The Association of Growth Differentiation Factor-15 with Left Ventricular Hypertrophy in Hypertensive Patients

Growth differentiation factor-15 (GDF-15) has been identified as an endogenous anti-hypertrophy effect. However, the association of plasma GDF-15 levels with left ventricular hypertrophy (LVH) in hypertension is poorly understood. We investigate the effect of plasma GDF-15 levels on left ventricular hypertrophy (LVH) in hypertension. We measured the plasma levels of GDF-15 in 299 untreated hypertensive patients which consisted of 99 with LVH and 200 without LVH using immunoradiometric assay. All subjects were examined by the ultrasonic cardiograph to determine Left ventricular (LV) internal diameters, septal thickness, and posterior wall thickness. The associations of GDF-15 with left ventricular mass index (LVMI), LV end-systolic and –diastolic diameters, LV wall thickness, and LV ejection fraction were evaluated. We found that plasma GDF-15 levels in hypertensive patients with LVH [median 1101, 25th–75th percentiles (879–1344) ng/L] were higher than that in hypertensive patients without LVH [median 516, 25th–75th percentiles (344–640) ng/L] (P<0.001). After adjustment for traditional covariates, plasma GDF-15 levels were independently related to LVMI (R² = 0.53; β = 0.624, P<0.001), LV interventricular septal thickness (R² = 0.23; β = 0.087, P<0.01) and LV posterior wall thickness (R² = 0.26; β = 0.103, P<0.05). Our cross-sectional data on a hospital-based sample indicate that plasma GDF-15 levels are associated with LVH in hypertensive patients.     

Assessment of the AquaCrop Model for Use in Simulation of Irrigated Winter Wheat Canopy Cover,Biomass, and Grain Yield in the North China Plain

Improving winter wheat water use efficiency in the North China Plain (NCP), China is essential in light of current irrigation water shortages. In this study, the AquaCrop model was used to calibrate, and validate winter wheat crop performance under various planting dates and irrigation application rates. All experiments were conducted at the Xiaotangshan experimental site in Beijing, China, during seasons of 2008/2009, 2009/2010, 2010/2011 and 2011/2012. This model was first calibrated using data from 2008/2009 and 2009/2010, and subsequently validated using data from 2010/2011 and 2011/2012. The results showed that the simulated canopy cover (CC), biomass yield (BY) and grain yield (GY) were consistent with the measured CC, BY and GY, with corresponding coefficients of determination (R²) of 0.93, 0.91 and 0.93, respectively. In addition, relationships between BY, GY and transpiration (T), (R² = 0.57 and 0.71, respectively) was observed. These results suggest that frequent irrigation with a small amount of water significantly improved BY and GY. Collectively, these results indicate that the AquaCrop model can be used in the evaluation of various winter wheat irrigation strategies. The AquaCrop model predicted winter wheat CC, BY and GY with acceptable accuracy. Therefore, we concluded that AquaCrop is a useful decision-making tool for use in efforts to optimize wheat winter planting dates, and irrigation strategies.     

Trends in First-Line Antiretroviral Therapy in Asia: Results from the TREAT Asia HIV Observational Database

Background

Antiretroviral therapy (ART) has evolved rapidly since its beginnings. This analysis describes trends in first-line ART use in Asia and their impact on treatment outcomes.

Methods

Patients in the TREAT Asia HIV Observational Database receiving first-line ART for ≥6 months were included. Predictors of treatment failure and treatment modification were assessed.

Results

Data from 4662 eligible patients was analysed. Patients started ART in 2003–2006 (n = 1419), 2007–2010 (n = 2690) and 2011–2013 (n = 553). During the observation period, tenofovir, zidovudine and abacavir use largely replaced stavudine. Stavudine was prescribed to 5.8% of ART starters in 2012/13. Efavirenz use increased at the expense of nevirapine, although both continue to be used extensively (47.5% and 34.5% of patients in 2012/13, respectively). Protease inhibitor use dropped after 2004. The rate of treatment failure or modification declined over time (22.1 [95%CI 20.7–23.5] events per 100 patient/years in 2003–2006, 15.8 [14.9–16.8] in 2007–2010, and 11.6 [9.4–14.2] in 2011–2013). Adjustment for ART regimen had little impact on the temporal decline in treatment failure rates but substantially attenuated the temporal decline in rates of modification due to adverse event. In the final multivariate model, treatment modification due to adverse event was significantly predicted by earlier period of ART initiation (hazard ratio 0.52 [95%CI 0.33–0.81], p = 0.004 for 2011–2013 versus 2003–2006), older age (1.56 [1.19–2.04], p = 0.001 for ≥50 years versus <30years), female sex (1.29 [1.11–1.50], p = 0.001 versus male), positive hepatitis C status (1.33 [1.06–1.66], p = 0.013 versus negative), and ART regimen (11.36 [6.28–20.54], p<0.001 for stavudine-based regimens versus tenofovir-based).

