Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

Practical challenges in lung cancer pathology: bedside care to treatment decisions.

PURPOSE OF REVIEW: Lung cancer is one of the most common malignancies in the whole world, and the pulmonologist is generally the first medical professional to meet the patient and decide what method of tumour sampling is preferable in each specific case. It is imperative for pulmonary physicians to be aware of the intricacies of the diagnostic process, and understand the multiple challenges that are encountered, from the moment the tissue specimen leaves their offices and is sent to the pathology laboratory, until the diagnosis reaches the patient and treating physician. RECENT FINDINGS: The new 2021 WHO classification of thoracic tumours recommended a minimum immunohistochemical (IHC) diagnostic panel for nonsmall cell lung cancer (NSCLC), and following publications of different institutional and country-based guidelines, advocated basic molecular testing for epithelial growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) and programmed cell death ligand 1 (PD-L1) to be initiated by the diagnosing pathologist in all cases of biopsy or resection specimens. In general, sequential testing for molecular biomarkers was not recommended due to tissue wastage, instead next generation sequencing (NGS) diagnostic panel was supported. SUMMARY: The lung cancer specimen has to undergo histologic diagnosis through a panel of IHC studies, and -preferably, a reflex molecular study by NGS including several targetable genes. Adequate communication and clinical information preclude the pathologist from "overusing" the tissue for additional studies, while focusing on preservation of material for molecular testing.

Modulations of ocean-atmosphere interactions on squid abundance over Southwest Atlantic.

Anthropogenic shifts in seas are reshaping fishing trends, with significant implications for aquatic food sources throughout this century. Examining a 21-year abundance dataset of Argentine shortfin squids Illex argentinus paired with a regional oceanic analysis, we noted strong correlations between squid annual abundance and sea surface temperature (SST) in January and February and eddy kinetic energy (EKE) from March to May in the Southwest Atlantic. A deeper analysis revealed combined ocean-atmosphere interactions, pinpointed as the primary mode in a rotated empirical orthogonal function analysis of SST. This pattern produced colder SST and amplified EKE in the surrounding seas, factors crucial for the unique life stages of squids. Future projections from the CMIP6 archive indicated that this ocean-atmosphere pattern, referred to as the Atlantic symmetric pattern, would persist in its cold SST phase, promoting increased squid abundance. However, rising SSTs due to global warming might counteract the abundance gains. Our findings uncover a previously unrecognized link between squids and specific environmental conditions governed by broader ocean-atmosphere interactions in the Southwest Atlantic. Integrating these insights with seasonal and decadal projections can offer invaluable information to stakeholders in squid fisheries and marine conservation under a changing climate.

Association between birth weight and insulin resistance in US adolescents: A retrospective cohort study exploring the role of concurrent body mass index.

BACKGROUND AND AIMS: This study aimed to investigate the association between birth weight (BW) and abnormal HOMA-IR in US adolescents aged 12-15 years. The role of concurrent body mass index (BMI) in adolescence was also examined. METHODS AND RESULTS: This retrospective cohort study included 3429 participants from NHANES with data in 1999-2020. HOMA-IR ≥2.3 was considered abnormal. Participants were classified as low (LBW; <2.5 kg), normal (NBW; 2.5-4.0 kg), or high (HBW; >4.0 kg) BW. Logistic regression was used to explore the association between BW and HOMA-IR. Mediation analysis was used to examine whether BMI z-score in adolescence mediated the association between BW and HOMA-IR. Compared with those in NBW, the odds ratios (95 % CI) of abnormal HOMA-IR in LBW and HBW groups were 1.26 (0.99-1.60), and 0.62 (0.47-0.83) respectively. The association between BW and abnormal HOMA-IR was consistent in all subgroups with no significant interactions. Mediation analysis showed that BW is associated with lower risk of HOMA-IR directly, but with higher risk indirectly via BMI in adolescence. CONCLUSION: There was a negative linear relationship between BW and the prevalence of abnormal HOMA-IR in adolescents aged 12-15 independent of concurrent BMI. Children who were born with LBW but had high BMI in adolescence were of particularly higher risk of insulin resistance.

Effect of a Mobile Game-Based Intervention to Enhance Child Safety: Randomized Controlled Trial.

