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.

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.

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.

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.

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.

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.

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.

Fat mass accumulation during childhood determines insulin sensitivity in early adulthood.

BACKGROUND/OBJECTIVES: Low birth weight and postnatal catch-up growth have been associated with an increased risk for diabetes mellitus type II (DMII). We evaluated the contribution of birth and adult size, body composition, and waist-to-hip ratio to DMII risk factors in young adulthood. METHODS: In a group of 136 young adults, aged 18-24 yr, insulin sensitivity and disposition index were determined by frequent sampling iv glucose tolerance test. The association of clinical parameters with these variables was analyzed with multiple regression modeling. In addition, differences in insulin sensitivity and disposition index, a measure for beta-cell function, were analyzed in four subgroups, young adults either born small for gestational age SGA with short stature (n = 25) or SGA with catch-up growth (n = 23) or born appropriate for gestational age with idiopathic short stature (n = 23) or with normal stature (controls) (n = 26). RESULTS: Fat mass was the only significant predictor of insulin sensitivity, whereas birth length and birth weight were not significant. After correction for age, gender, and adult body size, insulin sensitivity was significantly lower in subjects born SGA with catch-up growth compared with controls. None of the variables had a significant influence on disposition index, and there was no significant difference in disposition index between the subgroups. CONCLUSIONS: Our data show that a higher body fat mass at 21 yr is associated with reduced insulin sensitivity, independent of birth size. These findings have important implications for public health practice.

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.

Rapid identification and antimicrobial susceptibility testing reduce antibiotic use and accelerate pathogen-directed antibiotic use.

INTRODUCTION: Rapid bacterial identification and susceptibility tests can lead to earlier microbiological diagnosis and pathogen-directed, appropriate therapy. We studied whether accelerated diagnostics affected antibiotic use and patient outcomes. PATIENTS AND METHODS: A prospective randomized clinical trial was performed over a 2-year period. Inpatients were selected on the basis of a positive culture from normally sterile body fluids and randomly assigned to either a rapid intervention arm or the control arm. The intervention arm used the Vitek 2 automated identification and susceptibility testing device, combined with direct inoculation of blood cultures. In the control arm, the Vitek 1 system inoculated from subcultures was used. Follow-up was 4 weeks after randomization. RESULTS: A total of 1498 patients were randomized: 746 in the intervention arm and 752 in the control arm. For susceptibility testing, the rapid arm was 22 h faster than the control arm, and for identification, it was 13 h faster (P < 0.0001). In the rapid arm, antibiotic use was 6 defined daily doses lower per patient than in the control arm (P = 0.012). Whereas antibiotics were switched more in the rapid group on the day of randomization (P = 0.006), in the control group they were switched more on day two (P = 0.02). Mortality rates did not differ significantly between the two groups (17.6% versus 15.2%). CONCLUSIONS: While rapid bacterial identification and susceptibility testing led to earlier changes and a significant reduction in antibiotic use, they did not reduce mortality.

Influence of birth size and body composition on bone mineral density in early adulthood: the PROGRAM study.

BACKGROUND/OBJECTIVES: Low bone mineral density (BMD) may lead to osteoporosis and is associated with increased fracture risk. Associations between BMD and various factors have been reported. Our objective was to investigate whether birth size, lean body mass (LBM) and fat mass (FM) are determinants of BMD of the total body (BMD(TB)) and the lumbar spine (BMD(LS)). METHODS: In the PROgramming factors for GRowth And Metabolism (PROGRAM) study of a cohort of 312 young adults aged 18-24 years, BMD(TB) and BMD(LS) were determined by dual-energy X-ray absorptiometry (DXA). Subsequently, differences in BMD(TB) and BMD(LS) were analysed in four subgroups: young adults 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: Adult weight, LBM, FM and weight gain during childhood were the main positive determinants for BMD(TB) in early adulthood, whereas birth size had no influence (adjusted R(2) = 0.50). Gender, adult weight, LBM, FM and weight gain were the significant determinants of BMD(LS). In the subgroups, after correction for age, gender and adult body size, the ISS group had a significantly lower BMD(TB) than controls but there was no difference in BMD(LS) between the subgroups. CONCLUSIONS: Prenatal growth has no significant influence on BMD(TB) and BMD(LS) in early adulthood. Gender and postnatal growth, particularly weight gain, are the main positive determinants. To achieve a normal BMD in adulthood, healthcare workers should aim for a normal weight gain in children.

Anti-infective-treated central venous catheters for total parenteral nutrition or chemotherapy: a systematic review.

