Genome-wide analyses of early-onset acute myocardial infarction identify 29 novel loci by whole genome sequencing.

Early-onset acute myocardial infarction (AMI) may have a higher genetic predisposition than late-onset AMI. The present study aimed to identify and characterize germline variants that affect early-onset AMI using whole-genome sequencing (WGS). We performed a genome-wide association study based on the WGS of 1239 Koreans, including 596 early-onset AMI patients and 643 healthy individuals. Patients with AMI who underwent percutaneous coronary intervention (PCI) caused by atherothrombotic occlusive lesions were included in the study. A total of 29 novel loci were found to be associated with early-onset AMI. These loci are involved in thrombosis, fibrinolysis, inflammation, and lipid metabolism. One of the associated single nucleotide variants (SNVs), rs1614576, located upstream of PRKCB, is known to be associated with thrombus formation. Additionally, the results revealed a novel locus, rs78631167, located upstream of PLAUR which plays a critical role in regulating plasminogen activation and is related to fibrinolysis. The association between early-onset AMI and rs9357455, which is located upstream of PHACTR1 and regulates inflammation in AMI, was found. Moreover, we identified a lipid metabolism related genetic risk locus, rs5072, in the APOA1-AS gene. This study provides new evidence supporting the genetic association between early-onset AMI and thrombosis and fibrinolysis, as well as inflammation and lipid metabolism, by analyzing the whole-genome of 596 patients with early-onset AMI who have been treated with PCI. Our findings highlight potential genetic markers for the prediction and management of AMI, as well as for understanding the etiology of AMI.

Weight Changes and Unhealthy Weight Control Behaviors Are Associated With Dysmenorrhea in Young Women.

BACKGROUND: This study aimed to evaluate the prevalence of dysmenorrhea and to investigate the effect of weight changes or unhealthy weight control behaviors on dysmenorrhea in young Korean women. METHODS: We used large-scale data of women, aged 14 to 44 years, who participated in the Korean Study of Women's Health-Related Issues. Dysmenorrhea was measured using a visual analog scale and was categorized as none, mild, moderate, and severe according to the severity. Weight changes and unhealthy weight control behaviors (any of the behaviors, fasting/meal skipping, drugs, the use of unapproved dietary supplements, and one-food diets) over the past year were self-reported. We used multinomial logistic regression to investigate the association between weight changes or unhealthy weight control behaviors and dysmenorrhea. RESULTS: Of the 5,829 young women participating in the study, 5,245 (90.0%) participants experienced dysmenorrhea [2,184 (37.5%) had moderate and 1,358 (23.3%) had severe]. After adjusting for confounders, the odds ratios for moderate and severe dysmenorrhea in participants with weight changes ≥ 3 kg (vs. < 3 kg) were 1.19 (95% confidence interval: 1.05-1.35) and 1.25 (95% confidence interval: 1.08-1.45), respectively. The odds ratios in participants with any unhealthy weight control behaviors were 1.22 (95% confidence interval: 1.04-1.42) and 1.41 (95% confidence interval: 1.19-1.67) for those with moderate and severe dysmenorrhea, respectively. CONCLUSION: Weight changes (≥ 3 kg) or unhealthy weight control behaviors are common among young women, which may adversely affect dysmenorrhea. Therefore, attention needs to be paid to excessive weight changes and unhealthy weight control behaviors to improve dysmenorrhea in young women.

Impact of pre-pregnancy body mass index and gestational weight gain on the risk of maternal and infant pregnancy complications in Korean women.