Conclusions

The observed trends in first-line ART use in Asia reflect changes in drug availability, global treatment recommendations and prescriber preferences over the past decade. These changes have contributed to a declining rate of treatment modification due to adverse event, but not to reductions in treatment failure.     

Comparison and Relative Utility of Inequality Measurements: As Applied to Scotland’s Child Dental Health

This study compared and assessed the utility of tests of inequality on a series of very large population caries datasets. National cross-sectional caries datasets for Scotland’s 5-year-olds in 1993/94 (n = 5,078); 1995/96 (n = 6,240); 1997/98 (n = 6,584); 1999/00 (n = 6,781); 2002/03 (n = 9,747); 2003/04 (n = 10,956); 2005/06 (n = 10,945) and 2007/08 (n = 12,067) were obtained. Outcomes were based on the d₃mft metric (i.e. the number of decayed, missing and filled teeth). An area-based deprivation category (DepCat) measured the subjects’ socioeconomic status (SES). Simple absolute and relative inequality, Odds Ratios and the Significant Caries Index (SIC) as advocated by the World Health Organization were calculated. The measures of complex inequality applied to data were: the Slope Index of Inequality (absolute) and a variety of relative inequality tests i.e. Gini coefficient; Relative Index of Inequality; concentration curve; Koolman & Doorslaer’s transformed Concentration Index; Receiver Operator Curve and Population Attributable Risk (PAR). Additional tests used were plots of SIC deciles (SIC¹⁰) and a Scottish Caries Inequality Metric (SCIM¹⁰). Over the period, mean d₃mft improved from 3.1(95%CI 3.0–3.2) to 1.9(95%CI 1.8–1.9) and d₃mft = 0% from 41.1(95%CI 39.8–42.3) to 58.3(95%CI 57.8–59.7). Absolute simple and complex inequality decreased. Relative simple and complex inequality remained comparatively stable. Our results support the use of the SII and RII to measure complex absolute and relative SES inequalities alongside additional tests of complex relative inequality such as PAR and Koolman and Doorslaer’s transformed CI. The latter two have clear interpretations which may influence policy makers. Specialised dental metrics (i.e. SIC, SIC¹⁰ and SCIM¹⁰) permit the exploration of other important inequalities not determined by SES, and could be applied to many other types of disease where ranking of morbidity is possible e.g. obesity. More generally, the approaches described may be applied to study patterns of health inequality affecting worldwide populations.     

Developmental Dysplasia of the Hip,Age, BMI,Place of Residence and Tobacco Abuse Increase the Odds of Aseptic Loosening in Chinese Patients

Purpose

The purpose of this hospital-based case-control study was to evaluate the patient-related risk factors for aseptic loosening after total hip arthroplasty (THA) and total knee arthroplasty (TKA) in Chinese patients.

Methods

From January 2000 to December 2012, 67 patients undergoing THA and TKA who developed aseptic loosening were detected as case subjects and 336 patients without aseptic loosening, matched by the year of index surgery and type of surgery, were selected as controls. Conditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs).

Results

The demographic factors and comorbid conditions associated with a risk-adjusted increase in aseptic loosening (in decreasing order of significance) were a rural place of residence (OR = 2.28; 95% CI: 1.21–4.30; p = 0.011), body mass index (BMI) ≥28 kg/m² (vs. 18.5–28 kg/m²) (OR = 2.29; 95% CI: 1.19–4.41; p = 0.013), developmental dysplasia of the hip (DDH) (OR = 2.91; 95% CI: 1.11–7.66; p = 0.030), tobacco abuse (OR = 2.88; 95% CI: 1.05–7.89; p = 0.039), and age <45 years (vs. 45–65 years) (OR = 2.63; 95% CI: 1.01–6.80; p = 0.047).

Conclusions

Patients aged <45 years and those with a BMI of ≥28 kg/m², a preoperative diagnosis of DDH, history of tobacco abuse, or living in rural areas are at increased risk for aseptic loosening after THA and TKA in Chinese population. Additional systematic large-scale studies are needed to verify these results.     

