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Despite substantial advances in disease genetics, studies to date have largely focused on individuals of European descent. This limits further discoveries of novel functional genetic variants in other ethnic groups. To alleviate the paucity of East Asian population genome resources, we established the Korean Variant Archive 2 (KOVA 2), which is composed of 1896 whole-genome sequences and 3409 whole-exome sequences from healthy individuals of Korean ethnicity. This is the largest genome database from the ethnic Korean population to date, surpassing the 1909 Korean individuals deposited in gnomAD. The variants in KOVA 2 displayed all the known genetic features of those from previous genome databases, and we compiled data from Korean-specific runs of homozygosity, positively selected intervals, and structural variants. In doing so, we found loci, such as the loci ofADH1A/1BandUHRF1BP1, that are strongly selected in the Korean population relative to other East Asian populations. Our analysis of allele ages revealed a correlation between variant functionality and evolutionary age. The data can be browsed and downloaded from a public website (https://www.kobic.re.kr/kova/). We anticipate that KOVA 2 will serve as a valuable resource for genetic studies involving East Asian populations.

Currently there is no dedicated instrument for measuring nursing students' beliefs and attitudes about learning clinical skills in the service-learning (SL) environment. The National League for Nursing Student Satisfaction and Self-Confidence in Learning Scale (SCLS) was adapted as an SL assessment and administered to students in their final semester of a prelicensure baccalaureate program. Findings from this psychometric evaluation indicate that the SCLS is a reliable instrument for measuring student self-confidence in learning. Establishment of this tool provides evidence to ensure that judgments made about SL educational practices in clinical nursing courses are beneficial and credible.

Background Pulmonary carcinoids are rare neoplasms, accounting for approximately 1%–2% of all lung malignancies. A retrospective analysis was undertaken of all patients who underwent surgical resection of pulmonary carcinoid tumours across multiple institutions in Melbourne, Australia. Methods From May 2000 through April 2020, 241 patients who underwent surgical resection of pulmonary carcinoid tumours were retrospectively reviewed. Patient demographics, pathologic data, and long-term outcomes were recorded. Results Median age was 57.7 years and the majority of patients were female (58.9% vs. 41.1%). Typical carcinoid was present in 77.1%. Histological subtype was associated with several factors. Atypical carcinoid was more likely to have larger tumour size and nodal involvement. Overall survival for typical carcinoid at 5, 10, and 15 years was 98%, 95%, and 84%, and for atypical carcinoid was 88%, 82%, and 62%, respectively. Histological subtype and age were found to be independent predictors of overall survival, with worse outcomes for atypical and those above 60 years of age. Disease-free survival was related to sublobar resection (p Conclusion Excellent long-term outcomes can be achieved following surgical resection of pulmonary carcinoids. Atypical histology and lymph node involvement are significant prognostic factors, and sublobar resection should not be considered in patients with either of the above features. Typical carcinoid tumour without nodal involvement may be appropriate for sublobar resection. Typical and atypical carcinoid tumours should be considered distinct disease entities, and as such treated accordingly.

Even without direct evidence of God’s existence, about half of the world’s population believes in God. Although previous research has found that people arrive at such beliefs intuitively instead of analytically, relatively little research has aimed to understand what experiences encourage or legitimate theistic belief systems. Using cross-cultural correlational and experimental methods, we investigated whether the experience of inspiration encourages a belief in God. Participants who dispositionally experience more inspiration, were randomly assigned to relive or have an inspirational experience, or reported such experiences to be more inspirational all showed stronger belief in God. These effects were specific to inspiration (instead of adjacent affective experiences) and a belief in God (instead of other empirically unverifiable claims). Being inspired by someone or something (but not inspired to do something) offers a spiritually transcendent experience that elevates belief in God, in part because it makes people feel connected to something beyond themselves.

AimsGenome-wide association studies have shown an increased risk of type-2-diabetes (T2DM) in patients who carry single nucleotide polymorphisms in several genes. We investigated whether the same gene loci confer a risk for gestational diabetes mellitus (GDM) in women from Hawaii, and in particular, Pacific Islander and Filipino populations.MethodsBlood was collected from 291 women with GDM and 734 matched non-diabetic controls (Pacific Islanders: 71 GDM, 197 non-diabetic controls; Filipinos: 162 GDM, 395 controls; Japanese: 58 GDM, 142 controls). Maternal DNA was used to genotype and show allele frequencies of 25 different SNPs mapped to 18 different loci.ResultsAfter adjusting for age, BMI, parity and gravidity by multivariable logistic regression, several SNPs showed significant associations with GDM and were ethnicity specific. In particular, SNPs rs1113132 (EXT2), rs1111875 (HHEX), rs2237892 (KCNQ1), rs2237895 (KCNQ1), rs10830963 (MTNR1B) and rs13266634 (SLC30A8) showed significant associations with GDM in Filipinos. For Japanese, SNPs rs4402960 (IGFBP2) and rs2237892 (KCNQ1) were significantly associated with GDM. For Pacific Islanders, SNPs rs10830963 (MTNR1B) and rs13266634 (SLC30A8) showed significant associations with GDM. Individually, none of the SNPs showed a consistent association with GDM across all three investigated ethnicities.ConclusionSeveral SNPs associated with T2DM are found to confer increased risk for GDM in a multiethnic cohort in Hawaii.

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As planned home births increase, emerging evidence on the perinatal outcomes of newborns who were planned hospital births versus planned home births has been inconsistent, and a growing number of states have attempted to legislate community births. We sought to determine whether an association exists between neonatal hypoxic ischemic encephalopathy (HIE), a complication of ischemic birth injury, and planned location of birth.A case-control study design was used to compare data from neonates with HIE obtained from electronic health records at Kapiolani Medical Center for Women and Children in Honolulu, Hawaii, with data from neonates without HIE obtained from Hawaii state birth certificate data. A penalized backward stepwise logistic regression was performed to control for confounders.We included 164 neonates with HIE and 656 neonates in the control group. The odds of having been a planned home birth were 2.77 times higher in neonates with HIE compared with those without HIE (95% CI, 1.05-6.87). After adjusting for insurance, mode of birth, meconium fluid, maternal hypertension, and chorioamnionitis, neonates with HIE were still more likely to have been a planned home birth compared with those without HIE (odds ratio, 11.56; 95% CI, 1.37-118.77).Neonates with HIE were more likely to have been a planned home birth compared with neonates without HIE.

The natural history of a systemic right ventricle after an atrial switch procedure has yet to be fully characterised. We describe the case of the longest surviving patient at our institution who underwent a Mustard Baffle correction for dextro-transposition of great arteries in childhood. Over following decades he was reviewed regularly with deteriorating systemic right ventricle function. At around 50 years of age he developed worsening heart failure on maximal medical therapy. He was subsequently assessed for cardiac transplantation which he underwent successfully at the age of 55 years.