BACKGROUND/OBJECTIVE: Healthy weight maintenance before and during pregnancy has a significant effect on pregnancy outcomes; however, there are no specific guidelines for gestational weight gain in pregnant Korean women. Therefore, we investigated the impact of pre-pregnancy body mass index (BMI) and gestational weight gain on the risk of maternal and infant pregnancy complications in pregnant Korean women. METHODS: Study participants comprised 3454 singleton pregnant women from the Korean Pregnancy Outcome Study who had baseline examination and pregnancy outcome data. Maternal pre-pregnancy BMI and gestational weight gain were categorized according to the Asia-pacific regional guidelines and the Institute of Medicine recommendations, respectively. The primary outcome was any adverse outcomes, defined as the presence of one or more of the following: hypertensive disorders of pregnancy, gestational diabetes mellitus, peripartum depressive symptom, cesarean delivery, delivery complications, preterm birth, small or large weight infant, neonatal intensive care unit admission, or a congenital anomaly. Multiple logistic regression models were applied to examine the independent and combined impact of pre-pregnancy BMI and gestational weight gain on the risk of maternal and infant outcomes. RESULTS: Obesity before pregnancy significantly increased the risk of perinatal adverse outcomes by more than 2.5 times [odds ratio (OR): 2.512, 95% confidence interval (CI): 1.817-3.473]. Compared to that in women with appropriate gestational weight gain, women with excessive weight gain had a 36.4% incremental increase in the risk of any adverse outcomes [OR: 1.364, 95% CI: 1.115-1.670]. Moreover, women who were overweight or obese before pregnancy and had excessive gestational weight gain had a three-fold increase in the risk of adverse outcomes [OR: 3.460, 95% CI: 2.210-5.417]. CONCLUSION: This study highlights the need for appropriate weight recommendations before and during pregnancy to prevent perinatal complications in Korean women of childbearing age.

Factors associated with regularity and length of menstrual cycle: Korea Nurses' Health Study.

BACKGROUND: Menstrual cycle characteristics are linked to reproductive function and long-term health outcomes. This study aimed to evaluate menstrual cycle patterns, characterized by regularity and length, and associated factors among women in the Korea Nurses' Health Study. METHODS: A total of 9335 premenopausal women aged 22-45 years were included in this cross-sectional study. Regularity and length of menstrual cycles were self-reported, and their associations with reproductive, lifestyle, and occupational factors were examined using binomial and multinomial logistic regression models. Adjusted least-square means of menstrual distress, depressive symptoms, stress, fatigue, anxiety, and sleep problems were estimated according to menstrual cycle characteristics using generalized linear models. RESULTS: Twenty-one percent of nurses reported having irregular menstrual cycles (variability > 7 days). Ten percent, 64%, and 26% had menstrual cycle length of < 26, 26-31, and 32-50 days, respectively. Variability and length of cycles decreased with age and increased with age at menarche. Parous women showed low tendency of irregular cycles. Women with body mass index (BMI) > 25 kg/m2 had higher odds of irregular (odds ratio [OR] 1.68; 95% confidence interval [CI] 1.40-2.03) and long cycles (OR 1.31; 95% CI 1.08-1.58) than those with BMI 18.5- < 23 kg/m2. Irregular cycles were less common in women performing vigorous physical activity, but more common in those with prolonged standing or frequent heavy lifting at work. Frequent rotating night shift was associated with irregular cycles among nulliparous women. Levels of menstrual and premenstrual distress, depressive symptoms, perceived stress, physical and mental fatigue, anxiety, and sleep problems were higher in women with irregular cycles than in those with regular cycles (p < 0.001, each). CONCLUSIONS: The study suggests that irregular and long menstrual cycles are associated with reproductive, lifestyle, and occupational factors; also with menstrual distress and perceived health status. Our findings contribute to a better understanding of potential risk factors for menstrual dysfunction, and thus, may help improve women's health.

The Korean Pregnancy Outcome Study (KPOS): Study Design and Participants.

BACKGROUND: The Korean Pregnancy Outcome Study (KPOS) was established to investigate the determinants of adverse pregnancy outcomes among Korean women. METHODS: We recruited 4,537 pregnant women between 2013 and 2017 from two tertiary centers located in Seoul, Korea, and a total of 4,195 Korean women met inclusion criteria in the baseline analysis. A range of data on socio-demographics, past medical histories, reproductive information, health-related behaviors, psychological health and clinical information were obtained using interviewer-based questionnaires and clinical assessment at 12, 24, and 36 gestational weeks (GW), delivery and 6-8 weeks postpartum. Blood samplings were performed at 12, 24 and 36 GW, and placental tissues were obtained after delivery. The main outcome of this study was pregnancy-related complications including gestational diabetes mellitus (GDM), gestational hypertension, and screening positive for peripartum depression. Depression was assessed using the Korean version of the Edinburgh Postnatal Depression Scale, and a score of ≥10 indicated a positive screen for depression. RESULTS: Among 4,195 eligible pregnant women with a median age of 33.0 years, 3,565 (85.0%) pregnancy outcomes were available in this study, including 30 miscarriages, 16 stillbirths, and 3,519 deliveries. Mean gestational age was 38.8 GW, and mean birth weight was 3,236 gram. The prevalence of pregnancy complications of GDM, hypertensive disorders, and screening positive of depression during pregnancy and postpartum was 7.0%, 1.4%, 27.8%, and 16.6%, respectively. CONCLUSIONS: We designed KPOS to identify the determinants of pregnancy-related outcomes, and it may provide effective strategies for the prevention of pregnancy complications in Korean pregnant women.

