Myosteatosis and sarcopenia are linked to autonomous cortisol secretion in patients with aldosterone-producing adenomas.

Patients with adrenal aldosterone-producing adenomas (APA) face elevated cardiovascular risks, especially when cortisol is co-secreted, yet the impact on muscle health remains unclear. Myosteatosis, characterized by fatty infiltration into muscles, is linked to cardiometabolic diseases and decreased survival. We aimed to investigate the association between autonomous cortisol secretion (ACS) in APA and muscle quantity and quality. In this study, we analyzed data from 228 APA patients undergoing laparoscopic adrenalectomy between 2009 and 2024, assessing muscle composition via computed tomography. Intermuscular adipose tissue (IMAT), skeletal muscle area and density, visceral and subcutaneous adipose tissue area at L3 were measured. Comparisons were made between ACS and non-ACS groups. We found that among 228 patients, 76 (33.3%) had ACS. Those with ACS exhibited significantly higher IMAT area (P = 0.042) and lower skeletal muscle area (P = 0.002) and density (P < 0.001). Multivariable regression confirmed ACS positively associated with IMAT area and negatively associated with skeletal muscle area and density. At 1-year follow-up, ACS patients (n = 15) experienced decreased IMAT area (P = 0.001) and increased skeletal muscle area (P = 0.031) post-adrenalectomy, while those without ACS (n = 29) showed no IMAT change but increased visceral (P < 0.001) and subcutaneous (P = 0.008) adipose tissue area. In summary, myosteatosis and sarcopenia are linked to ACS in APA patients, and these parameters improve following adrenalectomy.

Evaluating the Protective Effectiveness of Rubber Glove Materials Against Organic Solvents Upon Repeated Exposure and Decontamination.

Background: Glove reuse poses risks, as chemicals can persist even after cleaning. Decontamination methods like thermal aeration, recommended by US OSHA, vary in effectiveness. Some studies show promising results, while others emphasize the importance of considering both permeation and tensile strength changes. This research advocates for informed glove reuse, emphasizing optimal thermal aeration temperatures and providing evidence to guide users in maintaining protection efficiency. Methods: The investigation evaluated Neoprene and Nitrile gloves (22 mils). Permeation tests with toluene and acetone adhered to American Society for Testing Materials (ASTM) F739 standards. Decontamination optimization involved aeration at various temperatures. The experiment proceeded with a maximum of 22 re-exposure cycles. Tensile strength and elongation were assessed following ASTM D 412 protocols. Breakthrough time differences were statistically analyzed using t-test and ANOVA. Results: At room temperature, glove residuals decreased, and standardized breakthrough time (SBT)2 was significantly lower than SBT1, indicating reduced protection. Higher temperature decontamination accelerated residual removal, with ΔSBT (SBT2/SBT1) exceeding 100%, signifying restored protection. Tensile tests showed stable neoprene properties postdecontamination. Results underscore thermal aeration's efficacy for gloves reuse, emphasizing temperature's pivotal role. Findings recommend meticulous management strategies, especially post-breakthrough, to uphold glove-protective performance. Conclusions: Thermal aeration at 100°C for 1 hour proves effective, restoring protection without compromising glove strength. The study, covering twenty cycles, suggests safe glove reuse with proper decontamination, reducing costs significantly. However, limitations in chemical-glove combinations and exclusive focus on specific gloves caution against broad generalization. The absence of regulatory directives on glove reuse highlight the importance of informed selection and rigorous decontamination validation for workplace safety practices.

Synthesis of Multisubstituted 1,2,3-Triazoles: Regioselective Formation and Reaction Mechanism.

A synthetically useful approach to functionalized triazoles is described via the reaction of ß-carbonyl phosphonates and azides. 1,4- and 1,5-disubstituted and 1,4,5-trisubstituted triazoles can be regio- and chemoselectively accessed under mild conditions in good to excellent yields (31 examples, up to 99%). A mechanism is proposed that rationalizes the avoidance of the 4-phosphonate byproducts, which is aligned with crystallographic and experimental evidence.

A study on the relationship between gut microbiota and intrahepatic cholestasis of pregnancy.

