Search

Abstract Insulin resistance causes multiple epidemic metabolic diseases, including type 2 diabetes, cardiovascular disease, and fatty liver, but is not routinely measured in epidemiological studies. To discover novel insulin resistance genes in the general population, we conducted genome-wide association studies in 382,129 individuals for triglyceride to HDL-cholesterol ratio (TG/HDL), a surrogate marker of insulin resistance calculable from commonly measured serum lipid profiles. We identified 251 independent loci, of which 62 were more strongly associated with TG/HDL compared to TG or HDL alone, suggesting them as insulin resistance loci. Candidate causal genes at these loci were prioritized by fine mapping with directions-of-effect and tissue specificity annotated through analysis of protein coding and expression quantitative trait variation. Directions-of-effect were corroborated in an independent cohort of individuals with directly measured insulin resistance. We highlight two phospholipase encoding genes, PLA2G12A and PLA2G6, which liberate arachidonic acid and improve insulin sensitivity, and VGLL3, a transcriptional co-factor that increases insulin resistance partially through enhanced adiposity. Finally, we implicate the anti-apoptotic gene TNFAIP8 as a sex-dimorphic insulin resistance factor, which acts by increasing visceral adiposity, specifically in females. In summary, our study identifies several candidate modulators of insulin resistance that have the potential to serve as biomarkers and pharmacological targets.

Adipose tissue plays a crucial role in maintaining metabolic homeostasis by storing lipids and glucose from circulation as intracellular fat. As peripheral tissues like adipose tissue become insulin resistant, decompensation of blood glucose levels occurs causing type 2 diabetes (T2D). Currently, modulating the glycocalyx, a layer of cell-surface glycans, is an underexplored pharmacological treatment strategy to improve glucose homeostasis in T2D patients. Here, we show a novel role for cell-surface heparan sulfate (HS) in establishing glucose uptake capacity and metabolic utilization in differentiated adipocytes. Using a combination of chemical and genetic interventions, we identified that HS modulates this metabolic phenotype by attenuating levels of Wnt signaling during adipogenesis. By engineering, the glycocalyx of pre-adipocytes with exogenous synthetic HS mimetics, we were able to enhance glucose clearance capacity after differentiation through modulation of Wnt ligand availability. These findings establish the cellular glycocalyx as a possible new target for therapeutic intervention in T2D patients by enhancing glucose clearance capacity independent of insulin secretion.

BackgroundContinuous glucose monitoring (CGM) is approved for insulin dosing decisions in the ambulatory setting, but not currently for inpatients. CGM has the capacity to reduce patient-provider contact in inpatients with coronavirus disease 2019 (COVID-19), thus potentially reducing in hospital virus transmission. However, there are sparse data on the accuracy and efficacy of CGM to titrate insulin doses in inpatients.MethodsUnder an emergency use protocol, CGM (Dexcom G6) was used alongside standard point-of-care (POC) glucose measurements in patients critically ill from complications of COVID-19 requiring intravenous (IV) insulin. Glycemic control during IV insulin therapy was retrospectively assessed comparing periods with and without adjunctive CGM use. Accuracy metrics were computed and Clarke Error Grid analysis performed comparing CGM glucose values with POC measurements.ResultsTwenty-four critically ill patients who met criteria for emergency use of CGM resulted in 47 333 CGM and 5677 POC glucose values. During IV insulin therapy, individuals' glycemic control improved when CGM was used (mean difference -30.7 mg/dL). Among 2194 matched CGM: POC glucose pairs, a high degree of concordance was observed with a mean absolute relative difference of 14.8% and 99.5% of CGM: POC pairs falling in Zones A and B of the Clarke Error Grid.ConclusionsContinuous glucose monitoring use in critically ill COVID-19 patients improved glycemic control during IV insulin therapy. Continuous glucose monitoring glucose data were highly concordant with POC glucose during IV insulin therapy in critically ill patients suggesting that CGM could substitute for POC measurements in inpatients thus reducing patient-provider contact and mitigating infection transmission.