Off-Flavor Removal from Sheep Placenta via Fermentation with Novel Yeast Strain Brettanomyces deamine kh3 Isolated from Traditional Apple Vinegar.

Animal placentae can be used as health-promoting food ingredients with various therapeutic efficacies, but their use is limited by their unpleasant odor and taste. This study aimed to investigate the possibility of deodorization of sheep placenta via yeast fermentation. A yeast strain was successfully isolated and identified as a novel Brettanomyces strain (Brettanomyces deamine kh3). The deodorizing efficacy of fermentation of the sheep placenta with B. deamine kh3 was evaluated by 42 panels, based on evaluation of preference, ranking, and aroma profiles, and compared with normal placenta and placenta fermented with B. bruxellensis. The results of the sensory evaluation indicated that fermentation of the sheep placenta with B. deamine kh3 may improve its palatability by increasing flavors such as that of grass (tree), rubber, and burnt, and by decreasing the odor and soy sauce flavor. Solid-phase microextraction-gas chromatography (SPME-GC) showed that major off-flavors in sheep placenta, such as ammonia, dimethyl disulfide, and 1,3-dioxolane, were completely diminished in the sheep placenta fermented with B. deamine kh3. This study presents those major volatile compounds, including 2-isobutyl\-4,4-dimethyl-1,3-dioxane, and 3-methyl-1-butanol, could be crucial in improving the palatability of the sheep placentae fermented with B. deamine kh3. This study provides a good starting point for the industrial application of a new deodorization method.

Factors affecting frontline Korean nurses' mental health during the COVID-19 pandemic.

AIM: To identify the factors affecting fear, anxiety and depressive symptoms among frontline nurses working with COVID-19 patients or are in charge of COVID-19 screening in Korea. BACKGROUND: Nurses are at a higher risk of COVID-19 infection because they are in closer, longer-duration contact with patients. These situations can negatively affect the mental health of nurses. METHODS: This study analysed data from COVID-19 module in the Korean Nurses' Health Study. Data from 906 participants were analysed. To identify the factors influencing mental health, descriptive statistics, Pearson's correlation and hierarchical multiple regression analyses were performed. RESULTS: Caring for patients who are COVID-19-positive increased levels of fear, anxiety and depressive symptoms of nurses. The hospital safety climate influenced mental well-being among nurses. CONCLUSION: Caring for patients with COVID-19 had a negative impact on fear, anxiety and depressive symptoms. However, the higher was the perceived hospital safety climate, the lower were the nurses' psychological symptoms. Further research on the mental health of nurses is warranted. IMPLICATIONS FOR NURSING AND HEALTH POLICY: Institutions should manage human resources to enable periodic rotation of nurses' work and working periods related to COVID-19. In addition, hospital managers should provide sufficient personal protective equipment, related education, and safety climate.

Refractory Dry Eye Syndrome after Transconjunctival Excision of the Palpebral Lobe of the Lacrimal Gland.

