Familial risk for endometriosis and its interaction with smoking, age at menarche and body mass index: a population-based cohort study among siblings.

OBJECTIVE: To quantify familial risk of endometriosis among full siblings and examine interactions between family history and smoking, age at menarche or body mass index (BMI). DESIGN, SETTING AND POPULATION: Population-based nationwide cohort study. METHODS: Using data from the Korean National Health Insurance and Screening Programme databases on kinship, healthcare utilisation, lifestyle and anthropometrics, we identified 2 109 288 women with full siblings and their environmental risk factors from 2002 to 2018. Familial risks were estimated using Cox proportional-hazards models, represented as incidence risk ratios (IRR) with 95% CI. Interaction between family history and smoking, age at menarche or BMI were assessed on an additive scale. MAIN OUTCOME MEASURES: IRR of endometriosis among women with and without affected siblings. RESULTS: From 19 195 women with affected siblings, 1126 developed endometriosis with an incidence of 35.45/10 000 person-years. Familial risk of endometriosis with versus without affected siblings was increased to IRR 2.75 (95% CI 2.25-3.36), and the highest risk was with affected twins (IRR 6.98; 95% CI 4.19-11.62). Women with both a family history and either smoking, early menarche or low BMI had a significantly higher risk of endometriosis compared with the general population and can be regarded as a high-risk group, the IRRs were 4.28 (95% CI 2.43-7.55), 3.47 (95% CI 2.82-4.26) and 3.09 (95% CI 2.68-3.56), respectively. Substantial effect modification of the associations was noted by smoking and early menarche, as their combined risk with family history exceeded the sum of their individual risks, which was also statistically significant. CONCLUSION: Genetic factors are the primary contributor to the familial aggregation of endometriosis. Significant gene-environment interaction exists between family history and smoking or early menarche. TWEETABLE ABSTRACT: Significant gene-environment interaction exists between family history of endometriosis and smoking or early menarche.

The incidence and survival of melanoma and nonmelanoma skin cancer in patients with vitiligo: a nationwide population-based matched cohort study in Korea.

BACKGROUND: While studies report a lower incidence of skin cancer in white patients with vitiligo compared with controls, the skin cancer incidence in Asian patients with vitiligo is unknown. OBJECTIVES: To quantify the incidence of melanoma and nonmelanoma skin cancer (NMSC) in Korean patients with vitiligo and compare it with matched nonvitiligo controls. METHODS: A retrospective matched cohort study was performed with 131 245 incident vitiligo cases and 2 624 900 age- and sex-matched (1 : 20) controls at index date, who were selected from the Korean National Health Insurance database between January 2005 and December 2017. Stratified Cox proportional hazards regression (stratified by sex, birth year and index year) was used to calculate the hazard ratio (HR) of skin cancer in patients with vitiligo. RESULTS: Patients with vitiligo were followed up for a mean duration of 6·34 years compared with a follow-up period of 6·27 years for matched controls. Ultraviolet (UV) treatment-adjusted HR for melanoma in patients with vitiligo was 3·32 [95% confidence interval (CI) 2·29-4·81] and 1·29 (95% CI 1·06-1·56) for NMSC. The HRs for melanoma and NMSC in the vitiligo population without a history of UV treatment were 3·37 (95% CI 2·32-4·90) and 1·35 (95% CI 1·11-1·64), respectively. CONCLUSIONS: In contrast to white patients with vitiligo, the risk of skin cancer was increased in the Korean vitiligo population. However, it is noteworthy that the skin cancer incidence in Korean patients with vitiligo was lower than that of their white counterparts. Owing to possible ethnic differences in the susceptibility to skin cancer, skin cancer surveillance in the vitiligo population may be adjusted for race. What's already known about this topic? Prior studies have reported a lower incidence of melanoma and nonmelanoma skin cancer (NMSC) in white patients with vitiligo compared with nonvitiligo controls. The skin cancer incidence in Asian patients with vitiligo is unknown. What does this study add? In contrast to white patients, the risk of both melanoma and NMSC was increased in Korean patients with vitiligo compared with controls. Owing to possible ethnic differences in susceptibility to skin cancer, skin cancer surveillance in the vitiligo population should be adjusted for race.

