Mutations in splicing factor genes are a major cause of autosomal dominant retinitis pigmentosa in Belgian families

Purpose : Autosomal dominant retinitis pigmentosa (adRP) is characterized by an extensive genetic heterogeneity, implicating 27 genes, which account for 50 to 70% of cases. Here 86 Belgian probands with possible adRP underwent genetic testing to unravel the molecular basis and to assess the contribution of the genes underlying their condition. Methods : Mutation detection methods evolved over the past ten years, including mutation specific methods (APEX chip analysis), linkage analysis, gene panel analysis (Sanger sequencing, targeted next-generation sequencing or whole exome sequencing), high-resolution copy number screening (customized microarray-based comparative genomic hybridization). Identified variants were classified following American College of Medical Genetics and Genomics (ACMG) recommendations. Results : Molecular genetic screening revealed mutations in 48/86 cases (56%). In total, 17 novel pathogenic mutations were identified: four missense mutations in RHO, five frameshift mutations in RP1, six mutations in genes encoding spliceosome components (SNRNP200, PRPF8, and PRPF31), one frameshift mutation in PRPH2, and one frameshift mutation in TOPORS. The proportion of RHO mutations in our cohort (14%) is higher than reported in a French adRP population (10.3%), but lower than reported elsewhere (16.5-30%). The prevalence of RP1 mutations (10.5%) is comparable to other populations (3.5%-10%). The mutation frequency in genes encoding splicing factors is unexpectedly high (altogether 19.8%), with PRPF31 the second most prevalent mutated gene (10.5%). PRPH2 mutations were found in 4.7% of the Belgian cohort. Two families (2.3%) have the recurrent NR2E3 mutation p.(Gly56Arg). The prevalence of the recurrent PROM1 mutation p.(Arg373Cys) was higher than anticipated (3.5%). Conclusions : Overall, we identified mutations in 48 of 86 Belgian adRP cases (56%), with the highest prevalence in RHO (14%), RP1 (10.5%) and PRPF31 (10.5%). Finally, we expanded the molecular spectrum of PRPH2, PRPF8, RHO, RP1, SNRNP200, and TOPORS-associated adRP by the identification of 17 novel mutations

The empirical replicability of task-based fMRI as a function of sample size

Replicating results (i.e. obtaining consistent results using a new independent dataset) is an essential part of good science. As replicability has consequences for theories derived from empirical studies, it is of utmost importance to better understand the underlying mechanisms influencing it. A popular tool for non-invasive neuroimaging studies is functional magnetic resonance imaging (fMRI). While the effect of underpowered studies is well documented, the empirical assessment of the interplay between sample size and replicability of results for task-based fMRI studies remains limited. In this work, we extend existing work on this assessment in two ways. Firstly, we use a large database of 1400 subjects performing four types of tasks from the IMAGEN project to subsample a series of independent samples of increasing size. Secondly, replicability is evaluated using a multi-dimensional framework consisting of 3 different measures: (un)conditional test-retest reliability, coherence and stability. We demonstrate not only a positive effect of sample size, but also a trade-off between spatial resolution and replicability. When replicability is assessed voxelwise or when observing small areas of activation, a larger sample size than typically used in fMRI is required to replicate results. On the other hand, when focussing on clusters of voxels, we observe a higher replicability. In addition, we observe variability in the size of clusters of activation between experimental paradigms or contrasts of parameter estimates within these

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P < 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P < 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223

Tintelnotia destructans as an emerging opportunistic pathogen: First case of T. destructans superinfection in herpetic keratitis.

Purpose: Only recently Tintelnotia was described as a new genus in the Phaeosphaeriaceae family of fungi containing two species, T. opuntiae and T. destructans. Until now, T. destructans keratitis was associated with contact lens wear and ocular trauma. We present the first case of T. destructans keratomycosis presenting as a superinfection in herpetic keratitis. Observations: We present a case of a 53-year-old woman who presented with a unilateral keratitis since 3 weeks without history of trauma or contact lens wear, not responding to topical ofloxacin. Polymerase Chain Reaction (PCR) of the corneal ulcer was positive for Herpes Simplex Virus type 1 (HSV-1). Signs and symptoms progressively improved after starting topical and systemic antiviral therapy. Six weeks later however, our patient presented with a new white infiltrate in the previous herpetic epithelial defect. In vivo confocal microscopy showed fungal hyphae and culture from corneal scrapings identified a hyphomycete. Intensive antimycotic therapy could not prevent a corneal perforation 1 week later. Penetrating keratoplasty was performed with intracameral injection of amphotericin B. Culture of the corneal button and PCR and sequence analysis on the fungal isolate confirmed the diagnosis of T. destructans keratomycosis. Six months after penetrating keratoplasty, biomicroscopy showed a clear graft without recurrence of fungal activity. Conclusions and importance: T. destructans is an emerging opportunistic pathogen causing severe keratomycosis. Despite intensive antimycotic therapy, rapid progression to corneal perforation can be seen. Early diagnosis using confocal microscopy, fungal culture and PCR can allow prompt initiation of treatment, which should be guided by in vitro susceptibility testing.status: Published onlin