Objective: Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disease associated with a high incidence of complications in the mid and late stages of gestation. This study investigates differences in the composition of intestinal flora among pregnant women diagnosed with ICP, employing Illumina MiSeq high-throughput sequencing technology. Methods: This case-control study obtained patient data from the hospital information system (HIS) and the laboratory information system (LIS). Fecal samples were collected from 25 pregnant women who did not undergo intestinal preparation before delivery between December 2020 and March 2021. Whole-genome analysis was performed. PCR was used to amplify the 16S rRNA V3-V4 variable region, which was then sequenced. Alpha and beta diversity were computed, and the maternal intestinal flora's abundance and composition characteristics were analyzed. Differences in intestinal flora between the two sample groups were examined. Results: Bacteroides and Proteobacteria exhibited positive correlations with TBIL and IBIL. Betaproteobacteria, Gammaproteobacteria, and Erysipeiotrichi showed positive correlations with TBIL, IBIL, and DBIL, while Lactobacillus, Delftia, and Odoribacter demonstrated positive correlations with ALT. Conclusion: The ICP group displayed significantly higher levels of total bile acid and ALT compared to the control group. The intestinal flora composition comprised four primary phyla: Firmicutes, Actinobacteria, Bacteroidetes, and Proteobacteria. ICP patients exhibited a lower relative abundance of intestinal flora across different levels of community composition when compared to the control group. Specific correlations between certain intestinal flora and clinical liver parameters were identified.

[Content, Distribution, Source Analysis, and Risk Assessment of PAHs in Arable Soils of Taiyuan].

PAHs (polycyclic aromatic hydrocarbons) accumulated in arable soils have significant impacts on farmland quality and human health, which has attracted wide attention from scientists and the public. A total of 22 arable soil samples were collected from Taiyuan, an old industrial city, including three districts (industrial zones, hilly areas, and sewage irrigation area), and the contents of 21 PAHs were detected using the GC-MS method. The sources of PAHs in soils were analyzed using the diagnostic ratios (DRs) method and positive matrix factorization (PMF) model, and the soil health risks were analyzed using the incremental lifetime cancer risk (ILCR) model. The results indicated that the average concentrations of Σ21PAHs and Σ16PAHs in arable soils of Taiyuan were 934.6 ng·g-1 and 787.7 ng·g-1, respectively, which were lower than the soil pollution risk screening value of agricultural land stipulated in GB 15168-2018. 3-5 rings PAHs were the dominant components, accounting for~90% of the Σ21PAHs. Approximately 60% of sites in industrial zones, 13% in hilly areas, and 33% in the sewage irrigation area had high PAHs contents larger than 1000 ng·g-1. The spatial distribution of PAHs showed that more severe PAHs pollution in the soil occurred in industrial areas than that in the other two districts. The DRs suggested that the combustion of coals, bio-masses, and traffic emissions were the dominant sources for PAHs pollution in arable soils in Taiyuan. The simulation results of the PMF model indicated that the sources and contribution rates of PAHs in cultivated soils were coal and biomass burning sources (59%), traffic sources (22%), and coking sources (19%). The risk assessment confirmed that the arable soils in Taiyuan had high potential carcinogenic risks; thus, more attention should be paid to the PAHs pollutions in arable soils.

Effect of nalbuphine plus ropivacaine on vaginal labor in epidural analgesia.

