A hypomorphic variant of choroideremia is associated with a novel intronic mutation that leads to exon skipping.

INTRODUCTION: Molecular confirmation of pathogenic sequence variants in the CHM gene is required prior to enrolment in retinal gene therapy clinical trials for choroideremia. Individuals with mild choroideremia have been reported. The molecular basis of genotype-phenotype associations is of clinical relevance since it may impact on selection for retinal gene therapy. METHODS AND MATERIALS: Genetic testing and RNA analysis were undertaken in a patient with mild choroideremia to confirm the pathogenicity of a novel intronic variant in CHM and to explore the mechanism underlying the mild clinical phenotype. RESULTS: A 42-year-old male presented with visual field loss. Fundoscopy and autofluorescence imaging demonstrated mild choroideremia for his age. Genetic analysis revealed a variant at a splice acceptor site in the CHM gene (c.1350-3C > G). RNA analysis demonstrated two out-of-frame transcripts, suggesting pathogenicity, without any detectable wildtype transcripts. One of the two out-of-frame transcripts is present in very low levels in healthy controls. DISCUSSION: Mild choroideremia may result from +3 or -3 splice site variants in CHM. It is presumed that the resulting mRNA transcripts may be partly functional, thereby preventing the development of the null phenotype. Choroideremia patients with such variants may present challenges for gene therapy since there may be residual transcript activity which could result in long-lasting visual function which is atypical for this disease.

Association between vision impairment and mortality: a systematic review and meta-analysis.

BACKGROUND: The number of individuals with vision impairment worldwide is increasing because of an ageing population. We aimed to systematically identify studies describing the association between vision impairment and mortality, and to assess the association between vision impairment and all-cause mortality. METHODS: For this systematic review and meta-analysis, we searched MEDLINE (Ovid), Embase, and Global Health database on Feb 1, 2020, for studies published in English between database inception and Feb 1, 2020. We included prospective and retrospective cohort studies that measured the association between vision impairment and all-cause mortality in people aged 40 years or older who were followed up for 1 year or more. In a protocol amendment, we also included randomised controlled trials that met the same criteria as for cohort studies, in which the association between visual impairment and mortality was independent of the study intervention. Studies that did not report age-adjusted mortality data, or that focused only on populations with specific health conditions were excluded. Two reviewers independently assessed study eligibility, extracted the data, and assessed risk of bias. We graded the overall certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations framework. We did a random-effects meta-analysis to calculate pooled maximally adjusted hazard ratios (HRs) for all-cause mortality for individuals with a visual acuity of <6/12 versus those with ≥6/12; <6/18 versus those with ≥6/18; <6/60 versus those with ≥6/18; and <6/60 versus those with ≥6/60. FINDINGS: Our searches identified 3845 articles, of which 28 studies, representing 30 cohorts (446 088 participants) from 12 countries, were included in the systematic review. The meta-analysis included 17 studies, representing 18 cohorts (47 998 participants). There was variability in the methods used to assess and report vision impairment. Pooled HRs for all-cause mortality were 1·29 (95% CI 1·20-1·39) for visual acuity <6/12 versus ≥6/12, with low heterogeneity between studies (n=15; τ2=0·01, I2=31·46%); 1·43 (1·22-1·68) for visual acuity <6/18 versus ≥6/18, with low heterogeneity between studies (n=2; τ2=0·0, I2=0·0%); 1·89 (1·45-2·47) for visual acuity <6/60 versus ≥6/18 (n=1); and 1·02 (0·79-1·32) for visual acuity <6/60 versus ≥6/60 (n=2; τ2=0·02, I2=25·04%). Three studies received an assessment of low risk of bias across all six domains, and six studies had a high risk of bias in one or more domains. Effect sizes were greater for studies that used best-corrected visual acuity compared with those that used presenting visual acuity as the vision assessment method (p=0·0055), but the effect sizes did not vary in terms of risk of bias, study design, or participant-level factors (ie, age). We judged the evidence to be of moderate certainty. INTERPRETATION: The hazard for all-cause mortality was higher in people with vision impairment compared with those that had normal vision or mild vision impairment, and the magnitude of this effect increased with more severe vision impairment. These findings have implications for promoting healthy longevity and achieving the Sustainable Development Goals. FUNDING: Wellcome Trust, Commonwealth Scholarship Commission, National Institutes of Health, Research to Prevent Blindness, the Queen Elizabeth Diamond Jubilee Trust, Moorfields Eye Charity, National Institute for Health Research, Moorfields Biomedical Research Centre, Sightsavers, the Fred Hollows Foundation, the Seva Foundation, the British Council for the Prevention of Blindness, and Christian Blind Mission.

