Common Genetic Variants Associated with Sudden Cardiac Death: The FinSCDgen Study

Background

Sudden cardiac death (SCD) accounts for up to half of cardiac mortality. The risk of SCD is heritable but the underlying genetic variants are largely unknown. We investigated whether common genetic variants predisposing to arrhythmia or related electrocardiographic phenotypes, including QT-interval prolongation, are associated with increased risk of SCD.

Methodology/Principal Findings

We studied the association between 28 candidate SNPs and SCD in a meta-analysis of four population cohorts (FINRISK 1992, 1997, 2002 and Health 2000, n = 27,629) and two forensic autopsy series (The Helsinki Sudden Death Study and The Tampere Autopsy Study, n = 694). We also studied the association between established cardiovascular risk factors and SCD. Causes of death were reviewed using registry-based health and autopsy data. Cox regression and logistic regression models were adjusted for age, sex, and geographic region. The total number of SCDs was 716. Two novel SNPs were associated with SCD: SCN5A rs41312391 (relative risk [RR] 1.27 per minor T allele, 95% CI 1.11–1.45, P = 3.4×10⁻⁴) and rs2200733 in 4q25 (RR 1.28 per minor T allele, 95% CI 1.11–1.48, P = 7.9×10⁻⁴). We also replicated the associations for 9p21 (rs2383207, RR 1.13 per G allele, 95% CI 1.01–1.26, P = 0.036), as well as for male sex, systolic blood pressure, diabetes, cigarette smoking, low physical activity, coronary heart disease, and digoxin use (P<0.05).

Conclusions/Significance

Two novel genetic variants, one in the cardiac sodium channel gene SCN5A and another at 4q25 previously associated with atrial fibrillation, are associated with SCD.     

Adolescence as risk factor for adverse pregnancy outcome in Central Africa--a cross-sectional study

Background

Sub-Saharan Africa has the highest rates of maternal and neonatal mortality worldwide. Young maternal age at delivery has been proposed as risk factor for adverse pregnancy outcome, yet there is insufficient data from Sub-Saharan Africa. The present study aimed to investigate the influence of maternal adolescence on pregnancy outcomes in the Central African country Gabon.

Methodology and Principal Findings

Data on maternal age, parity, birth weight, gestational age, maternal Plasmodium falciparum infection, use of bednets, and intake of intermittent preventive treatment of malaria in pregnancy were collected in a cross-sectional survey in 775 women giving birth in three mother-child health centers in Gabon. Adolescent women (≤16 years of age) had a significantly increased risk to deliver a baby with low birth weight in univariable analysis (22.8%, 13/57, vs. 9.3%, 67/718, OR: 2.9, 95% CI: 1.5–5.6) and young maternal age showed a statistically significant association with the risk for low birth weight in multivariable regression analysis after correction for established risk factors (OR: 2.7; 95% CI: 1.1–6.5). In further analysis adolescent women were shown to attend significantly less antenatal care visits than adult mothers (3.3±1.9 versus 4.4±1.9 mean visits, p<0.01, n = 356) and this difference accounted at least for part of the excess risk for low birth weight in adolescents.

Conclusion

Our data demonstrate the importance of adolescent age as risk factor for adverse pregnancy outcome. Antenatal care programs specifically tailored for the needs of adolescents may be necessary to improve the frequency of antenatal care visits and pregnancy outcomes in this risk group in Central Africa.     

Reduction of Maternal Mortality with Highly Active Antiretroviral Therapy in a Large Cohort of HIV-Infected Pregnant Women in Malawi and Mozambique

Background

HIV infection is a major contributor to maternal mortality in resource-limited settings. The Drug Resource Enhancement Against AIDS and Malnutrition Programme has been promoting HAART use during pregnancy and postpartum for Prevention-of-mother-to-child-HIV transmission (PMTCT) irrespective of maternal CD4 cell counts since 2002.

Methods

Records for all HIV+ pregnancies followed in Mozambique and Malawi from 6/2002 to 6/2010 were reviewed. The cohort was comprised by pregnancies where women were referred for PMTCT and started HAART during prenatal care (n = 8172, group 1) and pregnancies where women were referred on established HAART (n = 1978, group 2).