Background Consumption of a diet with high adherence to a Mediterranean diet pattern (MDP) has been associated with a favorable gastrointestinal tract (GIT) microbiome. A healthy GIT microbiome in pregnancy, as defined by increased alpha diversity, is associated with lower chance of adverse perinatal outcomes. This study aimed to evaluate the impact of adherence to an MDP on GIT microbial diversity longitudinally throughout pregnancy. Methods Adherence to MDP was scored by the Alternate Mediterranean (aMED) Diet Quality Score, after being applied to a validated Food Frequency Questionnaire. Association of aMED Scores with GIT alpha diversity profiles were compared linearly and across time using a linear mixed model, including covariates of age, body mass index (BMI), ethnicity, and parity. Results Forty-one participants of Filipino, Japanese, Native Hawaiian, and Non-Hispanic White descent provided dietary information and microbiome samples during each trimester of pregnancy. Alpha diversity profiles changed over gestation, with decreased microbial diversity in the third trimester. aMED scores positively correlated with Chao1 Index and Observed Species Number (r = 0.244, p = 0.017, and r = 0.233, p = 0.023, respectively). The strongest association was detected in the third trimester (Chao 1: r = 0.43, p = 0.020, Observed Species Number: r = 0.41, p = 0.026). Participants with higher aMED scores had higher relative abundance of Acidaminoacaeae at the family level (p = 0.0169), as well as higher abundance of several species known to increase production of short chain fatty acids within the GIT. Conclusions Adherence to MDP pattern is associated with increased maternal GIT microbial diversity, and promotes the abundance of bacteria that produce short chain fatty acids. Increased consumption of fruits, vegetables and legumes with low red meat consumption were key components driving this association. The effect of nutrition however, was less of an effect than pregnancy itself. Further studies are needed to determine if adherence to a Mediterranean diet translates not only into microbial health, but also into reduced risk of adverse pregnancy outcomes.

H2-O (human HLA-DO) is a relatively conserved nonclassical MHC class II (MHCII)–like molecule. H2-O interaction with human HLA-DM edits the repertoire of peptides presented to TCRs by MHCII. It was long hypothesized that human HLA-DM inhibition by H2-O provides protection from autoimmunity by preventing binding of the high-affinity self-peptides to MHCII. The available evidence supporting this hypothesis, however, was inconclusive. A possibility still remained that the effect of H2-O deficiency on autoimmunity could be better revealed by using H2-O–deficient mice that were already genetically predisposed to autoimmunity. In this study, we generated and used autoimmunity-prone mouse models for systemic lupus erythematosus and organ-specific autoimmunity (type 1 diabetes and multiple sclerosis) to definitively test whether H2-O prevents autoimmune pathology. Whereas our data failed to support any significance of H2-O in protection from autoimmunity, we found that it was critical for controlling a γ-herpesvirus, MHV68. Thus, we propose that H2-O editing of the MHCII peptide repertoire may have evolved as a safeguard against specific highly prevalent viral pathogens.

To describe racial/ethnic representation in United States (US) and Australian obstetric research, represented by the Maternal-Fetal Medicine Units Network (MFMU) and Australian Research Centre for Health of Women and Babies (ARCH) trials. MFMU studies were identified through PubMed and ARCH studies through their online publication listing from 2011 to 2016. Observational and randomized cohorts and primary and secondary data analyses were included. Studies with race-based enrollment were excluded. Racial/ethnic representation was expressed as the mean racial/ethnic percentages of the studies (i.e.,: studies weighted equally regardless of sample size). Racial/ethnic percentages in MFMU studies were compared to US registered births and ARCH compared to Australian census ancestry data. 38 MFMU studies included 580,282 women. Racial/ethnic representation (% [SD]) included White 41.7 [12.3], Hispanic 28.1 [15.4], Black 26.2 [12.3], Asian 3.6 [2.3], and American Indian/Alaskan Native (AI/AN) 0.2 [0.02]. No studies reported Native Hawaiian/other Pacific Islanders (NHOPI) separately. Comparatively, registered US births (%) were White 75.7, Hispanic 28.1, Black 16.1, Asian/Pacific Islander 7.1, and AI/AN 1.1, which differed from the MFMU (P = 0.02). 20 ARCH studies included 51,873 women. The most reported groups were White 76.5 [17.4], Asian 15.2 [14.8], and Aboriginal/Torres Strait Islander 13.9 [30.5], compared to census numbers of White 88.7, Asian 9.4, and Aboriginal/Torres Strait Islander 2.8 (P < 0.01). Two ARCH studies reported African ethnicity. There is racial diversity in studies by MFMU and ARCH, with opportunities to increase enrollment and enhanced reporting of Asian, AI/AN, and NHOPI races in MFMU studies and Black race in ARCH studies.

To assess the potential association of a thrombospondin 1 gene (THBS1) single-nucleotide polymorphism (rs1478604) with thrombospondin 1 (TSP-1) mRNA expression, as well as the risk of pterygium, in a pilot study. DNA and RNA were isolated from peripheral blood samples collected from normal volunteer subjects (n = 39). In addition, DNA was isolated from conjunctival tissue samples collected during pterygium excision surgeries (n = 42). Relative expression of TSP-1 mRNA was measured by quantitative RT-PCR, and rs1478604 genotype was determined using a TaqMan SNP genotyping assay. Genotype frequencies were compared with mRNA expression and between pterygium samples and normal controls. Expression of TSP-1 mRNA was significantly lower in the peripheral blood of normal subjects who were homozygous for the C allele of rs1478604 (CC) compared to TT and CT genotypes (p = 0.004). When we compared rs1478604 genotypes between normal and pterygium patients, we found that the CC genotype was also associated with an increased risk of pterygium compared to TT (odds ratio (OR) = 5.39, 95% CI [1.26–22.99], p = 0.028), CT (OR = 7.86, 95% CI [1.92–32.17], p = 0.003), and combined CT and TT genotypes (OR = 6.67; 95% CI = [1.75–25.37]; p = 0.003). We found that the C allele of rs1478604 was associated with both lower TSP-1 expression and higher risk of pterygium, possibly implicating TSP-1 in the pathogenesis of pterygium.

Intrauterine growth restriction (IUGR) is an obstetrical complication with an increased risk of perinatal mortality and morbidity. The uterus, once considered to be a sterile environment, has now been described in recent microbiome studies to harbor diverse commensal placenta microbiota, as well as potentially pathogenic flora known to cause infection. Therefore, in this pilot study, we tested whether IUGR was associated with changes to the reproductive microbiome. The reproductive microbiome was surveyed using 16S sequencing (20 IUGR, 20 controls). Alpha and beta diversity were compared, and differential taxa features associated with IUGR were identified. Microbial screening of the placenta demonstrated a diverse range of flora predominantly including Proteobacteria, Fusobacteria, Firmicutes, and Bacteroidetes. Neither alpha- nor beta-diversity was significantly different by IUGR status. However, at the taxa level, IUGR patients had significantly higher prevalence of Neisseriaceae, mucosal β-hemolytic bacteria known to uptake iron-bound host proteins including hemoglobin. Moreover, the increase in anaerobic bacteria such as Desulfovibrio reflects the emergence of a hypoxic environment in the IUGR placenta. Further analysis of the reproductive microbiome of IUGR samples showed lower levels of H

