Suicidal ideation and subsequent completed suicide in both psychiatric and non-psychiatric populations: a meta-analysis.

AIMS: Several authors claimed that expression of suicidal ideation is one of the most important predictors of completed suicide. However, the strength of the association between suicidal ideation and subsequent completed suicide has not been firmly established in different populations. Furthermore, the absolute suicide risk after expression of suicidal ideation is unknown. In this meta-analysis, we examined whether the expression of suicidal ideation predicted subsequent completed suicide in various populations, including both psychiatric and non-psychiatric populations. METHODS: A meta-analysis of cohort and case-control studies that assessed suicidal ideation as determinant for completed suicide in adults. Two independent reviewers screened 5726 articles for eligibility and extracted data of the 81 included studies. Pooled risk ratios were estimated in a random effects model stratified for different populations. Meta-regression analysis was used to determine suicide risk during the first year of follow-up. RESULTS: The risk for completed suicide was clearly higher in people who had expressed suicidal ideation compared with people who had not, with substantial variation between the different populations: risk ratio ranging from 2.35 (95% confidence interval (CI) 1.43-3.87) in affective disorder populations to 8.00 (95% CI 5.46-11.7) in non-psychiatric populations. In contrast, the suicide risk after expression of suicidal ideation in the first year of follow-up was higher in psychiatric patients (risk 1.40%, 95% CI 0.74-2.64) than in non-psychiatric participants (risk 0.23%, 95% CI 0.10-0.54). Past suicide attempt-adjusted risk ratios were not pooled due to large underreporting. CONCLUSIONS: Assessment of suicidal ideation is of priority in psychiatric patients. Expression of suicidal ideation in psychiatric patients should prompt secondary prevention strategies to reduce their substantial increased risk of suicide.

Safety of Anti-TNF Treatment in Liver Transplant Recipients: A Systematic Review and Meta-analysis.

BACKGROUND AND AIM: Little is known about the risk of serious infection when combining anti-tumour necrosis factor [TNF] therapy for refractory inflammatory bowel disease [IBD] with immunosuppression after liver transplantation [LT]. Our aim was to investigate the infection risk in this patient group by systematic review and meta-analysis of the available data. METHODS: A search was conducted for full papers and conference proceedings through September 2015, regarding liver transplant recipients and anti-TNF therapy. All studies were appraised using the adapted Newcastle-Ottawa Scale [NOS]. Two reviewers independently extracted patient data [age, duration of follow-up, number of all infections, number of serious infections, time since transplant]. As an additional control population, primary sclerosing cholangitis [PSC]-IBD patients from the Leiden University Medical Center [LUMC] LT cohort were used. Poisson regression was used to compare serious infections (according to International Conference on Harmonisation [ICH] definition) per patien-year follow-up between the anti-TNF and control groups. RESULTS: In all 465 articles and abstracts were identified, of which eight were included. These contained 53 post-LT patients on anti-TNF therapy and 23 post-LT patients not exposed to anti-TNF therapy. From the LUMC LT-cohort, 41 PSC patients with PSC-IBD not exposed to anti-TNF therapy were included as control population. The infection rate for TNF-exposed patients was 0.168 serious infections per patient year, compared with 0.149 in the control patients (rate ratio 1.12 [95% confidence interval: 0.233-5.404, P = 0.886]. When correcting for time since transplant, the infection rate was 0.194 in the TNF-exposed vs 0.115 in the non-exposed [p = 0.219]. CONCLUSIONS: No significant increase in the rate of serious infection was observed in LT recipients with PSC-IBD during exposure to anti-TNF therapy.

Meta-Regression of a Dose-Response Relationship of Methotrexate in Mono- and Combination Therapy in Disease-Modifying Antirheumatic Drug-Naive Early Rheumatoid Arthritis Patients.

