Maternal pre‐pregnancy obesity and child neurodevelopmental outcomes: a meta‐analysis

This review examined evidence of the association between maternal pre‐pregnancy overweight/obesity status and child neurodevelopmental outcomes. PubMed and PsycINFO databases were systematically searched for empirical studies published before April 2017 using keywords related to prenatal obesity and children's neurodevelopment. Of 1483 identified papers, 41 were included in the systematic review, and 32 articles representing 36 cohorts were included in the meta‐analysis. Findings indicated that compared with children of normal weight mothers, children whose mothers were overweight or obese prior to pregnancy were at increased risk for compromised neurodevelopmental outcomes (overweight: OR = 1.17, 95% CI [1.11, 1.24], I² = 65.51; obese: OR = 1.51; 95% CI [1.35, 1.69], I² = 79.63). Pre‐pregnancy obesity increased the risk of attention deficit–hyperactivity disorder (OR = 1.62; 95% CI [1.23, 2.14], I² = 70.15), autism spectrum disorder (OR = 1.36; 95% CI [1.08, 1.70], I² = 60.52), developmental delay (OR = 1.58; 95% CI [1.39, 1.79], I² = 75.77) and emotional/behavioural problems (OR = 1.42; 95% CI [1.26, 1.59], I² = 87.74). Given the current obesity prevalence among young adults and women of childbearing age, this association between maternal obesity during pregnancy and atypical child neurodevelopment represents a potentially high public health burden.     

Economic impact of genomic diagnostics for intermediate‐risk acute myeloid leukaemia

Acute Myeloid Leukaemia (AML) is a rare but serious group of diseases that require critical decision‐making for curative treatment. Over the past decade, scientific discovery has revealed dozens of prognostic gene mutations for AML while sequencing costs have plummeted. In this study, we compared the cost‐effectiveness of multigene integrative analysis (genomic analysis) with the standard molecular testing currently used for diagnosis of intermediate‐risk AML. We used a decision analytic model with data for costs and outcomes from British Columbia, Canada, to assess the long‐term (10‐year) economic impacts. Our results suggest that genomic analysis would result in a 26% increase in the use of first‐remission allogeneic stem cell transplantation. The resulting treatment decisions and downstream effects would come at an additional cost of $12 556 [2013 Canadian dollars (CAD)] per person and the incremental cost‐effectiveness ratio would be $49 493 per quality‐adjusted life‐year gained. Cost‐effectiveness was dependent on quality of life during the long‐term (5–10) years of survival, relapse rates following first‐remission chemotherapy and the upfront cost of transplantation. Non‐relapse mortality rates, short‐term quality of life and the cost of genomic sequencing had only minor impacts. Further research on post‐remission outcomes can lead to improvements in the cost‐effectiveness of curative treatments for AML.     

Comparison of multiparametric risk scores for predicting early mortality after transcatheter aortic valve implantation

Introduction

Surgical risk scores are widely used to identify patients at high surgical risk who may benefit from transcatheter aortic valve implantation (TAVI). A multiparametric TAVI mortality risk score based on a French registry (FRANCE-2) has recently been developed. The aim of our study was to compare the 30-day mortality prediction performance of the FRANCE-2, EuroSCORE II and STS scores.

Comparison of bleeding risk scores in patients with atrial fibrillation: insights from the RE‐LY trial

Background

Oral anticoagulation is the mainstay of stroke prevention in atrial fibrillation (AF), but must be balanced against the associated bleeding risk. Several risk scores have been proposed for prediction of bleeding events in patients with AF.

Objectives

To compare the performance of contemporary clinical bleeding risk scores in 18 113 patients with AF randomized to dabigatran 110 mg, 150 mg or warfarin in the RE‐LY trial.

Methods

HAS‐BLED, ORBIT, ATRIA and HEMORR₂HAGES bleeding risk scores were calculated based on clinical information at baseline. All major bleeding events were centrally adjudicated.

Results

There were 1182 (6.5%) major bleeding events during a median follow‐up of 2.0 years. For all the four schemes, high‐risk subgroups had higher risk of major bleeding (all P  < 0.001). The ORBIT score showed the best discrimination with c‐indices of 0.66, 0.66 and 0.62, respectively, for major, life‐threatening and intracranial bleeding, which were significantly better than for the HAS‐BLED score (difference in c‐indices: 0.050, 0.053 and 0.048, respectively, all P  < 0.05). The ORBIT score also showed the best calibration compared with previous data. Significant treatment interactions between the bleeding scores and the risk of major bleeding with dabigatran 150 mg BD versus warfarin were found for the ORBIT (P  = 0.0019), ATRIA (P  < 0.001) and HEMORR₂HAGES (P  < 0.001) scores. HAS‐BLED score showed a nonsignificant trend for interaction (P  = 0.0607).

