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Background: The occurrence of metabolic syndrome (MetS) and the gut microbiota composition are known to differ across ethnicities yet how these three factors are interwoven is unknown. Also, it is unknown what the relative contribution of the gut microbiota composition is to each MetS component and whether this differs between ethnicities. We therefore determined the occurrence of MetS and its components in the multi-ethnic HELIUS cohort and tested the overall and ethnic-specific associations with the gut microbiota composition., Methods: We included 16,209 treatment naïve participants of the HELIUS study, which were of Dutch, African Surinamese, South-Asian Surinamese, Ghanaian, Turkish, and Moroccan descent to analyze MetS and its components across ethnicities. In a subset (n = 3443), the gut microbiota composition (16S) was associated with MetS outcomes using linear and logistic regression models., Results: A differential, often sex-dependent, prevalence of MetS components and their combinations were observed across ethnicities. Increased blood pressure was commonly seen especially in Ghanaians, while South-Asian Surinamese and Turkish had higher MetS rates in general and were characterized by worse lipid-related measures. Regarding the gut microbiota, when ethnic-independent associations were assumed, a higher α-diversity, higher abundance of several ASVs (mostly for waist and triglyceride-related outcomes) and a trophic network of ASVs of Ruminococcaceae, Christensenellaceae, and Methanobrevibacter (RCM) bacteria were associated with better MetS outcomes. Statistically significant ethnic-specific associations were however noticed for α-diversity and the RCM trophic network. Associations were significant in the Dutch but not always in all other ethnicities. In Ghanaians, a higher α-diversity and RCM network abundance showed an aberrant positive association with high blood pressure measures compared to the other ethnicities. Even though adjustment for socioeconomic status-, lifestyle-, and diet-related variables often attenuated the effect size and/or the statistical significance of the ethnic-specific associations, an overall similar pattern across outcomes and ethnicities remained., Conclusions: The occurrence of MetS characteristics among ethnicities is heterogeneous. Both ethnic-independent and ethnic-specific associations were identified between the gut microbiota and MetS outcomes. Across multiple ethnicities, a one-size-fits-all approach may thus be reconsidered in regard to both the definition and/or treatment of MetS and its relation to the gut microbiota., (© 2024. The Author(s).)