Results

10,150 pregnancies were followed. Median (IQR) baseline values were age 26 years (IQR:23–30), CD4 count 392 cells/mm³ (IQR:258–563), Viral Load log₁₀ 3.9 (IQR:3.2–4.4), BMI 23.4 (IQR:21.5–25.7), Hemoglobin 10.0 (IQR: 9.0–11.0). 101 maternal deaths (0.99%) occurred during pregnancy to 6 weeks postpartum: 87 (1.1%) in group 1 and 14 (0.7%) in group 2. Mortality was 1.3% in women with <than 350 CD4 cells/mm³ and 0.7% in women with greater than 350 CD4s cells/mm³ [OR = 1.9 (CL 1.3–2.9) p = 0.001]. Mortality was higher in patients with shorter antenatal HAART: 22/991 (2.2%) if less than 30 days and 79/9159 (0.9%) if 31 days or greater [OR = 2.6 (CL 1.6–4.2) p<0.001]. By multivariate analysis, shorter antenatal HAART (p<0.001), baseline values for CD4 cell count (p = 0.012), hemoglobin (p = 0.02), and BMI (p<0.001) were associated with mortality. Four years later, survival was 92% for women with shorter antenatal HAART and 98% for women on established therapy prior to pregnancy, p = 0.001.

Conclusions

Antiretrovirals for PMTCT purposes have significant impact on maternal mortality as do CD4 counts and nutritional status. In resource-limited settings, PMTCT programs should provide universal HAART to all HIV+ pregnant women given its impact in prevention of maternal death.     

A signature of maternal anti-fetal rejection in spontaneous preterm birth: chronic chorioamnionitis, anti-human leukocyte antigen antibodies, and C4d

Background

Chronic chorioamnionitis is found in more than one-third of spontaneous preterm births. Chronic chorioamnionitis and villitis of unknown etiology represent maternal anti-fetal cellular rejection. Antibody-mediated rejection is another type of transplantation rejection. We investigated whether there was evidence for antibody-mediated rejection against the fetus in spontaneous preterm birth.

Methods and Findings

This cross-sectional study included women with (1) normal pregnancy and term delivery (n = 140) and (2) spontaneous preterm delivery (n = 140). We analyzed maternal and fetal sera for panel-reactive anti-HLA class I and class II antibodies, and determined C4d deposition on umbilical vein endothelium by immunohistochemistry. Maternal anti-HLA class I seropositivity in spontaneous preterm births was higher than in normal term births (48.6% vs. 32.1%, p = 0.005). Chronic chorioamnionitis was associated with a higher maternal anti-HLA class I seropositivity (p<0.01), significant in preterm and term birth. Villitis of unknown etiology was associated with increased maternal and fetal anti-HLA class I and II seropositivity (p<0.05, for each). Fetal anti-HLA seropositivity was closely related to maternal anti-HLA seropositivity in both groups (p<0.01, for each). C4d deposition on umbilical vein endothelium was more frequent in preterm labor than term labor (77.1% vs. 11.4%, p<0.001). Logistic regression analysis revealed that chronic chorioamnionitis (OR = 6.10, 95% CI 1.29–28.83), maternal anti-HLA class I seropositivity (OR = 5.90, 95% CI 1.60–21.83), and C4d deposition on umbilical vein endothelium (OR = 36.19, 95% CI 11.42–114.66) were associated with preterm labor and delivery.

Conclusions

A major subset of spontaneous preterm births has a signature of maternal anti-fetal cellular and antibody-mediated rejections with links to fetal graft-versus-host disease and alloimmune reactions.     

Ethnic Differences in Cardiometabolic Risk Profile at Age 5-6 Years: The ABCD Study

Background

To examine ethnic differences in cardiometabolic risk profile in early age, and explore whether such differences can be explained by differences in body mass index (BMI) or waist circumference (WC).

Method

Anthropometric measurements, blood pressure and (in a subsample) fasting blood were collected during a health check of 2,509 children aged 5–6 years. Four ethnic groups were distinguished: Dutch (n = 2,008; blood n = 1,300), African descent (n = 199; blood n = 105), Turkish (n = 108; blood n = 57) and Moroccan (n = 194; blood n = 94). Ethnic differences in diastolic and systolic blood pressure (DBP/SBP), fasting glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride levels were determined and the explanatory role of BMI and WC was examined with regression analysis.

