Exome sequence analysis identifies rare coding variants associated with a machine learning-based marker for coronary artery disease.

Coronary artery disease (CAD) exists on a spectrum of disease represented by a combination of risk factors and pathogenic processes. An in silico score for CAD built using machine learning and clinical data in electronic health records captures disease progression, severity and underdiagnosis on this spectrum and could enhance genetic discovery efforts for CAD. Here we tested associations of rare and ultrarare coding variants with the in silico score for CAD in the UK Biobank, All of Us Research Program and BioMe Biobank. We identified associations in 17 genes; of these, 14 show at least moderate levels of prior genetic, biological and/or clinical support for CAD. We also observed an excess of ultrarare coding variants in 321 aggregated CAD genes, suggesting more ultrarare variant associations await discovery. These results expand our understanding of the genetic etiology of CAD and illustrate how digital markers can enhance genetic association investigations for complex diseases.

Prospective randomized double-blind comparative study of topical acetyl zingerone with tetrahexyldecyl ascorbate versus tetrahexyldecyl ascorbate alone on facial photoaging.

BACKGROUND: Tetrahexydecyl ascorbate (THDA) is a lipophilic precursor to ascorbic acid that may be stabilized by acetyl zingerone (AZ). Studies have shown that the topical application of THDA may have photoprotective effects. Similarly, AZ has been shown to mitigate oxidative and inflammatory stress, thereby improving the appearance of photoaging. AIMS: To examine the effects of THDA and AZ (THDA-AZ) on skin photoaging compared to THDA alone. PATIENTS/METHODS: In this double-blind, randomized controlled trial, healthy individuals aged 30 to 65 were included and 44 participants were randomized to receive either THDA-AZ (THDA 5% + AZ 1%) or THDA only (THDA 5%) for 8 weeks. Facial photographs were taken at 0, 4, and 8 weeks to analyze wrinkle severity, pigment intensity, and redness intensity. A skin colorimeter was used to assess infraorbital pigmentation and erythema. Self-perception of skin and tolerability were assessed through questionnaires. RESULTS: Average wrinkle severity was significantly decreased in the THDA-AZ group at Weeks 4 and 8 by 0.75% (p = 0.023) and 3.72% (p = 0.048), respectively, compared to the THDA group where wrinkle severity at Weeks 4 and 8 was increased by 7.88% and 4.48%, respectively. Facial pigment intensity was significantly decreased in the THDA-AZ group by 4.10% (p = 0.0002) at Week 8 compared to a 0.69% decrease in the THDA group. Facial redness intensity was decreased in the THDA-AZ group at Weeks 4 and 8 by 3.73% (p = 0.0162) and 14.25% (p = 0.045), respectively, compared to the THDA group where at Weeks 4 and 8 erythema increased by 27.5% and 8.34%, respectively. There were no significant differences in either group for infraorbital pigmentation or erythema. CONCLUSIONS: Daily use of combined THDA and AZ may improve facial wrinkle severity, pigment intensity, and erythema to a greater extent than THDA. While THDA alone increases facial wrinkle severity and erythema, the addition of AZ reduces both.

Prediction of Venous Thromboembolism in Diverse Populations Using Machine Learning and Structured Electronic Health Records.

BACKGROUND: Venous thromboembolism (VTE) is a major cause of morbidity and mortality worldwide. Current risk assessment tools, such as the Caprini and Padua scores and Wells criteria, have limitations in their applicability and accuracy. This study aimed to develop machine learning models using structured electronic health record data to predict diagnosis and 1-year risk of VTE. METHODS: We trained and validated models on data from 159 001 participants in the Mount Sinai Data Warehouse. We then externally tested them on 401 723 participants in the UK Biobank and 123 039 participants in All of Us. All data sets contain populations of diverse ancestries and clinical histories. We used these data sets to develop small, medium, and large models with increasing features on a range of optimizing portability to maximizing performance. We make trained models publicly available in click-and-run format at https://doi.org/10.17632/tkwzysr4y6.6. RESULTS: In the holdout and external test sets, respectively, models achieved areas under the receiver operating characteristic curve of 0.80 to 0.83 and 0.72 to 0.82 for VTE diagnosis prediction and 0.76 to 0.78 and 0.64 to 0.69 for 1-year risk prediction, significantly outperforming the Padua score. Models also demonstrated robust performance across different VTE types and patient subsets, including ethnicity, age, and surgical and hospitalization status. Models identified both established and novel clinical features contributing to VTE risk, offering valuable insights into its underlying pathophysiology. CONCLUSIONS: Machine learning models using structured electronic health record data can significantly improve VTE diagnosis and 1-year risk prediction in diverse populations. Model probability scores exist on a continuum, affecting mortality risk in both healthy individuals and VTE cases. Integrating these models into electronic health record systems to generate real-time predictions may enhance VTE risk assessment, early detection, and preventative measures, ultimately reducing the morbidity and mortality associated with VTE.

