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Real-world data on continued effectiveness of nirmatrelvir/ritonavir against hospitalization and severe COVID-19 in the context of widespread booster mRNA vaccine uptake and more immune-evasive Omicron sub-variants are lacking. We conducted a retrospective cohort study in adult Singaporeans aged ≥60 years presenting to primary care with SARS-CoV-2 infection, during waves of Omicron BA.2/4/5/XBB transmission. Binary logistic regression was used to estimate the effect of treatment (receiving nirmatrelvir/ritonavir) on outcomes (hospitalization, severe COVID-19). Additional sensitivity analyses, including inverse-probability-of-treatment-weighting-adjusted analysis and adjustment using overlap weights, were performed to account for observed differences in baseline characteristics among treated/untreated cohorts. We included 3959 nirmatrelvir/ritonavir recipients and 139 379 untreated controls. Almost 95% received ≥3 doses of mRNA vaccines; 5.4% had preceding infection. Overall 26.5% of infections occurred during the Omicron XBB period and 1.7% were hospitalized. On multivariable logistic regression, receipt of nirmatrelvir/ritonavir was independently associated with lower odds of hospitalization (adjusted odds ratio [aOR] = 0.65, 95% CI = 0.50–0.85). Consistent estimates were obtained after inverse-probability-of-treatment-weighting adjustment (aOR for hospitalization = 0.60, 95% CI = 0.48–0.75) and adjustment using overlap weights (aOR for hospitalization = 0.64, 95% CI = 0.51–0.79). Although receipt of nirmatrelvir/ritonavir was associated with lower odds of severe COVID-19, it was not statistically significant. Outpatient usage of nirmatrelvir/ritonavir was independently associated with reduced odds of hospitalization amongst boosted older community-dwelling Singaporeans during successive waves of Omicron transmission, including Omicron XBB; however, it did not significantly reduce the already low risk of severe COVID-19 in a highly vaccinated population. [ABSTRACT FROM AUTHOR]

This article discusses the role of histone demethylase KDM5 in the maturation of cardiomyocytes, which are heart muscle cells. The post-natal maturation of mammalian hearts involves significant changes at the structural, metabolic, and electrophysiological levels. The study found that inhibiting KDM5-mediated histone methylation in human induced pluripotent stem cell-derived cardiomyocytes led to changes in gene expression related to oxidative phosphorylation, fatty acid metabolism, and myogenesis, indicating a more advanced state of cardiomyocyte maturity. This research contributes to our understanding of the molecular drivers of cardiomyocyte maturation and has potential implications for cell-based therapy and the study of heart diseases. Further studies are needed to establish the physiological relevance of KDM5 in the maturation of mammalian hearts. [Extracted from the article]

An air‐tolerant reversible complexation mediated polymerization (RCMP) technique, which can be carried out without prior deoxygenation, is developed. The system contains a monomer, an alkyl iodide initiating dormant species, air (oxygen), an aldehyde, N‐hydroxyphthalimide (NHPI), and a base. Oxygen is consumed via the NHPI‐catalyzed conversion of the aldehyde (RCHO) to a carboxylic acid (RCOOH). The generated RCOOH is further converted to a carboxylate anion (RCOO−) by the base. The RCOO− generated in situ works as an RCMP catalyst; the polymerization proceeds with the monomer, alkyl iodide dormant species, and RCOO− catalyst. Thus, the system is not only air‐tolerant but also does not require additional RCMP catalysts, which is a notable feature of this system. (NHPI is used as an oxidation catalyst for converting RCHO to RCOOH.) This technique is amenable to methyl methacrylate, butyl methacrylate, benzyl methacrylate, 2‐hydroxyethyl methacrylate, and styrene, yielding polymers with relatively low‐dispersity (Mw/Mn = 1.20−1.49), where Mw and Mn are the weight‐ and number‐average molecular weights, respectively. [ABSTRACT FROM AUTHOR]

Background: Gender dysphoria is defined as discomfort or distress that is caused by a discrepancy between a person's gender identity and that person's sex assigned at birth. The main objective of this study was to review the application, efficacy and outcomes of a novel surgical technique, peritoneal pull‐through technique vaginoplasty, in gender‐affirming surgery. Specific outcome parameters include (1) healing time (2) depth of cavity achieved (3) alleviation of dysphoria (4) morbidity of the surgery. Methods: This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement and PROSPERO registration obtained prior to commencement (PROSPERO CRD42020206736). A search was performed in OVID MEDLINE, EMBASE, Willey Online Library and PubMed. Specialty‐related journals, grey literature and reference lists of relevant articles were manually searched. Results: From 476 potentially relevant articles, 12 articles were analysed. The publications were all level 4 or level 5 evidence. Healing times were poorly reported or often not mentioned. Eight authors reported neovagina cavity depth of at least 13 cm and good patient satisfaction. Alleviation of dysphoria was not discussed by any of the publications and only six reported complications. Average follow up reported ranged from 6 weeks to 14.8 months. Conclusion: The application of peritoneal pull‐through vaginoplasty in gender‐affirming surgery is promising and novel. However, there is a paucity of data. Further research and longer‐term data are required to assess the efficacy and safety of this technique. Patients seeking this surgery overseas should be informed of the potential difficulties they may face. [ABSTRACT FROM AUTHOR]

Vaccination against COVID-19 was integral to controlling the pandemic that persisted with the continuous emergence of SARS-CoV-2 variants. Using a mathematical model describing SARS-CoV-2 within-host infection dynamics, we estimate differences in virus and immunity due to factors of infecting variant, age, and vaccination history (vaccination brand, number of doses and time since vaccination). We fit our model in a Bayesian framework to upper respiratory tract viral load measurements obtained from cases of Delta and Omicron infections in Singapore, of whom the majority only had one nasopharyngeal swab measurement. With this dataset, we are able to recreate similar trends in URT virus dynamics observed in past within-host modelling studies fitted to longitudinal patient data. We found that Omicron had higher R0,within values than Delta, indicating greater initial cell-to-cell spread of infection within the host. Moreover, heterogeneities in infection dynamics across patient subgroups could be recreated by fitting immunity-related parameters as vaccination history-specific, with or without age modification. Our model results are consistent with the notion of immunosenescence in SARS-CoV-2 infection in elderly individuals, and the issue of waning immunity with increased time since last vaccination. Lastly, vaccination was not found to subdue virus dynamics in Omicron infections as well as it had for Delta infections. This study provides insight into the influence of vaccine-elicited immunity on SARS-CoV-2 within-host dynamics, and the interplay between age and vaccination history. Furthermore, it demonstrates the need to disentangle host factors and changes in pathogen to discern factors influencing virus dynamics. Finally, this work demonstrates a way forward in the study of within-host virus dynamics, by use of viral load datasets including a large number of patients without repeated measurements. [ABSTRACT FROM AUTHOR]

Background: Asians are predisposed to a lean heart failure (HF) phenotype. Data on the 'obesity paradox', reported in Western populations, are scarce in Asia and have only utilised the traditional classification of body mass index (BMI). We aimed to investigate the association between obesity (defined by BMI and abdominal measures) and HF outcomes in Asia.Methods and Findings: Utilising the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry (11 Asian regions including Taiwan, Hong Kong, China, India, Malaysia, Thailand, Singapore, Indonesia, Philippines, Japan, and Korea; 46 centres with enrolment between 1 October 2012 and 6 October 2016), we prospectively examined 5,964 patients with symptomatic HF (mean age 61.3 ± 13.3 years, 26% women, mean BMI 25.3 ± 5.3 kg/m2, 16% with HF with preserved ejection fraction [HFpEF; ejection fraction ≥ 50%]), among whom 2,051 also had waist-to-height ratio (WHtR) measurements (mean age 60.8 ± 12.9 years, 24% women, mean BMI 25.0 ± 5.2 kg/m2, 7% HFpEF). Patients were categorised by BMI quartiles or WHtR quartiles or 4 combined groups of BMI (low, <24.5 kg/m2 [lean], or high, ≥24.5 kg/m2 [obese]) and WHtR (low, <0.55 [thin], or high, ≥0.55 [fat]). Cox proportional hazards models were used to examine a 1-year composite outcome (HF hospitalisation or mortality). Across BMI quartiles, higher BMI was associated with lower risk of the composite outcome (ptrend < 0.001). Contrastingly, higher WHtR was associated with higher risk of the composite outcome. Individuals in the lean-fat group, with low BMI and high WHtR (13.9%), were more likely to be women (35.4%) and to be from low-income countries (47.7%) (predominantly in South/Southeast Asia), and had higher prevalence of diabetes (46%), worse quality of life scores (63.3 ± 24.2), and a higher rate of the composite outcome (51/232; 22%), compared to the other groups (p < 0.05 for all). Following multivariable adjustment, the lean-fat group had higher adjusted risk of the composite outcome (hazard ratio 1.93, 95% CI 1.17-3.18, p = 0.01), compared to the obese-thin group, with high BMI and low WHtR. Results were consistent across both HF subtypes (HFpEF and HF with reduced ejection fraction [HFrEF]; pinteraction = 0.355). Selection bias and residual confounding are potential limitations of such multinational observational registries.Conclusions: In this cohort of Asian patients with HF, the 'obesity paradox' is observed only when defined using BMI, with WHtR showing the opposite association with the composite outcome. Lean-fat patients, with high WHtR and low BMI, have the worst outcomes. A direct correlation between high WHtR and the composite outcome is apparent in both HFpEF and HFrEF.Trial Registration: Asian Sudden Cardiac Death in HF (ASIAN-HF) Registry ClinicalTrials.gov Identifier: NCT01633398. [ABSTRACT FROM AUTHOR]