OBJECTIVE: To investigate a possible short-term dose-response relationship of initial treatment with methotrexate (MTX) in monotherapy and combination therapy in recent-onset rheumatoid arthritis (RA) patients. METHODS: A systematic literature search was performed on trials and cohorts, including early, disease-modifying antirheumatic drug (DMARD)-naive RA patients treated with MTX, with data on clinical results within 6 months from treatment start. Cohen's effect sizes were calculated for the Health Assessment Questionnaire (HAQ), erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) level, and/or Disease Activity Score (DAS)/in 28 joints (DAS28) in 4 treatment groups: MTX monotherapy, or MTX in combination with synthetic (cs) DMARDs, biologic (b) DMARDs, or glucocorticoids. Random-effects meta-regression analyses were performed for each outcome, with treatment group as the predictor corrected for baseline HAQ or disease activity and assessment point. RESULTS: Thirty-one studies including 5,589 patients were included. The meta-regression did not support higher effectiveness of increasing MTX dose in monotherapy. The number of treatment groups using combination therapy with csDMARDs was too small to perform meta-regression analyses. In combination therapy with glucocorticoids, a higher MTX dose was associated with higher (worse) outcome HAQ, but not with DAS/DAS28 or ESR/CRP level. In combination therapy with bDMARDs, a higher MTX dose was associated with higher outcome HAQ and DAS/DAS28, but not with ESR/CRP level. All effect sizes were small. CONCLUSION: In DMARD-naive, early RA patients who start MTX, either as monotherapy or in combination with bDMARDs or glucocorticoids, a higher initial dose of MTX was not associated with better clinical outcomes. This finding suggests that there is little short-term gain from starting with high compared to low MTX doses.

Metabolic health profile in young adults with Prader-Willi syndrome: results of a 2-year randomized, placebo-controlled, crossover GH trial.

CONTEXT: Patients with Prader-Willi syndrome (PWS) have an increased fat mass and decreased lean body mass. GH-treated young adults with PWS who have attained adult height benefit from continuation of growth hormone (GH) treatment, as GH maintained their improved body composition, whereas fat mass increased during the placebo period. Adults with PWS are predisposed to T2DM and cardiovascular disease. Whether GH affects metabolic health profile of this patient group is unknown. OBJECTIVE: To investigate the effects of GH vs placebo on metabolic health, in young adults with PWS who were GH-treated for many years during childhood and had attained adult height (AH). METHOD: A 2-year, randomized, double-blind, placebo-controlled crossover study with stratification for gender and BMI in 27 young adults with PWS. Intervention with GH (0·67 mg/m2 /day) and placebo, both for 1-year duration. RESULTS: Compared to placebo, GH treatment resulted in similar glucose and insulin levels during oral glucose tolerance test. Only fasting glucose and insulin were slightly higher during GH vs placebo (+0·2 mmol/l and +18·4 pmol/l), although both remained within normal ranges in both phases. Blood pressure and lipid profile were similar after GH vs placebo. At baseline (AH) and during GH, no patients had metabolic syndrome, while 1 developed it during placebo treatment. CONCLUSIONS: Growth hormone treatment has no adverse effects on metabolic health profile. Thus, GH-treated young adults with PWS who have attained AH benefit from continuation of GH treatment without safety concerns regarding metabolic health.

Age affects joint space narrowing in patients with early active rheumatoid arthritis.

BACKGROUND: Joint space narrowing (JSN) in rheumatoid arthritis (RA) may be a manifestation of (primary) osteoarthritis becoming more prominent with age. We investigated the severity and predictors of JSN progression among different age groups. METHODS: 10-year follow-up data of the BeSt study, a randomised controlled treat-to-target trial in early RA were used. Annual X-rays of hands and feet were scored using the Sharp/van der Heijde score (SHS). Subgroups were defined by age at baseline: ≥55, ≥40<55 and <40 years. JSN progression predictors were assessed by Poisson regression. RESULTS: Baseline JSN scores (median (IQR)) were higher in patients ≥55 (2.0 (0.0-6.0)) compared with the other age groups: 1.0 (0.0-3.0) ≥40<55 and 0.3 (0.0-3.0) <40, p<0.001. After 10 years, total JSN and SHS were similar in all age groups. In patients ≥55 the mean erythrocyte sedimentation rate (ESR) over time (relative risk 1.02 (95% CI 1.00 to 1.03)) and the combined presence of rheumatoid factor and anticitrullinated protein antibodies (RF+/ACPA+) (3.27 (1.25-8.53)) were significantly correlated with JSN progression. In patients <40 the baseline swollen joint count (SJC; 1.09 (1.01-1.18)) and ESR over time (1.04 (1.02-1.06)) were significantly associated. CONCLUSIONS: At baseline, patients with RA ≥55 years had more JSN than younger patients but after 10 years JSN scores were similar between age groups. Independent risk factors for JSN progression were baseline SJC and ESR over time in patients <40, RF+/ACPA+ and ESR over time in patients ≥55 years. This suggests that mechanisms leading to JSN progression are related to (residual) rheumatoid inflammation and vary between age groups. These mechanisms remain to be elucidated. TRIAL REGISTRATION NUMBERS: NTR262, NTR265.