As one of 17 clinical sites of the Environmental influences on Child Health Outcomes (ECHO) IDeA States Pediatric Clinical Trials Network (ISPCTN), the Hawai‘i IDeA Center for Pediatric and Adolescent Clinical Trials (HIPACT) was established in 2016 to participate in community-valued and scientifically-valid multi-center pediatric clinical trials to improve health and well-being of diverse multi-ethnic populations of Hawai‘i. Hawai‘i is home to large populations of diverse rural and underserved populations, including indigenous Hawaiian communities and immigrant populations of Pacific Islanders and Asians. Many of these communities experience significant health disparities, made worse by their geographic isolation and many socio-economic factors. In addition to providing opportunities for children and their families to participate in clinical trials, HIPACT's goal is to provide opportunities for junior faculty of the John A. Burns School of Medicine (JABSOM), University of Hawai‘i at Manoa, to acquire knowledge about and to develop skills in clinical trials. HIPACT's partners include the Hawai‘i Pacific Health with Kapi‘olani Medical Center for Women and Children, and Waianae Coast Comprehensive Health Center. HIPACT builds on the experiences gained through partnerships with the Mountain West IDeA Clinical and Translational Research-Infrastructure Network, and Research Centers in Minority Institutions Translational Research Network. Apart from participating in ECHO ISPCTN-sponsored studies, HIPACT junior faculty serve as committee members, Working Group leaders, Protocol Study Principal Investigators (PI) and site study PIs with ECHO ISPCTN. Through participation in ECHO ISPCTN, HIPACT has successfully increased the number of pediatric and maternal-fetal medicine faculty involved in the conduct of clinical trials.

The State of Hawai‘i ranks third in the nation for homelessness. Homelessness disproportionately affects the health care of pregnant mothers and their children. These homeless persons are at risk for malnutrition, physical and psychological trauma, injuries and chronic illnesses, and have difficulty accessing healthcare and social services. With the generous support of a Waiwai Ola grant from AlohaCare, a non-profit health plan in Hawai‘i, the Maternal-Fetal Medicine physicians at the University Health Partners of Hawai‘i created a pilot program with a midwife and medical assistant to provide prenatal health care and social services for homeless mothers on the island of O‘ahu. This innovative project has given the midwife and medical assistant opportunities to perform needs assessments for homeless mothers and pilot new mobile health devices out in the field that can be optimized for delivering prenatal and postpartum health care for the most vulnerable populations of homeless mothers and their newborns.

Breast cancer patients can switch hormonal therapy (HT) regimens due to treatment side effects or menopausal status change. We describe HT class switching from aromatase inhibitor (AI) to tamoxifen (TAM), and vice versa. In a cohort of 3,265 women diagnosed with hormone-receptor-positive breast cancer at Kaiser Permanente Northern California from 2005 to 2013, we analyzed prescription records, switching reasons, and treatment adherence post-switch by chart review, through 31 December 2014. There were 290 women who switched from AI to TAM (AI switchers), including 130 (45%) switchers during the first year of treatment; and 446 women who switched from TAM to AI (TAM switchers), including 120 (27%) switchers within the first year. After the switch, 136 (47%) AI switchers and 260 (58%) TAM switchers finished or remained on the planned therapy; 69 (24%) AI switchers and 99 (22%) TAM switchers discontinued therapy. AI side effects (73%), specifically joint pain/arthralgia and bone health issues, were the most common reasons for switching from AI to TAM, whereas from TAM to AI, it was menopausal status change (42%). Study findings highlight the need for better ways to control patient symptoms from HT to prevent discontinuation, and thus ensure best prognosis.

BackgroundA substantial portion of Mendelian disease patients suffers from genetic variants that are inherited in a recessive manner. A precise understanding of pathogenic recessive variants in a population would assist in pre-screening births of such patients. However, a systematic understanding of the contribution of recessive variants to Mendelian diseases is still lacking.MethodsGenetic diagnosis and variant discovery of 553 undiagnosed Korean patients with complex neurodevelopmental problems (KND for Korean NeuroDevelopmental cohort) were performed using whole exome sequencing of patients and their parents. Pathogenic variants were selected and evaluated based on a comparison to patient symptoms and genetic properties of the variants were analyzed.ResultsDisease-causing variants, including newly discovered variants, were identified in in 57.5% of the probands of the KND cohort. Of the 553 patients, 47.4% harbored variants that were previously reported as being pathogenic, and 35.1% of the previous reported pathogenic variants were inherited in a recessive manner. Genes that cause recessive disorders tend to be less constrained by loss-of-function variants and enriched in metabolic and mitochondrial pathways. This observation was applied to an estimation that approximately 1 in 17 healthy Korean individuals carry at least one of these pathogenic variants that develop severe neurodevelopmental problems in a recessive manner. Furthermore, the feasibility of these genes for carrier screening was evaluated.ConclusionsWe suggest that the odds are high for healthy individuals carrying a potentially pathogenic variant, and its genetic properties. Our results will serve as a foundation for recessive variant screening to reduce occurrences of rare Mendelian disease patients. Additionally, our results highlight the utility and necessity of whole exome sequencing-based diagnostics for improving patient care in a country with a centralized medical system.

Purpose: Dialysis access failure is a major cause of morbidity in patients with end-stage renal disease. The Fistula First Breakthrough Initiative (FFBI) dictates arteriovenous fistulae (AVFs) should be preferred over arteriovenous grafts (AVGs) as first line for surgically placed accesses. The purpose of this study was to compare patency rates of surgical dialysis accesses in our mature, urban population after the FFBI. Methods: Current dialysis patients with accesses placed between 2006 and 2011 were included. Patient characteristics, access outcomes, interventions, and survival outcomes were analyzed. Results: We report outcomes of 220 patients undergoing dialysis access. Of those 220, 75 received numerous accesses. All outcomes are evaluated as per access itself, that is, a patient may have numerous access types, each individually analyzed. Of the accesses, 138 were AVF and 190 were AVG. The average age of patients was 59.8 years. The groups were evenly matched in distribution of race and prevalence of hypertension, diabetes, coronary artery disease, and Peripheral Vascular Disease (PVD). Average number of complications requiring intervention per access were fewer with AVF than AVG (1.21 vs 1.72, P = .02). The AVF had greater rates of stenosis (51.4% vs 40.6%, P = .0182), whereas AVG had greater thrombosis rates (14.6% vs 31.9%, P < .001). Both AVF and AVG had similar primary patency (median: 186 vs 142 days, P = .1774) and 3-year secondary patency (59.2% vs 49.2%, P = .0945). Arteriovenous fistula in patients aged 60 years. Conclusions: Although complications requiring intervention are greater with AVG, primary and secondary patency rates are similar between AVF and AVG, except when considering AVF in patients aged

The purpose of this study is to evaluate the incidence of maternal cell contamination (MCC) in the first few milliliters of amniotic fluid withdrawn during amniocentesis.A prospective observational study was performed. The initial 2-3 ml of amniotic fluid withdrawn during amniocentesis was divided into direct analysis (uncultured) and cultured samples. A matching maternal buccal swab was obtained for MCC testing. MCC was determined by short-tandem repeat analysis. The primary outcome was measurement of clinically significant contamination (MCC 5%). Secondary outcomes included the determination of risk factors associated with MCC 5%. Outcomes were assessed by fisher's exact, independent t-test, binary logistic regression, and ANOVA.Direct analysis measured clinically significant contamination (MCC 5%) in 26% of specimens, while any amount of MCC was present in 68% of specimens. Cultured specimens had MCC 5% in 2%, and any amount of MCC in 24%. Only blood-tinged fluid was associated with an increased risk for MCC 5%. Larger volumes of the discard sample were not associated with increased incidence of MCC greater than 5%.A significant amount of MCC is present with direct analysis of the initial few milliliters of amniotic fluid withdrawn and is not influenced by the volume of the discard sample. Our results suggest that the first few milliliters of amniotic fluid be removed and discarded when direct analysis is utilized for prenatal genetic testing.