Introduction: Evaluation of bradykinesia is based on five motor tasks from the MDS-UPDRS. Visually scoring these motor tasks is subjective, resulting in significant interrater variability. Recent observations suggest that it may be easier to hear the characteristic features of bradykinesia, such as the decrement in sound intensity or force of repetitive movements. The objective is to evaluate whether audio signals derived during four MDS-UPDRS tasks can be used to detect and grade bradykinesia, using two machine learning models., Methods: 54 patients with Parkinson's disease and 28 healthy controls were filmed while executing the bradykinesia motor tasks. Several features were extracted from the audio signal, including number of taps, speed, sound intensity, decrement and freezes. For each motor task, two supervised machine learning models were trained, Logistic Regression (LR) and Support Vector Machine (SVM)., Results: Both classifiers were able to separate patients from controls reasonably well for the leg agility task, area under the receiver operating characteristic curve (AUC): 0.92 (95%CI: 0.78-0.99) for LR and 0.93 (0.81-1.00) for SVM. Also, models were able to differentiate less severe bradykinesia from severe bradykinesia, particularly for the pronation-supination motor task, with AUC: 0.90 (0.62-1.00) for LR and 0.82 (0.45-0.97) for SVM., Conclusion: This audio-based approach discriminates PD from healthy controls with moderate-high accuracy and separated individuals with less severe bradykinesia from those with severe bradykinesia. Sound analysis may contribute to the identification and monitoring of bradykinesia., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rui Araujo reports a relationship with Bial that includes: consulting or advisory and speaking and lecture fees. Rui Araujo reports a relationship with Roche that includes: speaking and lecture fees. Nienke de Vries reports a relationship with Netherlands Organisation for Health Research and Development that includes: funding grants. Nienke de Vries reports a relationship with The Michael J Fox Foundation that includes: funding grants. Bastiaan Bloem reports a relationship with Practical Neurology and Digital Biomarkers that includes: board membership. Bastiaan Bloem reports a relationship with Bial that includes: speaking and lecture fees. Bastiaan Bloem reports a relationship with AbbVie that includes: speaking and lecture fees. Bastiaan Bloem reports a relationship with Zambon that includes: speaking and lecture fees. Bastiaan Bloem reports a relationship with Roche that includes: speaking and lecture fees. Bastiaan Bloem reports a relationship with GE healthcare that includes: speaking and lecture fees. Bastiaan Bloem reports a relationship with Netherlands Organisation for Health Research and Development that includes: funding grants. Bastiaan Bloem reports a relationship with The Michael J Fox Foundation that includes: funding grants. Bastiaan Bloem reports a relationship with UCB that includes: funding grants. Bastiaan Bloem reports a relationship with AbbVie that includes: funding grants. Bastiaan Bloem reports a relationship with Stichting Parkinson fonds that includes: funding grants. Bastiaan Bloem reports a relationship with Hersenstichting Nederland that includes: funding grants. Bastiaan Bloem reports a relationship with Parkinson's foundation that includes: funding grants. Bastiaan Bloem reports a relationship with Verily Life Sciences LLC that includes: funding grants. Bastiaan Bloem reports a relationship with Horizon 2020 that includes: funding grants. Bastiaan Bloem reports a relationship with Topsector Life Sciences and Health that includes: funding grants. Bastiaan Bloem reports a relationship with Gatsby foundation that includes: funding grants. Bastiaan Bloem reports a relationship with Parkinson Vereniging that includes: funding grants. Bastiaan Bloem reports a relationship with Journal of Parkinson's Disease that includes: board membership. Bastiaan Bloem reports a relationship with Biogen that includes: board membership. Bastiaan Bloem reports a relationship with UCB that includes: board membership. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Accurate inference of genetic ancestry is crucial for population-based association studies, accounting for population heterogeneity and structure. This study analyzes genome-wide SNP data from the Netherlands Twin Register to compare genetic ancestry estimates. The focus is on the comparison of ancestry estimates between family members and individuals genotyped on multiple arrays (Affymetrix 6.0, Affymetrix Axiom, and Illumina GSA). Two conventional methods, principal component analysis and ADMIXTURE, were implemented to estimate ancestry, each serving its specific purpose, rather than for direct comparison. The results reveal that as the degree of genetic relatedness decreases, the Euclidean distances of genetic ancestry estimates between family members significantly increase (empirical p < 0.001), regardless of the estimation method and genotyping array. Ancestry estimates among individuals genotyped on multiple arrays also show statistically significant differences (empirical p < 0.001). Additionally, this study investigates the relationship between the ancestry estimates of non-identical twin offspring with ancestrally diverse parents and those with ancestrally similar parents. The results indicate a statistically significant weak correlation between the variation in ancestry estimates among offspring and differences in ancestry estimates among parents (Spearman's rho: 0.07, p = 0.005). This study highlights the utility of current methods in inferring genetic ancestry, emphasizing the importance of reference population composition in determining ancestry estimates.