The aim of the present study was to report two cases of refractory dry eye syndrome (DES) after transconjunctival excision of the palpebral lobe of the lacrimal gland. A 25-year-old female patient with a chief complaint of a palpable mass in both upper eyelids visited our medical center. Preoperative orbital computer tomography showed high-attenuation lesions in both lacrimal glands. Incisional biopsy of the lacrimal gland palpebral lobe via transconjunctival incision was performed in January 2019. At 1 month after the biopsy, a lack of tears and persistent corneal erosions were found in both eyes. Artificial tears, punctal occlusion, autologous serum eye drops, and therapeutic contact lenses were applied in an attempt to control the dry eye symptoms. The patient continues to suffer from intractable DES at 2.5 years after the procedure. The second case involved a 52-year-old female patient who visited our medical center with a chief complaint of a palpable mass in both upper eyelids. Bilateral orbital tumors were diagnosed with preoperative magnetic resonance imaging. An incisional biopsy of the lacrimal gland was performed. Immunoglobulin G4-related dacryoadenitis was confirmed through lacrimal palpebral lobe incisional biopsy. Intractable DES and corneal erosion of her left eye persisted thereafter. A transconjunctival incision is an effective approach for minimizing postoperative scars and is suitable for the biopsy of tumors that are visible through the conjunctiva. After a biopsy of the palpebral lobe of the main lacrimal glands, the secretion of reflex tears decreases due to damage to the secreting ducts of the main lacrimal glands. However, total tear secretion can be maintained by basal tear secretion from the accessory lacrimal glands. In this report, we describe two cases of refractory DES due to decreased total tear secretion, although only the palpebral lobes of the main lacrimal glands were biopsied.

Enantioselective total synthesis of (+)-ieodomycin A, (+)-ieodomycin B, and their three stereoisomers.

We describe a divergent and enantioselective total synthesis of (+)-ieodomycin A and (+)-ieodomycin B with three stereoisomers. The main advantage of the present synthesis is the late-stage elaboration of the side chain, which would afford a wide range of structurally diverse analogs with interesting bioactivities.

Maternal coffee intake and the risk of bleeding in early pregnancy: a cross-sectional analysis.

BACKGROUND: Caffeine can easily cross the placenta, and maternal caffeine intake, thus, has an effect on fetal growth. However, it is still unclear whether coffee consumption is an independent risk factor for bleeding in early pregnancy. The objective of this study was to examine the association between pre-pregnancy coffee consumption patterns and the risk of bleeding in early pregnancy. METHODS: A cross-sectional analysis was conducted among 3510 pregnant women from the Korean Pregnancy Outcome Study who underwent baseline examination and for whom the results of the pregnancy were available. Coffee consumption patterns before pregnancy were examined using a questionnaire. The participants were classified according to the frequency of coffee consumption into seldom (< 1 cup/week), light (< 1 cup/day), moderate (1 cup/day), and heavy coffee drinker (≥2 cups/day) groups. Bleeding in early pregnancy was defined as the occurrence of vaginal bleeding in the first 20 weeks of pregnancy. Multiple logistic regression models were applied to examine the association between pre-pregnancy coffee consumption and the risk of bleeding in early pregnancy, after adjusting for age, body mass index (BMI), systolic blood pressure, cigarette smoking and alcohol consumption behavior, previous and current physical activity levels, stress levels, history of depression, antenatal depressive symptoms during the first trimester, type of emesis, parity, and the number of livebirths, stillbirths, miscarriages, and abortions. RESULTS: Women who were light, moderate, and heavy coffee drinkers before pregnancy had adjusted ORs of 1.086, 1.225, and 1.358, respectively, for bleeding in early pregnancy. In a fully adjusted model, heavy coffee drinkers showed a significantly higher risk of bleeding in early pregnancy, even in women aged 35 years and younger (OR 1.680) and in those with a normal body mass index (OR 1.389), who were at relatively low risk for pregnancy-related complications. CONCLUSIONS: Our results showed that heavy coffee drinking was independently associated with a higher risk of bleeding in early pregnancy among pregnant Korean women, suggesting that caffeine intake before conception and during pregnancy should be reduced. Our study highlights the need for nutritional interventions for healthy coffee drinking among pregnant women in Korea.

Cytotoxic Furan- and Pyrrole-Containing Scalarane Sesterterpenoids Isolated from the Sponge Scalarispongia sp.