Studies have reported increased rates of long-term neuropsychiatric sequelae after SARS-CoV-2 infection using electronic health-record (EHR) data; however, the majority were conducted before Omicron and booster rollout. We estimated the long-term risks and excess burdens of pre–specified new-incident neuropsychiatric diagnoses after Delta versus Omicron BA.1/2 infection in a highly-vaccinated and boosted cohort of adult Singaporeans. The national SARS-CoV-2 testing registry was used to construct cohorts of Singaporean adults infected during periods of Delta and Omicron BA.1/2 predominance and a contemporaneous test-negative control group. New-incident neuropsychiatric diagnoses recorded in the national health care claims database were identified up to 300 days postinfection. Risks and excess burden were estimated using a doubly robust competing-risks survival analysis. 104 179 and 375 903 infected cases were assigned to Delta and Omicron cohorts and compared against test-negative controls (Delta: N = 666 575 and Omicron: N = 619 379). Elevated risk of cognition or memory disorders was consistently reported across Omicron (Adjusted hazards ratio [aHR], 1.24; 95% CI, 1.12–1.38) and Delta cohorts (aHR, 1.63; 95% CI, 1.39–1.92). Delta-variant infection was associated with an increased risk of anosmia or dysgeusia (aHR, 4.53; 95% CI, 2.78–7.41) and psychosis (aHR, 1.65; 95% CI, 1.22–2.22). By contrast, Omicron-variant infection was associated with a risk of abnormal involuntary movements (aHR, 1.93; 95% CI, 1.32–2.83). Risks of neuropsychiatric sequelae predominantly accrued in hospitalized individuals. A modestly increased risk of cognition and memory disorders at 300 days after SARS-CoV-2 infection was observed among adult Singaporeans infected during the Delta/Omicron BA.1/2 transmission. There was no overall increased risk of neuropsychiatric sequelae observed across other domains. Variant-specific differences were also observed in individual neuropsychiatric sequelae, including an elevated risk of anosmia or dysgeusia after Delta-variant infection. [ABSTRACT FROM AUTHOR]

Background Growing evidence suggests that some coronavirus disease 2019 (COVID-19) survivors experience a wide range of long-term postacute sequelae. We examined the postacute risk and burden of new-incident cardiovascular, cerebrovascular, and other thrombotic complications after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a highly vaccinated multiethnic Southeast Asian population, during Delta predominance. Methods This cohort study used national testing and healthcare claims databases in Singapore to build a cohort of individuals who had a positive SARS-CoV-2 test between 1 September and 30 November 2021 when Delta predominated community transmission. Concurrently, we constructed a test-negative control group by enrolling individuals between 13 April 2020 and 31 December 2022 with no evidence of SARS-CoV-2 infection. Participants in both groups were followed up for a median of 300 days. We estimated risks of new-incident cardiovascular, cerebrovascular, and other thrombotic complications using doubly robust competing-risks survival analysis. Risks were reported using 2 measures: hazard ratio (HR) and excess burden (EB) with 95% confidence intervals. Results We included 106 012 infected cases and 1 684 085 test-negative controls. Compared with the control group, individuals with COVID-19 exhibited increased risk (HR, 1.157 [1.069–1.252]) and excess burden (EB, 0.70 [.53–.88]) of new-incident cardiovascular and cerebrovascular complications. Risks decreased in a graded fashion for fully vaccinated (HR, 1.11 [1.02–1.22]) and boosted (HR, 1.10 [.92–1.32]) individuals. Conversely, risks and burdens of subsequent cardiovascular/cerebrovascular complications increased for hospitalized and severe COVID-19 cases (compared to nonhospitalized cases). Conclusions Increased risks and excess burdens of new-incident cardiovascular/cerebrovascular complications were reported among infected individuals; risks can be attenuated with vaccination and boosting. [ABSTRACT FROM AUTHOR]

Background: Comorbidities are common in patients with heart failure (HF) and complicate treatment and outcomes. We identified patterns of multimorbidity in Asian patients with HF and their association with patients' quality of life (QoL) and health outcomes.Methods and Findings: We used data on 6,480 patients with chronic HF (1,204 with preserved ejection fraction) enrolled between 1 October 2012 and 6 October 2016 in the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry. The ASIAN-HF registry is a prospective cohort study, with patients prospectively enrolled from in- and outpatient clinics from 11 Asian regions (Hong Kong, Taiwan, China, Japan, Korea, India, Malaysia, Thailand, Singapore, Indonesia, and Philippines). Latent class analysis was used to identify patterns of multimorbidity. The primary outcome was defined as a composite of all-cause mortality or HF hospitalization within 1 year. To assess differences in QoL, we used the Kansas City Cardiomyopathy Questionnaire. We identified 5 distinct multimorbidity groups: elderly/atrial fibrillation (AF) (N = 1,048; oldest, more AF), metabolic (N = 1,129; obesity, diabetes, hypertension), young (N = 1,759; youngest, low comorbidity rates, non-ischemic etiology), ischemic (N = 1,261; ischemic etiology), and lean diabetic (N = 1,283; diabetic, hypertensive, low prevalence of obesity, high prevalence of chronic kidney disease). Patients in the lean diabetic group had the worst QoL, more severe signs and symptoms of HF, and the highest rate of the primary combined outcome within 1 year (29% versus 11% in the young group) (p for all <0.001). Adjusting for confounders (demographics, New York Heart Association class, and medication) the lean diabetic (hazard ratio [HR] 1.79, 95% CI 1.46-2.22), elderly/AF (HR 1.57, 95% CI 1.26-1.96), ischemic (HR 1.51, 95% CI 1.22-1.88), and metabolic (HR 1.28, 95% CI 1.02-1.60) groups had higher rates of the primary combined outcome compared to the young group. Potential limitations include site selection and participation bias.Conclusions: Among Asian patients with HF, comorbidities naturally clustered in 5 distinct patterns, each differentially impacting patients' QoL and health outcomes. These data underscore the importance of studying multimorbidity in HF and the need for more comprehensive approaches in phenotyping patients with HF and multimorbidity.Trial Registration: ClinicalTrials.gov NCT01633398. [ABSTRACT FROM AUTHOR]

Objectives/Background In heart failure (HF), pulse pressure (PP) may reflect both vascular stiffness and left ventricular function, but its prognostic role in relation to ejection fraction (EF) is poorly understood. Methods In the Swedish Heart Failure Registry, we investigated the association between PP and 1-year mortality in patients with HF and reduced (HFrEF, < 40%), mid-range (HFmrEF, 40–49%) and preserved EF (HFpEF, ≥ 50%), using multivariable logistic regression and restricted cubic splines. Results Among 36,770 patients discharged alive or enrolled as out-patients with 1-year follow-up (mean age 74 ± 12 years, 63% men, 56% HFrEF, 21% HFmrEF, 23% HFpEF), crude one-year mortality was 18%. Mean PP increased across EF groups: 51 ± 16 in HFrEF, 57 ± 18 in HFmrEF, 60 ± 19 mm Hg in HFpEF. In crude regression splines, the association between PP and mortality was U-shaped in HFmrEF and HFpEF, but curvilinear with only low PP associated with mortality in HFrEF. In multivariable analyses, a significant interaction by EF group and PP was observed (p interaction = 0.015): low PP was associated with higher mortality in HFrEF (adjusted OR [1st vs. 4th quintile] = 1.40, 95% CI 1.18–1.67) and HFpEF (1.43, 1.14–1.81) but only by trend in HFmrEF; high PP had a trend towards higher mortality in HFmrEF (5th vs. 3rd quintile = 1.30, 1.00–1.69) and HFpEF (1.25, 0.98–1.61). Conclusions The association between PP and mortality in HF was influenced by EF. Low PP was independently associated with mortality in HFrEF and HFpEF and by trend in HFmrEF. High PP was independently associated with mortality by trend in HFmrEF and HFpEF. [ABSTRACT FROM AUTHOR]