Background and Aims: Detecting NASH remains challenging, while at-risk NASH (steatohepatitis and F≥ 2) tends to progress and is of interest for drug development and clinical application. We developed prediction models by supervised machine learning techniques, with clinical data and biomarkers to stage and grade patients with NAFLD., Approach and Results: Learning data were collected in the Liver Investigation: Testing Marker Utility in Steatohepatitis metacohort (966 biopsy-proven NAFLD adults), staged and graded according to NASH CRN. Conditions of interest were the clinical trial definition of NASH (NAS ≥ 4;53%), at-risk NASH (NASH with F ≥ 2;35%), significant (F ≥ 2;47%), and advanced fibrosis (F ≥ 3;28%). Thirty-five predictors were included. Missing data were handled by multiple imputations. Data were randomly split into training/validation (75/25) sets. A gradient boosting machine was applied to develop 2 models for each condition: clinical versus extended (clinical and biomarkers). Two variants of the NASH and at-risk NASH models were constructed: direct and composite models.Clinical gradient boosting machine models for steatosis/inflammation/ballooning had AUCs of 0.94/0.79/0.72. There were no improvements when biomarkers were included. The direct NASH model produced AUCs (clinical/extended) of 0.61/0.65. The composite NASH model performed significantly better (0.71) for both variants. The composite at-risk NASH model had an AUC of 0.83 (clinical and extended), an improvement over the direct model. Significant fibrosis models had AUCs (clinical/extended) of 0.76/0.78. The extended advanced fibrosis model (0.86) performed significantly better than the clinical version (0.82)., Conclusions: Detection of NASH and at-risk NASH can be improved by constructing independent machine learning models for each component, using only clinical predictors. Adding biomarkers only improved the accuracy of fibrosis., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The long-term outcome of first-episode schizophrenia needs improvement. Here, we evaluate the effectiveness of 5 years sustained specialist treatment (ST), ST including Parent groups (ST + P) or treatment as usual (TAU) on psychotic relapse and social functioning., Methods: A three condition randomized, parallel assigned, single-blind efficacy trial, in which 198 first-episode psychosis (FEP) patients aged 15-28 years were included. The effect on time to first relapse, first relapse rates, mean number of relapses per patient, and time to the improvement of social functioning were analyzed using Cox regression or ANOVA., Results: We found no significant differences between treatment conditions in the ITT analysis concerning time to first relapse, nor first relapse rate. Mean number of relapses per patient differed at a trend level between ST, ST + P or TAU conditions, respectively: 0.72; 0.62 or 1.02 ( p = 0.069). No evidence was found for differential effect of treatment conditions on social functioning., Conclusion: Five years sustained ST of FEP nor addition of parent groups increased time to first relapse or reduced first relapse rate, compared to sustained TAU. Indications for favorable effects of parent groups were found on relapses per patient.

Type 2 diabetes mellitus (T2D) is a prevalent disease often accompanied by the occurrence of dyslipidemia. Four and a half LIM domains 2 (FHL2) is a scaffolding protein, whose involvement in metabolic disease has recently been demonstrated. The association of human FHL2 with T2D and dyslipidemia in a multiethnic setting is unknown. Therefore, we used the large multiethnic Amsterdam-based Healthy Life in an Urban Setting (HELIUS) cohort to investigate FHL2 genetic loci and their potential role in T2D and dyslipidemia. Baseline data of 10,056 participants from the HELIUS study were available for analysis. The HELIUS study contained individuals of European Dutch, South Asian Surinamese, African Surinamese, Ghanaian, Turkish, and Moroccan descent living in Amsterdam and were randomly sampled from the municipality register. Nineteen FHL2 polymorphisms were genotyped, and associations with lipid panels and T2D status were investigated. We observed that seven FHL2 polymorphisms associated nominally with a pro-diabetogenic lipid profile including triglyceride (TG), high-density and low-density lipoprotein-cholesterol (HDL-C and LDL-C), and total cholesterol (TC) concentrations, but not with blood glucose concentrations or T2D status in the complete HELIUS cohort upon correcting for age, gender, BMI, and ancestry. Upon stratifying for ethnicity, we observed that only two of the nominally significant associations passed multiple testing adjustments, namely, the association of rs4640402 with increased TG and rs880427 with decreased HDL-C concentrations in the Ghanaian population. Our results highlight the effect of ethnicity on pro-diabetogenic selected lipid biomarkers within the HELIUS cohort, as well as the need for more large multiethnic cohort studies.

L -alpha glycerylphosphorylcholine (GPC), a nutritional supplement, has been demonstrated to improve neurological function. However, a new study suggests that GPC supplementation increases incident stroke risk thus its potential adverse effects warrant further investigation. Here we show that GPC promotes atherosclerosis in hyperlipidemic Apoe -/- mice. GPC can be metabolized to trimethylamine N-oxide, a pro-atherogenic agent, suggesting a potential molecular mechanism underlying the observed atherosclerosis progression. GPC supplementation shifted the gut microbial community structure, characterized by increased abundance of Parabacteroides , Ruminococcus , and Bacteroides and decreased abundance of Akkermansia , Lactobacillus , and Roseburia , as determined by 16S rRNA gene sequencing. These data are consistent with a reduction in fecal and cecal short chain fatty acids in GPC-fed mice. Additionally, we found that GPC supplementation led to an increased relative abundance of choline trimethylamine lyase ( cutC )-encoding bacteria via qPCR. Interrogation of host inflammatory signaling showed that GPC supplementation increased expression of the proinflammatory effectors CXCL13 and TIMP-1 and activated NF-κB and MAPK signaling pathways in human coronary artery endothelial cells. Finally, targeted and untargeted metabolomic analysis of murine plasma revealed additional metabolites associated with GPC supplementation and atherosclerosis. In summary, our results show GPC promotes atherosclerosis through multiple mechanisms and that caution should be applied when using GPC as a nutritional supplement.