Results

After adjustment for confounders, African descent children showed higher DBP (β2.22 mmHg; 95%CI:1.09–3.36) and HDL levels (β:0.09 mmol/l; 95%CI:0.03–0.16) compared to Dutch children (reference group). Turkish children showed higher SBP (β:1.89 mmHg; 95%CI:0.25–3.54), DBP (β:2.62 mmHg; 95%CI:1.11–4.13), glucose (β:0.12 mmol/L; 95%CI:0.00–0.25) and triglyceride levels (β:0.13 mmol/L; 95%CI:0.02–0.25). Higher BMI values were found in all non–Dutch groups (differences ranged from 0.53–1.03 kg/m²) and higher WC in Turkish (β:1.68 cm; 95%CI:0.99–2.38) and Moroccan (β:1.65 cm; 95%CI:1.11–2.19) children. BMI and WC partly explained the higher SBP/DBP and triglyceride levels in Turkish children.

Conclusion

Ethnic differences in cardiometabolic profile exist early in life and are partly explained by differences in BMI and WC. African children showed favourable HDL levels and Turkish children the most unfavourable overall profile, whereas their Moroccan peers have less increased cardiometabolic risk in spite of their high BMI and WC.     

Interaction between Alcohol Consumption and CYP 2C19 Gene Polymorphism in Relation to Oesophageal Squamous Cell Carcinoma

Objectives

The purpose of this study is to explore the relationship between the interactions of CYP2C19 gene polymorphisms and several environmental factors and oesophageal squamous cell carcinoma (OSCC).

Methods

In a case-control study of OSCC patients (n = 350) and healthy controls (n = 350), we investigated the roles of polymorphism in the CYP2C19 gene by the use of polymerase chain reaction - restriction fragment length polymorphism (PCR – RFLP) analysis.

Results

The CYP2C19^*3 AG+AA genotype was significantly more prevalent in OSCC patients (10.0% versus 3.43%; P<0.01). Multiple logistic regression analysis showed drinking (OR: 5.603, 95% CI: 3.431–11.112; P = 0.005) and smoking (OR: 4.341, 95% CI: 3.425–10.241; P = 0.001) was the independent risk factor of OSCC respectively, and there were significant interaction between CYP2C19^*3 and drinking (OR: 8.747, 95% CI: 6.321–18.122; P = 0.009).

Conclusions

The CYP2C19^*3 polymorphism and OSCC were synergistically and significantly associated in Chinese Han patients.     

Intake of Gnetum Africanum and Dacryodes Edulis, Imbalance of Oxidant/Antioxidant Status and Prevalence of Diabetic Retinopathy in Central Africans

Objective

To estimate the prevalence of DR and to correlate cardiometabolic, sociodemographic, and oxidant/antioxidant imbalance data to the prevalence of DR.

Design

This case-control study included type 2 DM (T2 DM) patients with DR (n = 66), T2 DM patients without DR (N = 84), and healthy controls (n = 45) without DR, in Kinshasa town. Diet, albuminemia, serum vitamins, and 8-isoprostane were examined.

Results

No intake of safou (OR = 2.7 95% CI 1.2–5.8; P = 0.014), low serum albumin <4.5 g/dL (OR-2.9 95% CI 1.4–5.9; P = 0.003), no intake of fumbwa (OR = 2.8 95% CI 1.2–6.5; P = 0.014), high 8-isoprostane (OR = 14.3 95% CI 4.5–46; P<0.0001), DM duration ≥5 years (OR = 3.8 95% CI 1.6–9.1; P = 0.003), and low serum vitamin C (OR = 4.5 95% CI 1.3–15.5; P = 0.016) were identified as the significant independent determinants of DR.

Conclusion

The important role of oxidant/antioxidant status imbalance and diet is demonstrated in DR.     

Financial incentive increases CPAP acceptance in patients from low socioeconomic background

Objective

We explored whether financial incentives have a role in patients′ decisions to accept (purchase) a continuous positive airway pressure (CPAP) device in a healthcare system that requires cost sharing.

Design

Longitudinal interventional study.

Patients

The group receiving financial incentive (n = 137, 50.8±10.6 years, apnea/hypopnea index (AHI) 38.7±19.9 events/hr) and the control group (n = 121, 50.9±10.3 years, AHI 39.9±22) underwent attendant titration and a two-week adaptation to CPAP. Patients in the control group had a co-payment of $330–660; the financial incentive group paid a subsidized price of $55.