Engineering of extracellular vesicles (EVs) without affecting biological functions remains a challenge, limiting the broad applications of EVs in biomedicine. Here, we report a method to equip EVs with various functional agents, including fluorophores, drugs, lipids, and bio-orthogonal chemicals, in an efficient and controlled manner by engineering parental cells with membrane fusogenic liposomes, while keeping the EVs intact. As a demonstration of how this method can be applied, we prepared EVs containing azide-lipids, and conjugated them with targeting peptides using copper-free click chemistry to enhance targeting efficacy to cancer cells. We believe that this liposome-based cellular engineering method will find utility in studying the biological roles of EVs and delivering therapeutic agents through their innate pathway.

IntroductionVentilator-associated pneumonia (VAP) is a common healthcare-associated infection in the intensive care unit (ICU). Probiotics are defined as live microorganisms that may confer health benefits when ingested. Prior randomised trials suggest that probiotics may prevent infections such as VAP and Clostridioides difficile–associated diarrhoea (CDAD). PROSPECT (Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial) is a multicentre, double-blinded, randomised controlled trial comparing the efficacy of the probiotic Lactobacillus rhamnosus GG with usual care versus usual care without probiotics in preventing VAP and other clinically important outcomes in critically ill patients admitted to the ICU.Methods and analysisThe objective of E-PROSPECT is to determine the incremental cost-effectiveness of L. rhamnosus GG plus usual care versus usual care without probiotics in critically ill patients. E-PROSPECT will be performed from the public healthcare payer’s perspective over a time horizon from ICU admission to hospital discharge.We will determine probabilities of in-ICU and in-hospital events from all patients alongside PROSPECT. We will retrieve unit costs for each resource use item using jurisdiction-specific public databases, supplemented by individual site unit costs if such databases are unavailable. Direct costs will include medications, personnel costs, radiology/laboratory testing, operative/non-operative procedures and per-day hospital ‘hoteling’ costs not otherwise encompassed. The primary outcome is the incremental cost per VAP prevented between the two treatment groups. Other clinical events such as CDAD, antibiotic-associated diarrhoea and in-hospital mortality will be included as secondary outcomes. We will perform pre-specified subgroup analyses (medical/surgical/trauma; age; frailty status; antibiotic use; prevalent vs no prevalent pneumonia) and probabilistic sensitivity analyses for VAP, then generate confidence intervals using the non-parametric bootstrapping approach.Ethics and disseminationStudy approval for E-PROSPECT was granted by the Hamilton Integrated Research Ethics Board of McMaster University on 29 July 2019. Informed consent was obtained from the patient or substitute decision-maker in PROSPECT. The findings of this study will be published in peer-reviewed journals.Trial registration numberNCT01782755; Pre-results.

Using positron emission tomography (PET) imaging, we determined the hepatic concentrations and hepatobiliary transport of [(11)C]rosuvastatin (IV injection) in the absence (n=6) and presence (n=4 of 6) of cyclosporine A (CsA, IV infusion) following a therapeutic dose of unlabeled rosuvastatin (RSV) (5 mg, PO) in healthy human volunteers. The sinusoidal uptake, sinusoidal efflux and biliary efflux clearance (mL/min) of [(11)C]rosuvastatin, estimated through compartment modeling were 1205.6±384.8, 16.2±11.2 and 5.1±1.8, respectively (n=6). CsA (blood concentration: 2.77±0.24 μM), an organic-anion-transporting polypeptide (OATP), Na(+)-taurocholate cotransporting polypeptide (NTCP) and breast cancer resistance protein (BCRP) inhibitor increased [(11)C]rosuvastatin systemic blood exposure (45%; p0.05) but didn’t affect its distribution into the kidneys. CsA increased plasma concentrations of coproporphyrin I and III and total bilirubin by 297±69%, 384±102% and 81±39%, respectively (p

BackgroundInfants born preterm compared with infants born at term are at an increased risk of dying and of serious morbidities in early life, and those who survive have higher rates of neurological impairments. It remains unclear whether exposure to repeat courses of prenatal corticosteroids can reduce these risks. This individual participant data (IPD) meta-analysis (MA) assessed whether repeat prenatal corticosteroid treatment given to women at ongoing risk of preterm birth in order to benefit their infants is modified by participant or treatment factors.Methods and findingsTrials were eligible for inclusion if they randomised women considered at risk of preterm birth who had already received an initial, single course of prenatal corticosteroid seven or more days previously and in which corticosteroids were compared with either placebo or no placebo. The primary outcomes for the infants were serious outcome, use of respiratory support, and birth weight z-scores; for the children, they were death or any neurosensory disability; and for the women, maternal sepsis. Studies were identified using the Cochrane Pregnancy and Childbirth search strategy. Date of last search was 20 January 2015. IPD were sought from investigators with eligible trials. Risk of bias was assessed using criteria from the Cochrane Collaboration. IPD were analysed using a one-stage approach. Eleven trials, conducted between 2002 and 2010, were identified as eligible, with five trials being from the United States, two from Canada, and one each from Australia and New Zealand, Finland, India, and the United Kingdom. All 11 trials were included, with 4,857 women and 5,915 infants contributing data. The mean gestational age at trial entry for the trials was between 27.4 weeks and 30.2 weeks. There was no significant difference in the proportion of infants with a serious outcome (relative risk [RR] 0.92, 95% confidence interval [CI] 0.82 to 1.04, 5,893 infants, 11 trials, p = 0.33 for heterogeneity). There was a reduction in the use of respiratory support in infants exposed to repeat prenatal corticosteroids compared with infants not exposed (RR 0.91, 95% CI 0.85 to 0.97, 5,791 infants, 10 trials, p = 0.64 for heterogeneity). The number needed to treat (NNT) to benefit was 21 (95% CI 14 to 41) women/fetus to prevent one infant from needing respiratory support. Birth weight z-scores were lower in the repeat corticosteroid group (mean difference -0.12, 95%CI -0.18 to -0.06, 5,902 infants, 11 trials, p = 0.80 for heterogeneity). No statistically significant differences were seen for any of the primary outcomes for the child (death or any neurosensory disability) or for the woman (maternal sepsis). The treatment effect varied little by reason the woman was considered to be at risk of preterm birth, the number of fetuses in utero, the gestational age when first trial treatment course was given, or the time prior to birth that the last dose was given. Infants exposed to between 2-5 courses of repeat corticosteroids showed a reduction in both serious outcome and the use of respiratory support compared with infants exposed to only a single repeat course. However, increasing numbers of repeat courses of corticosteroids were associated with larger reductions in birth z-scores for weight, length, and head circumference. Not all trials could provide data for all of the prespecified subgroups, so this limited the power to detect differences because event rates are low for some important maternal, infant, and childhood outcomes.ConclusionsIn this study, we found that repeat prenatal corticosteroids given to women at ongoing risk of preterm birth after an initial course reduced the likelihood of their infant needing respiratory support after birth and led to neonatal benefits. Body size measures at birth were lower in infants exposed to repeat prenatal corticosteroids. Our findings suggest that to provide clinical benefit with the least effect on growth, the number of repeat treatment courses should be limited to a maximum of three and the total dose to between 24 mg and 48 mg.