Physical activity (PA) at recommended levels contributes to the prevention of non-communicable diseases, such as atherosclerotic cardiovascular disease (asCVD) and type 2 diabetes mellitus (T2DM). Since the composition of the gut microbiota is strongly intertwined with dietary intake, the specific effect of exercise on the gut microbiota is not known. Moreover, multiple other factors, such as ethnicity, influence the composition of the gut microbiota, and this may be derived by distinct diet as well as PA patterns. Here we aim to untangle the associations between PA and the gut microbiota in a sample ( n = 1334) from the Healthy Life In an Urban Setting (HELIUS) multi-ethnic cohort. The associations of different food groups and gut microbiota were also analyzed. PA was monitored using subjective ( n = 1309) and objective ( n = 162) methods, and dietary intake was assessed with ethnic-specific food frequency questionnaire (FFQ). The gut microbiota was profiled using 16S rRNA gene amplicon sequencing, and the functional composition was generated with the Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt2). Associations were assessed using multivariable and machine learning models. In this cohort, a distinct gut microbiota composition was associated with meeting the Dutch PA norm as well as with dietary intake, e.g., grains. PA related parameters such as muscle strength and calf circumference correlated with gut microbiota diversity. Furthermore, gut microbial functionality differed between active and sedentary groups. Differential representation of ethnicities in active and sedentary groups in both monitor methods hampered the detection of ethnic-specific effects. In conclusion, both PA and dietary intake were associated with gut microbiota composition in our multi-ethnic cohort. Future studies should further elucidate the role of ethnicity and diet in this association.

Genetic differences between individuals underlie susceptibility to many diseases. Genome-wide association studies (GWAS) have discovered many susceptibility genes but were often limited to cohorts of predominantly European ancestry. Genetic diversity between individuals due to different ancestries and evolutionary histories shows that this approach has limitations. In order to gain a better understanding of the associated genetic variation, we need a more global genomics approach including a greater diversity. Here, we introduce the Healthy Life in an Urban Setting (HELIUS) cohort. The HELIUS cohort consists of participants living in Amsterdam, with a level of diversity that reflects the Dutch colonial and recent migration past. The current study includes 10,283 participants with genetic data available from seven groups of inhabitants, namely, Dutch, African Surinamese, South-Asian Surinamese, Turkish, Moroccan, Ghanaian, and Javanese Surinamese. First, we describe the genetic variation and admixture within the HELIUS cohort. Second, we show the challenges during imputation when having a genetically diverse cohort. Third, we conduct a body mass index (BMI) and height GWAS where we investigate the effects of a joint analysis of the entire cohort and a meta-analysis approach for the different subgroups. Finally, we construct polygenic scores for BMI and height and compare their predictive power across the different ethnic groups. Overall, we give a comprehensive overview of a genetically diverse cohort from Amsterdam. Our study emphasizes the importance of a less biased and more realistic representation of urban populations for mapping genetic associations with complex traits and disease risk for all., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ferwerda, Abdellaoui, Nieuwdorp and Zwinderman.)