Primary Prevention of Subclinical Atherosclerosis in Young Adults: JACC Review Topic of the Week.

There is growing evidence that the atherosclerotic process that leads to symptomatic cardiovascular disease (CVD) starts at an early age. In young adults, exposure to low-density lipoprotein-cholesterol and other cardiovascular risk factor (CVRF) mediators, even at levels considered within normal limits, increases the prevalence of subclinical atherosclerosis and is associated with greater risk of cardiovascular events later in life. The optimal CVRF targets to prevent CVD in asymptomatic young individuals (<40 years) are unknown. The randomized controlled PRECAD (Prevent Coronary Artery Disease) trial has been developed to assess the potential benefit of an aggressive control of CVRF in otherwise healthy young adults. The hypothesis of PRECAD is that in subjects aged 20 to 39 years without known CVD, maintaining low-density lipoprotein-cholesterol <70 mg/dL and strict control of blood pressure and glucose will prevent the onset of atherosclerosis and/or its progression. The primary endpoint will be the change in total atherosclerosis burden, a surrogate for CVD.

Severe hypertriglyceridemia: Existing and emerging therapies.

Severe hypertriglyceridemia (sHTG), defined as a triglyceride (TG) concentration ≥ 500 mg/dL (≥ 5.7 mmol/L) is an important risk factor for acute pancreatitis. Although lifestyle, some medications, and certain conditions such as diabetes may lead to HTG, sHTG results from a combination of major and minor genetic defects in proteins that regulate TG lipolysis. Familial chylomicronemia syndrome (FCS) is a rare disorder caused by complete loss of function in lipoprotein lipase (LPL) or LPL activating proteins due to two homozygous recessive traits or compound heterozygous traits. Multifactorial chylomicronemia syndrome (MCS) and sHTG are due to the accumulation of rare heterozygous variants and polygenic defects that predispose individuals to sHTG phenotypes. Until recently, treatment of sHTG focused on lifestyle interventions, control of secondary factors, and nonselective pharmacotherapies that had modest TG-lowering efficacy and no corresponding reductions in atherosclerotic cardiovascular disease events. Genetic discoveries have allowed for the development of novel pathway-specific therapeutics targeting LPL modulating proteins. New targets directed towards inhibition of apolipoprotein C-III (apoC-III), angiopoietin-like protein 3 (ANGPTL3), angiopoietin-like protein 4 (ANGPTL4), and fibroblast growth factor-21 (FGF21) offer far more efficacy in treating the various phenotypes of sHTG and opportunities to reduce the risk of acute pancreatitis and atherosclerotic cardiovascular disease events.

Viewing of clinical cases on social media by dentists: A cause of motivation or dissatisfaction?

Objective: To evaluate the thoughts and feelings of dentists viewing posted clinical cases (PCCs) on various social media (SM) platforms. Methods: A questionnaire was developed, validated and its reliability was established. It was distributed (in 2022) to 355 dentists who had graduated at least 2 years prior. It had three sections consisting of 20 items pertaining to general information, SM usage, and feelings. Descriptive data were reported using percentages. The chi-squared test was used for inferential analysis. P ≤ 0.05 was considered statistically significant. Results: The response rate was 92%. The majority of respondents were non-post-graduates (63%), and aged ≤40 years (90%) with clinical experience <5 years (41%). Dentists with the most clinical experience (>15 years) shared their clinical work significantly more than their counterparts (p < 0.05). Most of the dentists did not feel motivated after viewing the PCCs (41%), especially those aged >40 years (p = 0.037), and thought that viewing the PCCs was the reason for personal dissatisfaction (50%). They had a belief that they possess skills (36%) and knowledge (42%), but not the necessary equipment to replicate the PCCs (39%). Conclusions: The majority of dentists felt that viewing the PCCs on SM can cause personal dissatisfaction and lack of motivation. They had a belief that they possess the skills and knowledge to replicate the PCCs, but lack equipment. Investing resources in clinical workshops, mentorship, and the procurement of modern equipment early in the career of dentists may improve their mental well-being, satisfaction, and quality of treatment delivered to patients.