Tumour-free margins in vulvar squamous cell carcinoma: Does distance really matter?

BACKGROUND: There is no consensus on the width of tumour-free margins after surgery for vulvar squamous cell carcinoma (VSCC). Most current guidelines recommend tumour-free margins of ≥8 mm. The aim of this study was to investigate whether a margin of <8 mm is associated with an increased risk of local recurrence in VSCC. METHODS: A meta-analysis of the available literature and a cohort study of 148 VSCC patients seen at a referral centre from 2000 to 2012 was performed. The primary end-point of the cohort study was a histologically confirmed ipsilateral local recurrence within 2 years after primary treatment in relation to the margin distance. RESULTS: Based on 10 studies, the meta-analysis showed that a tumour-free margin of <8 mm is associated with a higher risk of local recurrence compared to a tumour-free margin of ≥8 mm (pooled risk ratio, 1.99 [95% confidence interval {CI}: 1.13-3.51], p = 0.02). In the cohort study, we found no clear difference in the risk of local recurrence in the <8 versus ≥8 mm group; however, 40% of the patients in the <8 mm group received additional treatment. Tumour-positive margin was the only independent risk factor for local recurrence in the multivariable analysis (hazard ratio, 0.21 [95% CI: 0.08-0.55]). CONCLUSIONS: This work provides important data to question the commonly used 8-mm margin as a prognosticator for local recurrence. More research is needed to address the question of whether additional treatment improves the prognosis in patients with a tumour-free margin of <8 mm.

The influence of age and approaching death on the course of nondopaminergic symptoms in Parkinson's disease.

INTRODUCTION: The influence of approaching death in addition to age and their interaction on the course of a broad spectrum of nondopaminergic features in Parkinson's disease (PD) has not been well studied. This study addresses this issue in a prospectively designed study. METHODS: During five years, the severity of axial symptoms, cognitive impairment, psychotic symptoms, autonomic dysfunction, depressive symptoms, and daytime sleepiness was annually evaluated in PD patients. For each domain a linear mixed-effect model was used to examine changes during follow-up and relations with age and death. RESULTS: Of 378 included patients, 43 died during follow-up. Higher age was associated with increased severity of all nondopaminergic features except depression, and with a higher rate of progression of axial symptoms and cognitive impairment. Patients who died during follow-up had a higher severity of all nondopaminergic features except autonomic dysfunction, and a higher rate of progression of axial symptoms, cognitive impairment, and psychotic symptoms, compared to patients who survived. CONCLUSION: This study shows that the severity of most nondopaminergic features and the progression rate of axial and psychotic symptoms and cognitive impairment increase before PD patients die, independent of the influence of age. An interaction between age and approaching death did not have a significant effect on the course of the symptoms. Improving our understanding of the fundamental biology underlying these factors and the interaction with factors intrinsic to the disease, may have profound implications for the treatment of PD.

Effect of birth size and catch-up growth on adult blood pressure and carotid intima-media thickness.

AIMS: To investigate the effect of birth size and weight gain during childhood on blood pressure and carotid intima-media thickness (cIMT) in young adulthood. METHODS: The relationship of birth size with systolic blood pressure (SBP), diastolic blood pressure (DBP), and cIMT was investigated in 243 adults, aged 18­24 years. SBP, DBP, and cIMT were also analyzed in 4 subgroups: subjects either born small for gestational age with short stature (SGA-S) or with catch-up growth (SGA-CU), or born appropriate for gestational age with idiopathic short stature or with normal stature (controls). RESULTS: Adult weight SDS and fat mass were positively related to SBP and DBP, adjusted for birthweight SDS which was not related to SBP and DBP. Birth size was also not related to cIMT. Subgroup analyses showed no differences in blood pressure between subgroups, but cIMT was significantly greater in SGA-CU subjects than in controls after correction for age, gender and artery diameter. This difference became borderline significant after additional correction for smoking and SBP. CONCLUSION: Not birth size but childhood weight gain, especially fat mass, determines young adult blood pressure. Postnatal catch-up growth appears to have a greater influence on cardiovascular disease markers than birth size.