Three furan-containing scalarane sesterterpenoids (1⁻3) and a novel pyrrole-containing analog (4) were isolated from the sponge Scalarispongia species. Compound 3, reported in the literature as a synthetic derivative of furoscalarol 2, was for the first time isolated from a natural source. During the separation performed using a silica column in the presence of methanol, 16-methoxy derivatives (5, 6) were obtained from the unintended reaction of 2. The isolated natural products 3 and 4 and the artifact 5 showed moderate to high cytotoxicity against six human cancer cell lines, whereas compound 6, the C-16 epimer of 5, showed no cytotoxicity at a concentration of 60 µΜ.

A Reconfigurable DNA Accordion Rack.

DNA nanostructure-based mechanical systems that control the distance between elements of interest have demonstrated great potential for various applications, including nanoplasmonic systems, molecular reactors, and other nanotechnology platforms. However, previously reported systems could not collectively manipulate a 2D or 3D nanoscale network of elements to various forms in multiple stages. A reconfigurable DNA accordion rack structure is introduced that is a DNA beam lattice that changes its conformation with a small amount of short-length DNA locks as the controlling input. The lattice shape of the 2D DNA accordion rack and the diameter and the height of the 3D DNA nanotubular structure made of the DNA accordion rack could be controlled. Furthermore, by sequentially repeating the detachment and the attachment of the different DNA locks using strand displacement, the shape reconfiguration was repeatedly carried out.

Flexoelectric in-plane switching (IPS) mode with ultra-high-transmittance, low-voltage, low-frequency, and a flicker-free image.

The demands for a power-saving mode for displaying static images are ubiquitous not only in portable devices but also in price tags and advertising panels. At a low-frequency driving in liquid crystal displays (LCDs) for low-power consumption, the flexoelectric effect arises even in calamitic liquid crystals and the optical appearance of this physical phenomenon is found to be unusually large, being noticed as an image-flickering. Although the inherent integrated optical transmittance of in-plane switching (IPS) mode is relatively lower than that of fringe-field switching (FFS) mode, the IPS mode shows no static image-flickering but an optical spike (the so-called optical bounce), at the transient moment between signal positive and negative frames. Here, we demonstrate an IPS mode using negative dielectric anisotropy of liquid crystals (Δε < 0) and fine-patterned electrodes (the width w of and the space l between electrodes ≤ 3 µm) with reduced operation voltage (up to 40.7% to a conventional FFS mode with Δε < 0), reduced optical bounce (up to 4.4%. to a conventional FFS mode with Δε < 0) and enhanced transmittance (up to 32.1% to a conventional IPS mode with Δε > 0). We believe the result will contribute not only to the scientific understanding of the optical appearance of flexoelectric effect but also pave the way for engineering of a superior low-power consumption LCD.

Saccharomonopyrones A-C, New α-Pyrones from a Marine Sediment-Derived Bacterium Saccharomonospora sp. CNQ-490.

Intensive study of the organic extract of the marine-derived bacterium Saccharomonospora sp. CNQ-490 has yielded three new α-pyrones, saccharomonopyrones A-C (1-3). The chemical structures of these compounds were assigned from the interpretation of 1D, 2D NMR and mass spectrometry data. Saccharomonopyrone A (1) is the first α-pyrone microbial natural product bearing the ethyl-butyl ether chain in the molecule, while saccharomonopyrones B and C possess unusual 3-methyl and a 6-alkyl side-chain within a 3,4,5,6-tetrasubstituted α-pyrone moiety. Saccharomonopyrone A exhibited weak antioxidant activity using a cation radical scavenging activity assay with an IC50 value of 140 µM.

Lysine-Rich Polypeptide Modulates Forkhead Box O3 and Phosphoinositide 3-Kinase-Protein Kinase B Pathway To Induce Apoptosis in Breast Cancer.

