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Population-based data on prevalence, causes of blindness and extent of ophthalmological coverage is required for efficient implementation and evaluation of ocular health programs. In view of the scarcity of prevalence data for visual impairment and blindness in Malaysia, this study aims to estimate the prevalence and causes of visual impairment (VI) in the elderly, using Rapid Assessment of Avoidable Blindness (RAAB) survey technique. Malaysia was divided into six regions, with each region consisting of 50 clusters. Multistage cluster sampling method was used and each cluster contained 50 residents aged 50 years and above. Eligible subjects were interviewed and pertinent demographic details, barriers to cataract surgery, medical and ocular history was noted. Subjects had visual acuity assessment with tumbling 'E' Snellen optotypes and ocular examination with direct ophthalmoscope. The primary cause of VI was documented. Results were calculated for individual zones and weighted average was used to obtain overall prevalence for the country. Inter-regional and overall prevalence for blindness, severe VI and moderate VI were determined. Causes of VI, cataract surgical coverage and barriers to cataract surgery were assessed. A total of 15,000 subjects were examined with a response rate of 95.3%. The age and gender-adjusted prevalence of blindness, severe visual impairment and moderate visual impairment were 1.2% (95% Confidence Interval: 1.0-1.4%), 1.0% (95%CI: 0.8-1.2%) and 5.9% (5.3-6.5%) respectively. Untreated cataract (58.6%), diabetic retinopathy (10.4%) and glaucoma (6.6%) were the commonest causes of blindness. Overall, 86.3% of the causes of blindness were avoidable. Cataract surgical coverage (CSC) in persons for blindness, severe visual impairment and moderate visual impairment was 90%, 86% and 66% respectively. Increased patient education and further expansion of ophthalmological services are required to reduce avoidable blindness even further in Malaysia.

AimTo identify the risk indicators for posterior capsular rupture (PCR) in the Malaysian Cataract Surgery Registry (CSR).MethodsData from the web-based CSR were collected for cataract surgery performed from 2008 to 2013. Data was contributed by 36 Malaysian Ministry of Health public hospitals. Information on patient's age, ethnicity, cause of cataract, ocular and systemic comorbidity, type of cataract surgery performed, local anaesthesia and surgeon's status was noted. Combined procedures and type of hospital admission were recorded. PCR risk indicators were identified using logistic regression analysis to produce adjusted OR for the variables of interest.ResultsA total of 150 213 cataract operations were registered with an overall PCR rate of 3.2%. Risk indicators for PCR from multiple logistic regression were advancing age, male gender (95% CI 1.04 to 1.17; OR 1.11), pseudoexfoliation (95% CI 1.02 to 1.82; OR 1.36), phacomorphic lens (95% CI 1.25 to 3.06; OR 1.96), diabetes mellitus (95% CI 1.13 to 1.29; OR 1.20) and renal failure (95% CI 1.09 to 1.55; OR 1.30). Surgical PCR risk factors were combined vitreoretinal surgery (95% CI 2.29 to 3.63; OR 2.88) and less experienced cataract surgeons. Extracapsular cataract extraction (95% CI 0.76 to 0.91; OR 0.83) and kinetic anaesthesia were associated with lower PCR rates.ConclusionsThis study was agreed with other studies for the risk factors of PCR with the exception of local anaesthesia given and type of cataract surgery. Better identification of high-risk patients for PCR decreases intraoperative complications and improves cataract surgical outcomes.