Preexisting heart failure is an underestimated risk factor in cardiac surgery.

BACKGROUND: Heart failure is characterised as a strong risk factor for systemic failure after cardiac surgery. However, the impact has never been substantiated. METHODS: Patients with heart failure (n = 48) - scheduled for elective ventricular reconstruction or external constraint device-were compared with a one-to-one matched control group of patients without heart failure undergoing cardiac surgery between 2006 and 2009. RESULTS: As expected, patients with heart failure more frequently experienced complications definitely related to pump failure (p = 0.01). However, complications not related to their pump failure were also more often observed, such as prolonged mechanical ventilation, sepsis and vasoplegia (p = 0.01). Overall, organ dysfunction-circulatory, renal, and pulmonary failure-was often observed in heart failure patients, contributing to a prolonged stay in the intensive care unit (p < 0.001) as well as in hospital (p = 0.01). CONCLUSION: The adverse postoperative course in patients with heart failure is not only directly related to circulatory failure, but merely reflects a systemic dysregulation. Our findings suggest that heart failure impacts outcome and should therefore be included in prevailing risk classification systems. Offensive perioperative treatment strategies, focused on the main complications in patients with heart failure, will lead to improved results after cardiac surgery.

Treatment effect modifiers for the patient education programme for Parkinson's disease.

AIM: A recent randomised controlled trial showed significant benefits for Parkinson's disease (PD) caregivers' psychosocial problems and need for help and a trend towards significant improvement of patients' quality of life after participation in the Patient Education Programme for Parkinson's disease (PEPP). Large variations in change scores were found, indicating variation in benefit. The aim of this study was to search for treatment effect modifiers. METHODS: Outcome measures were patients' quality of life [Parkinson's Disease Questionnaire (PDQ)-39] and caregivers' psychosocial burden [Belastungsfragebogen Parkinson Angehörigen kurzversion (BELA-A-k)]. Candidate treatment effect modifiers were participants' characteristics and baseline scores on psychological questionnaires (BELA-P/A-k, PDQ-39, EQ-5D, Self-rating Depression Scale) and patients' neuropsychological test scores (Mini Mental State Examination, National Adult Reading Test, Dutch version, Word Test, Behavioural Assessment of the Dysexecutive Syndrome rule shift, Trail Making Test, Stroop). Secondary analyses of data from a randomised controlled trial with 64 patients and 46 caregivers were performed using regression analyses with treatment group interaction terms. RESULTS: No significant modifiers were found for the patients. In the caregiver group, a higher MMSE score of the patient at baseline was found to be a significant predictor of a lower BELA-A-k Bothered by score post-intervention of the caregiver. CONCLUSIONS: A potential predictor of treatment benefit was found for caregivers of PD patients with better cognitive functioning. This study did not find treatment effect modifiers for PD patients: demographics, disease stage and time of diagnosis, cognitive functioning, level of baseline psychosocial burden, participating with or without a caregiver, and caregiver changes did not influence treatment outcome. The PEPP seems suitable for the majority of patients.

Validation of the web-based LUMINA questionnaire for recruiting large cohorts of migraineurs.

OBJECTIVE: To assess validity of a self-administered web-based migraine-questionnaire in diagnosing migraine aura for the use of epidemiological and genetic studies. METHODS: Self-reported migraineurs enrolled via the LUMINA website and completed a web-based questionnaire on headache and aura symptoms, after fulfilling screening criteria. Diagnoses were calculated using an algorithm based on the International Classification of Headache Disorders (ICHD-2), and semi-structured telephone-interviews were performed for final diagnoses. Logistic regression generated a prediction rule for aura. Algorithm-based diagnoses and predicted diagnoses were subsequently compared to the interview-derived diagnoses. RESULTS: In 1 year, we recruited 2397 migraineurs, of which 1067 were included in the validation. A seven-question subset provided higher sensitivity (86% vs. 45%), slightly lower specificity (75% vs. 95%), and similar positive predictive value (86% vs. 88%) in assessing aura when comparing with the ICHD-2-based algorithm. CONCLUSIONS: This questionnaire is accurate and reliable in diagnosing migraine aura among self-reported migraineurs and enables detection of more aura cases with low false-positive rate.