Incidence, survival, and risk of cardiovascular events in adult inflammatory myopathies in South Korea: a nationwide population-based study.

OBJECTIVE: Epidemiological studies on inflammatory myopathies (IMs) show widely variable results, and studies on Asians are lacking. Despite emerging interest in the cardiovascular disease (CVD) risk associated with IMs, the prevalence of CVD in IM patients and its impact on mortality remain unclear. We conducted a nationwide, population-based study on the incidence, mortality, and associated major CVD events of IMs in the Republic of Korea over 11 years. METHOD: Using the nationwide, population-based National Health Insurance claims database and the Rare Intractable Disease registration programme, we estimated incidence, mortality, and CVD occurrence. Survival was examined using the Kaplan-Meier method. Mortality rate in IMs with CVD was analysed by Cox proportional hazards regression. RESULTS: There were 3014 incident cases, 640 of whom died during the study period. The mean annual incidence was 7.16/106. Dermatomyositis (DM) and polymyositis (PM) had 5 year survival rates of 76.8% and 79.3%, respectively. Cardiovascular events occurred in 155 patients and 40.6% of IM patients with CVD died. Acute myocardial infarction in men had the highest risk of any CVD event in both DM [standardized incidence ratio (SIR) 4.2, 95% confidence interval (95% CI) 2.4-7.2] and PM (SIR 3.5, 95% CI 1.8-7.0). Haemorrhagic stroke had the highest hazard ratio (HR) in both DM (HR 2.31, 95% CI 1.13-4.70) and PM patients (HR 2.10, 95% CI 1.03-4.27) compared with the general population with CVD. CONCLUSION: We found persistently low incidence, poor survival, and high major CVD incidence in IMs, and increased mortality in IMs with CVD.

Effects of Per-diem payment on the duration of hospitalization and medical expenses according to the palliative care demonstration project in Korea.

OBJECTIVES: The aim of this study was to examine the impacts of a government-directed palliative care demonstration (PCD) project, Per-diem Payment System (PDPS), on length of stay (LOS), hospital costs, resource usage and healthcare quality during the searched period from January in 2009 to December in 2010. STUDY DESIGN: A retrospective claim data review. METHODS: Individuals who had been eligible for the palliative care payment policy, PDPS, during 2 years (from 2009 to 2010) were assigned to the case group including seven hospitals (n = 3117). Those (seven hospitals) who were not come eligible for the palliative care payment policy were assigned to the control group (n = 2347) with fee for service. The data used in this study were electronically submitted requests of payment to the Health Insurance Review Agency during the period January 2009 to December 2010. RESULTS: After the PCD project, the length of stay for palliative patients with cancer diseases decreased by 2.56% (ß = -0.026; p-value = 0.0001) among patients hospitalized in a PCD project compared with patients hospitalized in seven hospitals that was not designed as a PCD project. Compared with costs before the PCD project, costs decreased by 0.76% (ß = 0.013; p-value = 0.0001). CONCLUSIONS: We provided evidence regarding the change in the societal burden due to palliative care. Although there was a reduction of direct medical costs reported in limited number of hospitals, in the long term, we can anticipate an expanding impact on medical costs in all palliative hospitals. Copyright © 2016 John Wiley & Sons, Ltd.

Half-dose ganciclovir preemptive treatment of cytomegalovirus infection after pediatric allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Ganciclovir (GCV) has been widely used as preemptive therapy after hematopoietic stem cell transplantation (HSCT), although bone marrow suppression is a known accompaniment, with secondary infection or bleeding as potential complications. Our aim was to evaluate clinical outcomes in pediatric patients with low cytomegalovirus (CMV) antigenemia levels using half the dosage of GCV generally given preemptively. METHODS: Patients received half doses of intravenous GCV (5 mg/kg once daily, 6 days/week) at CMV antigenemia levels <10/200,000 cells. At higher levels of CMV antigenemia, conventional doses of GCV (5 mg/kg every 12 h) were administered. RESULTS: A total of 130 patients were evaluated, detecting CMV antigenemia in 87 (66.9%). Of these patients, 74 (85.1%) were treated preemptively with half-dose GCV, which proved effective as sole therapy in 51 (68.9%). CMV retinitis developed in 4 patients, 2 of whom initially were given half-dose GCV. All infections resolved successfully, with no CMV-related deaths. CMV seropositivity in recipients was the only significant risk factor for positive CMV antigenemia (hazard ratio [HR] = 10.05, P = 0.046). Compared with half-dose GCV administration, conventional GCV dosing resulted in a higher rate of severe neutropenia, defined as absolute neutrophil count <0.5 × 10(9) /L (HR = 4.30, P = 0.015). CONCLUSION: Half-dose GCV therapy at CMV antigenemia levels <10/200,000 cells is an effective and safe means of preemptively treating pediatric CMV infection after HSCT.