BACKGROUND: Various approaches using epidural analgesia have been employed for relieving labor pain and promoting spontaneous delivery. We aimed to evaluate the effect of nalbuphine and ropivacaine versus fentanyl and ropivacaine on the duration of delivery in parturients. METHODS: Clinical data of 160 full-term primiparous women who received either nalbuphine or fentanyl in combination with ropivacaine infusion for epidural labor analgesia in our hospital from December 2020 to May 2022 were retrospectively analyzed. The participants were divided into two groups based on anesthesia methods: nalbuphine group (NR group, n = 78) received 0.2 mg/mL nalbuphine combined with 0.1% ropivacaine hydrochloride for patient-controlled epidural analgesia (PCEA) and fentanyl group (FR group, n = 82) received 2 ug/mL fentanyl citrate and 0.1% ropivacaine hydrochloride for PCEA. Both groups received an epidural blockade for labor analgesia at lumbar 2-3 interspace. The duration of the first, second, and third stages of labor, the onset of analgesia, and time before delivery (T0), 15 min of analgesia (T1), 30 min of analgesia (T2), full opening of the uterine opening (T3),exerts force during childbirth(T4), heart rate (HR), blood pressure (BP), blood saturation (SpO2), visual analogue pain scale (VAS) score, Ramsay sedation score, and modified Bromage score, and 5 min were recorded at 2 h postpartum (T5). The neonatal Apgar score, neonatal behavioral neurological assessment (NBNA) score, maternal nausea, vomiting, and itchy skin were recorded. RESULTS: Compared with the FR group, the first stage of labor duration (p < 0.05) and total duration of labor (p < 0.05) were shortened and the onset of analgesia (p < 0.05) was increased in the NR group. NR group had lower incidence of urinary retention than FR group (p < 0.05). The maternal and neonatal investigational parameters and scores had no significant difference between the two groups. CONCLUSIONS: Nalbuphine combined with ropivacaine in epidural block labor has a faster onset of analgesia and has a lower incidence of urinary retention than fentanyl combined with ropivacaine, and nalbuphine shortens the duration of the first and total stages of labor. Both nalbuphine and fentanyl can reduce pain during labor, have little effect on maternal hemodynamics, and have no significant effect on neonatal Apgar or NBNA scores.

The Soft Prefabricated Orthopedic Insole Decreases Plantar Pressure during Uphill Walking with Heavy Load Carriage.

This study aimed to investigate the effect of varying the hardness of prefabricated orthopedic insoles on plantar pressure and muscle fatigue during uphill walking with a heavy backpack. Fifteen healthy male recreational athletes (age: 20.4 ± 1.0 years, height: 176.9 ± 5.7 cm, weight: 76.5 ± 9.0 kg) wore prefabricated orthopedic insoles with foot arch support; a heel cup with medium (MI), hard (HI), and soft (SI) relative hardnesses; and flat insoles (FI). They performed treadmill walking on uphill gradients with 25 kg backpacks. The plantar pressure and surface electromyographic activity were recorded separately, in 30 s and 6 min uphill treadmill walking trials, respectively. The HI, MI, and SI significantly decreased peak plantar pressure in the lateral heel compared to FI. The MI and SI significantly decreased the peak plantar pressure in the fifth metatarsal compared to FI. The MI significantly reduced the pressure-time integral in the lateral heel compared to FI. The HI significantly increased the peak plantar pressure and pressure-time integral in the toes compared to other insoles, and decreased the contact area in the metatarsal compared to SI. In conclusion, a prefabricated orthopedic insole made of soft material at the fore- and rearfoot, with midfoot arch support and a heel cup, may augment the advantages of plantar pressure distribution during uphill weighted walking.

Using Simulation Optimization to Solve Patient Appointment Scheduling and Examination Room Assignment Problems for Patients Undergoing Ultrasound Examination.

This study investigates patient appointment scheduling and examination room assignment problems involving patients who undergo ultrasound examination with considerations of multiple examination rooms, multiple types of patients, multiple body parts to be examined, and special restrictions. Following are the recommended time intervals based on the findings of three scenarios in this study: In Scenario 1, the time interval recommended for patients' arrival at the radiology department on the day of the examination is 18 min. In Scenario 2, it is best to assign patients to examination rooms based on weighted cumulative examination points. In Scenario 3, we recommend that three outpatients come to the radiology department every 18 min to undergo ultrasound examinations; the number of inpatients and emergency patients arriving for ultrasound examination is consistent with the original time interval distribution. Simulation optimization may provide solutions to the problems of appointment scheduling and examination room assignment problems to balance the workload of radiological technologists, maintain high equipment utilization rates, and reduce waiting times for patients undergoing ultrasound examination.

Role of contrast-enhanced ultrasonography in MR-guided focused ultrasound ablation on uterus fibroids: lesion selection and assessment of ablative effects.