Aims: Clinical features and outcomes in the novel phenotype heart failure with mid-range ejection fraction [HFmrEF, ejection fraction (EF) 40-49%] were compared with heart failure with reduced EF (HFrEF, EF <40%) and preserved EF (HFpEF, EF ≥50%).Methods and Results: In the Swedish Heart Failure Registry, we assessed the association between baseline characteristics and EF group using multivariable logistic regressions, and the association between EF group and all-cause mortality using multivariable Cox regressions. Of 42 061 patients, 56% had HFrEF, 21% had HFmrEF, and 23% had HFpEF. Characteristics were continuous for age (72 ± 12 vs. 74 ± 12 vs. 77 ± 11 years), proportion of women (29% vs. 39% vs. 55%), and 13 other characteristics. Coronary artery disease (CAD) was distinctly more common in HFrEF (54%) and HFmrEF (53%) vs. HFpEF (42%); adjusted odds ratio for CAD in HFmrEF vs. HFpEF was 1.52 [95% confidence interval (CI) 1.41-1.63]. For six additional characteristics HFmrEF resembled HFrEF, for seven characteristics HFmrEF resembled HFpEF, and for 10 characteristics there was no pattern. The adjusted hazard ratio (HR) for mortality in HFrEF vs. HFpEF was 1.35 (95% CI 1.14-1.60) at 30 days, 1.26 (95% CI 1.17-1.35) at 1 year, and 1.20 (95% CI 1.14-1.26) at 3 years. In contrast, HFmrEF and HFpEF had a similar prognosis (HR 1.06, 95% CI 0.86-1.30 at 30 days; HR 1.08, 95% CI 1.00-1.18 at 1 year; and HR 1.06, 95% CI 1.00-1.12 at 3 years). Three-year mortality was higher in HFmrEF than in HFpEF in the presence of CAD (HR 1.11, 95% CI 1.02-1.21), but not in the absence of CAD (HR 1.02, 95% CI 0.94-1.12; P for interaction <0.001).Conclusions: HFmrEF was an intermediate phenotype, except that CAD was more common in HFmrEF and HFrEF vs. HFpEF, crude all-cause mortality was lower in HFmrEF and HFrEF, adjusted all-cause mortality was lower in HFmrEF and HFpEF, and CAD portended a higher adjusted risk of death in HFmrEF and HFrEF. [ABSTRACT FROM AUTHOR]

Purpose To evaluate and compare changes in contrast sensitivity and ocular higher-order aberrations (HOAs) after femtosecond lenticule extraction (FLEx) and pseudo small-incision lenticule extraction (SMILE). Setting Singapore National Eye Centre, Singapore. Design Retrospective case series. Method Patients had femtosecond lenticule extraction (Group 1) or pseudo small-incision lenticule extraction (Group 2) between March 2010 and December 2011. The main outcome measures were manifest refraction, HOAs, and contrast sensitivity 1, 3, 6, and 12 months postoperatively. Results Fifty-two consecutive patients (102 eyes) were recruited, 21 patients (42 eyes) in Group 1 and the 31 patients (60 eyes) in Group 2. The uncorrected and corrected distance visual acuities were significantly better in Group 2 than in Group 1 at 12 months ( P = .032). There was no significant increase in 3rd- or 4th-order aberrations at 1 year and no significant difference between the 2 groups preoperatively or postoperatively. At 1 year, there was a significant increase in mesopic contrast sensitivity in Group 2 at 1.5 cycles per degree (cpd) ( P = .008) that was not found in Group 1, and photopic contrast sensitivity at 6.0 cpd was higher in Group 2 ( P = .027). Conclusions These results indicate that refractive lenticule extraction is safe and effective with no significant induction of HOAs or deterioration in contrast sensitivity at 1 year. Induction of HOAs was not significantly different between both variants of refractive lenticule extraction. However, there was significant improvement in photopic contrast sensitivity after pseudo small-incision lenticule extraction, which persisted through 1 year. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned. [ABSTRACT FROM AUTHOR]

Aim: To investigate the interplay of incident chronic kidney disease (CKD) and/or heart failure (HF) and their associations with prognosis in a large, population‐based cohort with type 2 diabetes (T2DM). Methods: Patients aged ≥18 years with new‐onset T2DM, without renal disease or HF at baseline, were identified from the territory‐wide Clinical Data Analysis Reporting System between 2000 and 2015. Patients were followed up until December 31, 2020 for incident CKD and/or HF and all‐cause mortality. Results: Among 102 488 patients (median age 66 years, 45.7% women, median follow‐up 7.5 years), new‐onset CKD occurred in 14 798 patients (14.4%), in whom 21.7% had HF. In contrast, among 9258 patients (9.0%) with new‐onset HF, 34.6% had CKD. The median time from baseline to incident CKD or HF (4.4 vs. 4.1 years) did not differ. However, the median (interquartile range) time until incident HF after CKD diagnosis was 1.7 (0.5‐3.6) years and was 1.2 (0.2‐3.4) years for incident CKD after HF diagnosis (P < 0.001). The crude incidence of CKD was higher than that of HF: 17.6 (95% confidence interval [CI] 17.3‐17.9) vs. 10.6 (95% CI 10.4‐10.9)/1000 person‐years, respectively, but incident HF was associated with a higher adjusted‐mortality than incident CKD. The presence of either condition (vs. CKD/HF‐free status) was associated with a three‐fold hazard of death, whereas concomitant HF and CKD conferred a six to seven‐fold adjusted hazard of mortality. Conclusion: Cardiorenal complications are common and are associated with high mortality risk among patients with new‐onset T2DM. Close surveillance of these dual complications is crucial to reduce the burden of disease. [ABSTRACT FROM AUTHOR]

Purpose: To examine the association of reproductive factors and major eye diseases, including glaucoma, age-related macular degeneration (AMD), diabetic retinopathy and cataract, in Asian women. Methods: The Singapore Malay Eye Study is a population-based cross-sectional epidemiological study which examined 3280 persons (78.7% response) of Malay ethnicity aged 40-80 years; 1704 were female. Information on reproductive factors and use of hormone replacement therapy (HRT) was collected using an interviewer-administered questionnaire. Glaucoma was defined according to the International Society for Geographical and Epidemiological Ophthalmology criteria. Retinal photographs were graded for AMD following the Wisconsin grading system, and diabetic retinopathy according to the modified Airlie House classification system. Cataract was graded according to the Lens Opacity Classification System III. Results: A total of 1176 women reported having experienced menopause by the time of the study with 1073 (91%) having a natural menopause, 88 (7.5%) a hysterectomy and 9 (0.8%) due to other reasons; HRT was used by 70 (6%) women. Women whose age at menopause was ≤52 years were 3.5 times more likely to have glaucoma (95% confidence interval, CI, 1.23-9.98, p value = 0.02) than those whose age at menopause was ≥53 years. Age of menopause was not associated with AMD (age-adjusted odds ratio, OR, 1.22, 95% CI 0.65-2.31), diabetic retinopathy (age-adjusted OR 1.01, 95% CI 0.66-1.54) or cataract (age-adjusted OR 1.38, 95% CI 0.95-2.00). Use of HRT was not associated with any of these eye diseases. Conclusion: Women who had menopause at a younger age were more likely to have glaucoma. This association needs to be confirmed in other studies. [ABSTRACT FROM AUTHOR]

Purpose: To describe the prevalence of lens opacities and cataract surgery in an older Malay population in Singapore. Methods: The Singapore Malay Eye Study is a population-based cross-sectional study of 3280 (78.7% response rate) Malay adults aged 40-80 years. Participants underwent a standardized clinical eye examination. Digital slit-lamp and retroillumination photographs were taken of both eyes of each participant and graded for age-related nuclear, cortical and posterior subcapsular (PSC) cataract, following the Wisconsin Cataract Grading System. Other lens opacities, including retrodots and vacuoles, were also graded. Information on medical and lifestyle factors was collected using questionnaires. The study sample was directly age-standardized to the Malay population in Singapore using the 2000 Singapore population census. Results: A total of 3054 (97.7%) and 3113 (99.6%) participants had gradable Topcon slit lamp and Neitz photographs, respectively. The overall age-adjusted prevalence of any cataract was 29.1%, and that of nuclear, cortical and PSC cataract were 12.9% (95% confidence interval, CI, 11.2-13.1%), 21.2% (95% CI 19.8-22.7%) and 9.7% (95% CI 8.8-10.8%), respectively. Age-adjusted prevalence of cataract surgery was 4.7% (95% CI 4.2-5.4%). Prevalence of all three cataract types and cataract surgery increased with age. Age-adjusted prevalence for retrodots and vacuoles were 19.7% (95% CI 18.3-21.1%) and 64.3% (95% CI 61.1-67.6%), respectively. Retrodots were found to be associated with prevalence of all three cataract types, while vacuoles were associated with cortical and PSC cataract prevalence. Conclusion: Lens opacities were common in this urban Malay population. Retrodots and vacuoles were found to be associated with age-related cataract. [ABSTRACT FROM AUTHOR]