Results

CPAP acceptance was 43% greater (p = 0.02) in the financial incentive group. CPAP acceptance among the low socioeconomic strata (n = 113) (adjusting for age, gender, BMI, tobacco smoking) was enhanced by financial incentive (OR, 95% CI) (3.43, 1.09–10.85), age (1.1, 1.03–1.17), AHI (>30 vs. <30) (4.87, 1.56–15.2), and by family/friends who had positive experience with CPAP (4.29, 1.05–17.51). Among average/high-income patients (n = 145) CPAP acceptance was affected by AHI (>30 vs. <30) (3.16, 1.14–8.75), living with a partner (8.82, 1.03–75.8) but not by the financial incentive. At one-year follow-up CPAP adherence was similar in the financial incentive and control groups, 35% and 39%, respectively (p = 0.82). Adherence rate was sensitive to education (+yr) (1.28, 1.06–1.55) and AHI (>30 vs. <30) (5.25, 1.34–18.5).

Conclusions

Minimizing cost sharing reduces a barrier for CPAP acceptance among low socioeconomic status patients. Thus, financial incentive should be applied as a policy to encourage CPAP treatment, especially among low socioeconomic strata patients.     

Job strain and alcohol intake: a collaborative meta-analysis of individual-participant data from 140,000 men and women

Background

The relationship between work-related stress and alcohol intake is uncertain. In order to add to the thus far inconsistent evidence from relatively small studies, we conducted individual-participant meta-analyses of the association between work-related stress (operationalised as self-reported job strain) and alcohol intake.

Methodology and Principal Findings

We analysed cross-sectional data from 12 European studies (n = 142 140) and longitudinal data from four studies (n = 48 646). Job strain and alcohol intake were self-reported. Job strain was analysed as a binary variable (strain vs. no strain). Alcohol intake was harmonised into the following categories: none, moderate (women: 1–14, men: 1–21 drinks/week), intermediate (women: 15–20, men: 22–27 drinks/week) and heavy (women: >20, men: >27 drinks/week). Cross-sectional associations were modelled using logistic regression and the results pooled in random effects meta-analyses. Longitudinal associations were examined using mixed effects logistic and modified Poisson regression. Compared to moderate drinkers, non-drinkers and (random effects odds ratio (OR): 1.10, 95% CI: 1.05, 1.14) and heavy drinkers (OR: 1.12, 95% CI: 1.00, 1.26) had higher odds of job strain. Intermediate drinkers, on the other hand, had lower odds of job strain (OR: 0.92, 95% CI: 0.86, 0.99). We found no clear evidence for longitudinal associations between job strain and alcohol intake.

Conclusions

Our findings suggest that compared to moderate drinkers, non-drinkers and heavy drinkers are more likely and intermediate drinkers less likely to report work-related stress.     

Analysis of clonal type-specific antibody reactions in Toxoplasma gondii seropositive humans from Germany by peptide-microarray

Background

Different clonal types of Toxoplasma gondii are thought to be associated with distinct clinical manifestations of infections. Serotyping is a novel technique which may allow to determine the clonal type of T. gondii humans are infected with and to extend typing studies to larger populations which include infected but non-diseased individuals.

Methodology

A peptide-microarray test for T. gondii serotyping was established with 54 previously published synthetic peptides, which mimic clonal type-specific epitopes. The test was applied to human sera (n = 174) collected from individuals with an acute T. gondii infection (n = 21), a latent T. gondii infection (n = 53) and from T. gondii-seropositive forest workers (n = 100).

Findings

The majority (n = 124; 71%) of all T. gondii seropositive human sera showed reactions against synthetic peptides with sequences specific for clonal type II (type II peptides). Type I and type III peptides were recognized by 42% (n = 73) or 16% (n = 28) of the human sera, respectively, while type II–III, type I–III or type I–II peptides were recognized by 49% (n = 85), 36% (n = 62) or 14% (n = 25) of the sera, respectively. Highest reaction intensities were observed with synthetic peptides mimicking type II-specific epitopes. A proportion of the sera (n = 22; 13%) showed no reaction with type-specific peptides. Individuals with acute toxoplasmosis reacted with a statistically significantly higher number of peptides as compared to individuals with latent T. gondii infection or seropositive forest workers.