Analysis of individual drug use as a time-varying determinant of exposure in prospective population-based cohort studies.

In pharmaco-epidemiology, the use of drugs is the determinant of interest when studying exposure-outcome associations. The increased availability of computerized information about drug use on an individual basis has greatly facilitated analyses of drug effects on a population-based scale. It seems likely that many negative findings in the early days of pharmaco-epidemiology can be explained by non-differential misclassification because of too simple (yes/no) exposure measures. In this paper, the authors discuss the importance of an adequate definition of drug exposure in pharmaco-epidemiological research and how this time-varying determinant can be analyzed in cohort studies. To reduce the risk of non-differential misclassification, a precise definition of exposure is mandatory and it is important to distinguish the complete follow-up period of a population into mutually exclusive episodes of non-use, past use and current use for each individual. By analyzing exposure to drugs as a time-dependent variable in a Cox regression model, cohort studies with complete coverage of all filled prescriptions can provide us with valid and precise risk estimates of drug-outcome associations. However, such estimates may be biased in the presence of time-dependent confounders which are themselves affected by prior exposure.

Growth patterns during childhood and the relationship with acylation-stimulating protein.

BACKGROUND/OBJECTIVES: Acylation-stimulating protein (ASP) is an adipose tissue-derived hormone, which stimulates glucose and free fatty acid (FFA) uptake into adipocytes. Changes in ASP metabolism are associated with alterations in lipid metabolism. As postnatal catch-up growth has been associated with dyslipidaemia in later life, we investigated the association between ASP and birth size, adult size and different growth patterns during childhood. METHODS: The associations were investigated by multiple regression analyses in 285 young adults, aged 18-24. Subsequently, differences in ASP were analysed in four clinically relevant subgroups, young adults either born small for gestational age with short stature (SGA-S) or with catch-up growth (SGA-CU), or born appropriate for gestational age with idiopathic short stature (ISS) or with normal stature (controls). RESULTS: Weight gain during childhood, particularly fat accumulation, was positively related to ASP levels in early adulthood, independent of birth size, age and gender. Foetal growth, reflected by birth size, was not related to ASP levels. Between the subgroups, no differences in ASP were found, but SGA-CU and ISS subjects had significantly higher levels of FFA. CONCLUSION: Exaggerated weight gain during childhood, but not foetal growth, contributes to alterations in ASP metabolism, which may be associated with impaired FFA uptake and delayed triglycerides clearance. Therefore, exaggerated weight gain during childhood should be prevented.

Meta-analysis of diagnostic test accuracy studies with multiple thresholds using survival methods.

Diagnostic tests play an important role in clinical practice. The objective of a diagnostic test accuracy study is to compare an experimental diagnostic test with a reference standard. The majority of these studies dichotomize test results into two categories: negative and positive. But often the underlying test results may be categorized into more than two, ordered, categories. This article concerns the situation where multiple studies have evaluated the same diagnostic test with the same multiple thresholds in a population of non-diseased and diseased individuals. Recently, bivariate meta-analysis has been proposed for the pooling of sensitivity and specificity, which are likely to be negatively correlated within studies. These ideas have been extended to the situation of diagnostic tests with multiple thresholds, leading to a multinomial model with multivariate normal between-study variation. This approach is efficient, but computer-intensive and its convergence is highly dependent on starting values. Moreover, monotonicity of the sensitivities/specificities for increasing thresholds is not guaranteed. Here, we propose a Poisson-correlated gamma frailty model, previously applied to a seemingly quite different situation, meta-analysis of paired survival curves. Since the approach is based on hazards, it guarantees monotonicity of the sensitivities/specificities for increasing thresholds. The approach is less efficient than the multinomial/normal approach. On the other hand, the Poisson-correlated gamma frailty model makes no assumptions on the relationship between sensitivity and specificity, gives consistent results, appears to be quite robust against different between-study variation models, and is computationally very fast and reliable with regard to the overall sensitivities/specificities.

Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease.

