The genomic landscape of familial glioma.

Glioma is a rare brain tumor with a poor prognosis. Familial glioma is a subset of glioma with a strong genetic predisposition that accounts for approximately 5% of glioma cases. We performed whole-genome sequencing on an exploratory cohort of 203 individuals from 189 families with a history of familial glioma and an additional validation cohort of 122 individuals from 115 families. We found significant enrichment of rare deleterious variants of seven genes in both cohorts, and the most significantly enriched gene was HERC2 (P = 0.0006). Furthermore, we identified rare noncoding variants in both cohorts that were predicted to affect transcription factor binding sites or cause cryptic splicing. Last, we selected a subset of discovered genes for validation by CRISPR knockdown screening and found that DMBT1, HP1BP3, and ZCH7B3 have profound impacts on proliferation. This study performs comprehensive surveillance of the genomic landscape of familial glioma.

Genome sequencing reveals underdiagnosis of primary ciliary dyskinesia in bronchiectasis.

BACKGROUND: Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis of PCD has management implications including addressing comorbidities, implementing genetic and fertility counselling and future access to PCD-specific treatments. Diagnostic testing can be complex; however, PCD genetic testing is moving rapidly from research into clinical diagnostics and would confirm the cause of bronchiectasis. METHODS: This observational study used genetic data from severe bronchiectasis patients recruited to the UK 100,000 Genomes Project and patients referred for gene panel testing within a tertiary respiratory hospital. Patients referred for genetic testing due to clinical suspicion of PCD were excluded from both analyses. Data were accessed from the British Thoracic Society audit, to investigate whether motile ciliopathies are underdiagnosed in people with bronchiectasis in the UK. RESULTS: Pathogenic or likely pathogenic variants were identified in motile ciliopathy genes in 17 (12%) out of 142 individuals by whole-genome sequencing. Similarly, in a single centre with access to pathological diagnostic facilities, 5-10% of patients received a PCD diagnosis by gene panel, often linked to normal/inconclusive nasal nitric oxide and cilia functional test results. In 4898 audited patients with bronchiectasis, <2% were tested for PCD and <1% received genetic testing. CONCLUSIONS: PCD is underdiagnosed as a cause of bronchiectasis. Increased uptake of genetic testing may help to identify bronchiectasis due to motile ciliopathies and ensure appropriate management.

Design and application of GB virus C (GBV-C) peptide microarrays for diagnosis of GBV-C/HIV-1 co-infection.

The main objectives of the design of GB virus C (GBV-C) peptide microarrays are the miniaturisation of antigen-antibody interaction assays, the simultaneous analysis of several peptide sequences and the reduction in the volume of serum required from patients since this always represents a limiting factor in studies to develop new systems for diagnosing human diseases. We herein report the design of a microarray immunoassay based on synthetic peptides derived from the GBV-C E2 protein to evaluate their diagnostic value in detecting anti-E2 antibodies in HIV-1 patients. To this end, peptide microarrays were initially prepared to identify the most relevant epitopes in the GBV-C E2 protein. Thus, 124 peptides composed of 18 amino acids covering the whole E2-protein sequence, with 15 residue overlaps, were spotted in triplicate onto γ-aminopropyl silane-functionalised adsorbent binding slides. The procedure to select the E2 protein epitopes was carried out using serum samples from HIV-1-infected patients. The samples had previously been tested for the presence or absence of GBV-C anti-E2 antibodies by means of the Abbott test. Thus, 11 specific epitopes in the GBV-C E2 protein were identified. Subsequently, peptide antigen microarrays were constructed using the E2 epitopes identified to detect GBV-C anti-E2 antibodies in the serum of HIV-1-infected patients with no known GBV-C co-infection. The 11 peptides selected identified anti-E2 GBV-C antibodies among HIV-1-infected patients, and a reactivity of 47 % was established. The potential antigenic peptides selected could be considered a useful tool for designing a new diagnostic system based on peptide microarrays to determine anti-GBV-C E2 antibodies in the serum of HIV-1-infected patients.

Classification of surgical procedures for epidemiologic assessment of sporadic Creutzfeldt-Jakob disease transmission by surgery.