It is currently unknown whether associations between gut microbiota composition and type 2 diabetes (T2D) differ according to the ethnic background of individuals. Thus, we studied these associations in participants from two ethnicities characterized by a high T2D prevalence and living in the same geographical area, using the Healthy Life In Urban Settings (HELIUS) study. We included 111 and 128 T2D participants on metformin (Met-T2D), 78 and 49 treatment-naïve T2D (TN-T2D) participants, as well as a 1:1 matched group of healthy controls from, respectively, African Surinamese and South-Asian Surinamese descent. Fecal microbiome profiles were obtained through 16S rRNA gene sequencing. Univariate and machine learning analyses were used to explore the associations between T2D and the composition and function of the gut microbiome in both ethnicities, comparing Met-T2D and TN-T2D participants to their respective healthy control. We found a lower α-diversity for South-Asian Surinamese TN-T2D participants but no significant associations between TN-T2D status and the abundance of bacterial taxa or functional pathways. In African Surinamese participants, we did not find any association between TN-T2D status and the gut microbiome. With respect to Met-T2D participants, we identified several bacterial taxa and functional pathways with a significantly altered abundance in both ethnicities. More alterations were observed in South-Asian Surinamese. Some altered taxa and pathways observed in both ethnicities were previously related to metformin use. This included a strong negative association between the abundance of Romboutsia and Met-T2D status. Other bacterial taxa were consistent with previous observations in T2D, including reduced butyrate producers such as Anaerostipes hadrus . Hence, our results highlighted both shared and unique gut microbial biomarkers of Met-T2D in individuals from different ethnicities but living in the same geographical area. Future research using higher-resolution shotgun sequencing is needed to clarify the role of ethnicity in the association between T2D and gut microbiota composition.

Introduction: Association between elevated cytokeratin 18 (CK-18) levels and hepatocyte death has made circulating CK-18 a candidate biomarker to differentiate non-alcoholic fatty liver from non-alcoholic steatohepatitis (NASH). Yet studies produced variable diagnostic performance. We aimed to provide summary estimates with increased precision for the accuracy of CK-18 (M30, M65) in detecting NASH and fibrosis among non-alcoholic fatty liver disease (NAFLD) adults., Methods: We searched five databases to retrieve studies evaluating CK-18 against a liver biopsy in NAFLD adults. Reference screening, data extraction and quality assessment (QUADAS-2) were independently conducted by two authors. Meta-analyses were performed for five groups based on the CK-18 antigens and target conditions, using one of two methods: linear mixed-effects multiple thresholds model or bivariate logit-normal random-effects model., Results: We included 41 studies, with data on 5,815 participants. A wide range of disease prevalence was observed. No study reported a pre-defined cut-off. Thirty of 41 studies provided sufficient data for inclusion in any of the meta-analyses. Summary AUC [95% CI] were: 0.75 [0.69-0.82] (M30) and 0.82 [0.69-0.91] (M65) for NASH; 0.73 [0.57-0.85] (M30) for fibrotic NASH; 0.68 (M30) for significant (F2-4) fibrosis; and 0.75 (M30) for advanced (F3-4) fibrosis. Thirteen studies used CK-18 as a component of a multimarker model., Conclusions: For M30 we found lower diagnostic accuracy to detect NASH compared to previous meta-analyses, indicating a limited ability to act as a stand-alone test, with better performance for M65. Additional external validation studies are needed to obtain credible estimates of the diagnostic accuracy of multimarker models., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: QMA is coordinator of the IMI2 LITMUS consortium. He reports research grant funding from Abbvie, Allergan/Tobira, AstraZeneca, GlaxoSmithKline, Glympse Bio, Novartis Pharma AG, Pfizer Ltd., Vertex; consultancy on behalf of Newcastle University for Abbott Laboratories, Acuitas Medical, Allergan/Tobira, Blade, BNN Cardio, Cirius, CymaBay, EcoR1, E3Bio, Eli Lilly & Company Ltd., Galmed, Genfit SA, Gilead, Grunthal, HistoIndex, Indalo, Imperial Innovations, Intercept Pharma Europe Ltd., Inventiva, IQVIA, Janssen, Kenes, Madrigal, MedImmune, Metacrine, NewGene, NGMBio, North Sea Therapeutics, Novartis, Novo Nordisk A/S, Pfizer Ltd., Poxel, ProSciento, Raptor Pharma, Servier, Viking Therapeutics; and speaker fees from Abbott Laboratories, Allergan/Tobira, BMS, Clinical Care Options, Falk, Fishawack, Genfit SA, Gilead, Integritas Communications, MedScape. MJB is a share-holder and employee of Pfizer. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Pruritus (itch) is a frequent, burdensome and difficult-to-treat symptom in patients with cholestasis. Fibrates are currently under investigation for the treatment of primary biliary cholangitis in patients with a suboptimal response to ursodeoxycholic acid. Moreover, there is empirical evidence for a possible antipruritic effect. We aim to prove this in a randomized controlled trial, including patients with cholestatic liver diseases other than primary biliary cholangitis that are accompanied by pruritus., Methods: A multicenter investigator-initiated, double-blind, randomized placebo-controlled trial to evaluate the effect of bezafibrate on cholestatic pruritus in 84 adult patients with primary biliary cholangitis or primary/secondary sclerosing cholangitis. Primary outcome is the proportion of patients with a reduction of itch intensity of 50% or more (measured on a Visual Analog Scale) after 21 days of treatment with bezafibrate 400 mg qid or placebo. Secondary outcomes include the effect of bezafibrate on a five-dimensional itch score, liver disease-specific quality of life, serum liver tests and autotaxin activity. Safety will be evaluated through serum parameters for kidney function and rhabdomyolysis as well as precise recording of (serious) adverse events. We provide a schematic overview of the study protocol and describe the methods used to recruit and randomize patients, collect and handle data and perform statistical analyses., Discussion: Given its favorable safety profile and anticholestatic properties, bezafibrate may become the new first-line treatment option for treating cholestatic pruritus., Trial Registration: Netherlands Trial Register, ID: NCT02701166 . Registered on 2 March 2016; Netherlands Trial Register, ID: NTR5436 . Registered on 3 August 2015.

