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.

Experience With and Awareness of Telemedicine Among Korean Outpatients During the COVID-19 Pandemic.

Introduction: Owing to the coronavirus disease 19 pandemic, the demand for telemedicine has increased. However, the awareness of and experience with telemedicine among the Korean population have not been investigated. Therefore, we examined Korean outpatients' experience with and awareness of telemedicine. Methods: From December 2020 to March 2021, we conducted a survey exploring the awareness of and experience with telemedicine of outpatients who were consecutively enrolled by family physicians from four hospitals. The participants completed questionnaires on sociodemographic characteristics and knowledge, experience, satisfaction, preference, and future considerations concerning telemedicine. We evaluated factors associated with satisfaction with telemedicine experiences using multivariate logistic regression analysis. Results: Among the 563 study participants, 364 participants had experience with telemedicine. More than 95% of the telemedicine visits were performed by telephone consultation, and the most common disease type for telemedicine visits was chronic diseases (67.5%). Overall, 82.4% of the participants were satisfied with telemedicine. More than 90% of the participants were satisfied with telemedicine in terms of saving time and money relative to hospital visits, no risk of infection, and convenience. According to the multivariate logistic regression analysis, adults aged ≥65 years (odds ratio [OR] 3.53, 95% confidence interval [CI] 1.44-8.68), residents of a metropolitan city (OR 6.8, 95% CI 1.41-32.55), and those with knowledge of telemedicine (OR 2.96, 95% CI 1.21-7.26) were more likely to be satisfied with their telemedicine experience, compared with their counterparts. For chronic diseases, participants with telemedicine experience were significantly more likely to prefer telemedicine for revisits, compared with those with no telemedicine experience. Nonetheless, most respondents recognized that telemedicine requires improvement. Conclusions: Most Korean outpatients showed high satisfaction with telemedicine. Telemedicine may be considered in various medical situations in the future. Therefore, building a practical system for telemedicine and changes in the medical environment are required.

End-of-life care needs for noncancer patients who want to die at home in South Korea.

AIM: The awareness for the need for end-of-life care has increased among noncancer patients. However, studies on the topic have rarely targeted the needs of noncancer patients who want to die at home. This study assessed the end-of-life care needs of noncancer patients who were receiving care and wanted to die at home. METHODS: A cross-sectional study design was used and involved 200 participants who were diagnosed as noncancer patients and receiving home care nursing. Data were collected on demographics, disease, Palliative Performance Scale (PPS) scores, and end-of-life care needs, in April and May, 2016. RESULTS: Among the six areas of care, "supporting fundamental needs" of patients required the most care, followed by "coordination among family or relatives." Multivariate analysis revealed that the duration of home care nursing held a significant association with end-of-life care needs. CONCLUSION: By reflecting on the comprehensive care needs of patients with chronic illnesses and including them in the care process, it will be possible to provide better quality palliative care to patients at home in the end-of-life stages.

Efficacy and Safety of On Demand Clomipramine for the Treatment of Premature Ejaculation: A Multicenter, Randomized, Double-Blind, Phase III Clinical Trial.

PURPOSE: The aim of the current trial was to assess the efficacy of on demand clomipramine 15 mg administered before sexual intercourse for the treatment of premature ejaculation. MATERIALS AND METHODS: A total of 159 patients at 5 centers in Korea were randomly assigned to 2 groups. The first group of 53 men received placebo and the second group of 106 received clomipramine 15 mg for 12 weeks. All patients were evaluated at the beginning of the study and every 4 weeks thereafter. Patients were instructed to ingest a tablet approximately 2 to 6 hours before sexual intercourse. Efficacy was assessed by scores on the IELT (Intravaginal Ejaculation Latency Time) and the PEDT (Premature Ejaculation Diagnostic Tool). RESULTS: Analyses of the IELT fold change in each group in the intent to treat population revealed that the IELT of the clomipramine 15 mg group was significantly increased 12 weeks after administration compared with the placebo group (mean ± SD 4.40 ± 5.29 vs 2.68 ± 2.03, p <0.05). The IELT fold change in the per protocol population also significantly differed between the clomipramine 15 mg group and the placebo group (mean 4.66 ± 5.64 vs 2.80 ± 2.19, p <0.05). There was a significant difference in the PEDT scores between the 2 groups (p <0.001). The most commonly reported adverse events were nausea in 15.7% of men and dizziness in 4.9%. Adverse events were mild to moderate in severity. CONCLUSIONS: The results of this multicenter, randomized, double-blind, placebo controlled, fixed dose clinical phase III study suggest that administering clomipramine 15 mg on demand to treat premature ejaculation is effective and safe.