OBJECTIVES: To determine whether contrast-enhanced ultrasonography (CEUS) can be used for selecting lesions and assessing the ablative effects of MRgFUS ablation on uterus fibroids, compared with MR imaging. METHODS: This retrospective study was approved by the institutional review board of our hospital. From April 2018 to November 2019, a total of 44 symptomatic fibroids in 38 patients who underwent MRgFUS ablation were included. The association between pre-ablation characteristics on CEUS/MR imaging and the non-perfusion volume (NPV) after ablation was analyzed using multivariable linear regression analysis. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve values was compared between the CEUS and MR imaging regression models. NPV after ablation was compared between CEUS and enhanced MR imaging. RESULTS: On CEUS, entangled branch vessels, fast-in, and fast-out patterns were significantly associated with NPV, with an AUC of 0.95 (95% CI; 0.88, 1.00). On MR imaging, hyper-intensity on T2-weighted images (T2WI), hyper-intense ring-like signal on T2WI images, and hyper-enhancement on contrast-enhanced T1WI images were correlated with NPV, with an AUC of 0.86 (95% CI; 0.70, 1.00). After ablation, no differences in NPV were noted between contrast-enhanced T1WI (84.13 ± 75.42 cm3) and CEUS (80.22 ± 76.49 cm3). CONCLUSIONS: Some pre-ablation characteristics of uterine fibroids on CEUS were associated with NPV after MRgFUS. CEUS may contribute to the evaluation of ablative outcomes and patient selection, similar to MR imaging. KEY POINTS: • Contrast-enhanced ultrasonography (CEUS) is effective for selecting the appropriate uterine fibroids before MR-guided focused ultrasound (MRgFUS) ablation and evaluating non-perfusion volumes (NPV) after ablation, as a potential alternative to MR imaging. • Before ablation, entangled branch vessels, fast-in, and fast-out patterns on CEUS were significantly associated with NPV after MRgFUS. • No significant differences in NPV were detected between contrast-enhanced T1WI and CEUS after ablation.

Contributions of Ergonomics, Psychological Factors, and Sleep Disturbances to Lower Back Pain Among Taiwanese Workers.

OBJECTIVE: We investigated the contributions of ergonomics, psychological factors, and sleep disturbances to lower back pain (LBP). METHODS: A nationwide survey of sampled 27,508 (2.6‰) Taiwanese workers was conducted in 2010. Definition of outcome was LBP affecting work performance in the past year. Predictor variables included age, body mass index, ergonomic factors, job control, psychological demands, and sleep disturbances. Mutually adjusted relative risks were examined using general linear models, followed by aPAR. RESULTS: 18,353 workers were included in the multivariate regression model. The three first significant risk factors to LBP included heavy lifting or awkward posture, sleep disturbances, and high psychological demands (aPAR = 13.5%, 8.7%, 5.7% respectively in men and 6.1%, 11.8%, 5.9% in women). CONCLUSIONS: In addition to ergonomic exposure, sleep disturbances and high psychological demands significantly contributed to LBP.

Gender- and age-related differences in distinct phenotypes of hypertrophic cardiomyopathy-associated mutation MYBPC3-E334K.

The mutation MYBPC3-E334K is a culprit mutation of hypertrophic cardiomyopathy (HCM). The pathogenicity of MYBPC3-E334K is conflicting in ClinVar because of the limited segregation data and the relatively high frequency in gnomAD (0.03% overall, with 0.3% in East Asians and 0.8% in Japanese). The main aim is to clarify the clinical importance and phenotype-genotype correlations in subjects with or without MYBPC3-E334K alone. The prevalence of MYBPC3-E334K was sequenced in 1017 HCM unrelated probands. The clinical features, morphology phenotypes, and electrical phenotypes were further analyzed according to the phenotype and genotype status in families with single-mutation MYBPC3-E334K. Nine of 1017 (0.88%) unrelated HCM probands were detected harboring MYBPC3-E334K, and three of them harbored a second variant in sarcomere protein gene. Family study and co-segregation analyses indicated that patients with single-mutation MYBPC3-E334K showed autosomal dominant mode of inheritance with incomplete penetrance. The overall disease penetrance was 52.6%, and the disease penetrance was higher in males than in females (100% in men vs 25% in women, p = 0.003). The mean age at diagnosis of males was approximately 25 years younger than females (36.57 ± 18.65 vs 62.33 ± 12.10, p = 0.062). The variant MYBPC3-E334K was classified as a likely pathogenic variant, and a second sarcomere variant did not reveal obvious cumulative effects. The patients harboring single-mutation MYBPC3-E334K had incomplete penetrance, and males demonstrated higher penetrance and early onset HCM than females. A second sarcomere variant did not reveal obvious cumulative effects.