BACKGROUND: Evidence supports the effectiveness of serious games in health education, but little is known about their effects on the psychosocial well-being of children in the general population. OBJECTIVE: This study aimed to investigate the potential of a mobile game-based safety education program in improving children's safety and psychosocial outcomes. METHODS: Safe City is a mobile roleplaying game specifically designed to educate children in Hong Kong about safety. This randomized controlled trial included 340 children in grades 4 through 6. Intervention arm participants (n=170) were instructed to play the Safe City mobile game for 4 weeks, whereas control arm participants (n=170) received a safety booklet. All participants completed a survey on safety knowledge and behaviors and psychosocial problems at baseline (T1), 1 month postintervention (T2), and 3 months postintervention (T3). Cumulative game scores and mini-game performance were analyzed as a proxy for the extent of exposure to the game. Outcome data were analyzed using 2-sample 2-tailed t tests to compare mean change from T1 to T2 and to T3 for intervention versus control arm participants. The association of game use with outcome changes postintervention was analyzed using generalized additive models. RESULTS: No significant differences were found in mean changes between the intervention and control arms. However, use analyses showed that higher game scores were associated with improvements in safe behavior (P=.03) and internalizing problems (P=.01) at T3. Matching and Spot the Danger mini-game performance significantly predicted improvements in safety knowledge at T2 and T3. CONCLUSIONS: Analysis of use has shown that playing the Safe City mobile game can result in significant improvements in safety knowledge and reductions in unsafe behavior and internalizing problems. These findings provide evidence for the positive impact of serious games on psychological and social well-being, highlighting the potential of technology-driven interventions to assist children in learning about safety and preventing injuries. TRIAL REGISTRATION: ClinicalTrials.org NCT04096196; https://clinicaltrials.gov/show/NCT04096196. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/17756.

The Urban Deployment Model: A Toolset for the Simulation and Performance Characterization of Radiation Detector Deployments in Urban Environments.

Static and mobile radiation detectors can be deployed in urban environments for a range of nuclear security applications, including radiological source search-and-tracking scenarios. Modeling detector performance for such applications is challenging, as it does not depend solely on the detector capabilities themselves. Many factors must be taken into consideration, including specific source and background signatures, the topology and constraints of the deployment environment, the presence of nuisance sources, and whether detectors are mobile or static. When considering the simultaneous deployment of multiple, heterogeneous detectors, assessment of the system-wide performance requires the simulation of the individual detectors, and a system-level analysis of the detection performance. In radiological source search-and-tracking scenarios, performance is mostly dominated by the probability of encounter, which depends on the specifics of a given deployment, e.g., static vs. mobile detectors or a combination of both modalities, the number of detectors deployed, the dynamic vs. static setting of false alarm rates, and individual vs. networked operation. The Urban Deployment Model (UDM) toolset was specifically developed to cover the gap in the available generic frameworks for the simulation of radiation detector deployments at city scales. UDM provides a unified and modular framework to support the simulation and performance characterization of heterogeneous detector deployments in urban environments. This paper presents the key components along the UDM workflow.

Development and Validation of Nerve-Targeted Bacteriochlorin Sensors.

We report an innovative approach to producing bacteriochlorins (bacs) via formal cycloaddition by subjecting a porphyrin to a trimolecular reaction. Bacs are near-infrared probes with the intrinsic ability to serve in multimodal imaging. However, despite their ability to fluoresce and chelate metal ions, existing bacs have thus offered limited ability to label biomolecules for target specificity or have lacked chemical purity, limiting their use in bio-imaging. In this work, bacs allowed a precise and controlled appending of clickable linkers, lending the porphyrinoids substantially more chemical stability, clickability, and solubility, rendering them more suitable for preclinical investigation. Our bac probes enable the targeted use of biomolecules in fluorescence imaging and Cerenkov luminescence for guided intraoperative imaging. Bacs' capacity for chelation provides opportunities for use in non-invasive positron emission tomography/computed tomography. Herein, we report the labeling of bacs with Hs1a, a (NaV1.7)-sodium-channel-binding peptide derived from the Chinese tarantula Cyriopagopus schmidti to yield Bac-Hs1a and radiolabeled Hs1a, which shuttles our bac sensor(s) to mouse nerves. In vivo, the bac sensor allowed us to observe high signal-to-background ratios in the nerves of animals injected with fluorescent Bac-Hs1a and radiolabeled Hs1a in all imaging modes. This study demonstrates that Bac-Hs1a and [64Cu]Cu-Bac-Hs1a accumulate in peripheral nerves, providing contrast and utility in the preclinical space. For the chemistry and bio-imaging fields, this study represents an exciting starting point for the modular manipulation of bacs, their development and use as probes for diagnosis, and their deployment as formidable multiplex nerve-imaging agents for use in routine imaging experiments.