Robots are becoming integral to society and industries due to their enormous advantages. Among the various categories of mobile robots, including wheeled robot, tracked robot, and legged robots, the latter stands out as a better choice for most field applications due to their adaptability across various terrains. The purpose of this review is to study the locomotion capabilities of quadruped robots and judge their suitability for climbing applications as most unexplored applications of automation and robotics are required to climb. This review explores the locomotion capabilities of quadruped robots. It covers different aspects of quadruped robots like types of legs, leg design, gait patterns, and their mathematical formulations, and types of motions like omnidirectional motion and body sway motion. It also emphasizes its fault-tolerant gait, adaptability, and reliability. The paper also focuses on slope and stair climbing, outlining design requirements and applications. The study includes an examination of the applicability of various gaits under different conditions and the methods for increasing stability without compromising speed. Overall, the review serves as a valuable resource for future research in this field.

The seven-transmembrane superfamily member 3 protein (TM7SF3) is a p53-regulated homeostatic factor that attenuates cellular stress and the unfolded protein response. Here we show that TM7SF3 localizes to nuclear speckles; eukaryotic nuclear bodies enriched in splicing factors. This unexpected location for a trans -membranal protein enables formation of stable complexes between TM7SF3 and pre-mRNA splicing factors including DHX15, LARP7, HNRNPU, RBM14, and HNRNPK. Indeed, TM7SF3 regulates alternative splicing of >330 genes, mainly at the 3'end of introns by directly modulating the activity of splicing factors such as HNRNPK. These effects are observed both in cell lines and primary human pancreatic islets. Accordingly, silencing of TM7SF3 results in differential expression of 1465 genes (about 7% of the human genome); with 844 and 621 genes being up- or down-regulated, respectively. Our findings implicate TM7SF3, as a resident protein of nuclear speckles and suggest a role for seven-transmembrane proteins as regulators of alternative splicing.

BackgroundAccelerated orthodontic treatment has gained popularity in recent years as patients seek shorter treatment durations. Microosteoperforations (MOPs) have emerged as a minimally invasive technique to expedite tooth movement. This study aims to compare the effectiveness of MOPs in accelerating orthodontic treatment with conventional methods. Materials and MethodsA randomized controlled trial was conducted on 60 orthodontic patients requiring dental alignment. The participants were divided into two groups: Group A (MOPs) and Group B (conventional orthodontic treatment). In Group A, MOPs were performed at the beginning of the treatment. Both groups received monthly orthodontic adjustments. Treatment duration, rate of tooth movement, and patient discomfort were measured and compared between the two groups. ResultsThe study found that in Group A, the treatment duration was reduced by 30% compared to Group B (P < 0.05). The rate of tooth movement in the MOPs group was 1.5 times higher than the conventional group (P < 0.01). Additionally, patient-reported discomfort levels were similar between the two groups. No adverse events related to MOPs were observed during the study. ConclusionMOPs significantly accelerate orthodontic treatment, reducing treatment duration by 30% and increasing the rate of tooth movement by 1.5 times compared to conventional methods. Importantly, MOPs are well-tolerated by patients, making them a valuable option for expediting orthodontic treatment with minimal discomfort. This study highlights the potential benefits of integrating MOPs into orthodontic practice to improve treatment efficiency and patient satisfaction.