Conclusions

Amongst the current clinical bleeding risk scores, the ORBIT score demonstrated the best discrimination and calibration. All the scores demonstrated, to a variable extent, an interaction with bleeding risk associated with dabigatran or warfarin.

     

Association between non-invasive liver fibrosis scores and occurrence of health adverse outcomes in older people

BackgroundThe relation between liver fibrosis scores and health outcomes in older people has been barely investigated. We aimed to evaluate the association of four liver fibrosis scores (fibrosis-4 -FIB-4-, NAFLD fibrosis score -NFS-, BARD and aspartate aminotransferase/alanine aminotransferase ratio -AST/ALT-) with mortality and incident disability at 6 years in an older population.MethodsWe studied 962 individuals aged ≥65 (mean age 74.4; female 55.5%) with a mean follow-up of 95.7 months, enrolled in the InCHIANTI study. The relationship between liver fibrosis scores and mortality and disability was assessed through Cox and log-binomial regressions.ResultsNFS and FIB-4 were associated with higher overall (aHR ranging 1.38–1.78 for intermediate risk of fibrosis and 1.60–2.02 for high risk) and cardiovascular (aHR ranging 1.76–2.90 for intermediate and 2.22–2.42 for high risk) mortality. AST/ALT and BARD were only associated with overall mortality. Only NFS and FIB-4 high risk classes were associated with incident disability (aRR ranging 1.93–2.76). Despite poor sensitivity, all scores showed high specificity (ranging 0.88–0.95).ConclusionHigher risk of liver fibrosis is associated with higher risk of poor health outcomes. Liver fibrosis scores may help to stratify the risk and, mainly, identify elderly patients with favorable prognosis.     

Diagnostic utility of an age‐specific cut‐off for d‐dimer for pulmonary embolism assessment when used with various pulmonary embolism risk scores

This retrospective cohort study compared the diagnostic utility (sensitivity, specificity and negative predictive value (NPV)) of the age‐times‐10 adjusted d‐dimer cut‐off used in combination with the original and simplified Well's pulmonary embolism (PE) scores and the original and simplified revised Geneva scores to identify patients in whom PE is classified as unlikely according to each score. The PE risk scores performed similarly with high sensitivity (97.6, 97.1, 96.9 and 97.1% respectively) and NPV (99.3, 99.3, 99.2 and 99.2% respectively). Each missed only one PE. The age‐times‐10 age‐adjusted d‐dimer assay cut‐off performed similarly with each of the clinical risk scores tested with high sensitivity and NPV.     

The effects of ovine placental lactogen and bovine growth hormone on hepatic and mammary gene expression in lactating sheep

The ability of ovine placental lactogen (oPL) to bind to the growth hormone receptor (GHR) raises the possibility that oPL may exert a growth hormone (GH)-like action on galactopoiesis. We have compared the effects of treating lactating ewes for 5 days with an equimolar dose (0.1 mg/kg/day, administered as two equal doses 12 hourly) of either bovine growth hormone (bGH) (n = 10), oPL (n = 10) or saline (n = 9) on hepatic and mammary GHR, insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) gene expression and hepatic GHR number. Hepatic GHR and IGFBP-3 mRNA were unaltered by bGH or oPL treatment. Hepatic IGF-I mRNAs increased following bGH (P < 0.05) but not oPL treatment. GHR gene expression was greater in liver compared to mammary gland extracts. There was no effect of either bGH or oPL treatment on mammary GHR, IGF-I or IGFBP-3 mRNA or hepatic GHR number. These studies confirm the galactopoietic effects of bGH in lactating ruminants and suggest that the mechanism of this action is not via increased hepatic GHR number or gene expression. In addition, the increase in hepatic but not mammary IGF-I mRNA with bGH treatment suggests an endocrine action of IGF-I on milk synthesis. These studies also demonstrate that an equimolar dose of oPL is not galactopoietic or somatogenic in the lactating ewe.     