Objective: To compare two validated closed-loop (CL) algorithms versus patient self-control with CSII in terms of glycemic control., Research Design and Methods: This study was a multicenter, randomized, three-way crossover, open-label trial in 48 patients with type 1 diabetes mellitus for at least 6 months, treated with continuous subcutaneous insulin infusion. Blood glucose was controlled for 23 h by the algorithm of the Universities of Pavia and Padova with a Safety Supervision Module developed at the Universities of Virginia and California at Santa Barbara (international artificial pancreas [iAP]), by the algorithm of University of Cambridge (CAM), or by patients themselves in open loop (OL) during three hospital admissions including meals and exercise. The main analysis was on an intention-to-treat basis. Main outcome measures included time spent in target (glucose levels between 3.9 and 8.0 mmol/L or between 3.9 and 10.0 mmol/L after meals)., Results: Time spent in the target range was similar in CL and OL: 62.6% for OL, 59.2% for iAP, and 58.3% for CAM. While mean glucose level was significantly lower in OL (7.19, 8.15, and 8.26 mmol/L, respectively) (overall P = 0.001), percentage of time spent in hypoglycemia (<3.9 mmol/L) was almost threefold reduced during CL (6.4%, 2.1%, and 2.0%) (overall P = 0.001) with less time ≤2.8 mmol/L (overall P = 0.038). There were no significant differences in outcomes between algorithms., Conclusions: Both CAM and iAP algorithms provide safe glycemic control.

Although the high mortality rate of pulmonary invasive aspergillosis (IA) in patients with prolonged chemotherapy-induced neutropenia (PCIN) can be reduced by timely diagnosis, a diagnostic test that reliably detects IA at an early stage is lacking. We hypothesized that an electronic nose (eNose) could fulfill this need. An eNose can discriminate various lung diseases through the analysis of exhaled volatile organic compounds (VOCs). An eNose is cheap and noninvasive and yields results within minutes. In a single-center prospective cohort study, we included patients who were treated with chemotherapy expected to result in PCIN. Based on standardized indications, a full diagnostic workup was performed to confirm invasive aspergillosis or to rule it out. Patients with no aspergillosis were considered controls, and patients with probable or proven aspergillosis were considered index cases. Exhaled breath was examined with a Cyranose 320 (Smith Detections, Pasadena, CA). The resulting data were analyzed using principal component reduction. The primary endpoint was cross-validated diagnostic accuracy, defined as the percentage of patients correctly classified using the leave-one-out method. Accuracy was validated by 100,000 random classifications. We included 46 subjects who underwent 16 diagnostic workups, resulting in 6 cases and 5 controls. The cross-validated accuracy of the eNose in diagnosing IA was 90.9% (P = 0.022; sensitivity, 100%; specificity, 83.3%). Receiver operating characteristic analysis showed an area under the curve of 0.93. These preliminary data indicate that PCIN patients with IA have a distinct exhaled VOC profile that can be detected with eNose technology. The diagnostic accuracy of the eNose for invasive aspergillosis warrants validation.