Risk Factors for Periprosthetic Joint Infection after Total Hip Arthroplasty and Total Knee Arthroplasty in Chinese Patients

Purpose

The purpose of this hospital-based case–control study was to evaluate the risk factors for periprosthetic joint infection (PJI) of total hip arthroplasty (THA) and total knee arthroplasty (TKA) in Chinese patients.

Method

From January 2000 to December 2012, 45 patients undergoing THA and TKA who developed PJI were recruited for case subjects; controls were 252 without PJI, matched by year of index for surgery and type of surgery. Conditional logistic regressions were run to compute odds ratios (ORs) and 95% confidence intervals (CIs).

Results

Demographic factors and comorbid conditions associated with an increased adjusted risk of PJI (in decreasing order of significance) were diabetes (OR = 5.47, 95% CI: 1.77–16.97; p = 0.003), age (65–75 vs. 45–65 years) (OR = 3.36, 95% CI: 1.30–8.69; p = 0.013), BMI (≥28 vs. 18.5–28 kg/m²) (OR = 2.77, 95% CI: 1.20–6.40; p = 0.017), place of residence (rural) (OR = 2.63, 95% CI: 1.13–6.10; p = 0.025) and alcohol abuse (OR = 2.95, 95% CI: 1.06–8.23; p = 0.039).

Conclusion

Patients with diabetes, older age, BMI of ≥28 kg/m² and alcohol abuse or living in rural areas, had increased PJI risk. Additional systematic large-scale studies are needed to verify these results.     

Insulin Sensitivity from Preschool to School Age in Patients with Severe Obesity

Background

Insulin sensitivity decreases at puberty transition, but little information has been provided on its earlier time-course. Aim of the present study was to describe the time-course of insulin sensitivity in severely obese children at the transition from preschool to school age.

Research design and methods

Retrospective study of a cohort of 47 severely obese [Body Mass Index (BMI) ≥99° percentile] preschoolers evaluated twice, once between 2 and 6 years of age, and once before age 8. Glucose tolerance, Whole Body Insulin Sensitivity Index (WBISI), Insulinogenic Index (IGI); β-cell demand index (BCDI) and Insulin Secretion-Sensitivity Index 2 (ISSI-2) were longitudinally estimated during the oral glucose tolerance test.

Results

After a median follow-up of 2.23 (1–4.52) y, obese patients showed significant decrease in WBISI (p<0.0001), and increase in fasting (p = 0.005) and 2 h glucose (2HG, p = 0.001). One child in preschool age and 4 school age children presented with 2HG between 7.8–11.1 mmol/l. Best predictors of WBISI, 2HG and BCDI in the school age were changes in BMI z-score (R² = 0.309; p = 0.002; β = −0.556), ISSI-2 (R² = 0.465; p<0.0001; β = −0.682), and BMI z-score (R² = 0.246; p = 0.008; 0.496), respectively.

Conclusions

In morbidly obese children, insulin sensitivity seems to decline even before pubertal transition, but changes in total adiposity can only partially explain this variation.     

Attempted Suicide in Bipolar Disorder: Risk Factors in a Cohort of 6086 Patients

Objective

Bipolar disorder is associated with high risk of self-harm and suicide. We wanted to investigate risk factors for attempted suicide in bipolar patients.

Method

This was a cohort study of 6086 bipolar patients (60% women) registered in the Swedish National Quality Register for Bipolar Disorder 2004–2011 and followed-up annually 2005–2012. Logistic regression was used to calculate adjusted odds ratios for fatal or non-fatal attempted suicide during follow-up.

Results

Recent affective episodes predicted attempted suicide during follow-up (men: odds ratio = 3.63, 95% CI = 1.76–7.51; women: odds ratio = 2.81, 95% CI = 1.78–4.44), as did previous suicide attempts (men: odds ratio = 3.93, 95% CI = 2.48–6.24; women: odds ratio = 4.24, 95% CI = 3.06–5.88) and recent psychiatric inpatient care (men: odds ratio = 3.57, 95% CI = 1.59–8,01; women: odds ratio = 2.68, 95% CI = 1.60–4.50). Further, those with many lifetime depressive episodes were more likely to attempt suicide. Comorbid substance use disorder was a predictor in men; many lifetime mixed episodes, early onset of mental disorder, personality disorder, and social problems related to the primary group were predictors in women.

Conclusion

The principal clinical implication of the present study is to pay attention to the risk of suicidal behaviour in bipolar patients with depressive features and more severe or unstable forms of the disorder.     