Racial residential segregation shapes the relationship between early childhood lead exposure and fourth-grade standardized test scores

Racial/ethnic disparities in academic performance may result from a confluence of adverse exposures that arise from structural racism and accrue to specific subpopulations. This study investigates childhood lead exposure, racial residential segregation, and early educational outcomes. Geocoded North Carolina birth data is linked to blood lead surveillance data and fourth-grade standardized test scores (n = 25,699). We constructed a census tract-level measure of racial isolation (RI) of the non-Hispanic Black (NHB) population. We fit generalized additive models of reading and mathematics test scores regressed on individual-level blood lead level (BLL) and neighborhood RI of NHB (RINHB). Models included an interaction term between BLL and RINHB. BLL and RINHB were associated with lower reading scores; among NHB children, an interaction was observed between BLL and RINHB. Reading scores for NHB children with BLLs of 1 to 3 µg/dL were similar across the range of RINHB values. For NHB children with BLLs of 4 µg/dL, reading scores were similar to those of NHB children with BLLs of 1 to 3 µg/dL at lower RINHB values (less racial isolation/segregation). At higher RINHB levels (greater racial isolation/segregation), children with BLLs of 4 µg/dL had lower reading scores than children with BLLs of 1 to 3 µg/dL. This pattern becomes more marked at higher BLLs. Higher BLL was associated with lower mathematics test scores among NHB and non-Hispanic White (NHW) children, but there was no evidence of an interaction. In conclusion, NHB children with high BLLs residing in high RINHB neighborhoods had worse reading scores.

In the United States, there are longstanding racial/ethnic disparities in academic performance and educational attainment, evidenced by lower high school and college graduation rates among some racial/ethnic groups, particularly Hispanic and non-Hispanic Black (NHB) individuals (1). These disparities, sometimes referred to as the “achievement gap,” may emerge in early childhood and persist over time (1). Academic performance in early childhood predicts later-life educational outcomes, including high school graduation (1), which relates to measures of health, socioeconomic status, and well-being in adulthood (2). Disparities in academic achievement in elementary school children may be preventable and warrant attention as potentially important foci for early intervention.It is widely agreed that positive and negative outcomes are determined by multiple forces, acting across the life course, yet surprisingly little is known about the interactions of those forces. A plethora of evidence demonstrates that lead exposure in young children, even at low levels, is associated with learning deficits and lower scores on intelligence and standardized tests (3–7). Adverse effects of childhood lead exposure persist into adulthood, affecting intelligence and socioeconomic status (SES) (8). Environmental exposures such as lead may be elevated in communities experiencing a multitude of disadvantages (9) such as poverty, deprivation, or segregation (10).Neighborhood characteristics, and poverty specifically, have been shown to relate to cognitive development in children (11), including verbal ability (12). However, there is a dearth of work examining relationships between cognitive and developmental outcomes and neighborhood characteristics beyond measures of SES. In particular, racial residential segregation (RRS)—the geographic separation of Black individuals and communities from other racial/ethnic groups (13)—has, through the concentration of poverty and poor physical and social environments, resulted in distinctive environments that may underlie racial disparities in health outcomes (14). RRS is linked with adverse health outcomes, including infant and adult mortality (15–19), adverse pregnancy outcomes (e.g., preterm birth, low birth weight) (20–22), and chronic diseases such as hypertension and type 2 diabetes (23–26). These associations often persist even after controlling for SES, suggesting that SES may not fully capture all pathways and processes through which segregation affects neighborhood environments, resources, and residents. Yet few, if any, studies have explored associations between neighborhood RRS and cognitive outcomes in children.Despite the potential for adverse neighborhood conditions to amplify health, cognitive, and developmental effects of lead (or other environmental exposures), effects of lead exposure are seldom evaluated alongside neighborhood contextual factors (e.g., deprivation, RRS). Thus, relationships and interactions among lead exposure and neighborhood context, and the impact on cognitive and developmental outcomes, may be important but are not thoroughly understood. Murine models of stress and lead exposure indicate that depauperate environments exacerbate the neurological impact of lead exposure (27). Similarly, human epidemiologic models suggest that stress exacerbates the impact of air pollution on asthma severity (28). The mechanism(s) for these combined effects are not fully understood, with potential explanations being priming of the stress response pathway, priming the inflammatory pathway, or both.Here, we examine the combined effect of social (RRS) and environmental (lead) exposures on key developmental outcomes. To do so, we construct a longitudinally linked spatiotemporal dataset that tracks children from time of birth to time of fourth-grade end-of-grade testing by linking multiple, statewide administrative datasets. We then estimate associations between key exposures and end-of-grade standardized test scores in reading and mathematics for fourth-grade public school students in North Carolina, including interaction terms between individual-level lead exposure and a neighborhood-level RRS measure (racial isolation of NHB individuals [RI_NHB]) to evaluate whether one exposure potentially augments susceptibility to another.     