ABCA1 Deficiency: A Rare Cause of Premature Coronary Artery Disease.

ATP-binding cassette transporter A1 (ABCA1) deficiency results in very low high-density lipoprotein cholesterol levels. Complete ABCA1 deficiency, or Tangier disease, is characterized by premature atherosclerotic cardiovascular disease, yellow-orange tonsils, hepatosplenomegaly, peripheral neuropathy, and corneal opacification. Early recognition of this condition can lead to regular monitoring for atherosclerotic cardiovascular symptoms and treatment of major modifiable risk factors. (Level of Difficulty: Beginner.).

Familial Hypercholesterolemia: Challenges for a High-Risk Population: JACC Focus Seminar 1/3.

The availability of statins, ezetimibe, and PCSK9 inhibitors has significantly improved the prognosis of familial hypercholesterolemia (FH). However, a great number of individuals with FH do not achieve guideline-recommended low-density lipoprotein (LDL) cholesterol levels despite maximal lipid-lowering therapy. Novel therapies that lower LDL independent of LDL receptor activity can help mitigate atherosclerotic cardiovascular disease risk in most homozygous FH and many heterozygous FH patients. However, access to novel therapies remains limited for heterozygous FH patients with persistent elevation of LDL cholesterol despite treatment with multiple classes of cholesterol-lowering therapies. Conduction of cardiovascular outcomes clinical trials in patients with FH can be challenging because of difficulty in recruitment and long periods of follow-up. In the future, the use of validated surrogate measures of atherosclerosis may allow for clinical trials with fewer study participants and shorter duration, thereby expediting access to novel treatments for patients with FH.

Clinical Trial Design for Triglyceride-Rich Lipoprotein-Lowering Therapies: JACC Focus Seminar 3/3.

Triglyceride-rich lipoproteins (TRLs) are a source of residual risk in patients with atherosclerotic cardiovascular disease, and are indirectly correlated with triglyceride (TG) levels. Previous clinical trials studying TG-lowering therapies have either failed to reduce major adverse cardiovascular events or shown no linkage of TG reduction with event reduction, particularly when these agents were tested on a background of statin therapy. Limitations in trial design may explain this lack of efficacy. With the advent of new RNA-silencing therapies in the TG metabolism pathway, there is renewed focus on reducing TRLs for major adverse cardiovascular event reduction. In this context, the pathophysiology of TRLs, pharmacological effects of TRL-lowering therapies, and optimal design of cardiovascular outcomes trials are major considerations.

Clinical Trial Design for Lipoprotein(a)-Lowering Therapies: JACC Focus Seminar 2/3.

Lipoprotein(a) [Lp(a)] is a source of residual risk in patients with atherosclerotic cardiovascular disease (ASCVD). Clinical trials of fully human monoclonal antibodies targeting proprotein convertase subtilisin kexin 9 have shown that reductions in Lp(a) concentrations may be a predictor of event reduction with this class of cholesterol-lowering therapy. With the advent of selective therapies targeting Lp(a) such as antisense oligonucleotides, small-interfering RNA-based therapies, and gene editing, lowering of Lp(a) may lead to reduction in ASCVD. The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein(a) Lowering with TQJ230 on Major Cardiovascular Events in Patients With CVD) outcomes trial is currently testing the effect of pelacarsen, an antisense oligonucleotide, on ASCVD risk. Olpasiran is a small-interfering RNA that is in a phase 3 clinical trial. As these therapies enter clinical trials, challenges in trial design will have to be addressed to optimize patient selection and outcomes.

Prospective Placebo-Controlled Assessment of Spore-Based Probiotic Supplementation on Sebum Production, Skin Barrier Function, and Acne.