The PI3K/AKT/FOXO3 pathway is one of the most frequently involved signaling pathways in cancer, including breast cancer. Therefore, we synthesized a novel lysine-rich polypeptide (Lys-PP) using de novo assembly method and evaluated its anticancer effect. We characterized the structural and physicochemical properties of Lys-PP using various techniques. Later, we used integrated approaches such as in silico, in vitro, and in vivo analysis to confirm the anticancer and therapeutic effect of Lys-PP. First, RNA sequencing suggests Lys-PP disrupted the central carbon metabolic pathway through the modulation of prolactin signaling. Additionally, docking analysis also confirmed the significant association of PI3K/AKT and FOXO3 pathway to induce an apoptotic effect on cancer. Second, Lys-PP exhibited a significant cytotoxicity effect against MDA-MB-231 but no cytotoxic effects on RAW 264.7 and HEK-293, respectively. The cytotoxic effect of Lys-PP-induced apoptosis by an increase in FOXO3a protein expression and a decrease in PI3K/AKT pathway was confirmed by quantitative real-time polymerase chain reaction, immunoblotting, and fluorescent microscopy. Later, immunohistochemistry and hematoxylin and eosin staining on MDA-MD-231 showed increased FOXO3a expression and cell death in the xenograft mice model. Further, liver function, metabolic health, or lipid profile upon Lys-PP showed the absence of significant modulation in the biomarkers except for kidney-related biomarkers. Overall, our comprehensive study provides the first evidence of Lys-PP antibreast cancer action, which could serve as a potential treatment in an alternative or complementary medicine practice.

Effect of the sodium-glucose cotransporter-2 inhibitor, DWP16001, as an add-on therapy to insulin for diabetic dogs: A pilot study.

BACKGROUND: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a novel class of anti-hyperglycaemic agents. OBJECTIVE: This study aimed to evaluate the safety and the adjuvant glycaemic control effect of an SGLT2 inhibitor, DWP16001, in diabetic dogs receiving insulin treatment. METHODS: Nineteen diabetic dogs receiving insulin treatment (NPH, porcine lente and glargine insulin) were divided into two groups according to dosing frequency: DWP TOD group (n = 10) and DWP SID group (n = 9). In the DWP TOD group, 0.025 mg/kg of DWP16001 was administered once every 3 days, whereas, in the DWP SID group, 0.025 mg/kg of DWP16001 was administered once a day. Food intake was maintained during the trial period. Hypoglycaemia, ketoacidosis or unexpected life-threatening reactions were assessed as adverse effects before and after DWP16001 administration. We compared insulin requirement reduction and blood glucose level control between two groups. RESULTS: No specific adverse effects were observed during the clinical trial, and haematological parameter remained unchanged. Moreover, the fasting glucose levels and daily insulin dose in the DWP TOD group were lower than the pre-administration values, but not significantly different for 8 weeks. Systolic blood pressure, fructosamine and insulin dose decreased significantly in the DWP SID group compared to the DWP TOD group at 8 weeks (p < 0.05) without affecting food consumption. Among these patients, 10 patients were monitored while receiving DWP16001 for 12 months (DWP TOD group n = 5, DWP SID group n = 5). The fasting glucose and fructosamine levels and daily insulin dose were reduced in both groups at 12 months compared with those before receiving DWP16001. CONCLUSION: When DWP16001, an SGLT2 inhibitor, was supplied to dogs with type 1 diabetes, no adverse effects were observed, and it was confirmed that the administered insulin dose can be reduced in controlling blood glucose.

Evaluation of acute, 28-day, 13-week repeated dose oral toxicity and genotoxicity of a herbal extract (HemoHIM G) from Angelica sinensis, Ligusticum chuanxiong, and Peaonia lactiflora.

HemoHIM G is a functional food ingredient composed of a triple herbal combination of Angelica sinensis, Ligusticum chuanxiong, and Paeonia lactiflora, to improve impaired immune function. Considering the pharmacological benefits of its constituent herbal components, HemoHIM G is anticipated to have various health benefits; however, its toxicity has not been thoroughly evaluated. Here, we conducted a comprehensive study to assess the safety of HemoHIM G in terms of acute oral toxicity, 13-week repeat-dose toxicity, and genotoxicity. In the oral acute toxicity study, Sprague-Dawley rats were orally administered a single dose of HemoHIM G at 5000 mg/kg/day, the limit dose for the acute study. No abnormal findings or adverse effects were observed in this study, as confirmed by gross pathology. A 13-week repeated-dose toxicity study was conducted with HemoHIM G at doses of 1250, 2500, and 5000 mg/kg/day to examine the subchronic toxicity in both male and female rats after 28 days of dose-range finding study. No test substance-related clinical signs or mortality was observed at any of the tested doses. Gross pathology, hematology, blood chemistry, and histopathology were within normal ranges, further supporting the safety of HemoHIM G. Therefore, the NOAEL of HemoHIM G was considered to be at 5000 mg/kg/day for both sexes of rats. Bacterial reverse mutation tests, a chromosome aberration test in human peripheral blood lymphocytes, and a mouse micronuclei test were conducted to identify the potential genotoxicity of HemoHIM G. HemoHIM G is non-mutagenic and non-clastogenic. Collectively, these findings provide valuable evidence for the safe use of HemoHIM G as a functional food ingredient.