Coagulase-negative staphylococci (CoNS), such as Staphylococcus capitis, are major causes of bloodstream infections in neonatal intensive care units (NICUs). Recently, a distinct clone of S. capitis (designated S. capitis NRCS-A) has emerged as an important pathogen in NICUs internationally., Coagulase-negative staphylococci (CoNS), such as Staphylococcus capitis, are major causes of bloodstream infections in neonatal intensive care units (NICUs). Recently, a distinct clone of S. capitis (designated S. capitis NRCS-A) has emerged as an important pathogen in NICUs internationally. Here, 122 S. capitis isolates from New Zealand (NZ) underwent whole-genome sequencing (WGS), and these data were supplemented with publicly available S. capitis sequence reads. Phylogenetic and comparative genomic analyses were performed, as were phenotypic assessments of antimicrobial resistance, biofilm formation, and plasmid segregational stability on representative isolates. A distinct lineage of S. capitis was identified in NZ associated with neonates and the NICU environment. Isolates from this lineage produced increased levels of biofilm, displayed higher levels of tolerance to chlorhexidine, and were multidrug resistant. Although similar to globally circulating NICU-associated S. capitis strains at a core-genome level, NZ NICU S. capitis isolates carried a novel stably maintained multidrug-resistant plasmid that was not present in non-NICU isolates. Neonatal blood culture isolates were indistinguishable from environmental S. capitis isolates found on fomites, such as stethoscopes and neonatal incubators, but were generally distinct from those isolates carried by NICU staff. This work implicates the NICU environment as a potential reservoir for neonatal sepsis caused by S. capitis and highlights the capacity of genomics-based tracking and surveillance to inform future hospital infection control practices aimed at containing the spread of this important neonatal pathogen.

Introduction: Intrauterine growth restriction (IUGR) is a major pregnancy complication with significant postnatal implications. IUGR is characterized by high placental oxidative stress (OS) and increased mitochondrial DNA (mtDNA) abundance that altogether alter the placental metabolism. Such alterations may be captured by changes in the expression of mitochondrial-encoded oxidative phosphorylation genes and glycolysis-regulatory genes.Study design: We aimed here to determine the association between the placental expression of all 13 protein-coding mitochondrial-encoded genes and seven key nuclear glycolysis-regulatory genes, PDK1, PDK2, PDK3, PDK4, PKLR, PKM, OGT, with IUGR, within a case-control study including 50 IUGR and 100 control pregnancies. We additionally assessed placental mtDNA abundance and OS.Results: Three mitochondrial genes, MT-ND5, MT-ND6, and MT-ATP6 were found negatively associated with IUGR, while one glycolysis-regulatory gene, PDK1 was positively associated with IUGR. mtDNA abundance and OS were positively associated with IUGR. Our study confirmed the existing data on IUGR inducing increased placental OS and mtDNA abundance. Further, our data highlighted the significant involvement of mitochondria and glucose metabolism in the OS-challenged IUGR placentas, which might modulate the placental expression of genes affecting the OXPHOS and promoting glycolysis.Brief rationale: By using banked placenta samples available at Icahn School of Medicine at Mount Sinai, this study aims at laying the foundation for the characterization of the role of mitochondria epi/genetics in IUGR. IUGR is a highly prevalent pregnancy outcome with long-term effects on the progeny that, at present, has limited tools that can be used for its diagnosis and characterization, thus limiting the efficacy of both clinical and public health interventions. The alterations of mitochondrial copy number, OS and mitochondrial and glycolysis-regulatory gene expression that we detected, together, provide the first evidence that these phenomena are playing an important role in the pathophysiology of IUGR. These findings suggest possible new research paths for the full characterization of mitochondrial biomarkers of IUGR.

Background The healthy adherer effect is a phenomenon in which patients who adhere to medical therapies tend to pursue health-seeking behaviors. Although the healthy adherer effect is supposed to affect health outcomes in patients with coronary artery disease, evaluation of its presence and extent is not easy. This study aimed to assess the relationship between medication adherence and lifestyle modifications and health-related quality of life among post-acute myocardial infarction (AMI) patients. Methods A cross-sectional study was conducted in 417 post-AMI patients who underwent percutaneous coronary intervention (PCI). Patients were recruited from 11 university hospitals from December 2015 to March 2016 in South Korea. Details regarding socio-demographic factors, six health behaviors (low-salt intake, low-fat diet and/or weight-loss diet, regular exercise, stress reduction in daily life, drinking in moderation, and smoking cessation), medication adherence using the Modified Morisky Scale (MMS), and HRQoL using the Coronary Revascularization Outcome Questionnaire (CROQ) were surveyed in a one-on-one interview. Results In the univariate logistic analysis, sex (female), age (≥70 years), MMS score (≥5), and CROQ score were associated with adherence to lifestyle modification. In the multiple logistic analysis, a high MMS score (≥5) was associated with adherence to lifestyle modification after adjusting for sex, age, marital status, education, and family income (adjusted odds ratio [OR] = 11.7, 95% confidence interval [CI] = 1.5–91.3). After further adjusting for the CROQ score, the association between high MMS score and adherence to lifestyle modification was significant (adjusted OR = 11.5, 95% CI = 1.4–93.3). Conclusions Adherence to medication was associated with adherence to lifestyle modification, suggesting the possible presence of the healthy adherer effect in post-AMI patients. After further adjusting for HRQoL, the association remained. To improve health outcome in post-AMI patients, early detection of patients with poor adherence to medication and lifestyle modification and motivational education programs to improve adherence are important. In addition, the healthy adherer effect should be considered in clinical research, in particular, in studies evaluating the effects of therapies on health outcomes. Electronic supplementary material The online version of this article (10.1186/s12955-018-0921-z) contains supplementary material, which is available to authorized users.

Purpose To report a case of eventual corneal endothelial cell failure after spontaneous resolution of corneal edema after failed Descemet membrane endothelial keratoplasty (DMEK). Methods Retrospective case report. Results A 56-year-old man with Fuchs endothelial corneal dystrophy underwent cataract and DMEK surgery in the left eye. The transplanted DMEK graft detached in the early postoperative period and formed a peripheral scroll. Despite graft detachment, corneal edema resolved with endothelial cell repopulation of the central cornea. The patient's uncorrected visual acuity 5 months after surgery was 20/25. However, by 7 months after this spontaneous improvement, the patient started to complain of worsening vision. At 2.5 years, recurrent corneal edema became clinically apparent, and no endothelial cells were visible by specular microscopy in the central cornea. Conclusions This case suggests that spontaneous healing of a large central Descemet membrane defect significantly diminishes the peripheral endothelial cell reserves and can lead to imminent bullous keratopathy. If there is any potential of corneal endothelial cells to regenerate after surgical removal of central Descemet membrane in Fuchs dystrophy, it is likely very limited.