Favorable QTL Alleles for Yield and Its Components Identified by Association Mapping in Chinese Upland Cotton Cultivars

Linkage disequilibrium based association mapping is a powerful tool for dissecting the genetic basis underlying complex traits. In this study, an association mapping panel consisting of 356 representative Upland cotton cultivars was constructed, evaluated in three environments and genotyped using 381 SSRs to detect molecular markers associated with lint yield and its components. The results showed that abundant phenotypic and moderate genetic diversities existed within this germplasm panel. The population could be divided into two subpopulations, and weak relatedness was detected between pair-wise accessions. LD decayed to the background (r ² = 0.1182, P≤0.01), r ² = 0.1 and r ² = 0.2 level within 12–13 cM, 17–18 cM and 3–4 cM, respectively, providing the potential for association mapping of agronomically important traits in Chinese Upland cotton. A total of 55 marker-trait associations were detected between 26 SSRs and seven lint yield traits, based on a mixed linear model (MLM) and Bonferroni correction (P≤0.05/145, −log₁₀ P≥3.46). Of which 41 could be detected in more than one environment and 17 markers were simultaneously associated with two or more traits. Many associations were consistent with QTLs identified by linkage mapping in previous reports. Phenotypic values of alleles of each loci in 41 stably detected associations were compared, and 23 favorable alleles were identified. Population frequency of each favorable allele in historically released cultivar groups was also evaluated. The QTLs detected in this study will be helpful in further understanding the genetic basis of lint yield and its components, and the favorable alleles may facilitate future high-yield breeding by genomic selection in Upland cotton.     

Proximal Tubule Dysfunction Is Associated with Podocyte Damage Biomarkers Nephrin and Vascular Endothelial Growth Factor in Type 2 Diabetes Mellitus Patients: A Cross-Sectional Study

Background

There is an ongoing debate as to whether early diabetic nephropathy in Type 2 diabetes mellitus may be attributed to the glomerulus or to the proximal tubule. Urinary excretion of nephrin and vascular endothelial growth factor may increase even in the normoalbuminuria stage. In the course of diabetic nephropathy, the proximal tubule may be involved in the uptake of urinary nephrin and vascular endothelial growth factor.

Materials and Methods

Two groups of consecutive Type 2 diabetes mellitus outpatients (38 normo-, 32 microalbuminuric) and 21 healthy subjects were enrolled in a cross-sectional study and evaluated concerning the relation of proximal tubule dysfunction with the podocyte biomarkers excretion, assessed by ELISA methods. The impact of advanced glycation end-products on this relation was also queried.

Results

Urinary alpha₁-microglobulin and kidney injury molecule-1 correlated with urinary albumin:creatinine ratio (R² = 0.269; p<0.001; R² = 0.125; p<0.001), nephrinuria (R² = 0.529; p<0.001; R² = 0.203; p<0.001), urinary vascular endothelial growth factor (R² = 0.709; p<0.001; R² = 0.360; p<0.001), urinary advanced glycation end-products (R² = 0.578; p<0.001; R² = 0.405; p<0.001), serum cystatin C (R² = 0.130; p<0.001; R² = 0.128; p<0.001), and glomerular filtration rate (R² = 0.167; p<0.001; R² = 0.166; p<0.001); nephrinuria and urinary vascular endothelial growth factor correlated with urinary albumin:creatinine ratio (R² = 0.498; p<0.001; R² = 0.227; p<0.001), urinary advanced glycation end-products (R² = 0.251; p<0.001; R² = 0.308; p<0.001), serum cystatin C (R² = 0.157; p<0.001; R² = 0.226; p<0.001), and glomerular filtration rate (R² = 0.087; p = 0.007; R² = 0.218; p<0.001).

Conclusions

In Type 2 diabetes mellitus there is an association of proximal tubule dysfunction with podocyte damage biomarkers, even in the normoalbuminuria stage. This observation suggests a potential role of the proximal tubule in urinary nephrin and urinary vascular endothelial growth factor processing in early diabetic nephropathy, a fact which could be related to advanced glycation end-products intervention. Podocyte damage and proximal tubule dysfunction biomarkers could be validated as a practical approach to the diagnosis of early diabetic nephropathy by further studies on larger cohorts.     