Conclusions

Type II-specific reactions were overrepresented and higher in intensity in the study population, which was in accord with genotyping studies on T. gondii oocysts previously conducted in the same area. There were also individuals with type I- or type III-specific reactions. Well-characterized reference sera and further specific peptide markers are needed to establish and to perform future serotyping approaches with higher resolution.     

Nitrosative and oxidative stresses contribute to post-ischemic liver injury following severe hemorrhagic shock: the role of hypoxemic resuscitation

Purpose

Hemorrhagic shock and resuscitation is frequently associated with liver ischemia-reperfusion injury. The aim of the study was to investigate whether hypoxemic resuscitation attenuates liver injury.

Methods

Anesthetized, mechanically ventilated New Zealand white rabbits were exsanguinated to a mean arterial pressure of 30 mmHg for 60 minutes. Resuscitation under normoxemia (Normox-Res group, n = 16, PaO₂ = 95–105 mmHg) or hypoxemia (Hypox-Res group, n = 15, PaO₂ = 35–40 mmHg) followed, modifying the FiO₂. Animals not subjected to shock constituted the sham group (n = 11, PaO₂ = 95–105 mmHg). Indices of the inflammatory, oxidative and nitrosative response were measured and histopathological and immunohistochemical studies of the liver were performed.

Results

Normox-Res group animals exhibited increased serum alanine aminotransferase, tumor necrosis factor - alpha, interleukin (IL) -1β and IL-6 levels compared with Hypox-Res and sham groups. Reactive oxygen species generation, malondialdehyde formation and myeloperoxidase activity were all elevated in Normox-Res rabbits compared with Hypox-Res and sham groups. Similarly, endothelial NO synthase and inducible NO synthase mRNA expression was up-regulated and nitrotyrosine immunostaining increased in animals resuscitated normoxemically, indicating a more intense nitrosative stress. Hypox-Res animals demonstrated a less prominent histopathologic injury which was similar to sham animals.

Conclusions

Hypoxemic resuscitation prevents liver reperfusion injury through attenuation of the inflammatory response and oxidative and nitrosative stresses.     

Gender inequity norms are associated with increased male-perpetrated rape and sexual risks for HIV infection in Botswana and Swaziland

Background

There is limited empirical research on the underlying gender inequity norms shaping gender-based violence, power, and HIV risks in sub-Saharan Africa, or how risk pathways may differ for men and women. This study is among the first to directly evaluate the adherence to gender inequity norms and epidemiological relationships with violence and sexual risks for HIV infection.

Methods

Data were derived from population-based cross-sectional samples recruited through two-stage probability sampling from the 5 highest HIV prevalence districts in Botswana and all districts in Swaziland (2004–5). Based on evidence of established risk factors for HIV infection, we aimed 1) to estimate the mean adherence to gender inequity norms for both men and women; and 2) to model the independent effects of higher adherence to gender inequity norms on a) male sexual dominance (male-controlled sexual decision making and rape (forced sex)); b) sexual risk practices (multiple/concurrent sex partners, transactional sex, unprotected sex with non-primary partner, intergenerational sex).

Findings

A total of 2049 individuals were included, n = 1255 from Botswana and n = 796 from Swaziland. In separate multivariate logistic regression analyses, higher gender inequity norms scores remained independently associated with increased male-controlled sexual decision making power (AORmen = 1.90, 95%CI:1.09–2.35; AORwomen = 2.05, 95%CI:1.32–2.49), perpetration of rape (AORmen = 2.19 95%CI:1.22–3.51), unprotected sex with a non-primary partner (AORmen = 1.90, 95%CI:1.14–2.31), intergenerational sex (AORwomen = 1.36, 95%CI:1.08–1.79), and multiple/concurrent sex partners (AORmen = 1.42, 95%CI:1.10–1.93).

Interpretation

These findings support the critical evidence-based need for gender-transformative HIV prevention efforts including legislation of women''s rights in two of the most HIV affected countries in the world.     

Novel, objective, multivariate biomarkers composed of plasma amino acid profiles for the diagnosis and assessment of inflammatory bowel disease

Background

Inflammatory bowel disease (IBD) is a chronic intestinal disorder that is associated with a limited number of clinical biomarkers. In order to facilitate the diagnosis of IBD and assess its disease activity, we investigated the potential of novel multivariate indexes using statistical modeling of plasma amino acid concentrations (aminogram).