A clinical scoring system for predicting tumor recurrence after percutaneous radiofrequency ablation for 3 cm or less hepatocellular carcinoma.

Preoperative prediction of tumor recurrence after radiofrequency ablation (RFA) in patients with early hepatocellular carcinoma (HCC) is helpful for clinical decision-making before treatment. A total of 162 patients with HCC of 3 cm or less who were completely ablated by percutaneous RFA were divided into a derivation cohort (n = 108) and a validation cohort (n = 54). Based on X-Tiles software, Kaplan-Meier curve analysis and COX multivariate analysis to obtain valuable predictive indicators, a clinical scoring system for predicting tumor recurrence was established. In the verall cohort, derivation cohort and validation cohort, we found circulating tumor cells (CTC) > 2/3.2 mL, alpha-fetoprotein (AFP) > 20 ng/mL, and des-γ-carboxyprothrombin (DCP) > 40 mAU/mL, maximum tumor diameter > 20 mm, and the number of multiple tumors (≥ 2) are independent risk factors affecting tumor recurrence. Each independent risk factor was assigned a score of 1 to construct a predictive clinical scoring system, and X-Tiles software was used to divide the clinical score into a low-risk group (0 score-1 score), a medium-risk group (2 scores-3 scores), and a high-risk group (4 scores-5 scores). The cumulative tumor recurrence rates of patients in the low-risk group, middle-risk group, and high-risk group in 1 year, 2 years, and 3 years were 19.4%/27.5%/30.9%, 37.0%/63.2%/79.9% and 68.2%/100%/100%, respectively (Low-risk group vs medium-risk group: P < 0.001; medium-risk group vs high-risk group: P < 0.001). This clinical scoring system can predict the prognosis of patients with HCC of 3 cm or smaller undergoing percutaneous RFA, which has certain application value for making preoperative clinical decisions.

Clinical and molecular characterization of seven patients with Danon disease.

Danon disease is an X-linked glycogen storage disease characterized by skeletal myopathy, cardiomyopathy and intellectual impairment. It is caused by a loss-of-function mutation in the lysosome-associated membrane protein-2 (LAMP2) gene. In the present study, exon and boarding intron analysis of 96 cardio disease-associated genes was performed in 770 patients with hypertrophic cardiomyopathy (HCM) using second-generation sequencing. Next, the identified mutations were confirmed in family members of the patients and 300 healthy controls. Detailed clinical, electrocardiographic (ECG) and echocardiographic findings were recorded. A pathogenic mutation in LAMP2 was identified in 7 patients who phenotypically presented with HCM. A total of four patients had a fragmented QRS complex (fQRS) on surface ECG. In addition, two patients presented with ventricular preexcitation with a short PR interval. Compared with the patients with protein kinase AMP-activated non-catalytic subunit γ2 syndrome and Fabry disease, the 7 patients with Danon disease presented at an earlier age, had a smaller left atrial size, a thinner maximal left ventricular wall thickness and a lower probability of pacemaker implantation. Compared with 12 sex- and age-matched patients with sarcomere-protein mutations, the 4 patients with Danon disease had a lower left ventricular outflow tract gradient and worse diastolic function. The present study provided a comprehensive comparison of different pathologies presenting with HCM and reported on features of early-onset Danon disease, including the characteristic preexcitation and fQRS on ECG. This may provide valuable information that may be utilized for the early diagnosis and treatment of patients with Danon disease. The present study was registered as a clinical trial with ClinicalTrials.gov (Sep. 2, 2016; registry no. NCT02888132).

Body volume estimation equation for male laborers in Taiwan.