Percentage of Body Fat Assessment Using Bioelectrical Impedance Analysis and Dual-Energy X-ray Absorptiometry in a Weight Loss Program for Obese or Overweight Chinese Adults

The current study aimed to compare the estimates of body fat percentage (%BF) by performing bioelectrical impedance analysis (BIA) and dual energy X-ray absorptiometry (DXA) in a sample of obese or overweight Chinese adults who participated in a weight-loss randomized control trial stratified by gender to determine whether or not BIA is a valid measurement tool. Among 189 adults [73 males, 116 females; age  = 41 to 74 years; mean body mass index (BMI)  = 27.3 kg/m²], assessments of %BF at the baseline and six months from the baseline were conducted by performing BIA and DXA. Bland-Altman analyses and multiple regression analyses were used to assess the relationships between %BF_BIA and %BF_DXA. Compared with DXA, BIA underestimated %BF [in males: 4.6, –2.4 to 11.7 (mean biases, 95% limit of agreement) at the baseline, 1.4, –7.4 to 10.2 at the endpoint, and 3.2, –4.8 to 11.3 in changes; in females: 5.1, –2.4 to 12.7; 2.2, –6.1 to 10.4; and 3.0, –4.8 to 10.7, respectively]. For males and females, %BFDXA proved to be a significant predictor of the difference between DXA and BIA at the baseline, the endpoint, and in changes when BMI and age were considered (in males: p<0.01 and R ²  = 23.1%, 24.1%, 20.7%, respectively; for females: p<0.001 and R ²  = 40.4%, 48.8%, 25.4%, respectively). The current study suggests that BIA provides a relatively accurate prediction of %BF in individuals with normal weight, overweight, or obesity after the end of weight-loss program, but less accurate prediction of %BF in obese individuals at baseline or weight change during the weight-loss intervention program.     

Determinants of Progression to AIDS and Death Following HIV Diagnosis: A Retrospective Cohort Study in Wuhan,China

Objective

To identify determinants associated with disease progression and death following human immunodeficiency virus (HIV) diagnosis.

Methods

Disease progression data from the diagnosis of HIV infection or acquiring immunodeficiency syndrome (AIDS) to February 29, 2012 were retrospectively collected from the national surveillance system databases and the national treatment database in Wuhan, China. Kaplan-Meier method, Logistic regression and Cox proportional hazards model were applied to identify the related factors of progression to AIDS or death following HIV diagnosis.

Results

By the end of February 2012, 181 of 691 HIV infectors developed to AIDS, and 129 of 470 AIDS patients died among whom 289 cases received concurrent HIV/AIDS diagnosis. Compared with men infected through homosexual behavior, injection drug users possessed sharply decreased hazard ratio (HR) for progression to AIDS following HIV diagnosis [HR = 0.31, 95% confidence interval (CI), 0.18–0.54, P = 4.01×10⁻⁵]. HIV infectors at least 60 years presented 1.15-fold (HR = 2.15, 95% CI, 1.15–4.03, P = 0.017) increased risk to develop AIDS when compared with those aged 17–29 years. Similarly, AIDS patients with diagnosis ages between 50 and 59 years were at a 1.60-fold higher risk of death (HR = 2.60, 95% CI, 1.18–5.72, P = 0.017) compared to those aged 19–29 years. AIDS patients with more CD4⁺ T-cells within 6 months at diagnosis (cell/µL) presented lower risk of death (HR = 0.29 for 50- vs <50, 95% CI, 0.15–0.59, P = 0.001). The highly active antiretroviral therapy (HAART) delayed progression to AIDS from HIV diagnosis (HR = 0.15, 95% CI, 0.07–0.34, P = 6.46×10⁻⁶) and reduced the risk of death after AIDS diagnosis (HR = 0.02, 95% CI, 0.01–0.04, P = 7.25×10⁻²⁵).

Conclusions

Progression to AIDS and death following HIV diagnosis differed in age at diagnosis, transmission categories, CD4⁺ T-cell counts and HAART. Effective interventions should target those at higher risk for morbidity or mortality, ensuring early diagnosis and timely treatment to slow down the disease progression.     

Economic Recession and Emergence of an HIV-1 Outbreak among Drug Injectors in Athens Metropolitan Area: A Longitudinal Study

Background

During 2011, a dramatic increase (1600%) of reported HIV-1 infections among injecting drug users (IDUs) was noted in Athens, Greece. We herein assess the potential causal pathways associated with this outbreak.

Methods

Our study employed high resolution HIV-1 phylogenetic and phylogeographic analyses. We examined also longitudinal data of ecological variables such as the annual growth of gross domestic product (GDP) of Greece in association with HIV-1 and HCV sentinel prevalence in IDUs, unemployment and homelessness rates and HIV transmission networks in Athens IDUs before and during economic recession (2008–2012).