Background & Aims: Postoperative ileus is characterized by delayed gastrointestinal (GI) transit and is a major determinant of recovery after colorectal surgery. Both laparoscopic surgery and fast-track multimodal perioperative care have been reported to improve clinical recovery. However, objective measures supporting faster GI recovery are lacking. Therefore, GI transit was measured following open and laparoscopic colorectal surgery with or without fast-track care., Methods: Patients (n = 93) requiring elective colonic surgery were randomized to laparoscopic or conventional surgery with fast-track multimodal management or standard care, resulting in 4 treatment arms. Gastric emptying and colonic transit were scintigraphically assessed from days 1 to 3 in 78 patients and compared with clinical parameters such as time to tolerance of solid food and/or bowel movement and time until (ready for) discharge., Results: A total of 71 patients without mechanical bowel obstructions or surgical complications requiring intervention were available for analysis. No differences in gastric emptying 24 hours after surgery between the different groups were observed (P = .61). However, the median colonic transit of patients undergoing laparoscopic/fast-track care was significantly faster compared with the laparoscopic/standard, open/fast-track, and open/standard care groups. Multiple linear regression analysis showed that both laparoscopic surgery and fast-track care were significant independent predictive factors of improved colonic transit. Both were associated with significantly faster clinical recovery and shorter time until tolerance of solid food and first bowel movement., Conclusions: Colonic transit recovers significantly faster after laparoscopic surgery and the fast-track program; laparoscopy and fast-track care lead to faster recovery of GI motility and improve clinical recovery., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to determine the effect of lymph node sampling and taking of blind biopsies as part of the surgical staging procedure for early ovarian cancer on disease-free survival (DFS) and overall survival (OS) in patients who received no adjuvant chemotherapy., Methods: In the EORTC ACTION Trial, 448 patients with early ovarian carcinoma were randomized between November 1990 and March 2000-224 patients to observation and 224 to adjuvant platin-based chemotherapy. Only patients allocated to observation were included for the current study. Analyses were performed in a subgroup of 75 optimally staged patients (group A), 46 patients in whom all staging steps were performed except para-aortic or pelvic lymph node sampling (group B), and 14 patients who fulfilled all staging criteria but in whom no blind peritoneal biopsies were taken (group C). The study group did not differ in stage distribution, cell type, or tumor grade., Results: Significantly improved 5-year DFS (P = 0.03) and 5-year OS (P = 0.01) were found in group A (optimally staged) versus group B (no lymph node sampling). A significant difference was also shown in 5-year DFS (P = 0.02) and 5-year OS (P = 0.003) between group A and group C (no blind biopsies). Recurrences occurred in 11 (14.6%) of 75 patients in group A, 16 (34.8%) of 46 patients in group B, and 5 (35.7%) of 14 in group C. The 5-year DFS in group A was 79% versus 61% and 64% in groups B and C, respectively. The 5-year OS decreased from 89% in group A to 71% in group B and 65% in group C., Conclusions: In this study, statistically significant differences were found in patients in whom para-aortic and pelvic lymph node sampling and taking of blind peritoneal biopsies were undertaken compared with patients in whom these staging steps had been omitted. These findings support the relevance of lymph node sampling and the taking of blind peritoneal biopsies in the surgical staging of early ovarian cancer.

Purpose: We compared prostate cancer detection rates achieved using an 8 and 12-core biopsy protocol in a clinical population to determine the significance of additional transition zone sampling on repeat biopsy., Materials and Methods: Between September 2004 and September 2007, 269 eligible patients with a clinical suspicion of prostate cancer referred to our department were randomized to an 8-core lateral (group 1) or a 12-core lateral and parasagittal (group 2) transrectal ultrasound guided prostate biopsy protocol. Study inclusion criteria were age dependent increased serum prostate specific antigen (1.25 ng/ml or greater at ages less than 50 years, 1.75 or greater at ages 50 to less than 60 years, 2.25 or greater at ages 60 to less than 70 years and 3.25 or greater at ages 70 years or greater), positive digital rectal examination and/or suspicious transrectal ultrasound. After negative first round biopsy patients underwent 12-core biopsy, including 4 transition zone cores., Results: Nine patients were excluded from analysis because of protocol violation or they did not complete the whole biopsy procedure due to discomfort. The cancer detection rate in groups 1 and 2 did not differ significantly (34.1% or 45 of 132 patients and 38.3% or 49 of 128, respectively, p = 0.48). Detected cancer median Gleason scores were similar in the groups. Of 109 patients who underwent repeat biopsy prostate cancer was detected in 20 (14.4%), of whom 9 had positive cores from the transition zone and 6 had positive biopsies only from the transition zone., Conclusions: There are no statistically significant differences in the prostate cancer detection rate between 8 and 12-core prostate biopsy protocols. Transition zone biopsies contribute to prostate cancer detection in a repeat biopsy protocol.