The Definition of Past Tuberculosis Affects the Magnitude of Association between Pulmonary Tuberculosis and Respiratory Dysfunction: Korea National Health and Nutrition Examination Survey, 2008-2012.

Tuberculosis (TB) is associated with an increased risk of chronic lung impairment. The aim of this study was to compare the clinical characteristics and lung functions according to definition of past TB. We used the population-based, Korea National Health and Nutrition Examination Survey (KNHANES) (2008-2012) to analyze 13,522 subjects age 40 years or older who underwent spirometry and chest X-ray (CXR). Subjects with TB lesions on CXR (with or without a history of TB) were older, more likely to be male, ever smokers, and of low socioeconomic status than subjects with only a history of TB or without evidence of TB. Airflow obstruction (AFO) was associated with only a history of TB (odds ratio [OR] 1.53, 95% confidence interval [CI] 0.95-2.46), only TB lesion on CXR (OR 2.37, 95% CI 1.80-3.12), and both a history and TB lesions on CXR (OR 4.47, 95% CI 3.07-6.51) after adjustment for gender, age, body mass index, education, income, and smoking amount (P for trend < 0.001). Spirometric restriction was associated with only a history of TB (OR 1.29, 95% CI 0.80-2.08), only TB lesions on CXR (OR 2.03, 95% CI 1.49-2.76), and both a history and TB lesions on CXR (OR 2.65, 95% CI 1.74-4.05) after adjustment for the above variables (P for trend < 0.001). How to define past TB in population study affects the magnitude of association between past TB and respiratory dysfunction. Without considering TB lesions on CXR, the association between TB and respiratory dysfunction could be underestimated.

Relationship between breast-feeding and bone mineral density among Korean women in the 2010 Korea National Health and Nutrition Examination Survey.

Breast-feeding has the deleterious effect of hypoestrogenemia coupled with loss of calcium in the maternal bone mass. It is not clear whether changes in bone metabolism in lactating women lead to changes in maternal bone mineral density (BMD) over a longer period. The aim of the present study was to investigate the relationship between the duration of breast-feeding and BMD in healthy South Korean women. We analyzed data from the 2010 Korea National Health and Nutrition Examination Survey, a cross-sectional survey of Korean citizens. A total of 1342 women older than 19 years were selected for analysis. In postmenopausal women, the duration of breast-feeding per child was associated with low lumbar spine BMD after adjustment for age, body mass index, smoking, alcohol intake, physical activity, serum 25-hydroxyvitamin D level, and daily intake of calcium and calories (P < 0.05, P trend < 0.005). Prolonged breast-feeding for more than 1 year per child was associated with a deleterious effect on lumbar spine BMD compared with never breast-feeding or a shorter duration of breast-feeding (P < 0.05). These effects were not shown in premenopausal women or in femur BMD. In conclusion, the duration of breast-feeding per child is negatively correlated with lumbar spine BMD in postmenopausal women, but not in premenopausal women. Although the cause of the different results between postmenopausal and premenopausal women is not clear, our findings suggest that proper protective strategies should be recommended during prolonged breast-feeding to maintain bone health later in life.

Association between the duration of palliative care service and survival in terminal cancer patients.

PURPOSE: Preliminary studies of early palliative care showed improved quality of life, less medical cost, and better survival time. But, most terminal cancer patients tend to be referred to palliative care late. For the proper care of terminal cancer patients, it is necessary to refer to hospice and palliative care timely. The aim of this study is to analyze the effect of the duration of palliative care services on the survival in terminal cancer patients. METHODS: We reviewed 609 patients who had died from terminal cancer between January 2010 and December 2012. We analyzed correlations of age, first Palliative Performance Scale (PPS) level, duration of palliative care service, and survival time. The Cox proportional hazards regression model was used for both univariate and multivariate analyses of survival. RESULTS: Duration of palliative care services was significantly correlated with survival time. In univariate Cox regression analysis, age, and each group of duration of palliative care service showed significant associations with survival. Final multivariate Cox regression model retained four parameters as independent prognostic factors for survival (age HR = 0.99 (p = 0.002), 1∼10 days HR = 2.64 (p < 0.001), 11∼30 days HR = 2.43 (p < 0.001), 31∼90 days HR = 1.87 (p < 0.001)). CONCLUSIONS: Shorter duration of palliative care services showed poor prognostic factor. Timely referral system from the end of chemotherapy is warranted.