Purpose of reviewType 2 diabetes (T2D) is a multifactorial, heritable syndrome characterized by dysregulated glucose homeostasis that results from impaired insulin secretion and insulin resistance. Genetic association studies have successfully identified hundreds of T2D risk loci implicating many genes in disease pathogenesis. In this review, we provide an overview of the recent T2D genetic studies from the past 3 years with particular focus on the effects of sample size and ancestral diversity on genetic discovery as well as discuss recent work on the use and limitations of genetic risk scores (GRS) for T2D risk prediction.Recent findingsRecent large-scale, multi-ancestry genetic studies of T2D have identified over 500 novel risk loci. The genetic variants (i.e., single nucleotide polymorphisms (SNPs)) marking these novel loci in general have smaller effect sizes than previously discovered loci. Inclusion of samples from diverse ancestral backgrounds shows a few ancestry specific loci marked by common variants, but overall, the majority of loci discovered are common across ancestries. Inclusion of common variant GRS, even with hundreds of loci, does not substantially increase T2D risk prediction over standard clinical risk factors such as age and family history. Common variant association studies of T2D have now identified over 700 T2D risk loci, half of which have been discovered in the past 3 years. These recent studies demonstrate that inclusion of ancestrally diverse samples can enhance locus discovery and improve accuracy of GRS for T2D risk prediction. GRS based on common variants, however, only minimally enhances risk prediction over standard clinical risk factors.

Objective To assess outcomes related to Lupus Therapeutics’ Patient Advocates for Lupus Studies (LT‐PALS), a peer‐to‐peer lupus clinical trial (LCT) education program designed to improve representation of diverse groups in LCTs. Patients with lupus and clinical trial participation experience were trained as peer educators (PALs) providing trial‐agnostic education to trial‐naive patients with lupus. Methods We used a two‐arm, randomized pretest/posttest study design to evaluate outcomes related to LCT participation: knowledge, attitudes, self‐efficacy, and intentions to participate in an LCT. Five academic medical centers piloted the program. The intervention group (IG) individually received peer‐to‐peer education sessions with trained PALs, primarily via telephone; the control group (CG) received a 3‐week waiting period. We conducted within/between‐group t‐tests and multiple linear regressions with posttest scores as dependent variables and participation in LT‐PALS as the exposure variable. Results The sample (n = 136) included 64 IG and 72 CG participants, with 67.7% identifying as Black. At posttest, IG participants had higher knowledge (P

BackgroundChronic kidney disease is associated with adverse outcomes among patients with established cardiovascular disease (CVD) or diabetes. Commonly used medications to treat CVD are less effective among patients with reduced kidney function.MethodsREDUCE-IT (Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial) was a multicenter, double-blind, placebo-controlled trial that randomly assigned statin-treated patients with elevated triglycerides (135-499 mg/dL) who had CVD or diabetes and 1 additional risk factor to treatment with icosapent ethyl (4 g daily) or placebo. Patients from REDUCE-IT were categorized by prespecified estimated glomerular filtration rate (eGFR) categories to analyze the effect of icosapent ethyl on the primary end point (composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina) and key secondary end point (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke).ResultsAmong the 8179 REDUCE-IT patients, median baseline eGFR was 75 mL·min-1·1.73 m-2 (range, 17-123 mL·min-1·1.73 m-2). There were no meaningful changes in median eGFR for icosapent ethyl versus placebo across study visits. Treatment with icosapent ethyl led to consistent reduction in both the primary and key secondary composite end points across baseline eGFR categories. Patients with eGFR