Aim: Different associations between epicardial adipose tissue (EAT) and cardiac function have been suggested in patients with heart failure with preserved (HFpEF) versus reduced and mildly reduced ejection fraction (HFrEF/HFmrEF). However, few studies have directly compared the association between EAT and left atrial (LA) and left ventricular (LV) function in patients with HFpEF and HFrEF/HFmrEF. Methods and results: We studied EAT thickness using transthoracic echocardiography in a multicentre cohort of 149 community‐dwelling controls without heart failure, 99 patients with HFpEF, and 366 patients with HFrEF/HFmrEF. EAT thickness was averaged from parasternal long‐axis and short‐axis views, respectively, and off‐line speckle tracking analysis was performed to quantify LA and LV function. Data were validated in an independent cohort of 626 controls, 243 patients with HFpEF, and 180 patients with HFrEF/HFmrEF. For LV function, LV global longitudinal strain (GLS) was measured in both derivation and validation cohorts. For LA function, LAGLS at reservoir, contractile and conduit phase were measured in the derivation cohort, and only LAGLS at reservoir phase was measured in the validation cohort. In the derivation cohort, EAT thickness was lower in HFrEF/HFmrEF (7.3 ± 2.5 mm) compared to HFpEF (8.3 ± 2.6 mm, p < 0.05) and controls (7.9 ± 1.8 mm, p < 0.05). Greater EAT thickness was associated with better LV and contractile LA function in HFrEF/HFmrEF, but not in HFpEF (p for interaction <0.05). These findings were confirmed in the validation cohort, where EAT thickness was lower in HFrEF/HFmrEF (6.7 ± 1.4 mm) compared to HFpEF (9.6 ± 2.8 mm; p < 0.05) and controls (7.7 ± 2.3 mm; p < 0.05). Greater EAT thickness was associated with better LV and reservoir LA function in patients with HFrEF/HFmrEF but worse LV and reservoir LA function in patients with HFpEF (p for interaction <0.05). Thickened EAT (EAT thickness >10 mm) was associated with LA dysfunction (LAGLS at reservoir phase <23%) in HFpEF, but not in HFrEF/HFmrEF. Conclusion: Epicardial adipose tissue thickness is greater in patients with HFpEF than HFrEF/HFmrEF. Increased EAT thickness is associated with worse LA and LV function in HFpEF but the opposite in HFrEF/HFmrEF. [ABSTRACT FROM AUTHOR]

Aim: Immunological checkpoint therapy is considered a powerful method for cancer therapy and acts by re-activating autologous T cells to kill the cancer cell. Myocarditis cases have been reported in cancer patients after immunological therapy; for example, nivolumab treatment is a monoclonal antibody that blocks programmed cell death-1/programmed cell death ligand-1 ligand interaction. This project provided insight into the inflammatory response as a benchmark to investigate the potential cardiotoxic effect of T cell response to the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis in regulating cardiomyocyte injury in vitro. Methods and Results: We investigated cardiomyopathy resulted from the PD-1/PD-L1 axis blockade using the anti-PD-1 antibody in Rockefeller University embryonic stem cells-derived cardiomyocytes (RUES2-CMs) and a melanoma tumor-bearing murine model. We found that nivolumab alone did not induce inflammatory-related proteins, including PD-L1 expression, and did not induce apoptosis, which was contrary to doxorubicin, a cardiotoxic chemotherapy drug. However, nivolumab was able to exacerbate the immune response by increasing cytokine and inflammatory gene expression in RUES2-CMs when co-cultured with CD4+ T lymphocytes and induced apoptosis. This effect was not observed when RUES2-CMs were co-cultured with CD8+ T lymphocytes. The in vivo model showed that the heart function of tumor-bearing mice was decreased after treatment with anti-PD-1 antibody and demonstrated a dilated left ventricle histological examination. The dilated left ventricle was associated with an infiltration of CD4+ and CD8+ T lymphocytes into the myocardium. PD-L1 and inflammatory-associated gene expression were significantly increased in anti-PD-1-treated tumor-bearing mice. Cleaved caspase-3 and mouse plasma cardiac troponin I expressions were increased significantly. Conclusion: PD-L1 expression on cardiomyocytes suppressed T-cell function. Blockade of PD-1 by nivolumab enhanced cardiomyocyte inflammation and apoptosis through the enhancement of T-cell response towards cardiomyocytes. [ABSTRACT FROM AUTHOR]

Introduction: Electrocardiographic QRS duration (QRSd) is a marker of electrical remodeling in heart failure with reduced ejection fraction (HFrEF). Differences in anthropometrics and left ventricular size have been postulated to contribute to variation of QRSd with sex, race, obesity, and sex-based response to resynchronization therapy. We controlled QRSd for body size as electroanatomic ratios and assessed their association with mortality. Hypothesis: We hypothesized that electrical remodeling quantified as increased electroanatomic ratios are associated with increased mortality. Methods: The Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry prospectively followed symptomatic HFrEF patients from 11 Asian regions. Electroanatomic ratios were derived as ratios of QRSd to body size (height; body surface area, BSA; body mass index, BMI). Cox proportional hazard models were used to assess the association between electroanatomic ratio and 1-year all-cause mortality. Results: The study included 4899 eligible patients (age 60±19 years, 78% male, LVEF 27.3±7.1 %, 50% ischemic etiology, 35% NYHA III/IV, QRSd 115.2±32.6 ms, height 164±8.9 cm, BSA 1.74±0.23 m2, BMI 24.9±5.1 kg/m2, LVEDV 178.7±65.5 mL). QRSd was not associated with mortality (p=0.142). However, QRSd indexed for body size was independently associated with mortality (QRS/BMI: HR 1.18, 95%CI 1.06-1.31, p=0.002; QRS/BSA: HR 1.17, 95%CI 1.05-1.31, p=0.005; QRS/height: HR 1.17, 95%CI 1.05-1.30, p=0.005). Sex-based differences were seen. QRS/BSA (interaction p=0.020 with sex) was associated with mortality in men (HR 1.21, 95% CI 1.07-1.37, p=0.003) but not in women (p=0.568). QRS/height (Interaction p=0.020 with sex) was associated with mortality in men (HR 1.20, 95% CI 1.07-1.36, p=0.003) but not in women (p=0.568). Conclusions: Electroanatomic ratios of QRS/BSA, QRS/BMI and QRS/height were independently associated with mortality in patients with HFrEF whereas QRSd alone was not. Sex modified association of QRSd indexed for body size with mortality. These findings merit further investigation. [ABSTRACT FROM AUTHOR]

Introduction: The clinical and echocardiographic correlates of atrial fibrillation (AF) among patients with heart failure and preserved versus reduced ejection fraction (HFpEF vs HFrEF) have not been not well studied in Asia. Hypothesis: There are regional differences in AF among Asian patients with HF. Methods: A total of 4541 patients with HFrEF (EF<40%) and 963 patients with HFpEF (EF≥50%) were enrolled from Northeast Asia (Korea, Japan, Taiwan, Hong Kong, and China), South Asia (India) and Southeast Asia (Thailand, Malaysia, Philippines, Indonesia, Singapore) in the prospective Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) study. AF was defined by history or baseline ECG. Outcomes (death or hospitalisation) were independently adjudicated. Results: Prevalence of AF was 22% in HFrEF (mean age 60±13, 78% male) and 38% in HFpEF (mean age 68±12, 47% male). Clinical correlates that differentially associated with AF in HFpEF vs HFrEF included age, region, and chronic kidney disease; whereas echocardiographic correlates that differentially associated with AF in HFpEF vs HFrEF included left atrial volume (Figure 1A). South Asians had the lowest prevalence of AF (6%, 12% in HFrEF, HFpEF) compared to Northeast Asians (39%, 49%) and Southeast Asians (21%, 37%)(p<0.001). Odds of AF were higher in Northeast Asians (adjusted OR 2.07, 95% CI 1.79-2.40) and lower in South Asians (adjusted OR 0.23, 95% CI 0.18-0.30) when compared to Southeast Asians. Differential odds of AF by region were mediated by both clinical and echocardiographic correlates (Figure 1B). There were striking differences in ethnic associations by region, where Indians from Southeast Asia had a higher odds of AF than Indians from South Asia (OR 2.49, 95% CI 1.68-3.70), and Chinese from Southeast Asia had lower odds of AF than Chinese from Northeast Asia (OR 0.80, 95% CI 0.66-0.98). AF increased the risk of the composite outcome of all-cause mortality and HF hospitalisations (adjusted OR 1.28, 95% CI 1.09-1.51), with similar prognostic impact in HFpEF and HFrEF (Pinteraction0.39). Conclusions: These findings highlight the regional differences in AF among Asian patients with HF. South Asians with HF have a strikingly low prevalence of AF, a difference deserving of further study. [ABSTRACT FROM AUTHOR]

Aims: Although trials have proven the group‐level effectiveness of various therapies for heart failure with reduced ejection fraction (HFrEF), important differences in absolute effectiveness exist between individuals. We developed and validated the LIFEtime‐perspective for Heart Failure (LIFE‐HF) model for the prediction of individual (lifetime) risk and treatment benefit in patients with HFrEF. Methods and results: Cox proportional hazards functions with age as the time scale were developed in the PARADIGM‐HF and ATMOSPHERE trials (n = 15 415). Outcomes were cardiovascular death, heart failure (HF) hospitalization or cardiovascular death, and non‐cardiovascular mortality. Predictors were age, sex, New York Heart Association class, prior HF hospitalization, diabetes mellitus, extracardiac vascular disease, systolic blood pressure, left ventricular ejection fraction, N‐terminal pro‐B‐type natriuretic peptide, and glomerular filtration rate. The functions were combined in life‐tables to predict individual overall and HF hospitalization‐free survival. External validation was performed in the SwedeHF registry, ASIAN‐HF registry, and DAPA‐HF trial (n = 51 286). Calibration of 2‐ to 10‐year risk was adequate, and c‐statistics were 0.65–0.74. An interactive tool was developed combining the model with hazard ratios from trials to allow estimation of an individual's (lifetime) risk and treatment benefit in clinical practice. Applying the tool to the development cohort, combined treatment with a mineralocorticoid receptor antagonist, sodium–glucose cotransporter 2 inhibitor, and angiotensin receptor–neprilysin inhibitor was estimated to afford a median of 2.5 (interquartile range [IQR] 1.7–3.7) and 3.7 (IQR 2.4–5.5) additional years of overall and HF hospitalization‐free survival, respectively. Conclusion: The LIFE‐HF model enables estimation of lifelong overall and HF hospitalization‐free survival, and (lifetime) treatment benefit for individual patients with HFrEF. It could serve as a tool to improve the management of HFrEF by facilitating personalized medicine and shared decision‐making. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Multimorbidity in patients with heart failure from 11 Asian regions: A prospective cohort study using the ASIAN-HF registry" which appeared in the previous issue of 2018.

