). Five of six subjects with both ADPKD and the high-risk FBN1 haplotype had associated vascular complications. In contrast, among the remaining nine individuals with PKD1 alone, seven had aortic assessments, and none were found to have aortic complications. Our experience suggests that when prominent features of connective tissue disease or vascular complications are found in ADPKD patients, alternative additional diagnoses should be considered, including the possibility of a coinherited FBN1 mutation responsible for Marfan syndrome or, alternatively, an associated milder FBN1 phenotype in the absence of sufficient other clinical features to allow Marfan syndrome to be diagnosed.

Familial phenotype differences in PKD11.

UNLABELLED: Familial phenotype differences in PKD1. BACKGROUND: Mutations within the PKD1 gene are responsible for the most common and most severe form of autosomal dominant polycystic kidney disease (ADPKD). Although it is known that there is a wide range of disease severity within PKD1 families, it is uncertain whether differences in clinical severity also occur among PKD1 families. METHODS: Ten large South Wales ADPKD families with at least 12 affected members were included in the study. From affected members, clinical information was obtained, including survival data and the presence of ADPKD-associated complications. Family members who were at risk of having inherited ADPKD but were proven to be non-affected were included as controls. Linkage and haplotype analysis were performed with highly polymorphic microsatellite markers closely linked to the PKD1 gene. Survival data were analyzed by the Kaplan-Meier method and the log rank test. Logistic regression analysis was used to test for differences in complication rates between families. RESULTS: Haplotype analysis revealed that each family had PKD1-linked disease with a unique disease-associated haplotype. Interfamily differences were observed in overall survival (P = 0.0004), renal survival (P = 0.0001), hypertension prevalence (P = 0.013), and hernia (P = 0.048). Individuals with hypertension had significantly worse overall (P = 0.0085) and renal (P = 0.03) survival compared with those without hypertension. No statistically significant differences in the prevalence of hypertension and hernia were observed among controls. CONCLUSION: We conclude that phenotype differences exist between PKD1 families, which, on the basis of having unique disease-associated haplotypes, are likely to be associated with a heterogeneous range of underlying PKD1 mutations.

Characterization of 34 novel and six known MTM1 gene mutations in 47 unrelated X-linked myotubular myopathy patients.

X-linked myotubular myopathy (XLMTM) is a congenital muscle disorder mainly affecting newborn males. Neonatal muscle weakness and hypotonia usually leads to a rapid demise. The responsible gene, MTM1, was isolated in 1996, and mutational data derived from 90 patients have been published. We report on our findings in a further 53 patients, using genomic DNA and mRNA screening protocols. Thirty-four novel mutations were identified in 37 cases, and six known mutations found in 10 other patients. The 34 new mutations include five large deletions, eight nonsense, six frameshift, five missense, and eight splice-site mutations, whereas two intronic variants causing partial exon skipping represent the first report on such a mechanism in MTM1. Two deletions, one involving exon 1, and the second exon 15, are the first defects to be identified in these exons. The heterogeneity of the mutations, their mutational origins, and the varied ethnic backgrounds of the patients, indicate that the majority of XLMTM families are affected by unique MTM1 mutations.

Novel and recurrent mutations in the PKD1 (polycystic kidney disease) gene.

A search has been conducted for disease-causing mutations in the PKD1 gene in 147 unrelated ADPKD index cases. Using the polymerase chain reaction with primer pairs located in the 3' single copy region of the gene and single-strand conformation polymorphism analysis, we detected novel aberrant bands in five individuals that were absent in 100 control samples. Sequencing revealed three nonsense mutations (Q4010X, E4024X, Q4041X), a frameshift mutation (12262 del 2 bp), and a missense mutation (G4031D). In addition, three polymorphisms were detected [12346 + 19delG, heterozygosity (0.13), I4044V (0.23), 12212-34C > A (0.07)]. The mutational mechanism for the recurrent mutation (Q4041X) is likely to be slipped mispairing of an adjacent direct imperfect repeat sequence.

Molecular analysis and clinical correlations of the Huntington's disease mutation.

The genetic mutation underlying Huntington's disease (HD) has been identified as an expansion and instability of a specific CAG repeat sequence in a gene (IT15) on chromosome 4. We have investigated the relation of the phenotype of HD to this molecular defect and assessed the feasibility of HD mutation analysis in diagnosis and prediction. Analysis of DNA from 449 HD patients (351 familial and 98 apparently isolated cases) revealed the mutation in more than 95% of patients from both groups. No molecular difference was found between patients presenting with psychiatric symptoms and those in whom chorea or other motor defects were the principal features; additionally, there was a wide range of age at onset for any specific repeat number, though the small group with juvenile onset and presenting with rigidity showed the largest expansions. The findings suggest that molecular analysis will be an accurate and specific diagnostic test for HD and valuable in presymptomatic detection in individuals at risk. However, such testing will require considerable caution to avoid serious difficulties; the well-established guidelines developed for the use of linked markers in relation to the prediction of HD should continue to be followed, though they will require reassessment in relation to use in diagnosis.

Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease.