In many parts of the world, perinatal transmission is the most common route of infection for hepatitis B virus. In the United States, sexual contact is the most common source of hepatitis B virus infection. As a result, it is essential that women's health care providers become aware of the recommended strategies used to identify women infected with hepatitis B and to subsequently reduce perinatal transmission, particularly now that immigration and globalization is more common and reproductive science makes pregnancy more possible for women with liver disease. This article reviews evidence-based strategies for management of hepatitis B infection during pregnancy.

Ulixertinib (BVD-523) is an ERK1/2 kinase inhibitor with potent preclinical activity in BRAF- and RAS-mutant cell lines. In this multicenter phase I trial (NCT01781429), 135 patients were enrolled to an accelerated 3 + 3 dose-escalation cohort and six distinct dose-expansion cohorts. Dose escalation included 27 patients, dosed from 10 to 900 mg twice daily and established the recommended phase II dose (RP2D) of 600 mg twice daily. Ulixertinib exposure was dose proportional to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108-patient expansion cohort, 32% of patients required dose reduction. The most common treatment-related adverse events were diarrhea (48%), fatigue (42%), nausea (41%), and dermatitis acneiform (31%). Partial responses were seen in 3 of 18 (17%) patients dosed at or above maximum tolerated dose and in 11 of 81 (14%) evaluable patients in dose expansion. Responses occurred in patients with NRAS-, BRAF V600–, and non–V600 BRAF-mutant solid tumors. Significance: Here, we describe the first-in-human dose-escalation study of an ERK1/2 inhibitor for the treatment of patients with advanced solid tumors. Ulixertinib has an acceptable safety profile with favorable pharmacokinetics and has shown early evidence of clinical activity in NRAS- and BRAF V600- and non-V600–mutant solid-tumor malignancies. Cancer Discov; 8(2); 184–95. ©2017 AACR. See related commentary by Smalley and Smalley, p. 140. This article is highlighted in the In This Issue feature, p. 127

Currently no recommendation exists to collect genital culture for Chlamydia trachomatis and Neisseria gonorrhoeae at diagnosis of spontaneous abortion. A retrospective cross sectional study was performed to identify first trimester abortions with concurrent genital culture collection in an emergency room setting. The results were compared to most current 2015 Center for Disease Control (CDC) statistics. Among women aged 15–24 the rate of C. trachomatis was increased to 20.0% and greater than CDC rate of 6.7% (RR 2.97, p

This study attempted to calculate and investigate the incidence of hospitalized acute myocardial infarction (AMI) and stroke in Korea. Using the National Health Insurance claim data, we investigated patients whose main diagnostic codes included AMI or stroke during 2006 to 2010. As a result, we found out that the number of AMI hospitalized patients had decreased since 2006 and amounted to 15,893 in 2010; and that the number of those with stroke had decreased since 2006 and amounted to 73,501 in 2010. The age-standardized incidence rate of hospitalized AMI, after adjustment for readmission, was 41.6 cases per 100,000-population in 2006, and had decreased to 29.4 cases in 2010 (for trend P < 0.001). In the case of stroke was estimated at 172.8 cases per 100,000-population in 2006, and had decreased to 135.1 cases in 2010 (for trend P < 0.001). In conclusion, the age-standardized incidence rates of both hospitalized AMI and stroke in Korea had decreased continuously during 2006 to 2010. We consider this decreasing trend due to the active use of pharmaceuticals, early vascular intervention, and the national cardio-cerebrovascular disease care project as the primary and secondary prevention efforts.

The recent increase in extensively drug-resistant bacterial pathogens and the associated increase of morbidity and mortality demonstrate the immediate need for new antibiotic backbones with novel mechanisms of action. Here, we report the development of the PepSAVI-MS pipeline for bioactive peptide discovery. This highly versatile platform employs mass spectrometry and statistics to identify bioactive peptide targets from complex biological samples. We validate the use of this platform through the successful identification of known bioactive peptides from a botanical species, Viola odorata. Using this pipeline, we have widened the known antimicrobial spectrum for V. odorata cyclotides, including antibacterial activity of cycloviolacin O2 against A. baumannii. We further demonstrate the broad applicability of the platform through the identification of novel anticancer activities for cycloviolacins by their cytotoxicity against ovarian, breast, and prostate cancer cell lines.

Immortalization of primary cells with telomerase is thought to maintain normal phenotypic properties and avoid chromosomal abnormalities and other cancer-associated changes that occur following simian virus 40 tumor antigen (SV40 Tag) induced immortalization. However, we report that the human telomerase reverse transcriptase (hTERT)-immortalized SWAN-71 trophoblast cell line has a near pentaploid 103∼119,XXXX[cp20] karyotype. Additionally, DNA typing analysis indicated that SWAN-71 cells have acquired microsatellite instability. In comparison, the post-crisis SV40-transformed trophoblast cell line 3A-subE was hypertriploid 69∼81,XX[cp20]. Both cell lines contained multiple specific clonal rearrangements. These findings emphasize the need to monitor for genetic instability in hTERT-immortalized cells.

Background: Castor oil is one of the most popular drugs for induction of labour in a non-medical setting; however, published data on safety and effectiveness of this compound to induce labour remain sparse. Aim: To assess the safety and effectiveness of castor oil for induction of labour in pregnancies with an ultrasound estimated gestational at birth of more than 40 weeks. Methods: Data were extracted from hospital-based records of all pregnant women who attended antenatal clinics on the Thai–Burmese border and who were more than 40 weeks pregnant. The effectiveness of castor oil to induce labour was expressed as time to birth and analysed with a Cox proportional hazards regression model. Measures associated with safety were fetal distress, meconium-stained amniotic fluid, tachysystole of the uterus, uterine rupture, abnormal maternal blood pressure during labour, Apgar scores, neonatal resuscitation, stillbirth, post-partum haemorrhage, severe diarrhoea and maternal death. Proportions were compared using Fisher's exact test. Results: Of 612 women with a gestation of more than 40 weeks, 205 received castor oil for induction and 407 did not. The time to birth was not significantly different between the two groups (hazard ratio 0.99 (95% confidence interval: 0.81 to 1.20; n = 509)). Castor oil use was not associated with any harmful effects on the mother or fetus. Conclusions: Castor oil for induction of labour had no effect on time to birth nor were there any harmful effects observed in this large series. Our findings leave no justification for recommending castor oil for this purpose.

Some patients may present quite a challenge for the health care team-from the receptionist to the social worker to the nurse and to the physician. An understanding of personality disorders can be helpful for the provider working with a complicated or "difficult" patient. Borderline personality disorder is relatively common in patients presenting with a complicated medical and psychosocial picture. Recognizing borderline personality disorder allows providers to better tailor treatment goals and expectations, manage personal reactions, set effective boundaries, and avoid potential confrontations with the difficult patient. Using a clinical case vignette, this article discusses the prevalence, etiology, diagnosis, and management of borderline personality disorder in the obstetrical and gynecological patient.