Korea4K: whole genome sequences of 4,157 Koreans with 107 phenotypes derived from extensive health check-ups.

BACKGROUND: Phenome-wide association studies (PheWASs) have been conducted on Asian populations, including Koreans, but many were based on chip or exome genotyping data. Such studies have limitations regarding whole genome-wide association analysis, making it crucial to have genome-to-phenome association information with the largest possible whole genome and matched phenome data to conduct further population-genome studies and develop health care services based on population genomics. RESULTS: Here, we present 4,157 whole genome sequences (Korea4K) coupled with 107 health check-up parameters as the largest genomic resource of the Korean Genome Project. It encompasses most of the variants with allele frequency >0.001 in Koreans, indicating that it sufficiently covered most of the common and rare genetic variants with commonly measured phenotypes for Koreans. Korea4K provides 45,537,252 variants, and half of them were not present in Korea1K (1,094 samples). We also identified 1,356 new genotype-phenotype associations that were not found by the Korea1K dataset. Phenomics analyses further revealed 24 significant genetic correlations, 14 pleiotropic associations, and 127 causal relationships based on Mendelian randomization among 37 traits. In addition, the Korea4K imputation reference panel, the largest Korean variants reference to date, showed a superior imputation performance to Korea1K across all allele frequency categories. CONCLUSIONS: Collectively, Korea4K provides not only the largest Korean genome data but also corresponding health check-up parameters and novel genome-phenome associations. The large-scale pathological whole genome-wide omics data will become a powerful set for genome-phenome level association studies to discover causal markers for the prediction and diagnosis of health conditions in future studies.

Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive.

The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of Ca(V)3.1 T-type Ca(2+) channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4- to 10-Hz synchronous neuronal activities arose from the IO and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking Ca(V)3.1 gene. Intracellular recordings in brain-stem slices revealed that the Ca(V)3.1-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4- to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of Ca(V)3.1 gene in the inferior olive by shRNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate Ca(V)3.1 channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, Ca(V)3.1 is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor.

Complementary Utility of Intravascular Lithotripsy With Atherectomy for Severely Calcified Coronary Stenoses in Contemporary Practice.

BACKGROUND: The effectiveness and safety of a contemporary combined approach that incorporates the novel intravascular lithotripsy (IVL) technology into conventional tools including atherectomy have yet to be studied. METHODS: We retrospectively included consecutive patients who underwent percutaneous coronary intervention (PCI) with IVL from March 2021 to February 2022. Effectiveness (residual stenosis of <30%) and safety outcomes (procedural complications and major adverse cardiovascular event [MACE] defined as a composite of all-cause death, myocardial infarction, or target vessel revascularization) were compared between patients undergoing IVL with and without atherectomy. RESULTS: A total of 109 patients underwent IVL, of whom 33 patients (30.3%) were treated with both IVL and atherectomy and had higher risk features including reduced cardiac function and more frequent use of mechanical circulatory support. Angiographic success for calcified de novo lesions was achieved in 85.7% and 90.6% of the combined and non-atherectomy groups, respectively (P=.49). Each group had one case of coronary perforation (P=.52) while major dissection occurred in 2 cases of calcific stent underexpansion in the combined group (6.1% vs 0%; P=.09). Thirty-day MACE occurred in 4.8% of patients including 3 deaths in the atherectomy group and 1 cardiac death and 1 myocardial infarction in the non-atherectomy group (P=.16). CONCLUSION: Procedural success and complications were similar in patients undergoing IVL with and without atherectomy when treating calcified de novo lesions. Those who required a combined approach represented a high-risk population with high mortality, suggesting that a multidisciplinary approach is needed to optimize case selection and care beyond PCI.