The voltage-gated sodium channel NaV 1.7 underlies endometriosis-associated chronic pelvic pain.

Chronic pelvic pain (CPP) is the primary symptom of endometriosis patients, but adequate treatments are lacking. Modulation of ion channels expressed by sensory nerves innervating the viscera has shown promise for the treatment of irritable bowel syndrome and overactive bladder. However, similar approaches for endometriosis-associated CPP remain underdeveloped. Here, we examined the role of the voltage-gated sodium (NaV ) channel NaV 1.7 in (i) the sensitivity of vagina-innervating sensory afferents and investigated whether (ii) NaV 1.7 inhibition reduces nociceptive signals from the vagina and (iii) ameliorates endometriosis-associated CPP. The mechanical responsiveness of vagina-innervating sensory afferents was assessed with ex vivo single-unit recording preparations. Pain evoked by vaginal distension (VD) was quantified by the visceromotor response (VMR) in vivo. In control mice, pharmacological activation of NaV 1.7 with OD1 sensitised vagina-innervating pelvic afferents to mechanical stimuli. Using a syngeneic mouse model of endometriosis, we established that endometriosis sensitised vagina-innervating pelvic afferents to mechanical stimuli. The highly selective NaV 1.7 inhibitor Tsp1a revealed that this afferent hypersensitivity occurred in a NaV 1.7-dependent manner. Moreover, in vivo intra-vaginal treatment with Tsp1a reduced the exaggerated VMRs to VD which is characteristic of mice with endometriosis. Conversely, Tsp1a did not alter ex vivo afferent mechanosensitivity nor in vivo VMRs to VD in Sham control mice. Collectively, these findings suggest that NaV 1.7 plays a crucial role in endometriosis-induced vaginal hyperalgesia. Importantly, NaV 1.7 inhibition selectively alleviated endometriosis-associated CPP without the loss of normal sensation, suggesting that selective targeting of NaV 1.7 could improve the quality of life of women with endometriosis.

PyQMC: An all-Python real-space quantum Monte Carlo module in PySCF.

We describe a new open-source Python-based package for high accuracy correlated electron calculations using quantum Monte Carlo (QMC) in real space: PyQMC. PyQMC implements modern versions of QMC algorithms in an accessible format, enabling algorithmic development and easy implementation of complex workflows. Tight integration with the PySCF environment allows for a simple comparison between QMC calculations and other many-body wave function techniques, as well as access to high accuracy trial wave functions.

Therapeutic Inhibition of Acid-Sensing Ion Channel 1a Recovers Heart Function After Ischemia-Reperfusion Injury.

BACKGROUND: Ischemia-reperfusion injury (IRI) is one of the major risk factors implicated in morbidity and mortality associated with cardiovascular disease. During cardiac ischemia, the buildup of acidic metabolites results in decreased intracellular and extracellular pH, which can reach as low as 6.0 to 6.5. The resulting tissue acidosis exacerbates ischemic injury and significantly affects cardiac function. METHODS: We used genetic and pharmacologic methods to investigate the role of acid-sensing ion channel 1a (ASIC1a) in cardiac IRI at the cellular and whole-organ level. Human induced pluripotent stem cell-derived cardiomyocytes as well as ex vivo and in vivo models of IRI were used to test the efficacy of ASIC1a inhibitors as pre- and postconditioning therapeutic agents. RESULTS: Analysis of human complex trait genetics indicates that variants in the ASIC1 genetic locus are significantly associated with cardiac and cerebrovascular ischemic injuries. Using human induced pluripotent stem cell-derived cardiomyocytes in vitro and murine ex vivo heart models, we demonstrate that genetic ablation of ASIC1a improves cardiomyocyte viability after acute IRI. Therapeutic blockade of ASIC1a using specific and potent pharmacologic inhibitors recapitulates this cardioprotective effect. We used an in vivo model of myocardial infarction and 2 models of ex vivo donor heart procurement and storage as clinical models to show that ASIC1a inhibition improves post-IRI cardiac viability. Use of ASIC1a inhibitors as preconditioning or postconditioning agents provided equivalent cardioprotection to benchmark drugs, including the sodium-hydrogen exchange inhibitor zoniporide. At the cellular and whole organ level, we show that acute exposure to ASIC1a inhibitors has no effect on cardiac ion channels regulating baseline electromechanical coupling and physiologic performance. CONCLUSIONS: Our data provide compelling evidence for a novel pharmacologic strategy involving ASIC1a blockade as a cardioprotective therapy to improve the viability of hearts subjected to IRI.