Probiotic supplementation has been shown to modulate the gut-skin axis. The goal of this study was to investigate whether oral spore-based probiotic ingestion modulates the gut microbiome, plasma short-chain fatty acids (SCFAs), and skin biophysical properties. This was a single-blinded, 8-week study (NCT03605108) in which 25 participants, 7 with noncystic acne, were assigned to take placebo capsules for the first 4 weeks, followed by 4 weeks of probiotic supplementation. Blood and stool collection, facial photography, sebum production, transepidermal water loss (TEWL), skin hydration measurements, and acne assessments were performed at baseline, 4, and 8 weeks. Probiotic supplementation resulted in a decreasing trend for the facial sebum excretion rate and increased TEWL overall. Subanalysis of the participants with acne showed improvement in total, noninflammatory, and inflammatory lesion counts, along with improvements in markers of gut permeability. The gut microbiome of the nonacne population had an increase in the relative abundance of Akkermansia, while the subpopulation of those with acne had an increase in the relative abundance of Lachnospiraceae and Ruminococcus gnavus. Probiotic supplementation augmented the circulating acetate/propionate ratio. There is preliminary evidence for the use of spore-based probiotic supplementation to shift the gut microbiome and augment short-chain fatty acids in those with and without acne. Further spore-based supplementation studies in those with noncystic acne are warranted.

Prospective, randomized, double-blind clinical study of split-body comparison of topical hydroquinone and hexylresorcinol for skin pigment appearance.

Dyspigmentation is a common cosmetic concern in dermatology. Currently, the first line topical medication in the United States is hydroquinone. Hydroquinone use is associated with potential safety concerns including cytotoxicity to melanocytes, systemic absorption, metabolism in distant organs, and production of potentially carcinogenic metabolites. Hexylresorcinol is an ingredient that has been used in food preservation and as antiseptic has been shown to inhibit tyrosinase in vitro and has been studied as a novel skin-lightening agent. To perform a double-blind randomized split-body investigation of comparison on topical hexylresorcinol and hydroquinone on face and hands to assess for change in the appearance of skin tone and pigmentation. Thirty-two healthy female participants ages 35-65 (50.93 ± 7.37) years old with skin type I-IV were randomized to using either topical 1% hexylresorcinol or 2% hydroquinone on the left or right side of the face and corresponding hand over 12 weeks. The topical preparation was applied twice a day to assigned areas. Standardized photos were taken of the face and colorimetric measurements were taken of both sides of the forehead, cheeks and each hand at baseline (Day 0), week 4, and week 12. Of the 32 participants, 3 were lost to follow-up and the remaining were included in the final analysis. Pigmentation measured by colorimeter and clinical grading were significantly decreased at 4 and 12 weeks relative to baseline with no difference between the HR and HQ groups. No adverse effects were noted with either intervention. Hexylresorcinol 1% is well-tolerated and equivalent to hydroquinone 2% in reducing the appearance of facial and hand pigment. Further studies with an expanded population and longer time course are warranted.Registration No.: NCT04345094.

Prospective Randomized, Double-Blind, Placebo-Controlled Study of a Standardized Oral Pomegranate Extract on the Gut Microbiome and Short-Chain Fatty Acids.

Punica granatum L., commonly known as the pomegranate, is an abundant source of polyphenols, including hydrolyzable ellagitannins, ellagic acid, anthocyanins, and other bioactive phytochemicals shown to be effective in defending against oxidative stress, and has immunomodulatory activities. Ellagitannins, and their hydrolyzed product ellagic acid, interact with the gut microbiota to yield secondary metabolites known as urolithins that may have health benefits. The objective of this study was to determine the effects of supplementation with a standardized punicalagin-enriched pomegranate extract, Pomella® (250 mg), on the gut microbiome, circulating short-chain fatty acids, and gut microbial-derived ellagitannin metabolite urolithins. A randomized, double-blind, placebo-controlled study was conducted over 4 weeks on healthy volunteers aged 25-55 years. Subjects were randomly assigned to receive either an oral supplement containing 75 mg of punicalagin or an oral placebo. Stool sample collection and venipuncture were performed to analyze the gut microbiome, SCFAs, and urolithin. There was no significant change in the gut microbial diversity in both cohorts after 4 weeks of intervention, but there was a significantly increased relative abundance of Coprococcus eutectus, Roseburia faecis, Roseburia inullnivorans, Ruminococcus bicirculans, Ruminococcus calidus, and Faecalibacterium prausnitzii. Pomegranate extract (PE) supplementation led to the augmentation of circulating propionate levels (p = 0.02) and an increasing trend for acetate levels (p = 0.12). The pomegranate extract (PE) supplementation group had an increased level of circulating urolithins compared to the placebo group (6.6% vs. 1.1%, p = 0.13). PE supplementation correlated with shifts in the gut microbiome and with higher circulating levels of propionate and acetate. Further studies should explore the implications in larger cohorts and over a longer duration.