Reproductive outcomes in women and men using complementary and alternative medicine treatment and not receiving artificial reproductive technology: a systematic review.

PURPOSE: Infertility is a global problem, but only a minority of couples access assisted reproductive technologies due to financial and sociocultural barriers. Complementary and alternative medicine are seen as another option. We aimed to determine the impact of complementary and alternative medicine on conception, miscarriage and live birth rates in couples not receiving assisted reproductive technology treatments. METHODS: The electronic databases EMBASE, PubMed, Web of Science and the Allied and Complementary Medicine Database were systematically searched before March 24th 2020. Reference lists of eligible studies were searched for relevant studies. Eligible studies included trials and observational studies that assessed a complementary or alternative medicine and conception, miscarriage or live births in men or women not undergoing fertility treatment. Data were extracted by two independent reviewers using a pre-designed data collection form. The study protocol was published in the PROSPERO database (CRD42018086980). RESULTS: Twenty randomized controlled trials were identified, including 2748 individuals. Most studies did not demonstrate any effect of a complementary or alternative medicine on pregnancy, live birth or miscarriage rates. Limited evidence was found for a positive effect of herbal therapies taken by women on conception rates. There was substantial diversity in quality across the studies. CONCLUSION: There is limited evidence of the effectiveness of complementary and alternative medicine on improving the chances of conception and live births, or increasing miscarriage risk. Owing to the generally sub-optimal quality and heterogeneous nature of the evidence, rigorous studies are needed to determine the impact of complementary and alternative medicine on fertility.

Single-bite versus double-bite technique for mapping biopsies during endoscopic surveillance for hereditary diffuse gastric cancer: a single-center, randomized trial.

BACKGROUND : Endoscopic surveillance is recommended in patients with hereditary diffuse gastric cancer (HDGC) who refuse or want to delay surgery. Because early signet-ring cell carcinoma (SRCC) can be inconspicuous, the current surveillance endoscopy protocol entails 30 random biopsies, which are time-consuming. This study aimed to compare single-bite and double-bite techniques in HDGC surveillance. METHODS : Between October 2017 and December 2018, consecutive patients referred for HDGC surveillance were prospectively randomized to the single- or double-bite arm. The primary outcome was the diagnostic yield for SRCC foci. Secondary outcomes were: procedural time for random biopsies; comfort score; biopsy size; and quality of specimens, the latter assessed by the presence of muscularis mucosa, crush artifact, and proportion usable for diagnostic assessment. RESULTS : 25 patients were randomized to the single-bite arm and 23 to the double-bite arm. SRCC foci were detected in three and four patients in the single- and double-bite arms, respectively (P = 0.70). The procedural time for the double-bite arm (12 minutes, interquartile range [IQR] 4) was significantly shorter than for the single-bite arm (15 minute, IQR 6; P = 0.01), but comfort scores were similar. The size of the biopsies in the double-bite arm was significantly smaller than in single-bite arm (2.5 mm vs. 3.0 mm; P < 0.001) but this did not affect the presence of muscularis mucosa (P = 0.73), artifact level (P = 0.11), and diagnostic utility (P = 0.051). CONCLUSION : For patients undergoing HDGC surveillance, the double-bite technique is significantly faster than the single-bite technique. The diagnostic yield for SRCC and the biopsy quality were similar across both groups.

The utility of a methylation panel in the assessment of clinical response to radiofrequency ablation for Barrett's esophagus.