A complex network of epigenetic factors participates in regulating the monoallelic expression of a small subset of genes (~1%) in the human genome. This phenomenon goes under the definition of genomic imprinting, a parent-of-origin effect that, when altered during early embryogenesis, may influence fetal development into adulthood. Pertubations in genomic imprinting have been associated with placental and fetal growth restrictions. We analyzed the differential DNA methylation of all known imprinted genes on 10 appropriate-for-gestational-age, clinically normal, placentas and 7 severe intrauterine growth-restricted placentas. Samples were pooled according to the diagnosis and analyzed by methylated DNA immunoprecipitation (MeDIP) on a tiling microarray platform. The distribution of the differentially methylated regions (DMRs) identified in growth-restricted placentas showed a slight tendency toward hypermethylation. Imprinted genes not expressed in placenta showed a unique DMR profile with the fewest hyper- and hypomethylated DMRs. Promoter and CpG island DMRs were sporadic and randomly distributed. The vast majority of DMR identified (~99%) were mapped in introns, showing no common sequence features. Also, by using the more advanced array data mining softwares, no significant patterns emerged. In contrast, differential methylation showed a highly significant correlation with gene length. Overall these data suggest that differential methylation changes in growth-restricted placentas occur throughout the genomic regions, encompassing genes actively expressed in the placenta. These findings warrant caution in interpreting the significance of genes carrying clustered DMRs because the distribution of DMRs in a gene may be attributed as a function of its length rather than as a specific biological role.

Loss of imprinting (LOI) is the reactivation of the silenced allele of an imprinted gene, leading to perturbation of monoallelic expression. We tested the hypothesis that LOI of PLAGL1, a representative maternally imprinted gene, occurs through an all-or-none process leading to a mixture of fully imprinted and nonimprinted cells. Herein using a quantitative RT-PCR-based experimental approach, we measured LOI at the single cell level in human trophoblasts and demonstrated a broad distribution of LOI among cells exhibiting LOI, with the mean centered at approximately 100% LOI. There was a significant (P < 0.01) increase in expression after 2 days of 5-aza-2'-deoxycytidine (AZA) treatment and a significant (P < 0.01) increase in LOI after both 1 and 2 days of AZA treatment, while the distribution remained broad and centered at approximately 100% LOI. We propose a transcriptional pulsing model to show that the broadness of the distribution reflects the stochastic nature of expression between the two alleles in each cell. The mean of the distribution of LOI in the cells is consistent with our hypothesis that LOI occurs by an all-or-none process. All-or-none LOI could lead to a second distinct cell population that may have a selective advantage, leading to variation of LOI in normal tissues, such as the placenta, or in neoplastic cells.

Genomic imprinting refers to silencing of one parental allele in the zygotes of gametes depending upon the parent of origin. Loss of imprinting (LOI) is the gain of function from the silent allele that can have a maximum effect of doubling the gene dosage. LOI may play a significant role in the etiology of intrauterine growth restriction (IUGR). Using placental tissue from ten normal and seven IUGR pregnancies, we conducted a systematic survey of the expression of a panel of 74 "putatively" imprinted genes using quantitative RT-PCR. We found that 52/74 ( approximately 70%) of the genes were expressed in human placentas. Nine of the 52 (17%) expressed genes were significantly differentially expressed between normal and IUGR placentas; five were upregulated (PHLDA2, ILK2, NNAT, CCDC86, PEG10) and four downregulated (PLAGL1, DHCR24, ZNF331, CDKAL1). We also assessed LOI profile of 14 imprinted genes in 14 normal and 24 IUGR placentas using a functional and sensitive assay developed in our laboratory. Little LOI was observed in any placentas for five of the genes (PEG10, PHLDA2, MEG3, EPS15, CD44). With the 149 heterozygosities examined, 40 (26.8%) exhibited LOI >3%. Some genes exhibited frequent LOI in placentas regardless of the disease status (IGF2, TP73, MEST, SLC22A18, PEG3), while others exhibited LOI only in IUGR placentas (PLAGL1, DLK1, H19, SNRPN). Importantly, there was no correlation between gene expression and LOI profile. Our study suggests that genomic imprinting may play a role in IUGR pathogenesis, but mechanisms other than LOI may contribute to dysregulation of imprinted genes.

Refugee and migrant populations are considered to be at high risk from sexually transmitted infection (STI) and HIV. Cross-sectional surveys for syphilis and HIV were conducted in antenatal clinics (ANCs) on the Thai-Burmese border. In Mae La refugee camp, the seroprevalence of HIV and syphilis were 0.2% (one of 500) (95% CI 0–1.1) and 0% (0 of 404) (95% CI 0–0.9) in 1997; and 0.4% (two of 500) (95% CI 0.1–1.4) and 0.4% (three of 741) (95% CI 0.1–1.2) in 2005, respectively; syphilis seroprevalence in migrant women in 2005 was 0 (0 of 234) (95% CI 0–1.6). The seroprevalence was lower than that reported from surrounding ANCs for Thai or Burmese women. Focus group discussions with HIV-negative and -positive pregnant refugee women established that aspects of Karen culture and isolation (geographical and political) had a significant protective role from HIV and STI. This survey has resulted in programmatic changes in services to pregnant women in this area.

Titanium plate has been widely used in several surgical fields, such as craniofacial reconstruction and orthopedic prosthesis. This prosthesis has been proved not only with good biocompatibility and mechanical strength, but also with light weight and low radiological interference. From October 1991 to May 1995, 6 patients underwent thoracic cage reconstruction with titanium plate in our hospital. They included 5 females and 1 male, with ages ranging from 26 to 62 years. Four of them suffered from primary chest wall tumors (2 desmoid tumors, 1 chondrosarcoma, and 1 hemangioma), one had a recurrent chest wall tumor from breast carcinoma, and one had thoracic hypoplasia. The thoracic cage defect ranged from 5 times 6 cm to 10 times 15 cm, and 1 to 3 titanium plates were used for the reconstruction. No paradoxical movement or other prosthesis-related complications have occurred during the follow-up period. We conclude that titanium plate is a good material for thoracic cage reconstruction.

Pulmonary function and gas exchange deteriorate after pulmonary resection. The vital capacity, tidal volume, and functional capacity decrease after pulmonary resection because of loss of effective lung volume and, therefore, affect the setting of the ventilator. Nineteen patients undergoing pulmonary resection were included in this study on the optimal tidal volume delivered by a ventilator. Five patients received mediastinal surgery or wedge resection of the lung, 4 had pneumonectomy, and 10 had lobectomy. Immediately after the pulmonary surgery, they were maintained with ventilatory support. Subsequently, a different setting of tidal volume on the ventilator was given for each patient, i.e., 6 ml/kg, 8 ml/kg, 10 mg/kg, and 14 ml/kg. For each setting of tidal volume, a hemodynamic study was performed including cardiac output and other parameters. With the examination of Wilk's Lambda test, there was no difference in association with different settings of tidal volume on blood pressure (F = 0.92, p = 0.51), pulmonary artery pressure (F = 0.95, p = 0.43), pulmonary vascular resistance (F = 0.24, p = 0.97), systemic vascular resistance (F = 0.42, p = 0.78), and cardiac output (F = 0.35, p = 0.93) in 3 different groups of patients. It is concluded that after pulmonary resection a patient's lungs can be inflated with a tidal volume to 14 ml/kg during ventilatory support without compromise of cardiovascular performance.