The associations of epicardial adipose tissue with coronary artery disease and coronary atherosclerosis.

Epicardial adipose tissue (EAT) is presumed to play an important role in the development of coronary artery disease (CAD). The purpose of our study was to examine the influence of EAT volume measured by cardiac CT on the severity and presence of CAD. A total of 209 subjects (114 normal subjects and 95 patients with CAD) underwent cardiac and abdominal computed tomography (CT) scan before diagnostic coronary angiography. Pixels with a threshold range of -190 to -30 Hounsfield units were identified as EAT. CAGE ≥ 20, CAGE ≥ 50, and modified Gensini index were used to define the extent and severity of CAD. While there was no significant difference in BMI and WC between the two groups, the mean EAT volume was higher in the CAD group than in the normal subjects (102.4 ± 41.87 cm(3) versus 125.36 ± 47.64 cm(3), P < 0.001). EAT was significantly associated with CAGE ≥ 20, CAGE ≥ 50, and Gensini score by linear regression analyses after adjusting for age, gender, smoking, and alcohol use. The severity of CAD increased linearly with each tertile increase in EAT volume (P for trend < 0.05). Similarly, the coronary artery calcium (CAC) score was also increased with each increase in EAT tertile (P = 0.002). In multivariate logistic regression models, EAT and VAT were significantly associated with the presence of CAD and CAC in age, gender, smoking, alcohol use, and BMI adjusted models. In conclusion, EAT volume measured by CT is associated with the presence and severity of CAD. EAT may give important information for risk evaluation in CAD.

Low Muscle Strength as Risk Factor for Non-Alcoholic Fatty Liver Disease in Different Metabolic Conditions.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) recently became a leading liver disease that threatens health worldwide. Low muscle strength, obesity, insulin resistance, and metabolic syndrome are recognized key factors for NAFLD. However, the impact of low muscle strength itself in different metabolic conditions has not been widely studied. METHODS: A cross-sectional analysis was performed of a sample of 5,427 participants from the 2019 Korea National Health and Nutrition Examination Survey. Relative handgrip strength (rHGS, defined as handgrip strength/body mass index) was used to assess muscle strength. The cut-off values for a low rHGS were 1.405 for men and 0.850 for women. NAFLD was diagnosed if the Hepatic Steatosis Index was >36. Participants were stratified according to insulin resistance, metabolic syndrome, and central obesity for the subgroup analyses. RESULTS: Complex sample multivariate logistic regression analysis revealed a significant association between low muscle strength and NAFLD after the adjustment for other confounders (odds ratio [OR], 1.92; P<0.001). In the insulin resistance, metabolic syndrome, and central obesity subgroups, a significant association between low muscle strength and NAFLD remained (OR, 1.66-4.19 depending on subgroup; all P<0.05), whereas it did not in the no central obesity group. CONCLUSION: This study demonstrated that low muscle strength is correlated with a risk of NAFLD. This relationship was independent of insulin resistance and metabolic syndrome but was dependent on the presence of central obesity.

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.

Efficacy and safety of diacerein and celecoxib combination therapy for knee osteoarthritis: A double-blind, randomized, placebo-controlled prospective study.

BACKGROUND: Osteoarthritis is a degenerative disease with a growing burden in South Korea. Corresponding drugs are commonly used for pain relief and joint function improvement. Specifically, symptomatic slow-acting drugs for osteoarthritis are frequently used, with diacerein being the most common symptomatic slow-acting drugs for osteoarthritis in South Korea. In this study, we evaluated the efficacy and safety of diacerein and celecoxib combination therapy in patients with osteoarthritis. METHODS: A total of 71 subjects were randomly assigned to group 1 (diacerein and celecoxib), 2 (diacerein and placebo), or 3 (celecoxib and placebo). The primary outcome measure was the change in the visual analog scale (VAS) score 12 weeks after treatment. RESULTS: The combination therapy group exhibited a significant decrease in the VAS score, alongside the other control monotherapy groups. Although there was no significant difference between the groups, the combination therapy group exhibited a greater decrease in the absolute value of the VAS score than the other groups. Four weeks after treatment, the combination therapy group showed significantly higher improvement in the stiffness and physical function categories of the Western Ontario and McMaster Universities Osteoarthritis Index than the other groups. Additionally, no serious adverse events occurred following combination therapy, with most adverse events being mild and resolving without specific treatment. CONCLUSIONS: Diacerein and celecoxib combination therapy is as safe and effective as corresponding monotherapies. A relatively early improvement in stiffness and physical function following treatment with this combination therapy indicates that physicians should consider this for the early-stage treatment of patients with symptomatic osteoarthritis.