BACKGROUND: Radiofrequency ablation (RFA) is an effective treatment for dysplastic Barrett's esophagus (BE), but recurrence can occur after initial response. Currently there is uncertainty about how to best define histological remission. A DNA methylation panel on esophageal samples was previously shown to have high diagnostic accuracy for BE. We aimed to investigate this biomarker panel in the assessment of response to RFA treatment. METHODS: We retrospectively analyzed esophageal and gastroesophageal junction (GEJ) biopsies from patients with BE before and after RFA treatment. We quantified the extent of intestinal metaplasia (IM) based on number of glands with goblet cells (IM-Score) and expression of the intestinal factor trefoil factor-3 (TFF3-Score). Promoter methylation of 3 genes (ZNF345, TFP12, ZNF569) was measured by methylight (Meth-Score) throughout the RFA treatment pathway. FINDINGS: We included 45 patients (11 non-dysplastic BE, 14 low-grade dysplasia, 20 high-grade dysplasia/intramucosal cancer). Meth-Scores were significantly higher in BE with and without dysplasia and GEJ with IM compared to GEJ without IM (P<·001). Meth-scores significantly correlated with the extent of IM at the GEJ measured both with IM-Scores (rho=66·0%, P<·001), and TFF3-Scores (rho=75·6%, P<·001). In patients with residual IM at the GEJ, RFA re-treatment brought about a 7·6-fold reduction in the methylation levels. The Meth-score had an area under the ROC curve of 95·1% (95%CI 91·1% - 99·1%) differentiating BE from normal GEJ. INTERPRETATION: A DNA methylation panel can discriminate between the extent of histological IM in esophageal and junctional biopsies and could be used to objectively quantify residual disease following RFA.

Association between vision impairment and mortality: protocol for a systematic review and meta-analysis.

INTRODUCTION: Due to growth and ageing of the world's population, the number of individuals worldwide with vision impairment (VI) and blindness is projected to increase rapidly over the coming decades. VI and blindness are an important cause of years lived with disability. However, the association of VI and blindness with mortality, including the risk of bias in published studies and certainty of the evidence, has not been adequately studied in an up-to-date systematic review and meta-analysis. METHODS AND ANALYSIS: The planned systematic review and meta-analysis will adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Databases, including MEDLINE Ovid, Embase Ovid and Global Health, will be searched for relevant studies. Two reviewers will then screen studies and review full texts to identify studies for inclusion. Data extraction will be performed, and for included studies, the risk of bias and certainty of the evidence will be assessed using the Grades of Recommendation, Assessment, Development and Evaluation approach. The prognostic factor in this study is visual function, which must have been measured using a standard objective ophthalmic clinical or research instrument. We will use standard criteria from WHO to categorise VI and blindness. All-cause mortality may be assessed by any method one or more years after baseline assessment of vision. Results from included studies will be meta-analysed according to relevant sections of the Meta-analysis Of Observational Studies in Epidemiology checklist. ETHICS AND DISSEMINATION: This review will only include published data; therefore, ethics approval will not be sought. The findings of this review and meta-analysis will be published in an open-access, peer-reviewed journal and will be included in the ongoing Lancet Global Health Commission on Global Eye Health.

Endoscopic measurement of gastric pH associates with persistent acid reflux in patients treated with proton-pump inhibitors for gastroesophageal reflux disease.

Background: Proton-pump inhibitors (PPIs) are the mainstay of gastroesophageal reflux disease (GERD) treatment, however, up to 30% of patients have a poor symptomatic response. PH-impedance is the gold standard to assess whether this is due to persistent acid reflux. We aimed to characterize clinical predictors of persistent esophageal acid reflux on PPIs including gastric pH measured during endoscopy. Methods: We prospectively recruited patients with GERD and/or Barrett's esophagus (BE) on PPIs. All patients completed a symptom questionnaire (RDQ) and underwent gastroscopy with gastric pH analysis, immediately followed by ambulatory 24-hour pH-impedance. We used a modified cut-off of 1.3% for pathological esophageal acid exposure time (AET). Multiple linear regression model was used to analyze the correlation between AET and predictive variables. Results: We recruited 122 patients, of which 92 (75.4%) were included in the final analysis [44 male (47.8%), median age 53 years (IQR: 43-66)]. Forty-four patients (47.8%) had persistent acid reflux with a median total AET of 2.2 (IQR1.2-5.0), as compared to 0.1 (IQR 0.0-0.2) in patients without persistent reflux (n=48; P<.001). There was no difference in age, gender, BMI, PPI-regimen, diagnosis of hiatus hernia or BE, and severity of symptoms between patients with normal and abnormal AET. Median gastric pH was significantly lower in patients with abnormal AET (5.8 vs 6.6, P=0.032) and it correlated with the total AET (P=.045; R2=12.0%). With a pH cut-off of 5.05, single point endoscopic gastric pH analysis had an area under the ROC curve (AUC) of 63.0% (95%CI 51.3-74.7) for prediction of pathological esophageal AET. Conclusions: Symptoms and clinical characteristics are not useful to predict persistent acid reflux in patients on PPIs. One-point gastric pH correlates with 24-hour esophageal AET and could guide clinicians to assess response to PPIs, however, its utility needs validation in larger studies.