[This corrects the article DOI: 10.1371/journal.pmed.1002541.]. [ABSTRACT FROM AUTHOR]

Aims: To examine sex differences in clinical characteristics, echocardiographic features, quality of life and 1-year death or heart failure (HF) hospitalization outcomes in patients with/without diabetes mellitus (DM).Methods and Results: Utilizing the Asian Sudden Cardiac Death in HF (ASIAN-HF) registry, 5255 patients (mean age 59.6 ± 13.1, 78% men) with symptomatic HF with reduced ejection fraction (HFrEF) were stratified by DM status to address the research aims. Despite similar prevalence of DM between Asian men (43%) and women (42%), the odds of DM increased at lower body mass index in women vs. men (≥ 23 vs. ≥ 27.5 kg/m2 , Pinteraction  = 0.014). DM was more strongly related to chronic kidney disease in women vs. men [adjusted odds ratio (OR) 1.85, 95% confidence interval (CI) 1.33-2.57 vs. OR 1.32, 95% CI 1.11-1.56, Pinteraction  = 0.009]. Sex also modified the relationship between DM and left ventricular geometry (Pinteraction  = 0.003), whereby DM was associated with a more concentric left ventricular geometry in women than men. Women had lower quality of life than men (P < 0.001), in both DM and non-DM groups. DM was associated with worse composite outcomes at 1 year in women vs. men [hazard ratio (HR) 1.79, 95% CI 1.24-2.60 vs. HR 1.32, 95% CI 1.12-1.56; Pinteraction  = 0.005).Conclusions: Asian women with HFrEF were more likely to have DM despite a lean body mass index, a greater burden of chronic kidney disease and more concentric left ventricular geometry, compared to men. Furthermore, DM confers worse quality of life, irrespective of sex, and a greater risk of adverse outcomes in women than men. These data underscore the need for sex-specific approaches to diabetes in patients with HF. [ABSTRACT FROM AUTHOR]

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem. Unfortunately, little is known about HFpEF across Asia.Methods and Results: We prospectively studied clinical characteristics, echocardiographic parameters and outcomes in 1204 patients with HFpEF (left ventricular ejection fraction ≥50%) from 11 Asian regions, grouped as Northeast Asia (Hong Kong, Taiwan, China, Japan, Korea, n = 543), South Asia (India, n = 252), and Southeast Asia (Malaysia, Thailand, Singapore, Indonesia, Philippines, n = 409). Mean age was 68 ±12 years (37% were < 65 years) and 50% were women. Seventy per cent of patients had ≥2 co-morbidities, most commonly hypertension (71%), followed by anaemia (57%), chronic kidney disease (50%), diabetes (45%), coronary artery disease (29%), atrial fibrillation (29%) and obesity (26%). Southeast Asian patients had the highest prevalence of all co-morbidities except atrial fibrillation, South Asians had the lowest prevalence of all co-morbidities except anaemia and obesity, and Northeast Asians had more atrial fibrillation. Left ventricular hypertrophy and concentric remodelling were most prominent among Southeast and South Asians, respectively (P < 0.001). Overall, 12.1% of patients died or were hospitalized for heart failure within 1 year. Southeast Asians were at higher risk for adverse outcomes, independent of co-morbidity burden and cardiac geometry.Conclusion: These first prospective multinational data from Asia show that HFpEF affects relatively young patients with a high burden of co-morbidities. Regional differences in types of co-morbidities, cardiac remodelling and outcomes of HFpEF across Asia have important implications for public health measures and global HFpEF trial design. [ABSTRACT FROM AUTHOR]

Background: Heart failure with preserved ejection fraction (HFpEF), traditionally considered a disease of the elderly, may also affect younger patients. However, little is known about HFpEF in the young.Methods: We prospectively enrolled 1203 patients with HFpEF (left ventricular ejection fraction ≥50%) from 11 Asian regions. We grouped HFpEF patients into very young (<55 years of age; n=157), young (55-64 years of age; n=284), older (65-74 years of age; n=355), and elderly (≥75 years of age; n=407) and compared clinical and echocardiographic characteristics, quality of life, and outcomes across age groups and between very young individuals with HFpEF and age- and sex-matched control subjects without heart failure.Results: Thirty-seven percent of our HFpEF population was <65 years of age. Younger age was associated with male preponderance and a higher prevalence of obesity (body mass index ≥30 kg/m2; 36% in very young HFpEF versus 16% in elderly) together with less renal impairment, atrial fibrillation, and hypertension (all P<0.001). Left ventricular filling pressures and prevalence of left ventricular hypertrophy were similar in very young and elderly HFpEF. Quality of life was better and death and heart failure hospitalization at 1 year occurred less frequently ( P<0.001) in the very young (7%) compared with elderly (21%) HFpEF. Compared with control subjects, very young HFpEF had a 3-fold higher death rate and twice the prevalence of hypertrophy.Conclusions: Young and very young patients with HFpEF display similar adverse cardiac remodeling compared with their older counterparts and very poor outcomes compared with control subjects without heart failure. Obesity may be a major driver of HFpEF in a high proportion of HFpEF in the young and very young. [ABSTRACT FROM AUTHOR]

Aim: To describe differences in patient characteristics and outcomes by ethnicity in patients with diabetes mellitus (DM) and heart failure (HF) with reduced ejection fraction (HFrEF, ejection fraction ≤35%) in a multi-ethnic cohort.Methods and Results: Patient level data from two cohorts (HF-ACTION and ASIAN-HF) were combined, and patients grouped by self-reported ethnicity. DM was defined as the presence of a clinical diagnosis and/or receiving anti-diabetic therapy. A total of 6214 (1324 whites, 674 blacks, 1297 Chinese, 1510 Indians, 717 Malays, 692 Japanese/Koreans) patients were included. The overall prevalence of DM was 39.5% (n = 2454). The prevalence of DM was lowest in whites (29.3%), followed by Japanese/Koreans (34.1%), blacks (35.9%), Chinese (42.3%), Indians (44.2%), and highest in Malays (51.9%). The correlation between age, sex, body mass index, coronary artery disease, hypertension, atrial fibrillation, peripheral vascular disease and chronic kidney disease with DM differed significantly by ethnicity (P for interaction <0.05). The strongest correlations were seen in Malay women, whites with obesity, Indians with coronary artery disease and hypertension, and blacks with chronic kidney disease. On multivariable analyses, DM was significantly associated with the composite of 1-year overall mortality/HF hospitalization (hazard ratio 1.37, 95% confidence interval 1.19-1.57; P < 0.001), with no interaction by ethnicity (P for interaction =0.31).Conclusions: There is marked heterogeneity in the prevalence and correlates of DM among different ethnic groups with HF worldwide. Subgroups particularly predisposed to DM warrant special attention, since DM increases the combined risk of morbidity and mortality in all ethnicities with HF. [ABSTRACT FROM AUTHOR]

Aims In patients with heart failure (HF), hospitalization rates are increasing, particularly for non-HF causes and over half may be avoidable. Self-monitoring of symptoms plays a key part in the early identification of deterioration. Our objective was to develop expert consensus for a core outcome set (COS) of symptoms to be monitored by patients, using validated single-item patient-reported outcome measures (PROMs), focused on the key priority of reducing admissions in HF. Methods and results A rigorous COS development process incorporating systematic review, modified e-Delphi and nominal group technique (NGT) methods. Participants included 24 HF patients, 4 carers, 29 HF nurses, and 9 doctors. In three Delphi and NGT rounds, participants rated potential outcomes on their importance before a HF or a non-HF admission using a 5-point Likert scale. Opinion change between rounds was assessed and a two-thirds threshold was used for outcome selection. Item generation using systematic review identified 100 validated single-item PROMs covering 34 symptoms or signs, relevant to admission for people with HF. De-duplication and formal consensus processes, resulted in a COS comprising eight symptoms and signs; shortness of breath, arm or leg swelling, abdomen bloating, palpitations, weight gain, chest pain, anxiety, and overall health. In the NGT, a numerical rating scale was selected as the optimal approach to symptom monitoring. Conclusion Recognition of a range of HF-specific and general symptoms, alongside comorbidities, is an important consideration for admission prevention. Further work is needed to validate and integrate the COS in routine care with the aim of facilitating faster identification of clinical deterioration. [ABSTRACT FROM AUTHOR]

