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Structural variants dysregulating FOXC2 cause lymphoedema distichiasis syndrome: a series of case reports
Get PDFBackground
Lymphoedema distichiasis syndrome (LDS) is an autosomal dominant inherited form of lymphoedema, typically presenting with lower limb lymphoedema from puberty and distichiasis from birth. For up to 97% of patients, a coding change in FOXC2 is identifiable. However, a number of case studies identifying structural variants (SVs) outside of the FOXC2 locus have been reported.
Methods
Using a range of approaches, including genome sequencing, we investigated whether we could identify SVs, which may be impacting FOXC2 in a series of unsolved cases. In silico tools were used to annotate these variants for potential insights into regulatory mechanisms.
Results
We identified five families with SVs impacting FOXC2. One with a mosaic deletion causing a truncated protein, and four with SVs impacting the non-coding portion of the genome downstream of FOXC2, likely causing dysregulation of the gene. A review of 28 patients in the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database with 16q24 deletions, including the whole of FOXC2, identified only two reported to have lymphoedema or distichiasis.
Conclusion
These additional cases bolster the evidence supporting FOXC2 as a monogenic cause of LDS. The fact that these SVs are not detected through panel testing underscores the recommendation for employing genome sequencing or array-comparative genomic hybridisation (CGH) in patients with suspected LDS who lack a genetic diagnosis. Public databases of patients with 16q24 deletions, incorporating FOXC2, but without lymphoedema reported, demand caution when interpreting deletions affecting the entirety of FOXC2. Work is required to explore the role of these putative regulatory elements whose dysregulation may cause this syndrome
Long-term exposure to aircraft noise and cardiovascular disease hospitalization and mortality near major airports in the UK, 2006–2015 – A small area study
Get PDFThe environmental disease burden from transport noise in Europe is considered second only to air pollution, but the majority of epidemiological studies relate to road noise. We examined associations between annual average day-evening-night (Lden) and night-time (Lnight) aircraft noise in 2006 and 2011 and cardiovascular disease (CVD) hospitalization and mortality. We used a small area design covering a population of 3.1 million living near London Heathrow, Gatwick, Birmingham and Manchester international airports in 2006-2015. Statistical analysis used Bayesian Poisson regression in linear and categorical analyses. We observed strong evidence of associations between aircraft noise and hospital admissions; for coronary heart disease admissions near London Heathrow, we found an increased risk of 0.44 % (95 % CrI 0.16 %, 0.73 %) and for all-CVD admissions near other airports an increased risk of 0.34 % (95 % CrI 0.04 %, 0.64 %) per 5 dB Lden for noise levels above 50 dB Lden (the cut-off level for available data). However, results were not fully consistent across airports and no associations were seen with stroke hospitalisation and mortality, nor with CVD or CHD mortality. Associations were smaller and less clear than our previous Heathrow study of similar design during 2001-5. Differences over time are likely to relate to changes in population, therefore population confounder structure, over time, as well as reductions in population aircraft noise exposure. Given the increasing evidence base showing associations between noise and cardiovascular disease, we recommend use of large cohorts with better control of confounding at individual-level to provide quantification of exposure-response relationships
A randomised control trial study evaluating a compulsive exercise group for adolescent inpatients with eating disorders
No full textPurpose
To evaluate the efficacy of a 7-session manualised group intervention for Compulsive Exercise (NEAT) as an adjuvant to inpatient treatment for adolescents with Anorexia Nervosa (AN).
Methods
Adolescents aged 12–17 consented to the study (N = 75). Using a randomised control design, they were allocated to the NEAT group with treatment as usual (NEAT + TAU) (N = 43), or to treatment as usual alone (TAU) (N = 32). Self-report measures of compulsive exercise and eating disorder psychopathology were administered at two timepoints to assess the efficacy of the intervention.
Results
51 participants completed the study (NEAT + TAU N = 27; TAU N = 24). Both groups saw a significant decrease in compulsive exercise and eating disorder psychopathology between timepoints. There were no significant differences between treatment groups on the outcome measures.
Conclusions
Intensive, multidisciplinary TAU, and NEAT group added to TAU were effective at reducing compulsive exercise and eating disorder symptoms. Clinical opinion and recommendations for further study are discussed. Treatment manual is made available below.
Level of evidence: Level I Evidence obtained from: at least one properly designed randomised controlled trials; systematic reviews and meta-analyses; experimental studies
Characterisation of a primary ciliary dyskinesia model generated from BMI1-transduced basal epithelial cells
Get PDFPrimary ciliary dyskinesia (PCD) is a rare genetic respiratory disorder caused by a reduction in cilia number or cilia dysmotility. Cilia dysmotility leads to breathing difficulties, concurrent infections and severe lung damage if not treated, with no therapies currently available. Improved airway epithelial cell models that mimic the disease phenotype are required for development of new therapeutics, as current models have limited potential of self-renewal in vitro. Here, we describe a human PCD cell model created by lentiviral transduction of airway basal epithelial cells with the BMI1 gene, a regulator of senescence. We report that the cells retain their proliferation and differentiation capacity for at least 19 passages and recapitulate the disease phenotype with immotile cilia lacking DNAH5 and other outer dynein arm proteins. Characterisation of the ion transport properties of these PCD cells grown at an air–liquid interface showed lower activity of the Na+ channel ENaC and enhanced CFTR activity compared to non-PCD cells, which might be linked to ciliary immotility. Our study provides a robust PCD model for therapeutic studies, opening new avenues to investigate the molecular mechanisms of this disease
Tuberculosis in adult migrants in Europe: a TBnet consensus statement.