Association of the Unstimulated Whole Salivary Cytokine IL-1ß Levels with Initial, Moderate and Severe Periodontitis. A Case Control Study.

Periodontitis (P) is a highly prevalent inflammatory disease of the oral cavity. The objective of the study was to evaluate the stages of pro-inflammatory cytokine IL-1ß in initial, moderate and severe periodontitis. One hundred and twenty two patients were included in the study. Periodontitis subjects had at least 20 natural teeth and ≥8 sites with pocket depths of >4 mm and clinical attachment loss (CAL). A questionnaire was used with respect to the socio demographic parameters which included age, gender, ethnicity, education, marital, residence and occupation. To categorize the severity of the disease, teeth were assessed for, Plaque index (PI), Bleeding on probing (BOP), CAL, missing tooth, tooth mobility and bone loss. Unstimulated whole saliva (UWS) was collected and Interleukin-1ß (IL-1ß) cytokine levels were analyzed using enzyme linked immunosorbent assay with microplate reader at 450 nm. Clinical parameters and salivary cytokine concentrations were assessed using one-way analysis of variance, whereas a correlation of cases with gender and severity of periodontitis was evaluated using chi-square test. Fifty-nine patients were healthy controls and 63 were periodontitis patients Thirty two percent (n = 20) had initial periodontitis, 40% (n = 25) suffered from moderate and 29% (n = 18) had severe periodontitis. Periodontitis subgroups were significantly different with regards to age and gender (p < 0.001). The mean PPD and CAL among the periodontitis patients (PPD, 3.52 ± 1.25 mm; CAL, 4.04 ± 1.64 mm) were significantly compromised (p < 0.05) compared to healthy controls (PPD, 1.52 ± 0.73 mm; CAL, 0.08 ± 0.28 mm). Increased levels of IL-1ß were associated with high CAL and PPD findings. UWS IL-1ß levels were higher in periodontitis patients compared to healthy individuals. In addition, cases of severe periodontitis showed significantly higher UWS IL-1ß levels compared to initial and moderate periodontitis patients. Comparative levels of salivary IL-1ß can be potentially used as a diagnostic tool for periodontitis identification and disease progression along with clinical parameters.

Development of small-molecule PCSK9 inhibitors for the treatment of hypercholesterolemia.

When secreted into the circulation, proprotein convertase subtilisin kexin type 9 (PCSK9) blocks the low-density lipoprotein receptors (LDL-R) and, as a consequence, low-density lipoprotein cholesterol (LDL-C) levels increase. Therefore, PCSK9 has emerged as a potential therapeutic target for lowering LDL-C levels and preventing atherosclerosis. The US Food and Drug Administration (FDA) has approved two monoclonal antibodies (mAbs) against PCSK9, but the expensive manufacturing process limits their use. Subsequently, there have been tremendous efforts to develop cost-effective small molecules specific to PCSK9 over the past few years. These small molecules are promising therapeutics that act by preventing the synthesis of PCSK9, its secretion from cells, or the PCSK9-LDRL interaction. In this review, we summarize recent developments in the discovery of small-molecule PCSK9 inhibitors, focusing on their design, therapeutic effects, specific targets, and mechanisms of action.

Integration of high-resolution optical and SAR satellite remote sensing datasets for aboveground biomass estimation in subtropical pine forest, Pakistan.