Epidemiology of Acute Myocarditis/Pericarditis in Hong Kong Adolescents Following Comirnaty Vaccination.

BACKGROUND: Age-specific incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination in Asia is lacking. This study aimed to study the clinical characteristics and incidence of acute myocarditis/pericarditis among Hong Kong adolescents following Comirnaty vaccination. METHODS: This is a population cohort study in Hong Kong that monitored adverse events following immunization through a pharmacovigilance system for coronavirus disease 2019 (COVID-19) vaccines. All adolescents aged between 12 and 17 years following Comirnaty vaccination were monitored under the COVID-19 vaccine adverse event response and evaluation program. The clinical characteristics and overall incidence of acute myocarditis/pericarditis in adolescents following Comirnaty vaccination were analyzed. RESULTS: Between 14 June 2021 and 4 September 2021, 33 Chinese adolescents who developed acute myocarditis/pericarditis following Comirnaty vaccination were identified. In total, 29 (87.88%) were male and 4 (12.12%) were female, with a median age of 15.25 years. And 27 (81.82%) and 6 (18.18%) cases developed acute myocarditis/pericarditis after receiving the second and first dose, respectively. All cases are mild and required only conservative management. The overall incidence of acute myocarditis/pericarditis was 18.52 (95% confidence interval [CI], 11.67-29.01) per 100 000 persons vaccinated. The incidence after the first and second doses were 3.37 (95% CI, 1.12-9.51) and 21.22 (95% CI, 13.78-32.28 per 100 000 persons vaccinated, respectively. Among male adolescents, the incidence after the first and second doses were 5.57 (95% CI, 2.38-12.53) and 37.32 (95% CI, 26.98-51.25) per 100 000 persons vaccinated. CONCLUSIONS: There is a significant increase in the risk of acute myocarditis/pericarditis following Comirnaty vaccination among Chinese male adolescents, especially after the second dose.

Nonalbuminuric Diabetic Kidney Disease and Risk of All-Cause Mortality and Cardiovascular and Kidney Outcomes in Type 2 Diabetes: Findings From the Hong Kong Diabetes Biobank.

RATIONALE & OBJECTIVE: Nonalbuminuric diabetic kidney disease (DKD) has become the prevailing DKD phenotype. We compared the risks of adverse outcomes among patients with this phenotype compared with other DKD phenotypes. STUDY DESIGN: Multicenter prospective cohort study. SETTINGS & PARTICIPANTS: 19,025 Chinese adults with type 2 diabetes enrolled in the Hong Kong Diabetes Biobank. EXPOSURES: DKD phenotypes defined by baseline estimated glomerular filtration rate (eGFR) and albuminuria: no DKD (no decreased eGFR or albuminuria), albuminuria without decreased eGFR, decreased eGFR without albuminuria, and albuminuria with decreased eGFR. OUTCOMES: All-cause mortality, cardiovascular disease (CVD) events, hospitalization for heart failure (HF), and chronic kidney disease (CKD) progression (incident kidney failure or sustained eGFR reduction ≥40%). ANALYTICAL APPROACH: Multivariable Cox proportional or cause-specific hazards models to estimate the relative risks of death, CVD, hospitalization for HF, and CKD progression. Multiple imputation was used for missing covariates. RESULTS: Mean participant age was 61.1 years, 58.3% were male, and mean diabetes duration was 11.1 years. During 54,260 person-years of follow-up, 438 deaths, 1,076 CVD events, 298 hospitalizations for HF, and 1,161 episodes of CKD progression occurred. Compared with the no-DKD subgroup, the subgroup with decreased eGFR without albuminuria had higher risks of all-cause mortality (hazard ratio [HR], 1.59 [95% CI, 1.04-2.44]), hospitalization for HF (HR, 3.08 [95% CI, 1.82-5.21]), and CKD progression (HR, 2.37 [95% CI, 1.63-3.43]), but the risk of CVD was not significantly greater (HR, 1.14 [95% CI, 0.88-1.48]). The risks of death, CVD, hospitalization for HF, and CKD progression were higher in the setting of albuminuria with or without decreased eGFR. A sensitivity analysis that excluded participants with baseline eGFR <30 mL/min/1.73 m2 yielded similar findings. LIMITATIONS: Potential misclassification because of drug use. CONCLUSIONS: Nonalbuminuric DKD was associated with higher risks of hospitalization for HF and of CKD progression than no DKD, regardless of baseline eGFR.