OBJECTIVE: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). We aimed to assess whether interaction between CAG repeat sizes in the mutant and normal allele could affect disease severity and progression. METHODS: Using linear regression and mixed-effects models, the influence of mutant and normal CAG repeat sizes interaction was assessed on 1) age at onset in 921 patients with HD, 2) clinical severity and progression in 512 of these patients with follow-up data available, and 3) basal ganglia volume on magnetic resonance images in 16 premanifest HD mutation carriers. RESULTS: Normal and mutant CAG repeat sizes interacted to influence 1) age at onset (p = 0.001), 2) severity or progression of motor, cognitive, and functional, but not behavioral, symptoms in patients with HD (all p < 0.05), and 3) in premanifest subjects, basal ganglia volumes (p < 0.05). In subjects with mutant CAG expansions in the low range, increasing size of the normal repeat correlated with more severe symptoms and pathology, whereas for those subjects with expansions in the high range, increasing size of the normal repeat correlated with less severe symptoms and pathology. CONCLUSIONS: Increasing CAG repeat size in normal HTT diminishes the association between mutant CAG repeat size and disease severity and progression in Huntington disease. The underlying mechanism may involve interaction of the polyglutamine domains of normal and mutant huntingtin (fragments) and needs further elucidation. These findings may have predictive value and are essential for the design and interpretation of future therapeutic trials.

Prevalence of subependymal giant cell tumors in patients with tuberous sclerosis and a review of the literature.

BACKGROUND AND PURPOSE: To investigate the prevalence of subependymal giant cell ependymomas (SEGA) in patients with tuberous sclerosis complex (TSC). METHODS: We performed a retrospective cross-sectional study in a cohort of 285 patients with known TSC. Institutional review board approval was obtained. We included all 214 TSC-patients who had received a contrast-enhanced computed tomography (CT) scan of the brain. The most recent scan was evaluated for SEGA and presence of hydrocephalus. Additionally, a literature search was performed, and pooled estimates of SEGA prevalence in TSC were calculated. We used descriptive statistics, two sample t-test, chi-squared-test, and meta-analysis as appropriate. RESULTS: Computed tomography showed radiological evidence of SEGA in 43 of the 214 TSC-patients (20%); 23 of 105 men (22%) and 20 of 109 women (18%; P = .52). Average maximum tumor size was 11.4 mm (range, 4-29 mm). Patients with SEGA (mean, 31 years; range, 16-58 years) were on average younger than patients without SEGA (mean, 37 years; range, 10-72 years; P = 0.007). No association between tumor size and patient age was detected. Nine patients had bilateral SEGA. Hydrocephalus was present in six of the 43 patients (14%). Meta-analysis of reported prevalence and our current study showed that studies using radiological evidence to diagnose SEGA gave a higher pooled estimate of the prevalence of SEGA in TSC (0.16; 95% CI: 0.12, 0.21) than studies using mainly histopathological evidence of SEGA (0.09; 95% CI: 0.07, 0.12). CONCLUSIONS: In our cohort, CT demonstrated evidence of SEGA in 20% of TSC-patients. Prevalence of SEGA in TSC is higher in studies using radiological evidence to diagnose SEGA than in studies using histopathological evidence.

Influence of birth size on body composition in early adulthood: the programming factors for growth and metabolism (PROGRAM)-study.

BACKGROUND/OBJECTIVES: Several studies have investigated the relationship of birth size with fat mass and lean body mass (LBM), but the findings differed greatly due to different ways of measuring FM and LBM, different study populations and age groups. We hypothesized that birth size has no influence on adult body composition, whereas weight gain during childhood has. METHODS: In the programming factors for growth and metabolism (PROGRAM)-study, a cohort of 312 young adults, aged 18-24 years, FM and LBM were determined by dual energy X-ray absorptiometry (DXA). Subsequently, differences in FM and LBM were analysed in four subgroups, young adults either born small for gestational age with short stature (SGA-S) or with catch-up growth (SGA-CU), or born appropriate for gestational age (AGA) with idiopathic short stature (ISS) or with normal stature (controls). RESULTS: Age, gender, adult height SDS and adult weight SDS were significant positive determinants of FM and LBM, whereas weight gain during childhood was positively significant for FM and negatively for LBM. Birth weight SDS tended to be significant and birth length SDS was not. Weight gain during childhood was positively correlated with waist : hip ratio and trunk fat : total fat ratio. SGA-CU subjects had significantly higher FM and significantly lower LBM than controls. CONCLUSION: Weight gain during childhood is an important determinant of body composition in young adulthood, whereas birth size is less important. In clinical practice, too much weight gain in childhood should be prevented as it results in a relatively high fat mass, especially in children with catch-up growth in weight, like SGA-CU subjects.