Methodology and Principal Findings

We measured fasting plasma aminograms in 387 IBD patients (Crohn''s disease (CD), n = 165; ulcerative colitis (UC), n = 222) and 210 healthy controls. Based on Fisher linear classifiers, multivariate indexes were developed from the aminogram in discovery samples (CD, n = 102; UC, n = 102; age and sex-matched healthy controls, n = 102) and internally validated. The indexes were used to discriminate between CD or UC patients and healthy controls, as well as between patients with active disease and those in remission. We assessed index performances using the area under the curve of the receiver operating characteristic (ROC AUC). We observed significant alterations to the plasma aminogram, including histidine and tryptophan. The multivariate indexes established from plasma aminograms were able to distinguish CD or UC patients from healthy controls with ROC AUCs of 0.940 (95% confidence interval (CI): 0.898–0.983) and 0.894 (95%CI: 0.853–0.935), respectively in validation samples (CD, n = 63; UC, n = 120; healthy controls, n = 108). In addition, other indexes appeared to be a measure of disease activity. These indexes distinguished active CD or UC patients from each remission patients with ROC AUCs of 0.894 (95%CI: 0.853–0.935) and 0.849 (95%CI: 0.770–0.928), and correlated with clinical disease activity indexes for CD (r_s = 0.592, 95%CI: 0.385–0.742, p<0.001) or UC (r_s = 0.598, 95%CI: 0.452–0.713, p<0.001), respectively.

Conclusions and Significance

In this study, we demonstrated that established multivariate indexes composed of plasma amino acid profiles can serve as novel, non-invasive, objective biomarkers for the diagnosis and monitoring of IBD, providing us with new insights into the pathophysiology of the disease.     

High incidence of unplanned pregnancy after antiretroviral therapy initiation: findings from a prospective cohort study in South Africa

Background

Increased fertility rates in HIV-infected women receiving antiretroviral therapy (ART) have been attributed to improved immunological function; it is unknown to what extent the rise in pregnancy rates is due to unintended pregnancies.

Methods

Non-pregnant women ages 18–35 from four public-sector ART clinics in Johannesburg, South Africa, were enrolled into a prospective cohort and followed from August 2009–March 2011. Fertility intentions, contraception and pregnancy status were measured longitudinally at participants'' routine ART clinic visits.

Findings

Of the 850 women enrolled, 822 (97%) had at least one follow-up visit and contributed 745.2 person-years (PY) at-risk for incident pregnancy. Overall, 170 pregnancies were detected in 161 women (incidence rate [IR]: 21.6/100 PY [95% confidence interval (CI): 18.5–25.2]). Of the 170 pregnancies, 105 (62%) were unplanned. Unmet need for contraception was 50% higher in women initiating ART in the past year as compared to women on ART>1 year (prevalence ratio 1.5 [95% CI: 1.1–2.0]); by two years post-ART initiation, nearly one quarter of women had at least one unplanned pregnancy. Cumulative incidence of pregnancy was equally high among recent ART initiators and ART experienced participants: 23.9% [95% CI: 16.4–34.1], 15.9% [12.0–20.8], and 21.0% [16.8–26.1] for women on ART 0–1 yr, >1 yr–2 yrs, and >2 yrs respectively (log-rank, p = 0.54). Eight hormonal contraceptive failures were detected [IR: 4.4 [95% CI: 2.2–8.9], 7/8 among women using injectable methods. Overall 47% (80/170) of pregnancies were not carried to term.

Conclusions

Rates of unintended pregnancies among women on ART are high, including women recently initiating ART with lower CD4 counts and higher viral loads. A substantial burden of pregnancy loss was observed. Integration of contraceptive services and counselling into ART care is necessary to reduce maternal and child health risks related to mistimed and unwanted pregnancies. Further research into injectable contraceptive failures on ART is warranted.     

Short fetal leukocyte telomere length and preterm prelabor rupture of the membranes

Background

Rupture of the fetal membranes is a common harbinger of imminent labor and delivery. Telomere shortening is a surrogate for oxidative stress (OS) and senescence. Fetal leukocyte and placental membrane DNA telomere lengths were evaluated to determine their association with preterm prelabor rupture of the membranes (pPROM) or spontaneous preterm births with intact membranes (PTB), compared to term birth.