Purpose: Awareness of eye conditions aids health promotion activities and leads to better outcomes. We examined factors influencing the lack of awareness of common eye conditions in a population. Methods: The Singapore Malay Eye Study examined 3280 (78.7% response) Malays aged 40-80 years. We included 2112 (64.4%) participants with at least one of five eye conditions: 1504 (71.2%) with cataract, 1013 (47.8%) with myopia, 270 (12.8%) with diabetic retinopathy, 181 (8.6%) with age-related macular degeneration and 150 (7.1%) with glaucoma. Lack of awareness was defined in the questionnaire as not answering 'yes' to previously being told by a doctor of having the eye condition. Results: Among 2112 participants, 83.2% were unaware of at least one of their eye conditions. After controlling for age, sex and socioeconomic factors, participants unaware of their eye condition were older (odds ratio, OR, 1.03, per 1 year, p < 0.001), had better visual acuity (OR 1.32, p = 0.04), lower education (OR 1.89, p < 0.001), poorer literacy (OR 1.44, p = 0.02), lower income (OR 1.73, p = 0.009), higher blood glucose (OR 1.08, per 1 mmol/L, p < 0.001), higher serum cholesterol (OR 1.20, per 1 mmol/L, p = 0.003), lower annual eye examination attendance (OR 2.08, p < 0.001) and were less likely to wear glasses (OR 2.90, p < 0.001) than those who were aware of their condition. Conclusions: In this community-based population, 80% of those with common eye conditions were unaware of their condition. [ABSTRACT FROM AUTHOR]

Purpose: To describe the prevalence and risk factors of diabetic retinopathy in Asian Malays. Design: Population-based cross-sectional study. Participants: Persons with diabetes of Malay ethnicity aged 40 to 80 years in Singapore. Methods: Diabetes mellitus was defined as random glucose of 11.1 mmol/l or more, use of diabetic medication, or a physician diagnosis of diabetes. Retinal photographs taken from both eyes were graded for diabetic retinopathy using the modified Airlie House classification system. Main Outcome Measures: Any diabetic retinopathy, retinopathy grades, macular edema, or vision-threatening retinopathy. Results: Of the 3261 persons who participated in this study, 757 (23.1%) had diabetes and gradable retinal photographs. In persons with diabetes, the overall prevalence of any retinopathy was 35.0% (95% confidence interval [CI], 28.2–43.4), the overall prevalence of macular edema was 5.7% (95% CI, 3.2–9.9), and the overall prevalence of vision-threatening retinopathy was 9.0% (95% CI, 5.8–13.8). Compared with men, women had significantly higher proportions with more severe diabetic retinopathy, moderate (12% vs. 4%) and severe (3% vs. 0.2%) nonproliferative retinopathy, proliferative retinopathy (7% vs. 2%), and vision-threatening retinopathy (13% vs. 3%). In multiple logistic regression, independent risk factors for any retinopathy were longer diabetes duration (odds ratio [OR], 1.07; 95% CI, 1.04–1.09, per year increase), higher hemoglobin A1 c (OR, 1.21; 95% CI, 1.10–1.33, per % increase), hypertension (OR, 1.85; 95% CI, 1.04–3.30), and higher pulse pressure (OR, 1.34, 95% CI, 1.19–1.51, per 10-mmHg increase); older age (OR, 0.73; 95% CI, 0.57–0.93, per decade increase) and higher total cholesterol levels (OR, 0.75; 95% CI, 0.63–0.89, per 1-mmol/l increase) were protective of any retinopathy. Vision-threatening retinopathy additionally was associated with previous stroke (OR, 3.74; 95% CI, 1.24–11.26), cardiovascular disease (OR, 2.23; 95% CI, 1.08–4.62), and chronic kidney disease (OR, 4.45; 95% CI, 2.18–9.07). Female gender was not an independent risk factor for diabetic retinopathy after adjusting for metabolic and socioeconomic risk factors. Conclusions: One in 10 Malay adults with diabetes in Singapore has vision-threatening diabetic retinopathy. Risk factors for retinopathy in this population are largely similar to white populations elsewhere, suggesting that control of these risk factors may reduce both the prevalence and impact of retinopathy. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. [Copyright &y& Elsevier]

Intestinal metaplasia (IM) is a pre-malignant condition of the gastric mucosa associated with increased gastric cancer (GC) risk. Analyzing 1,256 gastric samples (1,152 IMs) across 692 subjects from a prospective 10-year study, we identify 26 IM driver genes in diverse pathways including chromatin regulation (ARID1A) and intestinal homeostasis (SOX9). Single-cell and spatial profiles highlight changes in tissue ecology and IM lineage heterogeneity, including an intestinal stem-cell dominant cellular compartment linked to early malignancy. Expanded transcriptome profiling reveals expression-based molecular subtypes of IM associated with incomplete histology, antral/intestinal cell types, ARID1A mutations, inflammation, and microbial communities normally associated with the healthy oral tract. We demonstrate that combined clinical-genomic models outperform clinical-only models in predicting IMs likely to transform to GC. By highlighting strategies for accurately identifying IM patients at high GC risk and a role for microbial dysbiosis in IM progression, our results raise opportunities for GC precision prevention and interception. [Display omitted] • Genomic profiling reveals 26 intestinal metaplasia (IM) driver genes including SOX9 • IM lineage heterogeneity harbors a stem-cell subpopulation linked to malignancy • IM molecular subtypes are associated with inflammation and microbial communities • Genomic-clinical models improve identification of IMs at risk of GC progression Intestinal metaplasia (IM) is a pre-malignant condition linked to gastric cancer (GC). Huang et al. analyze a large prospective IM cohort, identifying driver genes, stem cell populations linked to GC, and molecular subtypes associated with inflammation and oral microbes. These results facilitate the use of genomics in GC precision prevention. [ABSTRACT FROM AUTHOR]

Background: Angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and β-blockers are guideline-recommended first-line therapies in heart failure (HF) with reduced ejection fraction (HFrEF). Previous studies showed that individual drug classes were under-dosed in many parts of Europe and Asia. In this study, we investigated the association of combined up-titration of ACEi/ARBs and β-blockers with all-cause mortality and its combination with hospitalization for HF.Methods and Results: A total of 6787 HFrEF patients (mean age 62.6 ± 13.2 years, 77.7% men, mean left ventricular ejection fraction 27.7 ± 7.2%) were enrolled in the prospective multinational European (BIOSTAT-CHF; n = 2100) and Asian (ASIAN-HF; n = 4687) studies. Outcomes were analysed according to achieved percentage of guideline-recommended target doses (GRTD) of combination ACEi/ARB and β-blocker therapy, adjusted for indication bias. Only 14% (n = 981) patients achieved ≥50% GRTD for both ACEi/ARB and β-blocker. The best outcomes were observed in patients who achieved 100% GRTD of both ACEi/ARB and β-blocker [hazard ratio (HR) 0.32, 95% confidence interval (CI) 0.26-0.39 vs. none]. Lower dose of combined therapy was associated with better outcomes than 100% GRTD of either monotherapy. Up-titrating β-blockers was associated with a consistent and greater reduction in hazards of all-cause mortality (HR for 100% GRTD: 0.40, 95% CI 0.25-0.63) than corresponding ACEi/ARB up-titration (HR 0.75, 95% CI 0.53-1.07).Conclusion: This study shows that best outcomes were observed in patients attaining GRTD for both ACEi/ARB and β-blockers, unfortunately this was rarely achieved. Achieving >50% GRTD of both drug classes was associated with better outcome than target dose of monotherapy. Up-titrating β-blockers to target dose was associated with greater mortality reduction than up-titrating ACEi/ARB. [ABSTRACT FROM AUTHOR]

Objective: Microvascular complications are common among patients with diabetes mellitus (DM). The presence of heart failure (HF) is presumed to be due to macrovascular disease (typically HF with reduced ejection fraction [HFrEF] following myocardial infarction). We hypothesized that HF with preserved ejection fraction (HFpEF) in patients with DM may be a manifestation of microvascular disease compared with HFrEF. The objective of this study was to examine the prevalence and association with clinical outcome of microvascular complications in patients with HF and DM.Research Design and Methods: We investigated the prevalence, association with clinical outcome, and cardiac structure and function of microvascular (neuropathy, nephropathy, and retinopathy) complications of DM in 2,800 prospectively enrolled participants with HF and DM (561 with HFpEF) from the Asian Sudden Cardiac Death In Heart Failure (ASIAN-HF) registry.Results: A total of 601 (21.5%) participants with DM had microvascular complications. Participants with DM and any (one or more) microvascular complications were more likely to have HFpEF (odds ratio 1.70 [95% CI 1.15-2.50]; P = 0.008). Furthermore, the likelihood of having HFpEF increased with an increasing number of microvascular complications (Ptrend < 0.001). Microvascular complications were associated with more left ventricular (LV) hypertrophy and a greater reduction in quality of life in HFpEF than HFrEF (Pinteraction < 0.001 for all). Compared with participants with DM and without microvascular complications, the adjusted hazard ratio for the composite outcome of all-cause death or HF hospitalization was 1.35 (95% CI 1.04-1.76) for participants with DM and microvascular complications regardless of HF type (Pinteraction = 0.112).Conclusions: Diabetic microvascular disease is more common, and related to greater LV remodeling, more impairment of quality in life, and similar adverse outcomes, in participants with HFpEF compared with HFrEF. HFpEF may be a clinical manifestation of microvascular disease in DM. [ABSTRACT FROM AUTHOR]