A Case of Corneal Melting in a Patient with HER2-Positive Breast Cancer

Trastuzumab is the cornerstone treatment for HER2-positive breast cancer. While ocular side effects are more commonly described after the use of the antibody-drug conjugate ado-trastuzumab emtansine, we here describe corneal melting in a 79-year-old patient after three cycles of trastuzumab monotherapy. Signs and symptoms persisted with subsequent trastuzumab cycles. The patient showed improvement after treatment with intense lubrication, topical antibiotics, and topical steroids. After tapering of steroids, there was recurrence of epitheliopathy after subsequent trastuzumab treatment, which subsided upon restarting topical steroids. Finally, the patient was kept on a low-dose topical steroid regimen which prevented further epitheliopathy during the next trastuzumab cycles

Pyrenocheata unguis-hominis: A new cause of fungal keratitis in a contact lens wearer

Purpose: Pyrenochaeta unguis-hominis (syn. Neocucurbitaria unguis-hominis) is a rare fungal species belonging to the Coelomycetes group, mostly isolated from infected nails and skin.We present a case of contact lens-related fungal keratitis caused by Pyrenochaeta unguis-hominis. Observations: We present a case of a 69-year-old woman with multiple risk factors for a fungal keratitis including ophthalmological history of herpetic keratitis, contact lens wear and chronic steroid use. At presentation, the corneal ulcer resembled a recurrent herpetic keratitis but evolved into a more dense stromal infiltrate despite antiviral therapy. Microscopic examination, culture and staining of corneal tissue obtained by scraping showed mycelia. PCR and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry confirmed the presence of Pyrenochaeta unguis-hominis. Topical antifungal treatment was able to dim the inflammation. Because of a persistent epithelial defect, an amniotic membrane transplantation was performed. Although corneal epithelium was restored, stromal scarring in the visual axis resulted in substantial vision loss. Conclusions: To our knowledge no other cases of fungal keratitis caused by Pyrenochaeta unguis-hominis have been described. Early diagnosis can allow prompt initiation of antifungal treatment, which should be guided by in vitro susceptibility testing

Accidental ocular chemical injury following alcohol-based hand sanitizer exposure : incidence and management

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Ligneous conjunctivitis mimicking preseptal cellulitis in a 3-month-old infant

Background Ligneous conjunctivitis is a very rare form of pseudomembranous conjunctivitis with few published cases in literature. We aim to describe the ocular findings and treatment in an infant with ligneous conjunctivitis resembling preseptal cellulitis on presentation. Materials and Methods Case report of a 3-month-old girl who was referred to a tertiary centre for ophthalmic assessment due to progressive eyelid oedema with no response to initiated topical and systemic antibiotics. Ethical approval has been achieved from the local ethics committee of the Ghent University Hospital and informed consent has been obtained from the parents of the child. Results Examination under general anaesthesia showed multiple, wood-like fibrinous pseudomembranes, originating from the conjunctiva, consistent with ligneous conjunctivitis. After careful removal of the coagulated exudate covering the cornea, a central corneal epithelial defect was evident without stromal infiltration. Histopathologic examination confirmed the predominance of fibrin within the pseudomembranes. Plasminogen activity was below the normal range. Genetic analysis did not identify a pathogenic variant in the PLG gene. The corneal epithelium re-epithelialised during the following days and the conjunctival lesions gradually subsided over the ensuing weeks whilst continuing heparin-containing artificial tears. Conclusion A high level of suspicion is warranted in atypical cases of preseptal cellulitis which show no response to antibiotic treatment. Particularly in young children, examination under general anesthesia is warranted to allow diagnosis of rare causes of secondary eyelid oedema. We report an infant with unilateral ligneous conjunctivitis who responded well to topical, commercially-available heparin-containing artificial tears treatment. This approach is an effective and easy first-line treatment option in this condition, particularly in milder phenotypes