Methods

Telomere lengths were quantified in cord blood leukocytes (n = 133) from three major groups: 1) pPROM (n = 28), 2) PTB (n = 69) and 3) uncomplicated full term births (controls, n = 35), using real-time quantitative PCR. Placental membrane specimens (n = 18) were used to correlate fetal leukocyte and placental telomere lengths. Telomere length differences among the groups were analyzed by ANOVA. Pearson correlation coefficients determined relationships between leukocyte and placental membrane telomere lengths.

Results

In pregnancies with intact membranes, fetal leukocyte telomere length was inversely proportional to gestational age. The mean telomere length decreased as gestation progressed, with the shortest at term. pPROM had telomere lengths (9962±3124 bp) that were significantly shorter than gestational age-matched PTB (11546±4348 bp, p = 0.04), but comparable to term births (9011±2497 bp, p = 0.31). Secondary analyses revealed no effects of race (African American vs. Caucasian) or intraamniotic infection on telomere length. A strong Pearson''s correlation was noted between fetal leukocyte and placental membrane telomere lengths (ρ = 0.77; p<0.01).

Conclusions

Fetal leukocyte telomere length is reduced in pPROM compared to PTB but is similar to term births. pPROM represents a placental membrane disease likely mediated by OS-induced senescence.     

The effectiveness of online cognitive behavioral treatment in routine clinical practice

Context

Randomized controlled trails have identified online cognitive behavioral therapy as an efficacious intervention in the management of common mental health disorders.

Objective

To assess the effectiveness of online CBT for different mental disorders in routine clinical practice.

Design

An uncontrolled before-after study, with measurements at baseline, posttest, 6-week follow-up, and 1-year follow-up.

Participants & Setting

1500 adult patients (female: 67%; mean age: 40 years) with a GP referral for psychotherapy were treated at a Dutch online mental health clinic for symptoms of depression (n = 413), panic disorder (n = 139), posttraumatic stress (n = 478), or burnout (n = 470).

Interventions

Manualized, web-based, therapist-assisted CBT, of which the efficacy was previously demonstrated in a series of controlled trials. Standardized duration of treatment varied from 5 weeks (online CBT for Posttraumatic stress) to 16 weeks (online CBT for Depression).

Main Outcome Measures

Validated self-report questionnaires of specific and general psychopathology, including the Beck Depression Inventory, the Impact of Event Scale, the Panic Disorder Severity Scale-Self Report, the Oldenburg Burnout Inventory, and the Depression Anxiety Stress Scales.

Results

Treatment adherence was 71% (n = 1071). Study attrition was 21% at posttest, 33% at 6-week FU and 65% at 1-year FU. Mixed-model repeated measures regression identified large short-term reductions in all measures of primary symptoms (d = 1.9±0.2 to d = 1.2±0.2; P<.001), which sustained up to one year after treatment. At posttest, rates of reliable improvement and recovery were 71% and 52% in the completer sample (full sample: 55%/40%). Patient satisfaction was high.

Conclusions

Results suggest that online therapist-assisted CBT may be as effective in routine practice as it is in clinical trials. Although pre-treatment withdrawal and long-term outcomes require further study, results warrant continued implementation of online CBT.     

Challenges in Developing a Validated Biomarker for Angiogenesis Inhibitors: The Motesanib Experience

Purpose

We sought to develop placental growth factor as a predictive pharmacodynamic biomarker for motesanib efficacy as first-line therapy in patients with advanced nonsquamous non–small-cell lung cancer.

Experimental Design

Placental growth factor was evaluated at baseline and study week 4 (after 3 weeks treatment) in an exploratory analysis of data from a randomized phase 2 study of motesanib 125 mg once daily plus carboplatin/paclitaxel and in a prespecified analysis of data from a randomized, double-blind phase 3 study of motesanib 125 mg once daily plus carboplatin/paclitaxel vs placebo plus carboplatin/paclitaxel (MONET1). Associations between fold-change from baseline in placental growth factor and overall survival were evaluated using Cox proportional hazards models.