High-density lipoprotein subclasses and cardiovascular disease and mortality in type 2 diabetes: analysis from the Hong Kong Diabetes Biobank.

OBJECTIVE: High-density lipoproteins (HDL) comprise particles of different size, density and composition and their vasoprotective functions may differ. Diabetes modifies the composition and function of HDL. We assessed associations of HDL size-based subclasses with incident cardiovascular disease (CVD) and mortality and their prognostic utility. RESEARCH DESIGN AND METHODS: HDL subclasses by nuclear magnetic resonance spectroscopy were determined in sera from 1991 fasted adults with type 2 diabetes (T2D) consecutively recruited from March 2014 to February 2015 in Hong Kong. HDL was divided into small, medium, large and very large subclasses. Associations (per SD increment) with outcomes were evaluated using multivariate Cox proportional hazards models. C-statistic, integrated discrimination index (IDI), and categorial and continuous net reclassification improvement (NRI) were used to assess predictive value. RESULTS: Over median (IQR) 5.2 (5.0-5.4) years, 125 participants developed incident CVD and 90 participants died. Small HDL particles (HDL-P) were inversely associated with incident CVD [hazard ratio (HR) 0.65 (95% CI 0.52, 0.81)] and all-cause mortality [0.47 (0.38, 0.59)] (false discovery rate < 0.05). Very large HDL-P were positively associated with all-cause mortality [1.75 (1.19, 2.58)]. Small HDL-P improved prediction of mortality [C-statistic 0.034 (0.013, 0.055), IDI 0.052 (0.014, 0.103), categorical NRI 0.156 (0.006, 0.252), and continuous NRI 0.571 (0.246, 0.851)] and CVD [IDI 0.017 (0.003, 0.038) and continuous NRI 0.282 (0.088, 0.486)] over the RECODe model. CONCLUSION: Small HDL-P were inversely associated with incident CVD and all-cause mortality and improved risk stratification for adverse outcomes in people with T2D. HDL-P may be used as markers for residual risk in people with T2D.

CTNNB1-related neurodevelopmental disorder in a Chinese population: A case series.

CTNNB1-related disorder is an autosomal dominant neurodevelopmental disorder characterized by a variable degree of cognitive impairment, microcephaly, truncal hypotonia, peripheral spasticity, visual defects, and dysmorphic features. In this case series, we report the clinical and molecular findings of nine Chinese patients affected by CTNNB1-related disorders. The facial features of these affected individuals appear to resemble what had been previously described, with thin upper lip (77.8%) and hypoplastic alae nasi (77.8%) being the most common. Frequently reported clinical characteristics in our cohort include developmental delay (100%), peripheral spasticity (88.9%), truncal hypotonia (66.7%), microcephaly (66.7%), and dystonia (44.4%). While various eye manifestations were reported, two affected individuals (22.2%) in our cohort had familial exudative vitreoretinopathy. One of the affected individuals had craniosynostosis, a feature not reported in the literature before. To our knowledge, this is the first reported Chinese case series of CTNNB1-related neurodevelopmental disorders. Further studies are required to look into whether ethnic differences play a role in phenotypic variations.

Vulnerability and resilience in children during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is having a profound impact on the health and development of children worldwide. There is limited evidence on the impact of COVID-19 and its related school closures and disease-containment measures on the psychosocial wellbeing of children; little research has been done on the characteristics of vulnerable groups and factors that promote resilience. METHODS: We conducted a large-scale cross-sectional population study of Hong Kong families with children aged 2-12 years. Parents completed an online survey on family demographics, child psychosocial wellbeing, functioning and lifestyle habits, parent-child interactions, and parental stress during school closures due to COVID-19. We used simple and multiple linear regression analyses to explore factors associated with child psychosocial problems and parental stress during the pandemic. RESULTS: The study included 29,202 individual families; of which 12,163 had children aged 2-5 years and 17,029 had children aged 6-12 years. The risk of child psychosocial problems was higher in children with special educational needs, and/or acute or chronic disease, mothers with mental illness, single-parent families, and low-income families. Delayed bedtime and/or inadequate sleep or exercise duration, extended use of electronic devices were associated with significantly higher parental stress and more psychosocial problems among pre-schoolers. CONCLUSIONS: This study identifies vulnerable groups of children and highlights the importance of strengthening family coherence, adequate sleep and exercise, and responsible use of electronic devices in promoting psychosocial wellbeing during the COVID-19 pandemic.