BACKGROUND: In this preparatory phase of a case-control study, we propose and evaluate a new tool for classifying surgical procedures (SPs) in categories useful for epidemiologic research on surgical transmission of sporadic Creutzfeldt-Jakob disease (sCJD). METHODS: All SPs reported to the Swedish National Hospital Discharge Registry in the period 1974-2002, and undergone by 212 Swedish patients with registered diagnosis of CJD at death, hospital discharge or notification, in the period 1987-2002, 1060 age-, sex- and residence-matched controls and 1340 randomly chosen population controls, were reclassified into one of six categories of hypothetical transmission risk level. For that purpose the following two attributes were used: non-disposable instruments involved; and highest assigned ad-hoc risk level for four tissues or anatomical structures contacting such instruments. RESULTS: A total of 1170 different SP codes were reclassified as follows: 3.1% in the high-risk, 59.1% in the lower-risk, 24.4% in the lowest-risk, and 2.1% in the no-risk groups, with 11.3% procedures negatively defined by rubric as "other than..." being assigned to two spurious diluted-high and diluted-lower risk categories. The high-risk group mainly comprised neurosurgical (53%) and ophthalmic (39%) procedures. Sensitivity of neurosurgery and of ophthalmic surgery excluding neurosurgery, for the high- and diluted-high risk vs. other categories was 46% and 84%, while specificity was 98% and 95%, respectively. Sensitivity analysis based on these indices revealed that non-significant odds ratio effects of 1.4 and 1.3 for neurosurgery and ophthalmic surgery corresponded to statistically significant values of 5.1 after reclassification. CONCLUSIONS: This classification might contribute to quantify effects masked by use of body-system SP-categories in case-control studies on sCJD transmission by surgery.

Determinants of health system delay among confirmed tuberculosis cases in Spain.

BACKGROUND: Health system delay (HSD) is an important issue in tuberculosis (TB) control. This report investigates HSD and associated factors in a cohort of Spanish culture-confirmed TB patients. METHODS: Data were collected from clinical records. Using logistic regression with two different cut-off points to define HSD (median and 75th percentile), adjusted odds ratios were used to estimate the association between HSD and different variables. RESULTS: A total of 5184 culture-confirmed TB cases were included. Median and 75th percentile HSD were 6 and 25 days respectively. HSD significantly greater than the median was associated with: age >44 years, past or present intravenous drug use, diagnosis at a primary-care centre, prior preventive therapy, positive histology, request for drug-sensitivity testing, presence of silicosis or neoplasia in addition to TB, presence of non-TB related symptoms, and gastrointestinal site. HSD greater than the 75th percentile was related to the same variables, with the exception of diagnosis at a primary-care centre, positive histology, silicosis, non-TB-related symptoms and gastrointestinal site, for which the association disappeared; in contrast, an association with female gender emerged. CONCLUSION: Despite free health care being universally available in Spain, there are some groups of TB patients whose treatment is unduly delayed.

Occupation and risk of malignant pleural mesothelioma: A case-control study in Spain.

BACKGROUND: The association of mesothelioma and asbestos exposure is well known, but some data suggest that probably many people are still being exposed to asbestos without knowing it. METHODS: Between 1993 and 1996, 132 cases (77% males) of histologically confirmed malignant pleural mesothelioma and 257 controls, residents in two provinces of Spain (Barcelona and C¿adiz), were interviewed. They were classified according to their probability and intensity of occupational asbestos exposure by a panel of industrial hygienists, based on a detailed occupational history. RESULTS: Age and sex-adjusted odds ratio (OR) for the highest probability of exposure to asbestos was 13.2 (95% confidence interval 6.4-27.3), and 27.1 (9. 28-79.3) for high intensity. A dose-response trend was observed for both, probability and intensity. Overall, 61% of cases and 42% of controls had ever worked in an occupation with risk of asbestos exposure, with an OR of 2.59 (1.60-4.22). In our population 62% of cases could be attributed to occupational asbestos exposure. CONCLUSIONS: A high risk of pleural mesothelioma due to occupational asbestos exposure is confirmed, but there is still a sizeable proportion for which no evidence of occupational exposure was found. Most of these cases could be due to other sources of asbestos exposure, mainly domestic or environmental.