This systematic review assesses the effect of anti-infective-treated central venous catheters (CVCs) on catheter-related bloodstream infection (CRBSI) in patients who received a CVC for total parenteral nutrition (TPN) or chemotherapy. Randomised controlled trials were retrieved from Medline and the Cochrane Library up to 14 October 2007. Two reviewers independently assessed trial quality and extracted data. Data for CRBSI were combined where appropriate, using a random effects model, and subgroup meta-analysis was carried out where applicable. The impact of the risk for CRBSI in the control group on the effect of anti-infective CVCs was studied by using meta-regression based on the bivariate meta-analysis model. Nine trials were included in the review. One trial showed that antibiotic-treated CVCs reduced the risk for CRBSI in outpatients with chemotherapy and a CVC in-situ during a period of about nine weeks. Eight trials did not find an overall significant benefit in favour of antiseptic-treated CVCs in patients who had a CVC during a mean of about two weeks. No relationship could be established between the effect of anti-infective-treated CVCs and the underlying risk for CRBSI, although nearly all trials had serious methodological shortcomings. Thus, available scientific evidence to prevent CRBSI by the use of anti-infective-treated CVCs in patients receiving chemotherapy or TPN is not sufficient as a basis to recommend their use. The recommendation of the Centers for Disease Control and Prevention to use antibiotic- or antiseptic-impregnated CVCs, when the risk for CRBSI remains high despite good hygienic practice, should therefore be limited to patients in the intensive care/perioperative setting.

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).

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.

Anti-infective-treated central venous catheters: a systematic review of randomized controlled trials.

OBJECTIVE: This systematic review assesses the effect of anti-infective-treated central venous catheters (CVCs) on catheter-related bloodstream infection (CRBSI) in the acute care setting. METHODS: Randomized controlled trials were retrieved from Medline and the Cochrane Library up to 15 January 2007. Two reviewers independently assessed trial quality and extracted data. Data for CRBSI were combined where appropriate, using a random effects model. The impact of the risk for CRBSI in the control group (baseline risk) on the benefit of anti-infective CVCs was studied by using meta-regression based on the binomial normal bivariate meta-analysis model. RESULTS: Twenty-one trials were included in the review. Mainly intensive care (IC) patients were studied. Eighteen trials showed that anti-infective CVCs reduced the risk of CRBSI. The number needed to treat (NNT) varied from 182 to 12, with baseline risks ranging from 1% to 10%. Nearly all trials had serious methodological shortcomings. Three trials comparing minocycline-rifampicin-treated catheters with antiseptic-treated catheters showed inconsistent results. One trial suggested that there is not any difference in CRBSI between heparin- and antiseptic-treated CVCs. CONCLUSION: Because the NNT is large when the baseline risk is low, the use of anti-infective-treated CVCs in the acute care setting should only be considered in situations in which background rates of CRBSI are high. The magnitude of benefit as calculated in this review should be interpreted with caution because of strong arguments in favor of a systematic overestimation of the effect. Which type of anti-infective catheter is most effective could not be established from the available data.

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.

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.

Randomized clinical trial of adenosine 5'-triphosphate in patients with advanced non-small-cell lung cancer.

BACKGROUND: Extracellular adenosine 5'-triphosphate (ATP) is involved in the regulation of a variety of biologic processes, including neurotransmission, muscle contraction, and liver glucose metabolism, via purinergic receptors. In nonrandomized studies involving patients with different tumor types including non-small-cell lung cancer (NSCLC), ATP infusion appeared to inhibit loss of weight and deterioration of quality of life (QOL) and performance status. We conducted a randomized clinical trial to evaluate the effects of ATP in patients with advanced NSCLC (stage IIIB or IV). METHODS: Fifty-eight patients were randomly assigned to receive either 10 intravenous 30-hour ATP infusions, with the infusions given at 2- to 4-week intervals, or no ATP. Outcome parameters were assessed every 4 weeks until 28 weeks. Between-group differences were tested for statistical significance by use of repeated-measures analysis, and reported P values are two-sided. RESULTS: Twenty-eight patients were allocated to receive ATP treatment and 30 received no ATP. Mean weight changes per 4-week period were -1.0 kg (95% confidence interval [CI] = -1.5 to -0.5) in the control group and 0.2 kg (95% CI = -0.2 to +0.6) in the ATP group (P =.002). Serum albumin concentration declined by -1.2 g/L (95% CI= -2.0 to -0.4) per 4 weeks in the control group but remained stable (0.0 g/L; 95% CI = -0.3 to +0.3) in the ATP group (P =.006). Elbow flexor muscle strength declined by -5.5% (95% CI = -9.6% to -1. 4%) per 4 weeks in the control group but remained stable (0.0%; 95% CI= -1.4% to +1.4%) in the ATP group (P =.01). A similar pattern was observed for knee extensor muscles (P =.02). The effects of ATP on body weight, muscle strength, and albumin concentration were especially marked in cachectic patients (P =.0002, P =.0001, and P =. 0001, respectively, for ATP versus no ATP). QOL score changes per 4-week period in the ATP group showed overall less deterioration than in the control group-physical scores (-0.2% versus -2.4%; P =. 0002); functional scores (+0.4% versus -5.5%; P =.02); psychologic scores (-0.7% versus -2.4%; P =.11); overall QOL score (+0.1% versus -3.5%; P =.0001). CONCLUSIONS: This randomized trial demonstrates that ATP has beneficial effects on weight, muscle strength, and QOL in patients with advanced NSCLC.

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.