Discussion on the Clinical Course of Adverse Effects after COVID-19 Vaccination: A Retrospective Analysis of Case Series in an Outpatient Department.

BACKGROUND: A total of 8,303 individuals (4.3%) with adverse reactions (n=191,860) after vaccination developed serious conditions or died. Such health developments could cause people not vaccinated yet or waiting for a booster shot to become fearful of the vaccination. METHODS: The 3-month (July-September 2021) clinical data of 41 patients from the family medicine department of a single medical center were analyzed retrospectively to determine risk factors and to investigate the clinical course to identify the cause of symptoms in detail. RESULTS: A significant number of older adults aged over 50 years reported experiencing general weakness (P=0.026) but fewer incidences of fever than patients aged 50 years or younger (P=0.011). Eighteen of the 41 patients were requested to visit more than twice or consult a specialist. In 14 patients, the symptoms were explained by other medical causes. CONCLUSION: The primary physician has a pivotal role in thoroughly evaluating patients who complain of adverse effects after vaccination, considering the broad multitude of symptoms and medical conditions presented. To thoroughly evaluate and appropriately advise patients with adverse reactions to their chosen vaccine, taking detailed medical history and nutritional counseling are required to identify possible underlying causes, resolve symptoms, and educate them on self-care and regarding vaccines.

Identification and validation of six acute myocardial infarction-associated variants, including a novel prognostic marker for cardiac mortality.

Background: Acute myocardial infarction (AMI) is one of the leading causes of death worldwide, and approximately half of AMI-related deaths occur before the affected individual reaches the hospital. The present study aimed to identify and validate genetic variants associated with AMI and their role as prognostic markers. Materials and methods: We conducted a replication study of 29 previously identified novel loci containing 85 genetic variants associated with early-onset AMI using a new independent set of 2,920 Koreans [88 patients with early- and 1,085 patients with late-onset AMI, who underwent percutaneous coronary intervention (PCI), and 1,747 healthy controls]. Results: Of the 85 previously reported early-onset variants, six were confirmed in our genome-wide association study with a false discovery rate of less than 0.05. Notably, rs12639023, a cis-eQTL located in the intergenic region between LINC02005 and CNTN3, significantly increased longitudinal cardiac mortality and recurrent AMI. CNTN3 is known to play a role in altering vascular permeability. Another variant, rs78631167, located upstream of PLAUR and known to function in fibrinolysis, was moderately replicated in this study. By surveying the nearby genomic region around rs78631167, we identified a significant novel locus (rs8109584) located 13 bp downstream of rs78631167. The present study showed that six of the early-onset variants of AMI are applicable to both early- and late-onset cases. Conclusion: Our results confirm markers that can potentially be utilized to predict, screen, prevent, and treat candidate patients with AMI and highlight the potential of rs12639023 as a prognostic marker for cardiac mortality in AMI.

Efficacy and safety of human placental extract solution on fatigue: a double-blind, randomized, placebo-controlled study.

Introduction. Fatigue is a common symptom, but only a few effective treatments are available. This study was conducted to assess the efficacy and safety of the human placental extract solution, which has been known to have a fatigue recovery effect. Methods. A total of 315 subjects were randomly assigned to three groups: group 1 (with Unicenta solution administration), group 2 (with exclusively human placental extract administration, excluding other ingredients from the Unicenta solution), and the placebo group. Subsequently, solutions were administered for four weeks. Results. The fatigue recovery rate was 71.00% in group 1, 71.72% in group 2, and 44.21% in the placebo group, which show statistically significant differences between the group 1 and the placebo group (P value = 0.0002), and between group 2 and the placebo group (P value = 0.0001). Conclusion. The human placental extract solution was effective in the improvement of fatigue.

Increasing Individual Target Glucose Levels to Prevent Hypoglycemia in Patients with Diabetes.