Purpose: To evaluate the relationships between chronic kidney disease (CKD) with retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness profiles of eyes in Asian and White populations. Design: Cross-sectional analysis. Participants: A total of 5066 Asian participants (1367 Malays, 1772 Indians, and 1927 Chinese) from the Singapore Epidemiology of Eye Diseases Study (SEED) were included, consisting of 9594 eyes for peripapillary RNFL analysis and 8661 eyes for GCIPL analysis. Additionally, 45 064 White participants (87 649 eyes) from the United Kingdom Biobank (UKBB) were included for both macular RNFL analysis and GCIPL analysis. Methods: Nonglaucoma participants aged ≥ 40 years with complete data for estimated glomerular filtration rate (eGFR) were included from both SEED and UKBB. In SEED, peripapillary RNFL and GCIPL thickness were measured by Cirrus HD-OCT 4000. In UKBB, macular RNFL and GCIPL were measured by Topcon 3D-OCT 1000 Mark II. Chronic kidney disease was defined as eGFR < 60 ml/min/1.73 m2 in both data sets. To evaluate the associations between kidney function status with RNFL and GCIPL thickness profiles, multivariable linear regression with generalized estimating equation models were performed in SEED and UKBB data sets separately. Main Outcome Measures: Average peripapillary and macular RNFL thickness and macular GCIPL thickness. Results: In SEED, after adjusting for age, gender, ethnicity, systolic blood pressure, antihypertensive medication, diabetes, hyperlipidemia, body mass index, smoking status, and intraocular pressure, presence of CKD (β = −1.31; 95% confidence interval [CI], −2.37 to −0.26; P = 0.015) and reduced eGFR (per 10 ml/min/1.73 m2; β = −0.32; 95% CI, −0.50 to −0.13; P = 0.001) were associated with thinner average peripapillary RNFL. Presence of CKD (β = −1.63; 95% CI, −2.42 to −0.84) and reduced eGFR (per 10 ml/min/1.73 m2; β = −0.30; 95% CI, −0.44 to −0.16) were consistently associated with thinner GCIPL in SEED (all P < 0.001). In UKBB, after adjusting for the above-mentioned covariates (except ethnicity), reduced eGFR (per 10 ml/min/1.73 m2; β = −0.06; 95% CI, −0.10 to −0.01; P = 0.008) was associated with thinner macular RNFL and CKD (β = −0.62; 95% CI, −1.16 to −0.08; P = 0.024) was associated with thinner average GCIPL. Conclusion: We consistently observed associations between CKD and thinning of RNFL and GCIPL across Asian and White populations' eyes. These findings further suggest that compromised kidney function is associated with RNFL and GCIPL thinning. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The Onduo Virtual Diabetes Clinic (VDC) for people with type 2 diabetes (T2D) combines a mobile app, remote lifestyle coaching, connected devices, and live video consultations with board-certified endocrinologists. Adults with T2D (n = 594) who were evaluated by a VDC endocrinologist, remotely prescribed and mailed a real-time continuous glucose monitoring (rtCGM) device and used ≥1 sensor completed a CGM satisfaction questionnaire. The CGM satisfaction score was 4.5 ± 0.8 out of 5. Most respondents (94.7%) agreed/strongly agreed that they were comfortable inserting the sensor remotely and that rtCGM use improved understanding of the impact of eating (97.0%), increased diabetes knowledge (95.7%), and helped improve diabetes control when not wearing the sensor (79.4%). HbA1c (n = 372) decreased from 7.7% ± 1.6% to 7.1% ± 1.2% (P

Purpose: To examine the 6-year incidence of visual impairment (VI) and identify risk factors associated with VI in a multiethnic Asian population. Design: Prospective, population-based, cohort study. Participants: Adults aged ≥ 40 years were recruited from the Singapore Epidemiology of Eye Diseases cohort study at baseline. Eligible subjects were re-examined after 6 years. Subjects included in the final analysis had a mean age of 56.1 ± 8.9 years, and 2801 (50.5%) were female. Methods: All participants underwent standardized examination and interviewer-administered questionnaire at baseline. Incidences were standardized to the Singapore Population Census 2010. A Poisson binomial regression model was used to evaluate the associations between baseline factors and incident presenting VI. Main Outcome Measures: Incident presenting VI was assessed at the 6-year follow-up visit. Visual impairment (presenting visual acuity < 20/40), low vision (presenting visual acuity < 20/40 but ≥ 20/200), and blindness (presenting visual acuity < 20/200) were defined based on United States definition. Results: A total of 5551 subjects (2188 Chinese, 1837 Indians, and 1526 Malays) were evaluated, of whom 514 developed incident presenting VI over 6 years. Malays had a higher incidence of low vision and blindness (13.0%; 0.6%) than Indians (7.0%; 0.1%) and Chinese (7.7%; 0.2%). Among Malay individuals with VI at baseline, 52.8% remained visually impaired after 6 years, which was considerably higher than Chinese (32.4%) and Indians (37.2%). Older age (per decade; relative risk [RR] = 1.59), a history of cardiovascular disease (RR = 1.38), current smoking (RR = 1.31), smaller housing type (1- to 2-room public flat; RR = 2.01), and no formal education (RR = 1.63) at baseline were associated with a higher risk of incident VI (all P ≤ 0.027). Older age (> 60 years) contributed the highest population attributable risk to incident VI (27.1%), followed by lower monthly income (Singapore dollar < $2000; 26.4%) and smaller housing type (24.7%). Overall, undercorrected refractive error (49.1%) and cataract (82.6%) were leading causes for low vision and blindness, respectively. This was consistently observed across the 3 ethnicities. Conclusions: In this multiethnic Asian population, Malays had a higher VI incidence compared to Indians and Chinese. Leading causes of VI are mostly treatable, suggesting that more efforts are needed to further mitigate preventable visual loss. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article.