In this study, we investigate stand-alone and combined Pleiades high-resolution passive optical and ALOS PALSAR active Synthetic Aperture Radar (SAR) satellite imagery for aboveground biomass (AGB) estimation in subtropical mountainous Chir Pine (Pinus roxburghii) forest in Murree Forest Division, Punjab, Pakistan. Spectral vegetation indices (NDVI, SAVI, etc.) and sigma nought HV-polarization backscatter dB values are derived from processing optical and SAR datasets, respectively, and modeled against field-measured AGB values through various regression models (linear, nonlinear, multi-linear). For combination of multiple spectral indices, NDVI, TNDVI, and MSAVI2 performed the best with model R2/RMSE values of 0.86/47.3 tons/ha. AGB modeling with SAR sigma nought dB values gives low model R2 value of 0.39. The multi-linear combination of SAR sigma nought dB values with spectral indices exhibits more variability as compared with the combined spectral indices model. The Leave-One-Out-Cross-Validation (LOOCV) results follow closely the behavior of the model statistics. SAR data reaches AGB saturation at around 120-140 tons/ha, with the region of high sensitivity around 50-130 tons/ha; the SAR-derived AGB results show clear underestimation at higher AGB values. The models involving only spectral indices underestimate AGB at low values (< 60 tons/ha). This study presents biomass estimation maps of the Chir Pine forest in the study area and also the suitability of optical and SAR satellite imagery for estimating various biomass ranges. The results of this work can be utilized towards environmental monitoring and policy-level applications, including forest ecosystem management, environmental impact assessment, and performance-based REDD+ payment distribution.

Recent advancements in g-C3N4-based photocatalysts for photocatalytic CO2 reduction: a mini review.

Carbon dioxide (CO2) is a very important micro-molecular resource. Using CO2 captured from the atmosphere for high-output synthesis of chemicals as raw materials has great significance and potential for various industrial applications. Since the industrial revolution in the 18th century, manmade CO2 emission has increased by 45%, which negatively impacts the planetary climate by the so-called greenhouse effect. Therefore, high-efficiency photocatalysis and photocatalysts for CO2 conversion have become the most important challenges and milestones throughout the world. In consideration of this, various catalysts have been explored. Among these, graphitic carbon nitride (g-C3N4) as a semiconductor is emerging as a highly promising photocatalyst for removing CO2 from the atmosphere. Moreover, due to its excellent chemical stability and unique band structure, g-C3N4 has exhibited significant application potential for photocatalysis. This review summarizes the advancements that have been made in the synthesis and photocatalytic applications of g-C3N4-based catalysts for CO2 reduction in recent years and explains the future challenges and prospects in this vital area of research.

The Skin and Gut Microbiome and Its Role in Common Dermatologic Conditions.

Microorganisms inhabit various areas of the body, including the gut and skin, and are important in maintaining homeostasis. Changes to the normal microflora due to genetic or environmental factors can contribute to the development of various disease states. In this review, we will discuss the relationship between the gut and skin microbiome and various dermatological diseases including acne, psoriasis, rosacea, and atopic dermatitis. In addition, we will discuss the impact of treatment on the microbiome and the role of probiotics.

Prospective randomized controlled pilot study on the effects of almond consumption on skin lipids and wrinkles.

OBJECTIVE: Almonds are a rich source of fatty acids and antioxidants, and their supplementation is known to significantly modulate serum lipids. The effects of almond on the skin's lipid barrier and the appearance of wrinkles have not yet been elucidated. The aim of this study was to investigate the effects of almond consumption on facial sebum production and wrinkles. METHODS: This was a prospective, investigator-blinded, randomized controlled trial in which subjects consumed 20% of their daily energy consumption in either almonds or a calorie-matched snack for 16 weeks. This study was completed at the UC Davis Dermatology clinic. Participants were a volunteer sample of generally healthy postmenopausal females with Fitzpatrick skin types 1 and 2. A facial photograph and image analysis system was used to obtain standardized photographs and information on wrinkle width and severity at 0, 8, and 16 weeks. Measurements of transepidermal water loss and sebum production were also completed at 0, 8, and 16 weeks. RESULTS: Fifty healthy postmenopausal females were recruited, 31 participants were enrolled, and 28 completed the study. Under photographic analysis, the almond group had significantly decreased wrinkle severity and width compared with the control group at 16 weeks (p < .02). Changes in skin barrier function were nonsignificant, measured by the transepidermal water loss (p = .65) between the almond and control groups relative to baseline after 16 weeks. No adverse effects were reported. CONCLUSION: Our study demonstrates that daily almond consumption may reduce wrinkle severity in postmenopausal females to potentially have natural antiaging benefits.