Results

IDU isolates sampled in 2011 and 2012 suggested transmission networks in 94.6% and 92.7% of the cases in striking contrast with the sporadic networking (5%) during 1998–2009. The geographic origin of most HIV-1 isolates was consistent with the recently documented migratory waves in Greece. The decline in GDP was inversely correlated with annual prevalence rates of HIV and HCV and with unemployment and homelessness rates in IDUs (all p<0.001). The slope of anti-HCV prevalence in the sentinel populations of IDUs and in “new” drug injectors was found 120 and 1.9-fold (p = 0.007, p = 0.08 respectively) higher in 2008–2012 (economic recession) compared with 2002–2006. The median (25th, 75th) size of transmission networks were 34 (12, 58) and 2 (2, 2) (p = 0.057) in 2008–2012 and 1998–2007, respectively. The coverage of harm reduction services was low throughout the study period.

Conclusions

Scaling-up harm reduction services and addressing social and structural factors related to the current economic crisis should be urgently considered in environments where HIV-1 outbreaks may occur.     

Plasma Adiponectin,Clinical Factors,and Patient Outcomes during the Acute Respiratory Distress Syndrome

Objective

Adiponectin (APN) is an anti-inflammatory hormone derived from adipose tissue that attenuates acute lung injury in rodents. In this study, we investigated the association between circulating APN and outcomes among patients with acute respiratory distress syndrome (ARDS).

Methods

We performed a retrospective cohort study using data and plasma samples from participants in the multicenter ARDS Network Fluid and Catheter Treatment Trial.

Results

Plasma APN concentrations were measured in 816 (81.6%) trial participants at baseline and in 568 (56.8%) subjects at both baseline and day 7 after enrollment. Clinical factors associated with baseline APN levels in multivariable-adjusted models included sex, body mass index, past medical history of cirrhosis, and central venous pressure (model R² = 9.7%). We did not observe an association between baseline APN and either severity of illness (APACHE III) or extent of lung injury (Lung Injury Score). Among patients who received right heart catheterization (n = 384), baseline APN was inversely related to mean pulmonary artery pressure (β = −0.015, R² 1.5%, p = 0.02); however, this association did not persist in multivariable models (β = −0.009, R² 0.5%, p = 0.20). Neither baseline APN levels [HR per quartile1.04 (95% CI 0.91–1.18), p = 0.61], nor change in APN level from baseline to day 7 [HR 1.04 (95% CI 0.89–1.23), p = 0.62)] were associated with 60 day mortality in Cox proportional hazards regression models. However, subgroup analysis identified an association between APN and mortality among patients who developed ARDS from extra-pulmonary etiologies [HR per quartile 1.31 (95% CI 1.08–1.57)]. APN levels did not correlate with mortality among patients developing ARDS in association with direct pulmonary injury [HR 0.96 (95% CI 0.83–1.13)], p_interaction = 0.016.

Conclusions

Plasma APN levels did not correlate with disease severity or mortality in a large cohort of patients with ARDS. However, higher APN levels were associated with increased mortality among patients developing ARDS from extra-pulmonary etiologies.     

Hyper-Theory-of-Mind in Children with Psychotic Experiences

Background

Alterations in Theory-of-Mind (ToM) are associated with psychotic disorder. In addition, studies in children have documented that alterations in ToM are associated with Psychotic Experiences (PE). Our aim was to examine associations between an exaggerated type of ToM (HyperToM) and PE in children. Children with this type of alteration in ToM infer mental states when none are obviously suggested, and predict behaviour on the basis of these erroneous beliefs. Individuals with HyperToM do not appear to have a conceptual deficit (i.e. lack of representational abilities), but rather they apply their theory of the minds of others in an incorrect or biased way.

Method

Hypotheses were tested in two studies with two independent samples: (i) a general population sample of 1630 Danish children aged 11–12 years, (ii) a population-based sample of 259 Dutch children aged 12–13 years, pertaining to a case-control sampling frame of children with auditory verbal hallucinations. Multinomial regression analyses were carried out to investigate the associations between PE and ToM and HyperToM respectively. Analyses were adjusted for gender and proxy measures of general intelligence.

Results

Low ToM score was significantly associated with PE in sample I (OR = 1.6 95%CI 1.1–2.3 χ²(4) = 12.42 p = 0.010), but not in sample II (OR = 0.9 95%CI 0.5–1.8 χ²(3) = 7.13 p = 0.816). HyperToM was significantly associated with PE both in sample I (OR = 1.8, 95%CI 1.2–2.7 χ²(3) = 10.11 p = 0.006) and II (OR = 4.6, 95%CI 1.3–16.2 χ²(2) = 7.56 p = 0.018). HyperToM was associated particularly with paranoid delusions in both sample I (OR = 2.0, 95%CI: 1.1–3.7% χ²(4) = 9.93 p = 0.021) and II (OR = 6.2 95%CI: 1.7–23.6% χ²(4) = 9.90 p = 0.044).

