Combining whole exome sequencing with in silico analysis and clinical data to identify candidate variants in pediatric left ventricular noncompaction.

BACKGROUND: Understanding the overall variant burden in pediatric patients with left ventricular noncompaction (LVNC) has clinical implications. Whole exome sequencing (WES) allows detection of coding variants in both candidate cardiomyopathy genes and those included on commercial panels. Other lines of evidence, including in silico analysis, are necessary to reduce the overwhelming number of variants to those most likely having a phenotypic impact. METHODS: Five families, including five pediatric probands with LVNC, 5 other affected, and 10 unaffected family members, had WES performed, followed by bioinformatics filtering and Sanger sequencing. Review of the HGMD, variant classification by ACMG guidelines, and clinical information were used to further refine complex genotypes. RESULTS: One nonsense and eleven missense variants were identified. In Family 1, affected siblings carried digenic heterozygous variants: E1350K-MYH7 and A276V-ANKRD1. The proband also carried heterozygous W143X-NRG1. Four affected members of Family 2 carried K184Q-MYH7 while unaffected members did not. In Family 3, homozygous A161T-MYH7 and heterozygous P4935T-OBSCN variants were identified in the proband with the latter being absent in his unaffected brother. In Family 4, proband's father and half-sibling have mild hypertrabeculation and carry T3796I-PLEC. The proband, carrying T3796I-PLEC and V2878A-OBSCN, demonstrated higher trabeculation burden. The proband in Family 5 carried four variants, R3247W-PLEC, C92Y-ERG, T1233M-NCOR2, and E54K-HIST1H4B. Application of ACMG criteria and clinical data revealed that W143X-NRG1, P4935T-OBSCN, and V2878A-OBSCN likely have no phenotypic role. CONCLUSIONS: We report nine variants, including novel T3796I-PLEC and biallelic A161T-MYH7, likely contributing to phenotypes ranging from asymptomatic hypertrabeculation to severe LVNC with heart failure.

Clinical and laboratory features of the most common Clostridium difficile ribotypes isolated in Belgium.

BACKGROUND: Previous studies comparing Clostridium difficile infection (CDI) due to different ribotypes have been conflicting, and many have only compared small numbers of cases or few ribotypes. AIM: To compare patient and episode characteristics for CDI due to different ribotypes. METHODS: The ribotyping results from 3333 toxin-producing isolates collected from 110 Belgian hospitals between October 2010 and December 2015 were matched to clinical data from the national CDI surveillance database. Data for ribotypes with at least 100 occurrences were compared. In addition, the national reference laboratory quantitatively measured the level of toxin production in five randomly chosen cultured isolates for each of the most common ribotypes. FINDINGS: Ribotypes with more than 100 occurrences were R014, R020, R002, R078, R027, R005 and R106 (Brazier classification). The median age for all patients was 79 years [patients with R027, 83 years (P<0.001); patients with R106, 73 years (P<0.001)]. In total, 10% of episodes were recurrences; values were higher for R027 (22%) and R106 (18%). CDI due to R078 was not significantly more likely to be community associated than healthcare associated (28% vs 24%; P=0.1). Complications occurred in 7% of all episodes, and 12% for those with R027 and R078. However, after adjusting for age, onset outside the hospital and recurrence, R027 was no longer associated with complications [odds ratio (OR) 1.3, 95% confidence interval (CI) 0.7-2.4], unlike R078 (OR 1.7, 95% CI 1.0-2.6; P=0.04). A positive stool toxin test and greater levels of toxin production in the cultured isolates were more likely for R078 and R027. CONCLUSION: Out of the seven most common ribotypes in hospital patients, R078 and R027 were associated with higher rates of complications. Infections with R027 and R106 were more likely to be recurrent. The presence of toxin in stools was most likely with R078, R027 and R106, with highest levels of toxin production in vitro for R078 and R027. R060 produced the lowest levels of toxin in vitro.

High rate of transmission among contacts in large London outbreak of isoniazid mono-resistant tuberculosis.

BACKGROUND: For a continuing London outbreak of isoniazid mono-resistant tuberculosis (TB), we aimed to determine transmission rates and risk factors for contacts of early cases, in order to inform future guidance on contact tracing. METHODS: Paper-based proformas were completed by TB nurses, and then analysed using EpiInfo/SAS statistical software. RESULTS: Forty community contacts (11%) became cases, 45 (13%) were recommended chemoprophylaxis and 270 (76%) were discharged clear of infection. The highest transmission rate was among contacts exposed to two or more cases (29% became cases) and close contacts of sputum smear-positive cases (22%). Other risk factors were being male and exposure to drug-using cases or cases with prison links. The number needed to be screened (NNS) to detect one case was lowest [5 (95% CI: 4-8)] for contacts of sputum smear-positive pulmonary cases, although the NNS was still only 20 (95% CI:8-72) for casual contacts of smear-positive cases. CONCLUSIONS: Transmission of disease to contacts was high (11%) compared with other documented outbreaks (0.7-2%). The results support recommended guidelines for contact tracing but also provide grounds to recommend, for outbreak cases, screening of casual contacts of smear-positive cases and contacts exposed to more than one case, drug users or prisoners.

Intrinsic risk factors for exercise-related lower limb injuries.

There is a significant risk of injury when undertaking physical activities. The risk factors for injury can be divided into extrinsic (environmental) and intrinsic (personal) factors. This article reviews the current literature on several intrinsic risk factors. Although there have been a large number of studies in this field, many are lacking in consistency of definitions and methodology. Many of the studies have been retrospective and it is often impossible to identify the baseline population. There is overwhelming evidence to suggest that female gender, age greater than 24 years, a high body mass index or a high percentage body fat (within military populations but not among civilians), low level of physical fitness at the commencement of a training programme and a past history of injury (in both populations) are risk factors for injury.

Biomechanical risk factors for exercise-related lower limb injuries.

There is a significant risk of injury when undertaking physical activities. Abnormal biomechanics of the lower limb has been implicated as a causative factor for injury. Although there have been a large number of studies in this field, many lack consistency of definitions and methodology. A large number of these studies have been retrospective, and it is often impossible to identify the baseline population. The evidence suggests that limitation of range of ankle dorsiflexion, limitation of range of hip eversion, excessive joint laxity, leg length discrepancy, an excessively supinated or pronated foot, excessively high or low arches of the foot and a large Q-angle are risk factors for injury. On the other hand, there is little convincing evidence that an abnormal range of ankle plantar flexion, genu varum or valgum or undue muscle tightness may be potential risk factors. All of these biomechanical abnormalities need further evaluation as potential risk factors for injury. Any trials undertaken must endeavour to define and describe their methods fully, and ensure that their results are reproducible.