Introduction: Microvascular inflammation has been postulated to play a key role in heart failure with preserved ejection fraction (HFpEF), especially in the presence of diabetes. In contrast to the wealth of preclinical data, clinical data on microvascular complications of diabetes in patients with HFpEF versus HF with reduced (HFrEF) are scarce. Methods: We investigated the prevalence, association with outcome and cardiac structure and function of the microvascular (neuropathy, nephropathy and retinopathy) complications of diabetes in 2,656 prospectively enrolled patients with diabetes and HF (536 with HFpEF) from the Asian Sudden Cardiac Death in Heart Failure (ASIAN-HF) registry. Results: A total of 601 (23%) patients had microvascular complications; nephropathy being the most prevalent followed by retinopathy (42%) and neuropathy (28%). Patients with HFpEF (LVEF ≥50%) more often had microvascular disease (28 vs. 21%), irrespective of confounders including duration of diabetes (Figure A; P <0.001). Compared to patients without diabetes, patients with diabetes and microvascular complications had higher filling pressures (E/e'>15, OR 2.36; 95%CI 1.49-3.76), regardless of EF (Pinteraction>0.1) and less left ventricular hypertrophy on echocardiography (Odds ratio [OR] 0.46; 95%CI 0.31- 0.67). Microvascular disease (vs no diabetes) was associated with higher rates of hospitalization for HF and/or mortality (hazard ratio [HR] 1.60, 95% CI 1.19, 2.15), irrespective of HF phenotype (Figure B; Pinteraction >0.5). Conclusion: Microvascular disease is more common in patients with diabetes and HFpEF, compared with diabetes and HFrEF, and correlates with higher filling pressures and worse clinical outcomes. These data support a key pathophysiologic role of microvascular disease in heart failure, particularly HFpEF. [ABSTRACT FROM AUTHOR]

Abstract Background Few simple risk models, without echocardiography have been developed for patients with heart failure (HF) and preserved left ventricular ejection fraction (LVEF) (HFpEF). Methods To develop a risk score to predict all-cause death for HFpEF patients, we examined 1277 HF patients with LVEF ≥50% and BNP ≥100 pg/ml in the CHART-2 Study, a large-scale prospective cohort study for HF in Japan. We selected the optimal subset of covariates for the score with Cox proportional hazard models and random survival forests (RSF). Results During the median 5.7-year follow-up, 576 deaths occurred. Cox models and RSF analyses consistently indicated age ≥75 years, albumin <3.7 g/dl, anemia, BMI <22 kg/m2, BNP ≥300 pg/ml (or NT-proBNP ≥1400 pg/ml), and BUN ≥25 mg/dl, as the important 6 prognostic variables. Incorporating these 6 variables, we developed a scoring system (3A3B score, with 2 points given to age ≥75 years and 1 point to the others based on the hazard ratios. The discrimination ability of the risk score was excellent (c-index 0.708). Regarding model goodness-of-fit, the overall gradient in 5-year risk was well captured by the score. The predictive accuracy of the 3A3B score was confirmed in the external validation cohorts from the TOPCAT trial (N = 835, c-index 0.652) and the ASIAN-HF registry (N = 170, c-index 0.741). Conclusions We developed a simple risk score to predict long-term prognosis of HFpEF patients. The 3A3B score, comprising 6 commonly available parameters in daily practice, has potential utility in the risk stratification and management of HFpEF patients. Highlights • We developed the 3A3B risk score to predict long-term prognosis of HFpEF patients. • The 3A3B score consists only 6 items (age, albumin, anemia, BMI, BNP/NT-proBNP, and BUN). • The discrimination ability of the risk score is excellent in both the derivation and the validation cohorts. • The overall gradient in 5-year risk is well captured by the score. [ABSTRACT FROM AUTHOR]

Background Testicular germ cell tumors are the most common cancer diagnosed in young men, and seminomas are the most common type of these cancers. There have been no exome-wide examinations of genes mutated in seminomas or of overall rates of nonsilent somatic mutations in these tumors. Objective The objective was to analyze somatic mutations in seminomas to determine which genes are affected and to determine rates of nonsilent mutations. Design, setting, and participants Eight seminomas and matched normal samples were surgically obtained from eight patients. Intervention DNA was extracted from tissue samples and exome sequenced on massively parallel Illumina DNA sequencers. Single-nucleotide polymorphism chip-based copy number analysis was also performed to assess copy number alterations. Outcome measurements and statistical analysis The DNA sequencing read data were analyzed to detect somatic mutations including single-nucleotide substitutions and short insertions and deletions. The detected mutations were validated by independent sequencing and further checked for subclonality. Results and limitations The rate of nonsynonymous somatic mutations averaged 0.31 mutations/Mb. We detected nonsilent somatic mutations in 96 genes that were not previously known to be mutated in seminomas, of which some may be driver mutations. Many of the mutations appear to have been present in subclonal populations. In addition, two genes, KIT and KRAS , were affected in two tumors each with mutations that were previously observed in other cancers and are presumably oncogenic. Conclusions Our study, the first report on exome sequencing of seminomas, detected somatic mutations in 96 new genes, several of which may be targetable drivers. Furthermore, our results show that seminoma mutation rates are five times higher than previously thought, but are nevertheless low compared to other common cancers. Similar low rates are seen in other cancers that also have excellent rates of remission achieved with chemotherapy. Patient summary We examined the DNA sequences of seminomas, the most common type of testicular germ cell cancer. Our study identified 96 new genes in which mutations occurred during seminoma development, some of which might contribute to cancer development or progression. The study also showed that the rates of DNA mutations during seminoma development are higher than previously thought, but still lower than for other common solid-organ cancers. Such low rates are also observed among other cancers that, like seminomas, show excellent rates of disease remission after chemotherapy. [ABSTRACT FROM AUTHOR]

Background: Retinal microvascular signs may provide insights into the structure and function of small vessels that are associated with renal disease. We examined the relationship of retinal microvascular signs with both prevalent and incident end-stage renal disease (ESRD) in a multi-ethnic Asian population. Methods: A total of 5763 subjects (aged ≥40 years) from two prospective population-based studies (the Singapore Malay Eye Study and the Singapore Prospective Study) were included for the current analysis. Retinopathy was graded using the modified Airlie House classification system. Retinal vascular parameters were measured using computer-assisted programs to quantify the retinal vessel widths (arteriolar and venular caliber) and retinal vascular network (fractal dimension). Data on ESRD was obtained by record linkage with the ESRD cases registered by National Registry of Diseases Office, Singapore. Multi-variable adjusted regression analyses were performed to assess the associations of baseline retinal vascular parameters and prevalent and incident ESRD. Results: At baseline, 21(0.36%) persons had prevalent ESRD. During a median follow-up of 4.3 years, 33 (0.57%) subjects developed ESRD. In our analyses, retinopathy was associated with prevalent ESRD (multi-variable adjusted odds ratio [OR], 3.21, 95% confidence interval [CI]: 1.28–8.05) and incident ESRD (multi-variable adjusted hazard ratio [HR], 2.51, 95%CI: 1.14–5.54). This association was largely seen in person with diabetes (HR, 2.60, 95%CI: 1.01–6.66) and not present in persons without diabetes (HR, 1.65, 95%CI: 0.14–18.98). Retinal arteriolar caliber, retinal venular caliber and retinal vascular fractal dimension were not associated with ESRD. Conclusion: Retinopathy signs in persons with diabetes are related to an increased risk of ESRD; however, other microvascular changes in the retina are not associated with ESRD. [ABSTRACT FROM AUTHOR]

Fibroadenomas are the most common breast tumors in women under 30 (refs. 1,2). Exome sequencing of eight fibroadenomas with matching whole-blood samples revealed recurrent somatic mutations solely in MED12, which encodes a Mediator complex subunit. Targeted sequencing of an additional 90 fibroadenomas confirmed highly frequent MED12 exon 2 mutations (58/98, 59%) that are probably somatic, with 71% of mutations occurring in codon 44. Using laser capture microdissection, we show that MED12 fibroadenoma mutations are present in stromal but not epithelial mammary cells. Expression profiling of MED12-mutated and wild-type fibroadenomas revealed that MED12 mutations are associated with dysregulated estrogen signaling and extracellular matrix organization. The fibroadenoma MED12 mutation spectrum is nearly identical to that of previously reported MED12 lesions in uterine leiomyoma but not those of other tumors. Benign tumors of the breast and uterus, both of which are key target tissues of estrogen, may thus share a common genetic basis underpinned by highly frequent and specific MED12 mutations. [ABSTRACT FROM AUTHOR]