Kidney disease, Framingham risk scores, and cardiac and mortality outcomes

Background

The Framingham equations were developed to predict incident coronary heart disease. It remains unknown how the presence of chronic kidney disease affects their performance.

Methods

Individuals without preexisting cardiovascular disease aged 45 to 74 years from the Atherosclerosis Risk in Communities and Cardiovascular Health Studies were analyzed. Using sex- and race-specific Cox models, we evaluated the 5-year risk of coronary heart disease and mortality events associated with both chronic kidney disease and Framingham risk score, the absolute risk of events caused by kidney disease, and model discrimination.

Results

Among 15,717 subjects, 756 (4.8%) had kidney disease. The Framingham risk score independently predicted cardiac and mortality events in all subgroups, whereas kidney disease predicted events in all subgroups except cardiac events in white women. After adjustment for traditional risk factors, the increase in cardiac and mortality events per 1000 person-years attributable to kidney disease was 4.3 and 13.7 for white men, 16.1 and 40.5 for African American men, 1.2 and 5.8 for white women, and 13.6 and 14.2 for African American women, respectively. This represented an additional 17,000 and 12,000 cardiac events and 63,000 and 19,000 deaths per year among whites and African Americans, respectively. Mortality rates attributable to kidney disease, diabetes, and smoking were comparable. Accounting for kidney disease improved discrimination for only mortality outcomes in white men and African American women.

Conclusions

Chronic kidney disease in a community-based population is an important predictor of cardiac and mortality events, particularly in African Americans, but it does not improve discrimination of Framingham equations.     

Extensive genetic diversity and substructuring among zebrafish strains revealed through copy number variant analysis

Copy number variants (CNVs) represent a substantial source of genomic variation in vertebrates and have been associated with numerous human diseases. Despite this, the extent of CNVs in the zebrafish, an important model for human disease, remains unknown. Using 80 zebrafish genomes, representing three commonly used laboratory strains and one native population, we constructed a genome-wide, high-resolution CNV map for the zebrafish comprising 6,080 CNV elements and encompassing 14.6% of the zebrafish reference genome. This amount of copy number variation is four times that previously observed in other vertebrates, including humans. Moreover, 69% of the CNV elements exhibited strain specificity, with the highest number observed for Tubingen. This variation likely arose, in part, from Tubingen's large founding size and composite population origin. Additional population genetic studies also provided important insight into the origins and substructure of these commonly used laboratory strains. This extensive variation among and within zebrafish strains may have functional effects that impact phenotype and, if not properly addressed, such extensive levels of germ-line variation and population substructure in this commonly used model organism can potentially confound studies intended for translation to human diseases.     

臂踝脉搏波传导速度与心血管危险因素的相关性

目的:探讨臂踝脉搏波传导速度(baPWV)与心血管危险因素及国人缺血性心血管疾病(ICVD)危险评分的相关性。方法: 2010年3月~7月天津市人民医院体检人群232例进行常规体检,应用全自动动脉硬化测定仪VBP-9测定双肢的baPWV,按代谢异常组分进行分组,分别比较各组临床基本资料、baPWV 及ICVD风险评分。结果: 随着代谢异常组分的增加,baPWV逐渐增加,代谢异常各组baPWV均高于对照组,各组间差异均有统计学意义(P<0.05)。不同组之间,体质量指数、收缩压、舒张压、空腹血糖、三酰甘油、10年风险评估随着代谢异常数目的增高而呈上升趋势,高密度脂蛋白胆固醇（HDL-C）随着代谢异常数目的增加而降低,各组间差异具有统计学意义（P<0.05）,糖尿病史、高血压病史、吸烟史各组间差异有统计学意义（P<0.05）。Logistic回归分析:baPWV影响因素中年龄 OR=1.06295%CI(1.009-1.118)、收缩压OR=1.08595%CI(1.032-1.139)、糖尿病史OR=5.65095%CI(1.735-18.395);国人ICVD危险评分与baPWV存在回归关系（r=0.531,P＜0.01）。 结论: 年龄、收缩压、糖尿病史是早期动脉粥样硬化的影响因素,各种主要心血管危险因素与baPWV测定值相关,ICVD评分与baPWV相关。     