Rapid screening of nanopore candidates in nanoporous single-layer graphene for selective separations using molecular visualization and interatomic potentials.

Nanoporous single-layer graphene is promising as an ideal membrane because of its extreme thinness, chemical resistance, and mechanical strength, provided that selective nanopores are successfully incorporated. However, screening and understanding the transport characteristics of the large number of possible pores in graphene are limited by the high computational requirements of molecular dynamics (MD) simulations and the difficulty in experimentally characterizing pores of known structures. MD simulations cannot readily simulate the large number of pores that are encountered in actual membranes to predict transport, and given the huge variety of possible pores, it is hard to narrow down which pores to simulate. Here, we report alternative routes to rapidly screen molecules and nanopores with negligible computational requirement to shortlist selective nanopore candidates. Through the 3D representation and visualization of the pores' and molecules' atoms with their van der Waals radii using open-source software, we could identify suitable C-passivated nanopores for both gas- and liquid-phase separation while accounting for the pore and molecule shapes. The method was validated by simulations reported in the literature and was applied to study the mass transport behavior across a given distribution of nanopores. We also designed a second method that accounts for Lennard-Jones and electrostatic interactions between atoms to screen selective non-C-passivated nanopores for gas separations. Overall, these visualization methods can reduce the computational requirements for pore screening and speed up selective pore identification for subsequent detailed MD simulations and guide the experimental design and interpretation of transport measurements in nanoporous atomically thin membranes.

Selective NaV1.1 activation rescues Dravet syndrome mice from seizures and premature death.

Dravet syndrome is a catastrophic, pharmacoresistant epileptic encephalopathy. Disease onset occurs in the first year of life, followed by developmental delay with cognitive and behavioral dysfunction and substantially elevated risk of premature death. The majority of affected individuals harbor a loss-of-function mutation in one allele of SCN1A, which encodes the voltage-gated sodium channel NaV1.1. Brain NaV1.1 is primarily localized to fast-spiking inhibitory interneurons; thus the mechanism of epileptogenesis in Dravet syndrome is hypothesized to be reduced inhibitory neurotransmission leading to brain hyperexcitability. We show that selective activation of NaV1.1 by venom peptide Hm1a restores the function of inhibitory interneurons from Dravet syndrome mice without affecting the firing of excitatory neurons. Intracerebroventricular infusion of Hm1a rescues Dravet syndrome mice from seizures and premature death. This precision medicine approach, which specifically targets the molecular deficit in Dravet syndrome, presents an opportunity for treatment of this intractable epilepsy.

Obesity, clinical, and genetic predictors for glycemic progression in Chinese patients with type 2 diabetes: A cohort study using the Hong Kong Diabetes Register and Hong Kong Diabetes Biobank.