Glycated hemoglobin A1C (HbA1C) level is used as a diagnostic marker for diabetes mellitus and a predictor of diabetes associated complications. Genome-wide association studies have identified genetic variants associated with HbA1C level. Most of these studies have been conducted in populations of European ancestry. Here we report the findings from a meta-analysis of genome-wide association studies of HbA1C levels in 6,682 non-diabetic subjects of Chinese, Malay and South Asian ancestries. We also sought to examine the associations between HbA1C associated SNPs and microvascular complications associated with diabetes mellitus, namely chronic kidney disease and retinopathy. A cluster of 6 SNPs on chromosome 17 showed an association with HbA1C which achieved genome-wide significance in the Malays but not in Chinese and Asian Indians. No other variants achieved genome-wide significance in the individual studies or in the meta-analysis. When we investigated the reproducibility of the findings that emerged from the European studies, six loci out of fifteen were found to be associated with HbA1C with effect sizes similar to those reported in the populations of European ancestry and P-value ≤ 0.05. No convincing associations with chronic kidney disease and retinopathy were identified in this study. [ABSTRACT FROM AUTHOR]

Introduction: C-reactive protein (CRP) levels are associated with cardiovascular disease and systemic inflammation. We assessed whether CRP-associated loci were associated with serum CRP and retinal markers of microvascular disease, in Asian populations. Methods: Genome-wide association analysis (GWAS) for serum CRP was performed in East-Asian Chinese (N = 2,434) and Malays (N = 2,542) and South-Asian Indians (N = 2,538) from Singapore. Leveraging on GWAS data, we assessed, in silico, association levels among the Singaporean datasets for 22 recently identified CRP-associated loci. At loci where directional inconsistencies were observed, quantification of inter-ethnic linkage disequilibrium (LD) difference was determined. Next, we assessed association for a variant at CRP and retinal vessel traits [central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE)] in a total of 24,132 subjects of East-Asian, South-Asian and European ancestry. Results: Serum CRP was associated with SNPs in/near APOE, CRP, HNF1A and LEPR (p-values ≤4.7×10−8) after meta-analysis of Singaporean populations. Using a candidate-SNP approach, we further replicated SNPs at 4 additional loci that had been recently identified to be associated with serum CRP (IL6R, GCKR, IL6 and IL1F10) (p-values ≤0.009), in the Singaporean datasets. SNPs from these 8 loci explained 4.05% of variance in serum CRP. Two SNPs (rs2847281 and rs6901250) were detected to be significant (p-value ≤0.036) but with opposite effect directions in the Singaporean populations as compared to original European studies. At these loci we did not detect significant inter-population LD differences. We further did not observe a significant association between CRP variant and CRVE or CRAE levels after meta-analysis of all Singaporean and European datasets (p-value >0.058). Conclusions: Common variants associated with serum CRP, first detected in primarily European studies, are also associated with CRP levels in East-Asian and South-Asian populations. We did not find a causal link between CRP and retinal measures of microvascular disease. [ABSTRACT FROM AUTHOR]

Objective: To compare anterior segment parameters measured using a semi-automatic software (Zhongshan Angle Assessment Program, ZAP) applied to anterior segment optical coherence tomography (AS-OCT) images, with commonly used instruments. Methods: Cross-sectional study of a total of 1069 subjects (1069 eyes) from three population-based studies of adults aged 40–80 years. All subjects underwent AS-OCT imaging and ZAP software was applied to determine anterior chamber depth (ACD), central corneal thickness (CCT), anterior and keratometry (K) – readings. These were compared to auto-refraction, keratometry and ocular biometry measured using an IOLMaster, ultrasound pachymeter and auto-refractor respectively. Agreements between AS-OCT (ZAP) and clinical instrument modalities were described using Bland-Altman, 95% limits of agreement (LOA). Results: The mean age of our subjects was 56.9±9.5 years and 50.9% were male. The mean AS-OCT (ZAP) parameters of our study cohort were: ACD 3.29±0.35 mm, CCT 560.75±35.07 µm; K-reading 46.79±2.72 D. There was good agreement between the measurements from ZAP analysis and each instrument and no violations in the assumptions of the LOA; albeit with a systematic bias for each comparison: AS-OCT consistently measured a deeper ACD compared to IOLMaster (95% LOA −0.24, 0.55); and a thicker CCT for the AS-OCT compared to ultrasound pachymetry (16.8±0.53 µm 95% LOA −17.3, 50.8). AS-OCT had good agreement with auto-refractor with at least 95% of the measurements within the prediction interval (P value <0.001). Conclusion: This study demonstrates that there is good agreement between the measurements from the AS-OCT (ZAP) and conventional tools. However, small systematic biases remain that suggest that these measurement tools may not be interchanged. [ABSTRACT FROM AUTHOR]

Central corneal thickness (CCT) is associated with eye conditions including keratoconus and glaucoma. We performed a meta-analysis on >20,000 individuals in European and Asian populations that identified 16 new loci associated with CCT at genome-wide significance (P < 5 × 10?8). We further showed that 2 CCT-associated loci, FOXO1 and FNDC3B, conferred relatively large risks for keratoconus in 2 cohorts with 874 cases and 6,085 controls (rs2721051 near FOXO1 had odds ratio (OR) = 1.62, 95% confidence interval (CI) = 1.4-1.88, P = 2.7 × 10?10, and rs4894535 in FNDC3B had OR = 1.47, 95% CI = 1.29-1.68, P = 4.9 × 10?9). FNDC3B was also associated with primary open-angle glaucoma (P = 5.6 × 10?4; tested in 3 cohorts with 2,979 cases and 7,399 controls). Further analyses implicate the collagen and extracellular matrix pathways in the regulation of CCT. [ABSTRACT FROM AUTHOR]

A bstract Background: To describe the rationale and study design of a follow-up epidemiological eye study among Singaporean Malay adults. Design: Follow-up prospective population-based study. Participants: Participants of the Singapore Malay Eye Study (SiMES-1), which was conducted from August 2004 to June 2006. Methods: This is a follow-up study of the 3280 participants who participated in the SiMES-1 and are residing in Singapore. All participants of this follow-up study will undergo various standardized validated questionnaires on socio-demographics, quality of life and impact of visual impairment. Participants will undergo assessment of blood pressure, anthropometry, presenting and best corrected visual acuity, subjective refraction, ocular biometry, slit lamp and dilated eye examination, Goldmann tonometry, optic disc imaging, digital lens and retinal photography. Retinal tomography, retinal optical coherence topography and fundus autofluorescence will also be performed. Gonioscopy and visual fields examination will be performed on selected individuals. Main Outcome Measures: Incidence, risk factors and impact of visual impairment and major eye diseases. Results: A total of 3280 people who participated in the SiMES-1 will be contacted and invited to participate in this follow-up study. It is estimated that 12.8% of the participants will be deceased and there will be an 80% participation rate for the survivors of SiMES-1 (approximately 2288 participants). Conclusion: SiMES-2 will be one of the few follow-up epidemiological eye studies among Asians and will determine the cumulative 6-year incidence, progression, risk factors and impact of major eye diseases in Singaporean Malay adults. [ABSTRACT FROM AUTHOR]

Genome-wide association studies (GWAS) have become the preferred experimental design in exploring the genetic etiology of complex human traits and diseases. Standard SNP-based meta-analytic approaches have been utilized to integrate the results from multiple experiments. This fundamentally assumes that the patterns of linkage disequilibrium (LD) between the underlying causal variants and the directly genotyped SNPs are similar across the populations for the same SNPs to emerge with surrogate evidence of disease association. We introduce a novel strategy for assessing regional evidence of phenotypic association that explicitly incorporates the extent of LD in the region. This provides a natural framework for combining evidence from multi-ethnic studies of both dichotomous and quantitative traits that (i) accommodates different patterns of LD, (ii) integrates different genotyping platforms and (iii) allows for the presence of allelic heterogeneity between the populations. Our method can also be generalized to perform gene-based or pathway-based analyses. Applying this method on real GWAS data in type 2 diabetes (T2D) boosted the association evidence in regions well-established for T2D etiology in three diverse South-East Asian populations, as well as identified two novel gene regions and a biologically convincing pathway that are subsequently validated with data from the Wellcome Trust Case Control Consortium. [ABSTRACT FROM AUTHOR]

Recent reports have identified a north-south cline in genetic variation in East and South-East Asia, but these studies have not formally explored the basis of these clinical differences. Understanding the origins of these variations may provide valuable insights in tracking down the functional variants in genomic regions identified by genetic association studies. Here we investigate the genetic basis of these differences with genome-wide data from the HapMap, the Human Genome Diversity Project and the Singapore Genome Variation Project. We implemented four bioinformatic measures to discover genomic regions that are considerably differentiated either between two Han Chinese populations in the north and south of China, or across 22 populations in East and South-East Asia. These measures prioritized genomic stretches with: (i) regional differences in the allelic spectrum for SNPs common to the two Han Chinese populations; (ii) differential evidence of positive selection between the two populations as quantified by integrated haplotype score (iHS) and cross-population extended haplotype homozygosity (XP-EHH); (iii) significant correlation between allele frequencies and geographical latitudes of the 22 populations. We also explored the extent of linkage disequilibrium variations in these regions, which is important in combining genetic association studies from North and South Chinese. Two of the regions that emerged are found in HLA class I and II, suggesting that the HLA imputation panel from the HapMap may not be directly applicable to every Chinese sample. This has important implications to autoimmune studies that plan to impute the classical HLA alleles to fine map the SNP association signals. [ABSTRACT FROM AUTHOR]