The role of biomarkers in risk-based early detection of lung cancer may enable screening to become cost effective and widely accessible. EarlyCDT-Lung is an example of such a blood-based autoantibody biomarker which may improve accessibility to Low dose Computed Tomography (LDCT) screening for those at highest risk. We randomized 12 208 individuals aged 50–75 at high risk of developing lung cancer to either the test or to standard clinical care. Outcomes were ascertained from Register of Deaths and Cancer Registry. Cox proportional hazards models were used to estimate the hazard ratio of the rate of deaths from all causes and lung cancer. Additional analyses were performed for cases of lung cancer diagnosed within two years of the initial test. After 5 years 326 lung cancers were detected (2.7% of those enrolled). The total number of deaths reported from all causes in the intervention group was 344 compared to 388 in the control group. There were 73 lung cancer deaths in the intervention arm and 90 in the controls (Adjusted HR 0.789 (0.636, 0.978). An analysis of cases of lung cancer detected within 2 years of randomization in the intervention group showed that there were 34 deaths from all causes and 29 from lung cancer. In the control group there were 56 deaths with 49 from lung cancer. In those diagnosed with lung cancer within 2 years of randomization the hazard ratio for all cause mortality was 0.615 (0.401,0.942) and for lung cancer 0.598 (0.378, 0.946). Further large-scale studies of the role of biomarkers to target lung cancer screening, in addition to LDCT, are likely to provide additional value.

The large membrane protein PIEZO1 assembles as trimers to form exceptional mechanical force-sensing ion channels of eukaryotes. When these channels are activated by force, cell membrane permeability to calcium ions and other ions increases rapidly, coupling force to cell function through ionic control. In humans and other species, PIEZO1 is both widely expressed and functional across major systems that include the cardiovascular, haematological and musculoskeletal systems, thereby serving diverse needs. In this narrative review of the scientific literature, we address what has been learned about PIEZO1 from associations of its gene variation with human characteristics. A particular physiological importance of PIEZO1 is emerging in lymphatics and thus in the control of tissue fluid homeostasis with relevance to the disease conditions of non-immune fetal hydrops and generalized lymphatic dysplasia. Other vascular relevance is seen in lower limb venous varicosities. PIEZO1 may be non-essential in red blood cells but the amplification of its function by gene variation quite selectively alters these cells, leading to haemolytic anaemia and other related disturbances that may be only mildly adverse and confer survival advantage. We speculate on what else might be learned in humans, guided by knowledge from PIEZO1 studies in mice, and describe how knowledge accumulated to date highlights new opportunities for PIEZO1 understanding and pathways to patient benefit.

Aims This study aimed to explore the rapid effects of dapagliflozin in heart failure with reduced ejection fraction (HFrEF). Methods and results We studied the functional, echocardiographic, electrophysiological, lung ultrasound, ambulatory blood pressure (BP), microvascular and macrovascular function, and biochemical effects of 2 week treatment with dapagliflozin in 19 type 2 diabetic HFrEF patients in a double‐blind, crossover, placebo‐controlled trial. Dapagliflozin had no significant effect on clinical, functional, or quality of life parameters. Dapagliflozin reduced systolic BP [114 (105, 131) vs. 106 (98, 113) mmHg, P < 0.01] and diastolic BP [71 (61, 78) vs. 62 (55, 70) mmHg, P < 0.01]. There was no effect on cardiac chamber size, ventricular systolic function, lung ultrasound, or arterial wave reflection. Dapagliflozin increased creatinine [117 (92, 129) vs. 122 (107, 135) μmol/L, P < 0.05] and haemoglobin [135 (118, 138) vs. 136 (123, 144) g/L, P < 0.05]. There was a reduction in ventricular ectopy [1.4 (0.1, 2.9) vs. 0.2 (0.1, 1.4) %, P < 0.05] and an increase in standard deviation of normal heart beat intervals [70 (58, 90) vs. 74 (62, 103), P < 0.05]. Unexpectedly, dapagliflozin increased high‐sensitivity troponin T [25 (19, 37) vs. 28 (20, 42) ng/L, P < 0.01] and reduced reactive hyperaemia index [1.29 (1.21, 1.56) vs. 1.40 (1.23, 1.84), P < 0.05]. Conclusions After 2 weeks, while multiple parameters supported BP reduction and haemoconcentration with dapagliflozin, reduction in cardiac filling pressure, lung water, and functional improvement was not shown. Reduced ventricular ectopic burden suggests an early antiarrhythmic benefit. The small increase in troponin T and the reduction in the reactive hyperaemia index warrant further mechanistic exploration in this treatment of proven mortality benefit in HFrEF.