BACKGROUND: Type 2 diabetes (T2D) is a progressive disease whereby there is often deterioration in glucose control despite escalation in treatment. There is significant heterogeneity to this progression of glycemia after onset of diabetes, yet the factors that influence glycemic progression are not well understood. Given the tremendous burden of diabetes in the Chinese population, and limited knowledge on factors that influence glycemia, we aim to identify the clinical and genetic predictors for glycemic progression in Chinese patients with T2D. METHODS AND FINDINGS: In 1995-2007, 7,091 insulin-naïve Chinese patients (mean age 56.8 ± 13.3 [SD] years; mean age of T2D onset 51.1 ± 12.7 years; 47% men; 28.4% current or ex-smokers; median duration of diabetes 4 [IQR: 1-9] years; mean HbA1c 7.4% ± 1.7%; mean body mass index [BMI] 25.3 ± 4.0 kg/m2) were followed prospectively in the Hong Kong Diabetes Register. We examined associations of BMI and other clinical and genetic factors with glycemic progression defined as requirement of continuous insulin treatment, or 2 consecutive HbA1c ≥8.5% while on ≥2 oral glucose-lowering drugs (OGLDs), with validation in another multicenter cohort of Hong Kong Diabetes Biobank. During a median follow-up period of 8.8 (IQR: 4.8-13.3) years, incidence of glycemic progression was 48.0 (95% confidence interval [CI] 46.3-49.8) per 1,000 person-years with 2,519 patients started on insulin. Among the latter, 33.2% had a lag period of 1.3 years before insulin was initiated. Risk of progression was associated with extremes of BMI and high HbA1c. On multivariate Cox analysis, early age at diagnosis, microvascular complications, high triglyceride levels, and tobacco use were additional independent predictors for glycemic progression. A polygenic risk score (PRS) including 123 known risk variants for T2D also predicted rapid progression to insulin therapy (hazard ratio [HR]: 1.07 [95% CI 1.03-1.12] per SD; P = 0.001), with validation in the replication cohort (HR: 1.24 [95% CI 1.06-1.46] per SD; P = 0.008). A PRS using 63 BMI-related variants predicted BMI (beta [SE] = 0.312 [0.057] per SD; P = 5.84 × 10-8) but not glycemic progression (HR: 1.01 [95% CI 0.96-1.05] per SD; P = 0.747). Limitations of this study include potential misdiagnosis of T2D and lack of detailed data of drug use during follow-up in the replication cohort. CONCLUSIONS: Our results show that approximately 5% of patients with T2D failed OGLDs annually in this clinic-based cohort. The independent associations of modifiable and genetic risk factors allow more precise identification of high-risk patients for early intensive control of multiple risk factors to prevent glycemic progression.

Mortality Among Children with Down syndrome in Hong Kong: A Population-Based Cohort Study from Birth.

OBJECTIVES: To describe the mortality patterns, comorbidities, and attendance at accident and emergency departments among children with Down syndrome in Hong Kong. STUDY DESIGN: This is a population-based, retrospective cohort study of live births of children with Down syndrome delivered between 1995 and 2014, as identified from territory-wide hospitalization data in Hong Kong. The Kaplan-Meier product limit method was adopted to estimate the survival probabilities of children with Down syndrome by selected demographic and clinical characteristics. Cox regression analyses were conducted to examine associations of comorbidities and accident and emergency department accident and emergency departments attendances with mortality patterns. RESULTS: There were 1010 live births of children with Down syndrome in Hong Kong within the study period and the average rate of live births with Down syndrome was 8.0 per 10 000 live births (95% CI, 6.8-9.30). The rate of live births with Down syndrome over the past 2 decades decreased from 11.8 per 10 000 live births in 1995 to 3.4 per 10 000 in 2014. Eighty-three patients with Down syndrome died during this period. The overall 6-month and 1- and 5-year survival probabilities were 95.8%, 94.4%, and 92.6%, respectively. There was a significant decrease in mortality rates over the study period, particularly among those born between 2000-2004 and 2005-2009 compared with those born between 1995 and 1999 (P < .05). Patients with Down syndrome without congenital cardiovascular anomalies and without low birth weight had lower mortality rates than those with these diagnoses. CONCLUSIONS: Over the past 2 decades, the early life mortality of children with Down syndrome in Hong Kong has improved significantly along with a reduction in Down syndrome live births.

Noninvasive prenatal paternity testing by means of SNP-based targeted sequencing.

OBJECTIVE: To develop a method for noninvasive prenatal paternity testing based on targeted sequencing of single nucleotide polymorphisms (SNPs). METHOD: SNPs were selected based on population genetics data. Target-SNPs in cell-free DNA extracted from maternal blood (maternal cfDNA) were analyzed by targeted sequencing wherein target enrichment was based on multiplex amplification using QIAseq Targeted DNA Panels with Unique Molecular Identifiers. Fetal SNP genotypes were called using a novel bioinformatics algorithm, and the combined paternity indices (CPIs) and resultant paternity probabilities were calculated. RESULTS: Fetal SNP genotypes obtained from targeted sequencing of maternal cfDNA were 100% concordant with those from amniotic fluid-derived fetal genomic DNA. From an initial panel of 356 target-SNPs, an average of 148 were included in paternity calculations in 15 family trio cases, generating paternity probabilities of greater than 99.9999%. All paternity results were confirmed by short-tandem-repeat analysis. The high specificity of the methodology was validated by successful paternity discrimination between biological fathers and their siblings and by large separations between the CPIs calculated for the biological fathers and those for 60 unrelated men. CONCLUSION: The novel method is highly effective, with substantial improvements over similar approaches in terms of reduced number of target-SNPs, increased accuracy, and reduced costs.