Expression of cubilin in mouse testes and Leydig cells.

Cubilin (cubn) is a receptor for vitamins and various protein ligands. Cubn lacks a transmembrane domain but anchors to apical membranes by forming complexes with Amnionless or Megalin. In an effort to better understand the uptake of nutrients in testis, we analysed cubn expression in the developing mice testes. In testes, cubn mRNA increased from birth to adulthood. In the inter-stitium and isolated seminiferous tubules, neonatal increase in cubn mRNA until 14 days post-partum (pp) was followed by a marked increase at puberty (28 days pp). Cubn was found in the gonocytes, spermatogonia, spermatocytes and spermatids in the developing testes. In adult testes, strong Cubn immunoreactivity was found in the elongating spermatids, suggesting the role of Cubn in endocytosis during early spermiogenesis. In Sertoli cells and peritubular cells, Cubn immunoreactivity was weak throughout the testis development. In the inter-stitium, Cubn immunoreactivity was found in foetal Leydig cells, was weak to negligible in the stem cells and progenitor Leydig cells and was strong in immature and adult Leydig cells, demonstrating a positive association between Cubn and steroidogenic activity of Leydig cells. Collectively, these results suggest that Cubn may participate in the endocytotic uptake of nutrients in germ cells and somatic cells, supporting the spermatogenesis and steroidogenesis in mouse testes.

Percutaneous radiofrequency ablation for symptomatic uterine leiomyomas: a systematic review and meta-analysis.

PURPOSE: To evaluate the efficacy and safety of percutaneous radiofrequency ablation (RFA) in the treatment of uterine leiomyomas. MATERIALS AND METHODS: Medline, Embase, and Cochrane databases were searched through August 2014 for all relevant studies on RFA for uterine leiomyomas. The efficacy and safety of RFA were assessed using the outcome measures of tumor volume, symptom severity score, health-related quality of life (HRQL) score, procedure-related complications, and reintervention. The authors calculated pooled event rates with 95% confidence intervals using random-effects model to assess the effects of RFA. RESULTS: Eight observational studies were identified as eligible for inclusion in this meta-analysis and included 370 patients. All analyzed outcomes showed statistically significant improvements from baseline to final follow-up. Twenty-seven complications were identified and five of them qualified as major complications. Five patients required reintervention after RFA. CONCLUSIONS: Percutaneous RFA is an effective and safe treatment for patients with uterine leiomyomas.

Nodular Fasciitis of the Breast: A Case and Literature Review.

Nodular fasciitis is a benign fibroblastic proliferation in soft tissue that is most commonly found in the upper extremities, trunk, head, and neck region. Its occurrence in the breast has been rarely reported. The most characteristic features are the sudden appearance and rapid growth of a palpable lesion. Nodular fasciitis can clinically, radiologically, and histopathologically mimic a breast carcinoma. We present a case of nodular fasciitis of the breast and a review of the relevant literature.

Role of second-look ultrasound examinations for MR-detected lesions in patients with breast cancer.