Hypoglycemia is one of the severe complications of diabetes. To prevent hypoglycemia, an emphasis is placed on maintaining an appropriate balance between nutrition, activity, and treatment, which can be achieved by the repetition of self-trials based on self-monitoring. Clinicians routinely focus on patients' contribution, including timely intake of an adequate amount of carbohydrates, physical activity, antidiabetic medication, and abstinence from alcohol. Recently, many guidelines have highlighted the importance of clinicians' factors and recommend individualized treatments according to lifestyle patterns and specific needs following the de-intensification of treatment. The optimal value of hemoglobin A1c (HbA1c) levels for blood glucose level regulation remains controversial among countries, but it generally does not exceed 8.0%. In populations that are at a risk of hypoglycemia, such as the older adults, it is advisable to adjust the target blood glucose level to less than 8.0%. Meanwhile, a blood glucose level of 7.0%-7.5% is generally recommended for healthy older adults. If the expected lifetime is shorter than 10 years or in patients with chronic kidney disease and severe cardiovascular disease, the HbA1c level target can be increased to 7.5%-8.0%. For even shorter lifetime expectancy, the target can be adjusted up to 8.0%-9.0%. To prevent hypoglycemia, the target blood glucose level needs to be adjusted, particularly in older adult patients. Ultimately, it is important to identify the maximum blood glucose levels that do not cause hypoglycemia and the minimum blood glucose levels that do not cause hyperglycemia-associated complications.

Exercise Strategies to Prevent Hypoglycemia in Patients with Diabetes.

The importance of adopting healthy exercise routines has been repeatedly emphasized to individuals with diabetes mellitus (DM). However, knowledge about the risk of exercise-induced hypoglycemia is limited. Regular exercise reduces and delays the onset of DM-related complications particularly in individuals who already have DM. However, an excessive exercise can lead to hypoglycemia. Excessive exercise in the evening can cause hypoglycemia while sleeping. Furthermore, if individuals with DM want to have a greater amount of exercise, the exercise duration rather than intensity must be increased. In weight resistance exercises, it is beneficial to first increase the number of repetitions, followed by the number of sets and gradually the weight of resistance. When performing intermittent high-intensity training within a short time period, hypoglycemia may develop for an extended period after exercise. In addition to adjusting exercise regimens, the medication doses must be modified accordingly. Delaying exercise, adjusting the number of snacks consumed prior to exercise, reducing insulin dose before exercise, and injecting insulin into the abdomen rather than the limbs prevent exercise-induced hypoglycemia prior to a spontaneous exercise. Ultimately, with personal knowledge on how to prevent hypoglycemia, the effects of exercise can be maximized in individuals with DM, and a healthy lifestyle can prevent future complications.

Identification of the most active interleukin-32 isoform.

Cytokines are crucial in host defence against pathogens such as bacteria, viruses, fungi and parasites. A newly described cytokine, interleukin-32 (IL-32), induces various proinflammatory cytokines (tumour necrosis factor-alpha, IL-1beta, IL-6) and chemokines in both human and mouse cells through the nuclear factor-kappaB and p38 mitogen-activated protein kinase inflammatory signal pathway. The IL-32 primarily acts on monocytic cells rather than T cells. In an attempt to isolate the IL-32 soluble receptor, we used an IL-32 ligand-affinity column to purify neutrophil proteinase 3, which is a serine proteinase involved in many inflammatory diseases. IL-32 has biological activity associated with Mycobacterium tuberculosis and chronic proinflammatory diseases such as rheumatoid arthritis. IL-32 is transcribed as six alternative splice variants and the biological activity of each individual isoform remains unknown. Here, we cloned the complementary DNA of the four IL-32 isoforms (alpha, beta, gamma and delta) that are the most representative IL-32 transcripts. To produce recombinant protein with a high yield, the amino acids of two cysteine residues were mutated to serine residues, because serine residues are not conserved among different species. The multi-step purified recombinant IL-32 isoform proteins were assessed for their biological activities with different cytokine assays. The gamma isoform of IL-32 was the most active, although all isoforms were biologically active. The present study will provide a specific target to neutralize endogenous IL-32, which may contribute to basic and clinical immunology.

Association of Lung Function with Serum 25-Hydroxyvitamin D Level according to the Presence of Past Pulmonary Tuberculosis in Korean Adults.