Conclusion

Specific alterations in ToM may be associated with specific types of psychotic experiences. HyperToM may index risk for developing psychosis and paranoid delusions in particular.     

The Associations between Immunity-Related Genes and Breast Cancer Prognosis in Korean Women

We investigated the role of common genetic variation in immune-related genes on breast cancer disease-free survival (DFS) in Korean women. 107 breast cancer patients of the Seoul Breast Cancer Study (SEBCS) were selected for this study. A total of 2,432 tag single nucleotide polymorphisms (SNPs) in 283 immune-related genes were genotyped with the GoldenGate Oligonucleotide pool assay (OPA). A multivariate Cox-proportional hazard model and polygenic risk score model were used to estimate the effects of SNPs on breast cancer prognosis. Harrell’s C index was calculated to estimate the predictive accuracy of polygenic risk score model. Subsequently, an extended gene set enrichment analysis (GSEA-SNP) was conducted to approximate the biological pathway. In addition, to confirm our results with current evidence, previous studies were systematically reviewed. Sixty-two SNPs were statistically significant at p-value less than 0.05. The most significant SNPs were rs1952438 in SOCS4 gene (hazard ratio (HR) = 11.99, 95% CI = 3.62–39.72, P = 4.84E-05), rs2289278 in TSLP gene (HR = 4.25, 95% CI = 2.10–8.62, P = 5.99E-05) and rs2074724 in HGF gene (HR = 4.63, 95% CI = 2.18–9.87, P = 7.04E-05). In the polygenic risk score model, the HR of women in the 3^rd tertile was 6.78 (95% CI = 1.48–31.06) compared to patients in the 1^st tertile of polygenic risk score. Harrell’s C index was 0.813 with total patients and 0.924 in 4-fold cross validation. In the pathway analysis, 18 pathways were significantly associated with breast cancer prognosis (P<0.1). The IL-6R, IL-8, IL-10RB, IL-12A, and IL-12B was associated with the prognosis of cancer in data of both our study and a previous study. Therefore, our results suggest that genetic polymorphisms in immune-related genes have relevance to breast cancer prognosis among Korean women.     

Force Control Is Related to Low-Frequency Oscillations in Force and Surface EMG

Force variability during constant force tasks is directly related to oscillations below 0.5 Hz in force. However, it is unknown whether such oscillations exist in muscle activity. The purpose of this paper, therefore, was to determine whether oscillations below 0.5 Hz in force are evident in the activation of muscle. Fourteen young adults (21.07±2.76 years, 7 women) performed constant isometric force tasks at 5% and 30% MVC by abducting the left index finger. We recorded the force output from the index finger and surface EMG from the first dorsal interosseous (FDI) muscle and quantified the following outcomes: 1) variability of force using the SD of force; 2) power spectrum of force below 2 Hz; 3) EMG bursts; 4) power spectrum of EMG bursts below 2 Hz; and 5) power spectrum of the interference EMG from 10–300 Hz. The SD of force increased significantly from 5 to 30% MVC and this increase was significantly related to the increase in force oscillations below 0.5 Hz (R ² = 0.82). For both force levels, the power spectrum for force and EMG burst was similar and contained most of the power from 0–0.5 Hz. Force and EMG burst oscillations below 0.5 Hz were highly coherent (coherence = 0.68). The increase in force oscillations below 0.5 Hz from 5 to 30% MVC was related to an increase in EMG burst oscillations below 0.5 Hz (R ² = 0.51). Finally, there was a strong association between the increase in EMG burst oscillations below 0.5 Hz and the interference EMG from 35–60 Hz (R ² = 0.95). In conclusion, this finding demonstrates that bursting of the EMG signal contains low-frequency oscillations below 0.5 Hz, which are associated with oscillations in force below 0.5 Hz.     

Meta-Analysis of EGFR Tyrosine Kinase Inhibitors Compared with Chemotherapy as Second-Line Treatment in Pretreated Advanced Non-Small Cell Lung Cancer

Background

Since efficacy and safety of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) versus chemotherapy in the treatment of patients with pretreated advanced non-small cell lung cancer (NSCLC) remain controversial, we performed a meta-analysis to compare them.