PURPOSE: To assess the clinical value of second-look ultrasound (US) examination for the evaluation of additional enhancing lesions detected on magnetic resonance (MR) imaging. MATERIALS AND METHODS: Between May 2008 and February 2011, 794 consecutive patients with histologically confirmed breast cancer underwent breast MR imaging. We included 101 patients with 132 additional enhancing breast lesions detected on MR imaging who underwent second-look US.  The imaging features and lesion category according to the Breast Imaging and Reporting and Data System (BI-RADS) were assessed with MR and US imaging, respectively. RESULTS: According to the BI-RADS system, 67 lesions (50.8 %) were classified as category 0, 33 lesions (25.0 %) as category 3, and 32 lesions (24.2 %) as category 4. Of the 67 indeterminate lesions on MR imaging, 34 (50.7 %) were demonstrated on second-look US. 11 of these 34 lesions showed suspicious sonographic features, including 1 lesion that showed malignancy (9.1 %, 1/11). Most of the suspicious lesions on MR imaging (26 of 32 BI-RADS category 4 lesions, 81.3 %) were demonstrated on second-look US, and 17 were malignant (65.4 %, 17/26). Of the 6 BI-RADS category 4 lesions without sonographic correlation, 1 was malignant (16.7 %, 1/6). CONCLUSION: Second-look US examination was useful for evaluating MR-detected lesions in patients with breast cancer.

Effect of neoadjuvant chemotherapy on postoperative morbidity and mortality in patients with locally advanced gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy has been shown to improve the rate of complete (R0) resection and downstaging in patients with localized gastric cancer. There are few reports, however, regarding its impact on postoperative morbidity and mortality. The aims of this study were to analyse complication and mortality rates after neoadjuvant chemotherapy using a modified regimen of folinic acid, 5-fluorouracil and oxaliplatin (mFOLFOX6) for locally advanced gastric cancer (AGC), compared with rates in patients who underwent surgery without neoadjuvant chemotherapy. METHODS: Data were collected from patients with AGC enrolled in a phase II trial of four cycles of neoadjuvant mFOLFOX6 followed by surgery, between January 2005 and June 2008 at two of three institutions, and compared with those from a cohort of patients with AGC who underwent surgery alone at one of the institutions in 2006. RESULTS: Among 51 patients who received neoadjuvant chemotherapy, there were no deaths and a morbidity rate of 24 per cent after surgery. Comparison of 48 patients in one institution who received neoadjuvant chemotherapy with 92 patients who had surgery alone in the same institution showed no increase in postoperative morbidity (23 versus 29 per cent; P = 0·417). Combined resection was the only risk factor for postoperative morbidity after neoadjuvant chemotherapy. CONCLUSION: Neoadjuvant chemotherapy with mFOLFOX is a safe treatment for patients with localized AGC, and does not increase postoperative morbidity or mortality.

An excess of cosmic ray electrons at energies of 300-800 GeV.

Galactic cosmic rays consist of protons, electrons and ions, most of which are believed to be accelerated to relativistic speeds in supernova remnants. All components of the cosmic rays show an intensity that decreases as a power law with increasing energy (for example as E(-2.7)). Electrons in particular lose energy rapidly through synchrotron and inverse Compton processes, resulting in a relatively short lifetime (about 10(5) years) and a rapidly falling intensity, which raises the possibility of seeing the contribution from individual nearby sources (less than one kiloparsec away). Here we report an excess of galactic cosmic-ray electrons at energies of approximately 300-800 GeV, which indicates a nearby source of energetic electrons. Such a source could be an unseen astrophysical object (such as a pulsar or micro-quasar) that accelerates electrons to those energies, or the electrons could arise from the annihilation of dark matter particles (such as a Kaluza-Klein particle with a mass of about 620 GeV).

Maintenance Crude Protein Requirement of Penned Female Korean Spotted Deer (Cervus nippon).

This study was conducted to evaluate the protein requirement for maintenance of 2-year-old female Korean spotted deer. In the course of the experiment, each of three hand-reared female spotted deer was fed three diets that were iso-calorically formulated to contain low (approximately 7%), medium (12%), and high (17%) levels of crude protein (CP). Each of six trials included a 5-day transition, a 10-day preliminary, and a 7-day collection period. Dietary protein levels affected the apparent digestibility of CP (p<0.05) but not the apparent digestibility of dry matter, organic matter, or acid detergent fiber. All of the deer showed a positive CP balance on all of the diets. The maintenance CP requirement estimated by regression analysis was 4.17 g/kg metabolic body weight (W(0.75))·d. The maintenance digestible CP requirement was 1.42 g/kg W(0.75)·d. The metabolic fecal CP was 1.95 g/kg W(0.75)·d. The blood urea nitrogen of spotted deer increased (p<0.05) as the dietary protein levels increased.