BACKGROUND: Vitamin D deficiency is associated with an increased risk of pulmonary tuberculosis (PTB) infection and the treatment outcome. The aim of this study was to examine the relationship between the serum 25-hydroxyvitamin D (25[OH]D) level and lung function in Korean adults according to whether or not there is a history of PTB. METHODS: The data for subjects aged 19 years or older from the Korea National Health and Nutrition Examination Survey 2008-2012 who underwent spirometry, chest radiography, and serum 25(OH)D level measurement were analyzed. RESULTS: Evidence of past PTB infection was found in 1,482 (9.6%) of 15,516 subjects. The serum 25(OH)D level was lower in the group with past PTB than in the non-PTB group (P=0.013). Respiratory dysfunction was more common in the past PTB group than in the non-PTB group (restrictive pattern, 14.0% vs. 9.6%; obstructive pattern, 29.6% vs. 8.2%; both P<0.001). After adjusting for age, sex, height, and season, the mean difference in forced expiratory volume in 1 second (FEV1) between the highest and lowest quartiles of 25(OH)D was 100.2 mL (standard error=49.3 mL, P for trend=0.049) in the past PTB group and 34.7 mL (standard error=13.6 mL, P=0.009) in the nonPTB group. CONCLUSION: FEV1 tended to increase as the vitamin D quartile increased in both study groups. This relationship was more pronounced in subjects with a history of PTB. A higher serum 25(OH)D level might be beneficial in preserving lung function after PTB infection.

Tolerability and adequate therapeutic dosage of oral clomipramine for the treatment of premature ejaculation: A randomized, double-blind, placebo-controlled, fixed-dose, parallel-grouped clinical study.

To evaluate the adequate therapeutic dosage of clomipramine 15 mg/day and clomipramine 30 mg/day in male patients with premature ejaculation (PE), this study enrolled men aged 20-65 years who met diagnostic criteria for PE including Intravaginal Ejaculation Latency Time (IELT) less than 2 min for at least 75% of their sexual intercourses. Subjects received placebo, clomipramine 15 mg, or clomipramine 30 mg prn (2~6 h before intercourse) for 4 weeks. Efficacy was assessed using fold change, percentile change, and mean change of IELT, as well as Drug Coitus Interval Time (DCIT). A total of 101 patients were randomized into the placebo group, clomipramine 15 mg group, and clomipramine 30 mg group. Analyses of fold changes of IELT in each group revealed that the IELT of both the clomipramine 15 mg group and clomipramine 30 mg group was significantly increased 4 weeks after administration than the placebo group. Adverse events were reported by 11.76, 32.35, and 57.57% of patients in the placebo group, clomipramine 15 mg group, and clomipramine 30 mg group, respectively. Most common adverse events in the clomipramine treatment groups were gastrointestinal disorders and psychiatric disorders of mild to moderate severity. On-demand regimen of clomipramine 15 mg resulted in a significant improvement in IELT and was superior to a regimen of clomipramine 30 mg in terms of risk-to-benefit ratio.

CD44-Targeting PLGA Nanoparticles Incorporating Paclitaxel and FAK siRNA Overcome Chemoresistance in Epithelial Ovarian Cancer.

Chemotherapy is commonly used in the treatment of ovarian cancer, yet most ovarian cancers harbor inherent resistance or develop acquired resistance. Therefore, novel therapeutic approaches to overcome chemoresistance are required. In this study, we developed a hyaluronic acid-labeled poly(d,l-lactide-co-glycolide) nanoparticle (HA-PLGA-NP) encapsulating both paclitaxel (PTX) and focal adhesion kinase (FAK) siRNA as a selective delivery system against chemoresistant ovarian cancer. The mean size and zeta potential of the HA-PLGA-NP were 220 nm and -7.3 mV, respectively. Incorporation efficiencies for PTX and FAK siRNA in the HA-PLGA-NPs were 77% and 85%, respectively. HA-PLGA-NP showed higher binding efficiency for CD44-positive tumor cells as compared with CD44-negative cells. HA-PLGA (PTX+FAK siRNA)-NP caused increased cytotoxicity and apoptosis in drug-resistant tumor cells. Treatment of human epithelial ovarian cancer tumor models HeyA8-MDR (P < 0.001) and SKOV3-TR (P < 0.001) with HA-PLGA (PTX+FAK siRNA)-NP resulted in significant inhibition of tumor growth. Moreover, in a drug-resistant, patient-derived xenograft (PDX) model, HA-PLGA (PTX+FAK siRNA)-NP significantly inhibited tumor growth compared with PTX alone (P < 0.002). Taken together, HA-PLGA-NP acts as an effective and selective delivery system for both the chemotherapeutic and the siRNA in order to overcome chemoresistance in ovarian carcinoma.Significance: These findings demonstrate the efficacy of a novel, selective, two-in-one delivery system to overcome chemoresistance in epithelial ovarian cancer. Cancer Res; 78(21); 6247-56. ©2018 AACR.