The purpose of this study was to develop a body volume (BV) estimation equation for male laborers in Taiwan with body weight (W) and stature height (H) as initial estimators. A three-dimensional (3D) body scanner and a 3D foot scanner were used to measure the 3D range data of 100 male laborers in this study. Subjects' BV was extracted from the 3D body model, and H and W were used as independent variables in regression analysis. The results show that the final BV estimation equation is BV = 1122.927 × W0.972, with R2 = 0.949. Thirty extra male subjects were scanned to compare this BV estimation equation with those in previous studies. The results show that this BV estimation equation had the smallest absolute mean difference at 1.1458 L and the smallest standard error of the estimate at 2.48% in comparison.

Preoperative evaluation and prediction of clinical scores for hepatocellular carcinoma microvascular invasion: a single-center retrospective analysis.

INTRODUCTION: Microvascular invasion (MVI) of is generally considered to be an important prognostic factor for hepatocellular carcinoma (HCC) after operation, An accurate prediction of MVI before operation is helpful for clinical decision-making before operation. MATERIAL AND METHODS: A retrospective analysis of 227 cases of hepatocellular carcinoma patients after hepatectomy has been confirmed the pathological result whether there was MVI, and has been determined the independent risk factors of MVI. Based on these independent risk factors, we constructed a clinical scoring risk model for predicting MVI. RESULTS: Among the 227 patients with HCC, 74 (34.6%) were MVI positive. Using receiver operating characteristic (ROC) curve and logistic regression model, we found that alpha-fetoprotein(AFP)≥158 ng/mL(odds ratio[OR] = 4.152,95% confidence interval [95%CI]:1.602∼10.760,p = 0.003), Des-γ-carboxy prothrombin (DCP)≥178mAU/mL(OR = 9.730,95%CI:3.392∼27.910,p < 0.001), circulating tumor cells (CTCs)≥3/3.2 ml(OR = 7.747,95%CI:3.019∼19.881,P < 0.001), maximum tumor diameter≥59 mm(OR = 3.467,95%CI:1.368∼8.669,p = 0.008) and tumor margin unsmoothness(OR = 0.235,95%CI:0.096∼0.573,p = 0.001) were independent risk factors for MVI, they predicted that the area under the curve of MVI was 0.752, 0.777, 0.857, 0.743 and 0.333, respectively. Based on these five independent risk factors, we constructed a clinical scoring risk model for predicting MVI. The model predicts that the area under the curve of MVI is 0.922, and its prevalence rate from 0 to 5 are 3.1%(1/32), 5.3%(4/76), 12.2%(5/41), 66.7%(20/30), 87.9%(29/33), 100%(15/15), respectively (P < 0.001). CONCLUSION: Based on AFP, DCP, CTC, maximum tumor diameter and tumor margin unsmoothness, we constructed a model to predict the risk of MVI clinical score, so as to make a more accurate individualized treatment plan before operation, which has important clinical significance and application prospect to improve the curative effect of HCC.

Low-Intensity Extracorporeal Shock Wave Therapy Ameliorates the Overactive Bladder: A Prospective Pilot Study.

OBJECTIVE: In the present clinical trial, we evaluated the therapeutic effects of low-intensity extracorporeal shockwave therapy (LiESWT) on overactive bladder (OAB). METHODS: Female subjects with ages of 20-75 years and who have been clinically diagnosed with OAB were included in the study. The LiESWT (DUOLITH SD1 T-TOP, AG) applicator was placed on the suprapubic skin area and applied with an intensity of 0.25 mJ/mm2, 3000 pulses, and 3 pulses/second. To assess the therapeutic efficacy, all subjects were required to complete the validated OAB symptoms and life bothersome questionnaires, 3-day urinary diary, uroflowmetry, and post-voided residual urine (PVR) measurement at 4 weeks of LiESWT (W4), 8 weeks of LiESWT (W8), 1-month follow-up (F1), and 3-month follow-up (F3) after LiESWT. RESULT: 82 subjects with the mean age of 56.5 ± 1.2 years were enrolled. The questionnaire scores were significantly improved at W4, W8, F1, and F3 as compared to baseline data (W0). At W8, the mean values of functional bladder capacity were meaningfully increased. According to the 3-day urinary diary, daytime frequency, urgency, and nocturia were significantly decreased. The uroflowmetry results showed that the mean voided urine volume and the maximal flow rate (Q max) were noticeably increased. PVR volume was also significantly decreased. CONCLUSIONS: The data demonstrated that 8-week LiESWT ameliorated the OAB symptoms, promoted the uroflow parameters, and improved the quality of life (QoL) in OAB patients, suggesting that LiESWT might serve as an alternative noninvasive therapy for OAB.