The molecular analysis of a specific CAG repeat sequence in the Huntington's disease gene in 440 Huntington's disease patients and 360 normal controls reveals a range of 30-70 repeats in affected individuals and 9-34 in normals. We find significant negative correlations between the number of repeats on the HD chromosome and age at onset, regardless of sex of the transmitting parent, and between the number of repeats on the normal paternal allele and age at onset in individuals with maternally transmitted disease. This effect of the normal paternal allele may account for the weaker age at onset correlation between affected sib pairs with disease of maternal as opposed to paternal origin and suggests that normal gene function varies because of the size of the repeat in the normal range and a sex-specific modifying effect.

Immunohistological evidence for second or somatic mutations as the underlying cause of dystrophin expression by isolated fibres in Xp21 muscular dystrophy of Duchenne-type severity.

Using five monoclonal antibodies against different parts of the dystrophin molecule, we have studied the dystrophin composition of 17 dystrophin-positive fibres in a muscle biopsy from a boy with Xp21 muscular dystrophy of Duchenne-type severity. The fibres showed five distinct, reproducible, immunoreactive dystrophin profiles. All the profiles included both the N-terminal and the C-terminal domains, but between these domains, different fibres were negative for different antibodies, suggesting the somatic loss of certain exons. We interpret this as the first in situ evidence of an individual having different patterns of missing exons leading to restoration of the reading frame in various ways in the original germline frame-shifting deletion of exons 35-43. It follows that various somatic mutations had taken place in different fibres.

Huntington's disease: predictive testing and the molecular genetics laboratory.

We describe the laboratory-related aspects of a series of 40 completed presymptomatic tests for Huntington's disease, using linked DNA markers. Pedigree structure and marker heterozygosity are shown to be important factors, both in the number of laboratory analyses required to give an informative situation and the residual uncertainty of the final estimate. Specific problems encountered by the testing laboratory are described, with possible ways of avoiding them, and the close links required between laboratory and clinical staff are emphasised.

Presymptomatic testing for Huntington's disease in Wales 1987-90.

Between 1987 and 1990 a large series of at-risk individuals has been referred to our Huntington's disease (HD) presymptomatic testing programme. A detailed protocol for assessment and counselling has been followed. Out of 238 serious inquiries, 36% were potentially suitable for the testing programme, but 19% chose not to continue. Reasons for exclusion included the presence of clinical features of HD and being under the age of 18 years. Out of 40 final results given to 38 individuals, 23 indicated a lowered risk, 11 an increased risk, while five results were uninformative, two of these becoming informative on repeat testing. This series contained more women than men, and was disproportionately from the higher socio-economic groups. Motives for requesting a test principally related to child-bearing, informing existing children, and planning for the future. No significant psychiatric symptoms have been reported in the short term, but difficult counselling problems were presented by the high proportion of applicants who already showed clinical signs of HD. It is concluded that a detailed counselling protocol is essential in testing for HD, as many applicants are ill-prepared; this will assume even greater importance when the HD gene is identified and a test for specific mutations is available. The experience of presymptomatic testing for HD provides important general lessons which are likely to be applicable to other inherited neurological and psychiatric disorders.

Five years experience of predictive testing for myotonic dystrophy using linked DNA markers.

We report on a 5 year experience in providing presymptomatic and prenatal molecular diagnostic services for myotonic dystrophy, using closely linked markers, representing 235 completed results in 161 families. Only 10 analyses (4.3%) proved uninformative, but a further 5 requests (1.9%) could not be reported because of uncertainty in clinical status. Seven of 81 (8.6%) patients considered to be at low risk on clinical grounds were found to be at high risk of carrying the gene. The importance of interpreting molecular results in conjunction with clinical findings is emphasised by the illustrative examples provided. Careful clinical examination and appropriate investigation remain a cornerstone of diagnosis in myotonic dystrophy and are crucial if errors in assigning genotype status by molecular means are to be minimised.

Exclusion testing in pregnancy for Huntington's disease.

The results of DNA analysis are presented for a series of 90 couples, with one partner at 50% risk for Huntington's disease (HD), who were referred for exclusion testing in pregnancy over a three year period. Thirty-seven couples were studied in detail. The aims of the study were to evaluate attitudes towards prenatal testing, before pregnancy and afterwards, and the effectiveness of our counseling and methods of organising the service. Problems which could arise in relation to presymptomatic testing are documented. It is concluded that exclusion testing is a valuable form of prediction for some couples, particularly where family structure does not permit prediction for the person at risk. The need for intensive counselling was highlighted by the difficulties experienced by many couples in understanding how the test worked. Particular ethical and organisational problems may arise which require careful consideration beforehand and some recommendations are made. The proportion of couples who will continue to request exclusion testing as pre-symptomatic testing becomes more widely applicable remains unknown.

Linkage disequilibrium in Huntington's disease: an improved localisation for the gene.

The search for the Huntington's disease gene has recently concentrated on the telomere of the short arm of chromosome 4. The evidence suggesting this position has been based on single crossover events, but there is conflicting evidence regarding the position of the gene relative to the most terminal markers. We have found significant linkage disequilibrium between the markers D4S98 (probe BS731B-C) and D4S95 (probe BS674E-D) and HD, which supports a localisation for the gene proximal to D4S90 and makes a telomeric localisation unlikely. This disequilibrium may also prove to be important in the future in allowing modification of risk estimates based on genetic linkage.