Multi-ancestry Genome-Wide Association Study of Early Childhood Caries.

Early childhood caries (ECC) is the most common non-communicable childhood disease. It is an important health problem with known environmental and social/behavioral influences that lacks evidence for specific associated genetic risk loci. To address this knowledge gap, we conducted a genome-wide association study of ECC in a multi-ancestry population of U.S. preschool-age children (n=6,103) participating in a community-based epidemiologic study of early childhood oral health. Calibrated examiners used ICDAS criteria to measure ECC with the primary trait using the dmfs index with decay classified as macroscopic enamel loss (ICDAS ≥3). We estimated heritability, concordance rates, and conducted genome-wide association analyses to estimate overall genetic effects; the effects stratified by sex, household water fluoride, and dietary sugar; and leveraged the combined gene/gene-environment effects using the 2-degree-of-freedom (2df) joint test. The common genetic variants explained 24% of the phenotypic variance (heritability) of the primary ECC trait and the concordance rate was higher with a higher degree of relatedness. We identified 21 novel non-overlapping genome-wide significant loci for ECC. Two loci, namely RP11-856F16 . 2 (rs74606067) and SLC41A3 (rs71327750) showed evidence of association with dental caries in external cohorts, namely the GLIDE consortium adult cohort (n=∼487,000) and the GLIDE pediatric cohort (n=19,000), respectively. The gene-based tests identified TAAR6 as a genome-wide significant gene. Implicated genes have relevant biological functions including roles in tooth development and taste. These novel associations expand the genomics knowledge base for this common childhood disease and underscore the importance of accounting for sex and pertinent environmental exposures in genetic investigations of oral health.

Fucosyl neoglycoprotein binds to mouse epididymal spermatozoa and inhibits sperm binding to the egg zona pellucida.

Glycan epitopes of cellular glycoconjugates act as versatile biochemical signals, and this sugar coding plays an important role in cell-to-cell recognition processes. In this study, our aims were to determine the distribution of sperm receptors with activity for fucosyl- and galactosyl glycans and to address whether monosugar neoglycoproteins functionally mimic the binding between zona pellucida (ZP) glycoproteins and spermatozoa. In mouse epididymal spermatozoa with intact acrosomes, fucopyranosyl bovine serum albumin (BSA-Fuc) bound to the segment of the acrosome, the equatorial segment, and the postacrosome region of the sperm head. Galactosyl BSA (BSA-Gal) binding activity was similar to that of BSA-Fuc, but was weaker. In acrosome-reacted spermatozoa treated with the Ca(2+) ionophore A23187, BSA-zuc binding was lost in the apical segment of the acrosome but remained in the equatorial segment and postacrosome regions. BSA-Gal binding to the equatorial region was increased. In the presence of 2.5 µg ml(-1) BSA-Fuc, in vitro sperm-ZP binding was significantly decreased, indicating that fucosyl BSA functionally mimics ZP glycoproteins during sperm-egg ZP interactions. At the same concentration, BSA-Gal was not effective. Fucosyl BSA that efficiently inhibited the sperm-ZP binding can mimic the ZP glycoconjugate and has potential for use as a sperm fertility control agent in mouse.

Genetic variants of AICDA/CASP14 associated with childhood brain tumor.

We conducted a hospital-based case-control study in Korea to investigate whether apoptosis- and cell cycle control-related genes are associated with childhood brain tumor. Incident brain tumor cases (N = 70) and non-cancer controls (N = 140), frequency-matched by age and gender, were selected from 3 teaching hospitals in Seoul between 2003 and 2006. Tag single nucleotide polymorphisms (SNPs) (N = 297) in 30 genes related to apoptosis and cell cycle control were selected using a pairwise linkage-disequilibrium-based algorithm. Five tag SNPs in 2 genes (AICDA and CASP14) remained significant after adjusted multiple tests. The most significant association with childhood brain tumor risk was for IVS1-401G>C in the AICDA gene [odds ratio (OR) = 2.8; 95% confidence interval (95%CI) = 1.25-6.46]; the polymorphism *9276A>C of CASP14 was associated with decreased brain tumor risk (OR = 0.4; 95%CI = 0.19-0.95). We concluded that genetic polymorphisms in AICDA and CASP14 are associated with risk for brain tumor in Korean children.