Introduction: Real-world management of patients with hepatocellular carcinoma (HCC) is crucially challenging in the current rapidly evolving clinical environment which includes the need for respecting patient preferences and autonomy. In this context, regional/national treatment guidelines nuanced to local demographics have increasing importance in guiding disease management. We report here real-world data on clinical outcomes in HCC from a validation of the Consensus Guidelines for HCC at the National Cancer Centre Singapore (NCCS). Method: We evaluated the NCCS guidelines using prospectively collected real-world data, comparing the efficacy of treatment received using overall survival (OS) and progression-free survival (PFS). Treatment outcomes were also independently evaluated against 2 external sets of guidelines, the Barcelona Clinic Liver Cancer (BCLC) and Hong Kong Liver Cancer (HKLC). Results: Overall treatment compliance to the NCCS guidelines was 79.2%. Superior median OS was observed in patients receiving treatment compliant with NCCS guidelines for early (nonestimable vs. 23.5 months p < 0.0001), locally advanced (28.1 vs. 22.2 months p = 0.0216) and locally advanced with macrovascular invasion (10.3 vs. 3.3 months p = 0.0013) but not for metastatic HCC (8.1 vs. 6.8 months p = 0.6300), but PFS was similar. Better clinical outcomes were seen in BCLC C patients who received treatment compliant with NCCS guidelines than in patients with treatment only allowed by BCLC guidelines (median OS 14.2 vs. 7.4 months p = 0.0002; median PFS 6.1 vs. 4.0 months p = 0.0286). Clinical outcomes were, however, similar for patients across all HKLC stages receiving NCCS-recommended treatment regardless of whether their treatment was allowed by HKLC. Conclusion: The high overall compliance rate and satisfactory clinical outcomes of patients managed according to the NCCS guidelines confirm its validity. This validation using real-world data considers patient and treating clinician preferences, thus providing a realistic analysis of the usefulness of the NCCS guidelines when applied in the clinics.

ABSTRACT Background Lung cancer is the commonest cause of cancer deaths worldwide. Although strongly associated with smoking, predisposition to lung cancer is also heritable with multiple common risk variants identified. Rarely, dominantly inherited non-small-cell lung cancer (NSCLC) has been reported due to somatic mutations in EGFR/ErbB1 and ERBB2. Methods Germline exome sequencing was performed in a multi-generation family with autosomal dominant NSCLC, including an affected child. Tumour samples were also sequenced. Full-length wild-type (wtErbB3) and mutant ERBB3 (mutErbB3) constructs were transfected into HeLa cells. Protein expression, stability, and sub-cellular localisation were assessed; and cellular proliferation, pAkt/Akt, and pERK levels were determined. Results A novel germline variant in ERBB3 (c.1946T>G: p.Iso649Arg), coding for receptor tyrosineprotein kinase erbB-3 (ErbB3), was identified, with appropriate segregation. There was no loss-of-heterozygosity in tumour samples. Both wtErbB3 and mutErbB3 were stably expressed. MutErbB3-transfected cells demonstrated an increased ratio of the 80kD form (which enhances proliferation) compared to the full-length (180kD) form. MutErbB3 and wtErbB3 had similar punctate cytoplasmic localisation pre- and post-EGF stimulation; however, EGFR levels decreased faster post-stimulation in mutErbB3-transfected cells, suggesting more rapid processing of the mutErbB3/EGFR heterodimer. Cellular proliferation was increased in mutErbB3-transfected cells compared to wtErbB3 transfection. MutErbB3-transfected cells also showed decreased pAkt/tAkt ratios and increased pERK/tERK 30 minutes post-stimulation compared to wtErbB3 transfection, demonstrating altered signalling pathway activation by mutErbB3. Cumulatively, these results support this mutation as tumorogenic. Conclusions This is the first reported family with a germline ERBB3 mutation causing heritable NSCLC, furthering understanding of the ErbB family pathway in oncogenesis. Competing Interest Statement The authors have declared no competing interest. Footnotes * ↵* Joint senior authors * Disclaimers: The authors declare no competing financial interests. * Abbreviations CNV copy number variation; EGFR Epidermal Growth Factor Receptor; GWAS genome-wide association studies; MAF minor allele frequency; NSCLC non-smallcell lung cancer; TKIs tyrosine kinase inhibitors.