Methods

An internet search of several databases was performed, including PubMed, Embase, and the Cochrane database. Randomized trials that compared an EGFR-TKI with chemotherapy in the second-line setting were included. The outcomes were progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and grade 3–4 toxicities. The PFS, OS for the EGFR mutation-positive (EGFR M⁺) and EGFR mutation-negative (EGFR M⁻) subgroups were pooled. The pooled hazard ratios (HRs) and odds ratios (ORs) with their corresponding confidence intervals (CIs) were calculated on the STATA software.

Results

Our meta-analysis combined 3,825 patients from 10 randomized trials. Overall, EGFR-TKIs and second-line chemotherapy have equivalent efficacy in terms of PFS (HR, 1.03; 95%CI, 0.87–1.21; P = 0.73; I² = 78.7%, P_{heterogeneity}<0.001), OS (HR, 1.00; 95%CI, 0.92–1.08; P = 0.90; I² = 0.0%, P_{heterogeneity} = 0.88), and ORR (OR, 1.34; 95%CI, 0.86–2.08; P = 0.20; I² = 73.1%, P_{heterogeneity}<0.001). However, subgroup analysis based on EGFR mutation status showed that second-line chemotherapy significantly improved PFS (HR, 1.35; 95%CI, 1.09–1.66; P = 0.01; I² = 55.7%, P_{heterogeneity} = 0.046) for EGFR M⁻ patients, whereas OS was equal (HR, 0.96; 95%CI, 0.77–1.19; P = 0.69; I² = 0.0%, P_{heterogeneity} = 0.43); EGFR-TKIs significantly improved PFS (HR, 0.28; 95%CI, 0.15–0.53; P<0.001; I² = 4.1%, P_{heterogeneity} = 0.35) for EGFR M⁺ patients, whereas OS was equal (HR, 0.86; 95%CI, 0.44–1.68; P = 0.65; I² = 0.0%, P_{heterogeneity} = 0.77). Compared with chemotherapy, EGFR-TKIs led to more grade 3–4 rash, but less fatigue/asthenia disorder, leukopenia and thrombocytopenia.

Conclusions

Our analysis suggests that chemotherapy in the second-line setting can prolong PFS in EGFR M⁻ patients, whereas it has no impact on OS. EGFR-TKIs seem superior over chemotherapy as second-line therapy for EGFR M⁺ patients. Our findings support obtaining information on EGFR mutational status before initiation of second-line treatment.     

The Effects of Calcium Channel Blockers in the Prevention of Stroke in Adults with Hypertension: A Meta-Analysis of Data from 273,543 Participants in 31 Randomized Controlled Trials

Background

Hypertension is a major risk factor for the development of stroke. It is well known that lowering blood pressure decreases the risk of stroke in people with moderate to severe hypertension. However, the specific effects of calcium channel blockers (CCBs) against stroke in patients with hypertension as compared to no treatment and other antihypertensive drug classes are not known.

Methods and Findings

This systematic review and meta-analysis of randomized controlled trials (RCTs) evaluated CCBs effect on stroke in patients with hypertension in studies of CCBs versus placebo, angiotensin-converting-enzyme inhibitors (ACEIs), β-adrenergic blockers, and diuretics. The PUBMED, MEDLINE, EMBASE, OVID, CNKI, MEDCH, and WANFANG databases were searched for trials published in English or Chinese during the period January 1, 1996 to July 31, 2012. A total of 177 reports were collected, among them 31 RCTs with 273,543 participants (including 130,466 experimental subjects and 143,077 controls) met the inclusion criteria. In these trials a total of 9,550 stroke events (4,145 in experimental group and 5,405 in control group) were reported. CCBs significantly decreased the incidence of stroke compared with placebo (OR = 0.68, 95% CI 0.61–0.75, p<1×10⁻⁵), β-adrenergic blockers combined with diuretics (OR = 0.89, 95% CI 0.83–0.95, p = 7×10⁻⁵) and β-adrenergic blockers (OR = 0.79, 95% CI 0.72–0.87, p<1×10⁻⁵), statistically significant difference was not found between CCBs and ACEIs (OR = 0.92, 95% CI 0.8–1.02, p = 0.12) or diuretics (OR = 0.95, 95% CI 0.84–1.07, p = 0.39).

Conclusion

In a pooled analysis of data of 31 RCTs measuring the effect of CCBs on stroke, CCBs reduced stroke more than placebo and β-adrenergic blockers, but were not different than ACEIs and diuretics. More head to head RCTs are warranted.