Weight loss in Huntington disease increases with higher CAG repeat number.

OBJECTIVE: Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded number of CAG repeats in the huntingtin gene. A hallmark of HD is unintended weight loss, the cause of which is unknown. In order to elucidate the underlying mechanisms of weight loss in HD, we studied its relation to other disease characteristics including motor, cognitive, and behavioral disturbances and CAG repeat number. METHODS: In 517 patients with early stage HD, we applied mixed-effects model analyses to correlate weight changes over 3 years to CAG repeat number and various components of the Unified Huntington's Disease Rating Scale (UHDRS). We also assessed the relation between CAG repeat number and body weight and caloric intake in the R6/2 mouse model of HD. RESULTS: In patients with HD, mean body mass index decreased with -0.15 units per year (p < 0.001). However, no single UHDRS component, including motor, cognitive, and behavioral scores, was independently associated with the rate of weight loss. Patients with HD with a higher CAG repeat number had a faster rate of weight loss. Similarly, R6/2 mice with a larger CAG repeat length had a lower body weight, whereas caloric intake increased with larger CAG repeat length. CONCLUSIONS: Weight loss in Huntington disease (HD) is directly linked to CAG repeat length and is likely to result from a hypermetabolic state. Other signs and symptoms of HD are unlikely to contribute to weight loss in early disease stages. Elucidation of the responsible mechanisms could lead to effective energy-based therapeutics.

Fat mass and apolipoprotein E genotype influence serum lipoprotein levels in early adulthood, whereas birth size does not.

BACKGROUND/OBJECTIVES: An association between an unfavorable lipid profile and low birth weight has been reported, although this association remains controversial. We hypothesized that birth size does not have any influence on serum lipid levels but fat accumulation during childhood has. METHODS: In the PROgramming factors for GRowth And Metabolism study, a cohort of 297 young adults, aged 18-24 yr, the influence of clinical parameters on total cholesterol, triglycerides, low-density lipoprotein, high-density lipoprotein, lipoprotein a, and apolipoprotein (apo) A-1 and apoB was analyzed with multiple regression modeling. In addition, differences in these lipid levels and ApoE genotype prevalence were analyzed in four subgroups: young adults either born small for gestational age with short stature or with catch-up growth, or born appropriate for gestational age with idiopathic short stature or with normal stature (controls). RESULTS: Birth length sd score (SDS) and birth weight SDS were no significant determinants of the serum lipid levels, whereas gender, ApoE genotype, adult height SDS, adult weight SDS, and fat mass were. Comparison of the subgroups showed that small for gestational age with short stature subjects had a significantly higher apoB than controls. There were no other significant differences in lipid levels or ApoE genotype prevalence among the four subgroups. CONCLUSIONS: ApoE genotype is an important genetic determinant of lipid levels in young adulthood. Furthermore, fat accumulation during childhood significantly determines serum lipid levels, whereas birth size has no significant contribution. For public health practice, this means that parents and their children need to be informed about the risks of fat accumulation during childhood.

Bivariate random effects meta-analysis of ROC curves.

Meta-analysis of receiver operating characteristic (ROC)-curve data is often done with fixed-effects models, which suffer many shortcomings. Some random-effects models have been proposed to execute a meta-analysis of ROC-curve data, but these models are not often used in practice. Straightforward modeling techniques for multivariate random-effects meta-analysis of ROC-curve data are needed. The 1st aim of this article is to present a practical method that addresses the drawbacks of the fixed-effects summary ROC (SROC) method of Littenberg and Moses. Sensitivities and specificities are analyzed simultaneously using a bivariate random-effects model. The 2nd aim is to show that other SROC curves can also be derived from the bivariate model through different characterizations of the estimated bivariate normal distribution. Thereby the authors show that the bivariate random-effects approach not only extends the SROC approach but also provides a unifying framework for other approaches. The authors bring the statistical meta-analysis of ROC-curve data back into a framework of relatively standard multivariate meta-analysis with random effects. The analyses were carried out using the software package SAS (Proc NLMIXED).