IntroductionOur study aimed to examine the relationship between cardiovascular diseases (CVD) with peripapillary retinal fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thickness profiles in a large multi-ethnic Asian population study.Methods6,024 Asian subjects were analyzed in this study. All participants underwent standardized examinations, including spectral domain OCT imaging (Cirrus HD-OCT; Carl Zeiss Meditec). In total, 9,188 eyes were included for peripapillary RNFL analysis (2,417 Malays; 3,240 Indians; 3,531 Chinese), and 9,270 eyes (2,449 Malays, 3,271 Indians, 3,550 Chinese) for GCIPL analysis. History of CVD was defined as a self-reported clinical history of stroke, myocardial infarction, or angina. Multivariable linear regression models with generalized estimating equations were performed, adjusting for age, gender, ethnicity, diabetes, hypertension, hyperlipidaemia, chronic kidney disease, body mass index, current smoking status, and intraocular pressure.ResultsWe observed a significant association between CVD history and thinner average RNFL (β = −1.63; 95% CI, −2.70 to −0.56; p = 0.003). This association was consistent for superior (β = −1.79, 95% CI, −3.48 to −0.10; p = 0.038) and inferior RNFL quadrant (β = −2.14, 95% CI, −3.96 to −0.32; p = 0.021). Of the CVD types, myocardial infarction particularly showed significant association with average (β = −1.75, 95% CI, −3.08 to −0.42; p = 0.010), superior (β = −2.22, 95% CI, −4.36 to −0.09; p = 0.041) and inferior (β = −2.42, 95% CI, −4.64 to −0.20; p = 0.033) RNFL thinning. Among ethnic groups, the association between CVD and average RNFL was particularly prominent in Indian eyes (β = −1.92, 95% CI, −3.52 to −0.33; p = 0.018). CVD was not significantly associated with average GCIPL thickness, albeit a consistent negative direction of association was observed (β = −0.22, 95% CI, −1.15 to 0.71; p = 0.641).DiscussionIn this large multi-ethnic Asian population study, we observed significant association between CVD history and RNFL thinning. This finding further validates the impact of impaired systemic circulation on RNFL thickness.

Abstract Studies using machine learning (ML) approaches have reported high diagnostic accuracies for glaucoma detection. However, none assessed model performance across ethnicities. The aim of the study is to externally validate ML models for glaucoma detection from optical coherence tomography (OCT) data. We performed a prospective, cross-sectional study, where 514 Asians (257 glaucoma/257 controls) were enrolled to construct ML models for glaucoma detection, which was then tested on 356 Asians (183 glaucoma/173 controls) and 138 Caucasians (57 glaucoma/81 controls). We used the retinal nerve fibre layer (RNFL) thickness values produced by the compensation model, which is a multiple regression model fitted on healthy subjects that corrects the RNFL profile for anatomical factors and the original OCT data (measured) to build two classifiers, respectively. Both the ML models (area under the receiver operating [AUC] = 0.96 and accuracy = 92%) outperformed the measured data (AUC = 0.93; P