Comparison of sentinel lymph node biopsy and elective neck dissection for early oral cavity squamous cell carcinoma patients with clinically node-negative necks: systematic review and meta-analysis.

OBJECTIVE: This study aimed to compare the prognostic utility of sentinel node biopsy and elective neck dissection in early stage clinically node-negative oral cavity squamous cell carcinoma patients. METHOD: PubMed, Scopus, Embase, Web of Science and Cochrane Library databases were searched up to March 2022. Hazard ratios, Kaplan-Meier curves, p-values and survival outcomes were extracted. RESULTS: Twelve studies involving 10 583 patients were included. No significant differences in overall survival between sentinel node biopsy and elective neck dissection groups were found. Heterogeneity was not detected in pooled overall survival, disease-free survival and disease-specific survival analyses (all I2 less than 50). In subgroup analyses by follow-up period, sentinel node biopsy and elective neck dissection had similar prognostic value. CONCLUSION: Sentinel node biopsy might be a valuable alternative to elective neck dissection for the management of early stage clinically node-negative oral cavity squamous cell carcinoma.

Serum biomarker panels for the diagnosis of gastric adenocarcinoma.

BACKGROUND: Currently, serum biomarkers, which are sufficiently sensitive and specific for early detection and risk classification of gastric adenocarcinoma do not exist. Therefore, this study identified a panel of serum biomarkers for the diagnosis of gastric adenocarcinoma. METHODS: A 29-plex array platform with 29 biomarkers, consisting of 11 proteins discovered through proteomics and 18 previously known to be cancer-associated, was constructed. A test/training set consisting of 120 gastric adenocarcinoma and 120 control samples were examined. After 13 proteins were selected as candidate biomarkers, multivariate classification analyses were used to identify algorithms for diagnostic biomarker combinations. These algorithms were independently validated using a set of 95 gastric adenocarcinoma and 51 control samples. RESULTS: Epidermal growth factor receptor (EGFR), pro-apolipoprotein A1 (proApoA1), apolipoprotein A1, transthyretin (TTR), regulated upon activation, normally T-expressed and presumably secreted (RANTES), D-dimer, vitronectin (VN), interleukin-6, α-2 macroglobulin, C-reactive protein and plasminogen activator inhibitor-1 were selected as classifiers in the two algorithms. These algorithms differentiated between the majority of gastric adenocarcinoma and control serum samples in the training/test set with high accuracy (>88%). These algorithms also accurately classified in the validation set (>85%). CONCLUSION: Two panels of combinatorial biomarkers, including EGFR, TTR, RANTES, and VN, are developed, which are less invasive method for the diagnosis of gastric adenocarcinoma. They could supplement clinical gastroscopic evaluation of symptomatic patients to enhance diagnostic accuracy.

A gene-specific primer extension and liquid bead array system for killer-cell immunoglobulin-like receptor genotyping.

A simple and accurate method for killer-cell immunoglobulin-like receptor (KIR) genotyping is developed using KIR gene-specific primer extension (GSPE) followed by bead array hybridization (GSPE method). After amplification of exons 4, 5, and 9, KIR GSPE and bead array hybridization were performed to verify the presence or absence of 16 KIR subfamilies. GSPE method was validated with natural killer/KIR reference panel I consisting of 48 cell types provided by 13th International Histocompatibility Working Group (IHWG) and genomic DNA from 17 peripheral blood cells, 8 cell lines, and 8 buccal cells. The results of reference panel from GSPE method were 100% concordant with the IHWG reference typing information. All genomic DNAs except reference panel were typed for KIR genes with sequence-specific primer methods and showed 100% identical typing results using this novel system. In addition, GSPE method can obtain results in 8 h from DNA with 10 ng genomic DNA in a 96-well-based assay format.