Results

In the phase 2 study, serum placental growth factor increased from baseline a mean 2.8-fold at study week 4. Patients with ≥2.2-fold change from baseline in placental growth factor (n = 18) had significantly longer overall survival than those with <2.2-fold change (n = 19; 22.9 vs 7.9 months; hazard ratio, 0.30; 95% CI, 0.12–0.74; P = 0.009). Consequently, placental growth factor was investigated as a pharmacodynamic biomarker in the phase 3 MONET1 study. There was no association between log-transformed placental growth factor fold-change from baseline to week 4 (continuous variable) and overall survival (hazard ratio, 0.98; 95% CI, 0.79–1.22; P = 0.868). MONET1 did not meet its primary endpoint of overall survival. Likewise, median overall survival was similar among patients with ≥2.0-fold change in placental growth factor (n = 229) compared with <2.0-fold change (n = 127; 14.8 vs 13.8 months; hazard ratio, 0.88; 95% CI, 0.67–1.15, P = 0.340).

Conclusions

Our results illustrate the challenges of successfully translating phase 2 biomarker results into phase 3 studies.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00460317","term_id":"NCT00460317"}}NCT00460317, {"type":"clinical-trial","attrs":{"text":"NCT00369070","term_id":"NCT00369070"}}NCT00369070     

Risk factors for obesity: further evidence for stronger effects on overweight children and adolescents compared to normal-weight subjects

Background

We recently showed that in preschoolers risk factors for overweight show stronger associations with BMI in children with high BMI values. However, it is unclear whether these findings might also pertain to adolescents.

Methods

We extracted data on 3–10 year-old (n = 7,237) and 11–17 year-old (n = 5,986) children from a representative cross-sectional German health survey (KiGGS) conducted between 2003 and 2006 and calculated quantile regression models for each age group. We used z-scores of children''s body mass index (BMI) as outcome variable and maternal BMI, maternal smoking in pregnancy, low parental socioeconomic status, exclusive formula-feeding and high TV viewing time as explanatory variables.

Results

In both age groups, the estimated effects of all risk factors except formula-feeding on BMI z-score were greatest for children with the highest BMI z-score. The median BMI z-score of 11–17 year-old children with high TV viewing time, for example, was 0.11 [95% CI: 0.03, 0.19] units higher than the median BMI z-score of teenage children with low TV viewing time. This risk factor was associated with an average difference of 0.18 [0.06, 0.30] units at the 90^th percentile of BMI z-score and of 0.20 [0.07, 0.33] units at the 97^th percentile.

Conclusions

We confirmed that risk factors for childhood overweight are associated with greater shifts in the upper parts of the children''s BMI distribution than in the middle and lower parts. These findings pertain also to teenagers and might possibly help to explain the secular shift in the upper BMI percentiles in children and adolescents.     

Elevated peripheral visfatin levels in narcoleptic patients

Objective

Narcolepsy is a severe sleep disorder that is characterized by excessive daytime sleepiness, cataplexies and a tendency towards obesity. Recent discoveries indicate that the major pathophysiology is a loss of hypocretin (orexin) producing neurons due to immunologically mediated degeneration. Visfatin is a recently described proinflammatory adipokine. It is identical to the immune modulating pre-B-cell colony enhancing factor (PBEF). Our study examines the hypothesis that visfatin levels are altered in narcoleptic patients.

Methods

For the analysis, a total of n = 54 patients (n = 18 males and n = 36 females) with the diagnosis of narcolepsy according to DSM-IV and the International Classification of Sleep Disorders were examined (BMI mean 30.3±5.5, age mean 52.5±16.1 years). As a control group 39 unrelated (n = 12 males and n = 27 females) healthy volunteers with no sleep disorder according to DSM-IV were included (BMI mean 28.5±4.6, age mean 51.1±13.6 years). Peripheral visfatin levels were measured using a commercial enzyme immunoassay kit with a measurement range from 0.1–1000 ng/ml. Narcolepsy symptoms, severity and frequency of symptoms as well as the total duration of various aspects of the symptomatology were assessed by unstructured and structured clinical interviews in including the Stanford Center for Narcolepsy Sleep Inventory.

Results

Circulating visfatin was found to be significantly increased in HLA DR2 positive narcoleptic patients compared to controls.

Conclusion

Taken together, our results add to the evidence of disturbed immunological regulation in patients with narcolepsy.