Rare individuals report repeated unprotected HIV-1 sexual exposures, yet remain seronegative for years. We investigated the possibility that reduced in vitro CD4(+) T cell susceptibility to HIV-1 infection protects such highly exposed seronegative (ES) individuals. Susceptibility to three R5-tropic HIV-1 isolates, regardless of inoculating dose, was remarkably similar between 81 ES and 33 low-risk controls. In 94% (99/105) of donors, we observed a 1.36 log-unit range in HIV-1(JR-CSF) production, with similar results for HIV-1(1192). The median frequency of intracellular Gag(+) T cells after single-round infection was similar in ES (5.2%) and controls (7.2%), p = 0.456. However, in repeated testing, CD4(+) T cells from two controls (6.1%) and four ES (4.9%) exhibited a 10- to 2500-fold reduction in HIV-1 production and required 5- to 12-fold greater HIV-1(1192) and HIV-1(JR-CSF) inocula to establish infection (TCID(50)). Reduced viral entry cannot explain the low producer phenotype; no differences in CCR5 receptor density or beta-chemokine production were observed. In conclusion, we have identified a remarkably narrow range of HIV-1 susceptibility in seronegative donors regardless of risk activity, which can be applied as a benchmark to assess vaccine-induced antiviral effector activities. However, CD4(+) T cells from a subset of individuals demonstrated reduced HIV-1 susceptibility unexplained by impaired entry, lending support to the possibility that cellular restriction of HIV-1 may account for continued seronegativity in some of those having repeated sexual exposure. Identifying the host-virus interactions responsible for diminished in vitro susceptibility may contribute to the development of novel therapeutic strategies.

Objective To assess the safety of benzyl benzoate lotion (BBL) and permethrin, topical treatments for scabies, during pregnancy. Design A retrospective controlled cohort study. Population Refugee and migrant women attending antenatal clinics (ANC) on the Thai–Burmese border between August 1993 and April 2006. Methods Women treated with either BBL (25%) or permethrin (4%) were identified from a manual search of antenatal records. Each case of scabies was matched with four scabies-free controls for gravidity, age, smoking status, malaria, period of treatment and gestational age at treatment. Conditional Poisson regression was used to estimate risk ratios for outcomes of pregnancy (proportion of abortions, congenital abnormalities, neonatal deaths, stillbirths and premature babies), mean birthweight and estimated median gestational age, for scabies and scabies-free women, independently for BBL and permethrin. Results There were no statistically significant differences in pregnancy outcomes between women who were treated with either BBL (n= 444) compared with their matched controls (n= 1,776) or permethrin (n= 196) treated women and their matched controls (n= 784). Overall, only 10.9% (n= 66) of treatments were in the first trimester. Retreatment rates were higher with BBL 16.4%, than permethrin 9.7%, P= 0.038. Scabies was more common during cooler periods. Conclusion We found no evidence of adverse effects on pregnancy outcome due to topical 25% BBL or 4% permethrin.

CD4+ T cell depletion and dysfunction are the hallmark of HIV-1 disease. Our primary objectives were to define the diversity of the CD4+ T cell receptor Vbeta (TCRBV) repertoire in subjects with HIV-1 infection by CDR3 (complementarity-determining region) length spectratyping and to determine the correlates of CD4+ repertoire perturbation and its restoration with virus suppression. During primary HIV-1 infection, the proportion of perturbed CD4+ TCRBV subfamilies was significantly greater compared to HIV-1 seronegative subjects (median 48% vs. 10%, P = 0.0159). During chronic infection, the extent of repertoire perturbation was significantly associated with higher levels of plasma viremia (Spearman Correlation coefficient, R = 0.65, P = 0.049) and disease progression. Restoration of the repertoire with antiretroviral therapy was variable despite adequate virologic suppression. We speculate that the use of immunomodulators as an adjunct to antiretroviral drugs may enhance immune reconstitution in persons with suboptimal increases in CD4+ T cell counts despite adequate virus suppression.

Sunlight and psoralen and ultraviolet A (PUVA) are risk factors for the development of squamous cell carcinoma (SCC) and, to a lesser extent, basal cell carcinoma (BCC). Ultraviolet B (UVB) therapy, used for the treatment of psoriasis, might also increase the risk of these tumors. We studied the relation of skin cancer incidence to UVB use among 1380 adult subjects enrolled in a long-term safety trial of PUVA therapy. We used negative binomial regression models to quantify the association between UVB and the development of non-melanoma skin cancer (NMSC), controlling for known confounders. High UVB exposure (≥300 treatments vs

Epidemiological studies have demonstrated that areca quid chewing can be an independent risk factor for developing esophageal cancer. However, no studies are available to elucidate the mechanisms of how areca induces carcinogenesis in the esophagus. Since the areca nut in Taiwan contains a high concentration of safrole, a well-known carcinogenic agent, we analyzed safrole-DNA adducts by the 32P-postlabelling method in tissue specimens from esophageal cancer patients. In total, we evaluated 47 patients with esophageal cancer (16 areca chewers and 31 non-chewers) who underwent esophagectomy at the National Taiwan University Hospital between 1996 and 2002. Of the individuals with a history of habitual areca chewing (14 cigarette smokers and two non-smokers), one of the tumor tissue samples and five of the normal esophageal mucosa samples were positive for safrole-DNA adducts. All patients positive for safrole-DNA adducts were also cigarette smokers. Such adducts could not be found in patients who did not chew areca, irrespective of their habits of alcohol consumption or cigarette smoking (p

Twin reversed arterial perfusion sequence and epigastric heteropagus conjoined twins may appear similar antenatally. Three-dimensional ultrasound evaluated the relationship of a completely formed fetus and an adjacent second body consisting of a pelvis with 2 lower extremities, confirming the final diagnosis when two-dimensional ultrasound was unsuccessful. Three-dimensional ultrasound is useful in diagnosing epigastric heteropagus conjoined twins.

To determine the influence of host genetics on human immunodeficiency virus (HIV) type 1 infection, we examined 94 repeatedly exposed seronegative (ES) individuals for polymorphisms in multiple genes and compared the results with those for 316 HIV-1-seropositive and 425 HIV-1-seronegative individuals. The frequency of homozygous C-C chemokine receptor (CCR) 5- Delta 32 was higher in ES (3.2%) than in HIV-1-seropositive individuals (0.0%; P=.012). However, the CCR5-59029A, CCR2-64I, stromal cell-derived factor (SDF)-1-3'A, RANTES (regulated on activation, normally T cell-expressed and -secreted)-403A, and RANTES-28G polymorphisms were not associated with resistance to HIV-1 infection. Furthermore, we identified novel variants in the DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin) repeat region and observed that heterozygous DC-SIGN reduced the risk of HIV-1 infection (3.2% in ES individuals vs. 0.0% in HIV-1-seropositive individuals; P=.011).