Genetic analysis of monoallelic double MYH7 mutations responsible for familial hypertrophic cardiomyopathy.

ß­myosin heavy chain (MHC) 7 (MYH7) is the dominant pathogenic gene that harbors mutations in 20­30% of cases of familial hypertrophic cardiomyopathy (HCM). The aim of this study was to elucidate the distribution and type of genetic variations among Chinese HCM families. From 2013 to 2017, the clinical data of 387 HCM probands and their families were collected. Targeted exome­sequencing technology was used in all probands, and the selected mutations were subsequently verified by Sanger sequencing in the probands, family members and 300 healthy ethnic­matched volunteers. Three­dimensional models were created using Swiss­PdbViewer 4.1, and further genetic analyses were performed to determine sequence conservation and frequency of the mutations. Among the 5 probands with double MYH7 mutations, 4 carried compound heterozygous mutations, and 1 carried monoallelic double mutations (A934V and E1387K). Four family members of the proband with monoallelic double mutations had the same mutation as the proband. Echocardiography and 12­lead electrocardiography revealed abnormalities in the proband and 3 of the 4 carriers. The probands with compound heterozygous mutation had a higher left ventricular mass as revealed by echocardiography and higher QRS, SV1 and RV5+SV1 amplitudes than those with monoallelic double mutations (P<0.05). Simulation of the 3D structure of mutated proteins showed that the replacement of alanine by valine affected the flexibility of the MHC neck domain in case of the A934V mutation, whereas reactivity of the MHC rod domain was affected in the case of the E1387K mutation. In conclusion, we identified several novel HCM­causing MYH7 mutations. More importantly, this is the first study to report a rare HCM family with monoallelic double mutations.

Novel phenotype-genotype correlations of hypertrophic cardiomyopathy caused by mutation in α-actin and myosin-binding protein genes in three unrelated Chinese families.

BACKGROUND: The correlations between genotype and phenotype in hypertrophic cardiomyopathy (HCM) have not been established. Mutation of α-actin gene (ACTC1) is a rare cause of HCM. This study aimed to explore novel genotype-phenotype correlations in HCM patients with the variants in ACTC1 and myosin-binding protein (MYBPC3) genes in three unrelated Chinese families. METHODS: Clinical, electrocardiographic, and echocardiographic examinations were performed in three Han pedigrees. Exon and boarding intron analysis of 96 cardio-disease-related genes was performed using second-generation sequencing on three probands. The candidate variants were validated in 14 available family members and 300 unrelated healthy controls by bi-directional Sanger sequencing. The pathogenicity and conservation were calculated using MutationTaster, PolyPhen-2, SIFT, and Clustal X. Pathogenicity classification of the variants was based on American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: Nine members fulfilled diagnostic criteria for HCM with clinical characteristics, electrocardiographic, and echocardiographic findings. Two candidate variants in ACTC1 p.Asp26Asn (ACTC1-D26N) and MYBPC3 p.Arg215Cys (MYBPC3-R215C) were identified in patients. Only ACTC1-D26N strongly co-segregated with the HCM phenotype. Seven patients who harbored variant ACTC-D26N only were diagnosed with non-obstructive HCM, and four of these patients exhibited a triphasic left ventricular (LV) filling pattern. Two patients carrying both ACTC1-D26N and MYBPC3-R215C variants showed a higher LV outflow tract pressure gradient. Bioinformatics analysis revealed that the two variants were deleterious and highly conserved across species. According to ACMG guidelines, ACTC1-D26N is classified as a likely pathogenic mutation. The second variation MYBPC3-R215C may function as a genetic modifier, which remains uncertain here. CONCLUSIONS: Novel p.(Asp26Asn) mutation of ACTC1 was associated with HCM phenotype, and the penetrance is extremely high (∼81.8%) in adults. The second variation, MYBPC3-R215C may function as a genetic modifier, which remains uncertain here.