Get PDFINTRODUCTION: Global migration has increased in recent decades due to war, conflict, persecutions, and natural disasters, but also secondary to increased opportunities related to work or study. Migrants' risk of tuberculosis (TB) differs by reasons for migration, socioeconomic status, mode of travel and TB risk in transit, TB incidence and healthcare provision in country of origin. Despite advances in TB care for migrants and new treatment strategies, decisions for the management of migrants at risk of TB often rely on expert opinions, rather than clinical evidence. METHODS: A systematic literature search was conducted, studies were mapped to different recommendation groups and included studies were synthesized by meta-analysis where appropriate. Current evidence on diagnosis of active TB in migrants entering the European Union /European Economic Area (EU/EEA) &UK including the clinical presentation and diagnostic delay, treatment outcomes of drug susceptible TB, prevalence and treatment outcomes of multidrug/rifampicin-resistant (MDR/RR)-TB and TB/HIV co-infection was summarised. A consensus process was used based on the evidence. RESULTS: We document a higher vulnerability of migrants for TB, including an increased risk of extrapulmonary TB, MDR/RR-TB, TB/HIV co-infection and worse TB treatment outcomes compared to host populations. Consensus recommendations include screening of migrants for TB/ latent TB infection (LTBI) according to country data; a minimal package for TB care in drug susceptible and MDR/RR-TB; implementation of migrant-sensitive strategies; free healthcare and preventive treatment for migrants with HIV co-infection. CONCLUSION: Dedicated care for TB prevention and treatment in migrant populations within the EU/EEA &UK is essential
The British Society for Rheumatology guideline for the management of foot health in inflammatory arthritis
Get PDFHealth outcomes and drug utilisation in children with Noonan syndrome: a European cohort study.
Get PDFBACKGROUND: Noonan Syndrome (NS) is a rare multisystemic disorder with heterogeneous phenotypic manifestations. The aim of this study was to analyse rates of survival, hospitalisation, surgeries and prescriptions in children born with NS in the first 10 years of life. METHODS: This is a multi-centre population-based cohort study. Data on 175 liveborn children diagnosed with NS from 11 EUROCAT congenital anomaly registries were linked to healthcare databases. Each registry applied a common data model to standardise data and run common syntax scripts to produce aggregated results which were pooled using random effects meta-analyses. RESULTS: Mortality rates were high in the first year of life with 5.4% (95%CI 1.5%-10.1%) of children dying before the age of 1 year with a further 2% dying up to age 5. In the first year, 87.9% (95%CI 75.3%-94.3%) of children were hospitalized and the median Length Of hospital Stay (LOS) was 15.3 days (95%CI 9.3-21.2). After the first year, the proportion of children hospitalized remained higher than 70%, but the LOS decreased to 1.3 days per year. In the first 5 years, 65.2% of children underwent a median of two surgical procedures. The median age at first surgery was 29 weeks. The proportion of children with an antibiotic prescription increased from 53.6% at age 1 to 62.4% yearly until 4 years of age. CONCLUSIONS: Children with NS have high mortality and morbidity not only in the first year of life but also up to five years of age. This study evaluated the health burden of NS and provided information for clinicians, health-care providers and families
Parental Awareness and Practices of Self-medication with Antibiotics among Hospitalised Children in Pakistan: Findings and Implications from a Cross-sectional Study
Get PDFIntroduction:
Antimicrobial resistance (AMR) is a global threat appreciably impacting on morbidity, mortality and costs, especially in low- and middle-income countries. The excessive use of antibiotics, especially in ambulatory care, is a primary factor increasing AMR. This includes inappropriate dispensing of antibiotics without a prescription for essentially viral infections, which is prevalent in Pakistan. This needs addressing to reduce AMR.
Materials and Methods:
A cross-sectional study was conducted among three district hospitals to extract data from parents of children up to 12 years concerning their awareness, practices and rationale of self-medication with antibiotics for their children.
Results:
Four hundred and thirty-eight parents participated in the study, with the majority between 30 and 39 years (65.5%) and possessing secondary school education (28.5%). 27.6% of parents stated that they knew the name of at least one antibiotic, with the majority knowing the name of amoxicillin (33%) and co-amoxiclav (19%). The prevalence of self-medication for their children was high at 63%, principally for self-limiting conditions including sore throats (27.1%), high fever (22.4%), nasal discharges (20.9%) and coughs (17.7%). The most commonly consumed antibiotics among their children were amoxicillin (33.6%), co-amoxiclav (18.1%) and azithromycin (15.2%), with the common reasons for self-medication including similar signs and symptoms to before (42.6%) and financial constraints (39%). Increasing education levels and familiarity with antibiotic names were associated with higher antibiotic usage (P < 0.001).
Conclusions:
Self-medication with antibiotics among their children for essentially self-limiting conditions was common. Appropriate corrective measures, including targeted educational initiatives, are urgently need to address ongoing concerns and associated rising AMR
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