Impact of socioeconomic status on disease phenotype,genomic landscape and outcomes in myelodysplastic syndromes

Genetic and epigenetic alterations contribute to the biological and clinical characteristics of myelodysplastic syndromes (MDS), but a role for socioeconomic environment remains unclear. Here, socioeconomic status (SES) for 283 MDS patients was estimated using the Scottish Index of Multiple Deprivation tool. Indices were assigned to quintile categorical indicators ranked from SES1 (lowest) to SES5 (highest). Clinicopathological features and outcomes between SES quintiles containing 15%, 20%, 19%, 30% and 16% of patients were compared. Prognostic scores identified lower‐risk MDS in 82% of patients, with higher‐risk disease in 18%. SES quintiles did not associate with age, gender, cytogenetics, International Prognostic scores or, in sub‐analysis (n = 95), driver mutations. The odds ratio of a diagnosis of refractory anaemia was greater than other MDS sub‐types in SES5 (OR 1·9, P = 0·024). Most patients (91%) exclusively received supportive care. SES did not associate with leukaemic transformation or cause of death. Cox regression models confirmed male gender (P < 0·05), disease‐risk (P < 0·0001) and age (P < 0·01) as independent predictors of leukaemia‐free survival, with leukaemic transformation an additional determinant of overall survival (P = 0·07). Thus, if access to healthcare is equitable, SES does not determine disease biology or survival in MDS patients receiving supportive treatment; additional studies are required to determine whether outcomes following disease‐modifying therapies are influenced by SES.     

Identifying young adults at high risk of cardiometabolic disease using cluster analysis and the Framingham 30-yr risk score

Background and aimsCurrent strategies to reduce cardiovascular disease (CVD) risk in young adults are largely limited to those at extremes of risk. In cohort studies we have shown cluster analysis identified a large sub-group of adolescents with multiple risk factors. This study examined if individuals classified at ‘high-risk’ by cluster analysis could also be identified by their Framingham risk scores.Methods and resultsRaine Study data at 17- (n = 1048) and 20-years (n = 1120) identified high- and low-risk groups by cluster analysis using continuous measures of systolic BP, BMI, triglycerides and insulin resistance. We assessed:- CVD risk at 20-years using the Framingham 30 yr-risk-score in the high- and low-risk clusters, and cluster stability from adolescence to adulthood.Cluster analysis at 17- and 20-years identified a high-risk group comprising, 17.9% and 21.3%, respectively of the cohort. In contrast, only 1.2% and 3.4%, respectively, met the metabolic syndrome criteria, all of whom were within the high-risk cluster. Compared with the low-risk cluster, Framingham scores of the high-risk cluster were elevated in males (9.4%; 99%CI 8.3, 10.6 vs 6.0%; 99%CI 5.7, 6.2) and females (4.9%; 99%CI 4.4, 5.4 vs 3.2%; 99%CI 3.0, 3.3) (both P < 0.0001). A score >8 for males and >4 for females identified those at high CVD risk with 99% confidence.ConclusionCluster analysis using multiple risk factors identified ～20% of young adults at high CVD risk. Application of our Framingham 30 yr-risk cut-offs to individuals allows identification of more young people with multiple risk factors for CVD than conventional metabolic syndrome criteria.     

Osteoporosis: From concepts to T scores and now absolute fracture risk

The definition of osteoporosis has always been challenging. Historically the clinical definition could only be based on the presence or occurrence of an osteoporotic fracture. However waiting for a fracture to occur before making a diagnosis has limitations, not least that high risk individuals cannot be identified for treatment prior to fracture. With the availability of bone density measurements, the definition moved to the use of T-scores. Whilst widely used, this approach has limitations that include low sensitivity and not taking into account other variables that influence bone strength and extra-skeletal risk factors. In view of the limitations of using T scores in isolation, there has been a move towards assessment of individualised risk that incorporates multiple risk factors (with or without bone density measurement) to help predict future fracture risk. This approach potentially allows identification and treatment of individuals at high risk of fracture, the condition that needs to be treated as opposed to treating low bone density. Indeed bone density (where measured) becomes one of the many risk factors without a threshold interpretation for any given value. Numerous tools are available that have varying sensitivity, specificity, utility, applicability to, and that have been validated for any given population. Of the available tools, the World Health Organisation Fracture Risk Assessment Tool (FRAX) calculator has been extensively studied. It is available more widely, with country specific utility with and without bone density measurements, which is important in regions with scarce access to bone densitometry. FRAX is the only tool available that is India specific.