Background: Myoclonus-dystonia (M-D) is a movement disorder frequently caused by mutations in the epsilon-sarcoglycan gene (SGCE, DYT11). In several M-D families, psychiatric symptoms accompanying the motor symptoms have been reported, but a shared genetic etiology remains unclear., Objective: To assess neuropsychologic functioning and psychopathology in DYT11 mutation carriers (MC) and their family members using standardized neuropsychologic and psychiatric measures., Methods: Cognitive and behavioural characteristics of 27 DYT11 MC (14 symptomatic and 13 asymptomatic) and 42 control subjects from 1 large Dutch M-D family were studied. Neuropsychologic tests encompassed memory, language, mental speed, concentration, visuospatial function, and executive functions. Psychiatric assessment addressed qualitative (according to Diagnostic and Statistical Manual-IV criteria) as well as quantitative measures of depression, anxiety, panic attacks, and obsessive-compulsive disorder (OCD), using selfadministered and interview-based scales., Results: No differences were observed on tests of cognitive functioning between DYT11 MC and controls. The frequency of Diagnostic and Statistical Manual-IV diagnoses was higher in the symptomatic DYT11 MC than in controls. The symptomatic DYT11 MC showed more depressive and anxiety symptoms, including panic attacks but no increase of OCD compared with controls. No differences were found between asymptomatic DYT11 MC and controls on any of the psychopathologic tests., Conclusions: Neither cognitive dysfunction nor OCD seems to be associated with the DYT11 phenotype in this large Dutch pedigree. Depressive and anxiety symptoms are increased in symptomatic, but not in asymptomatic DYT11 MC. Future research has to be carried out to determine whether the psychiatric symptoms are part of or secondary to the DYT11 phenotype.

We present an approach to association studies involving a dozen or so ;response' variables and a few hundred ;explanatory' variables which emphasizes transparency, simplicity, and protection against spurious results. The methods proposed are largely non-parametric, and they are systematically rounded-off by the Benjamini-Hochberg method of multiple testing. An application to the detection of associations between risk factors of heart disease and genetic polymorphisms using the REGRESS dataset provides ample illustration of our approach. Special attention is paid to book-keeping and information-management aspects of data analysis, which allow the creation of an informative and reasonably digestible ;map of relationships'---the end-product of an association study as far as statistics is concerned.

Background and Aim of the Study: Clinical decision-making in an individual elderly patient with severe aortic stenosis (AS) is difficult. The prognosis is influenced by increased age and various cardiac morbidity and comorbidity, and the benefit of surgery is uncertain because the prognosis with conservative treatment has rarely been described. The study aim was to identify those patients who would gain from surgical therapy., Methods: The long-term survival of a cohort of elderly patients after an initial diagnosis of severe aortic stenosis was analyzed. Multivariate analysis was used to develop patient profiles on the basis of four main variables of age, severity of AS, cardiac morbidity, and comorbidity, to illustrate the benefit of surgical treatment over conservative treatment., Results: A total of 280 consecutive patients aged > or = 70 years (median age 78 years) with a first-time diagnosis of isolated AS made between 1991 and 1993 was included. Of these patients, 120 underwent surgery. The seven-year predicted survival ranged from 6.9% to 83% in surgically treated patient, and from 0.6% to 48% in conservatively treated patients. The benefit of surgical treatment over conservative treatment was greatest in patients aged < 80 years, with a more critical AS, cardiac morbidity, and without (7-year survival 78% versus 14%) or with (7-year survival 56% versus 1%) comorbidity. Minimal benefit was seen in patients aged > 80 years with a less critical AS and without cardiac morbidity., Conclusion: This model illustrated the benefit of surgical treatment over conservative treatment in 16 different profiles of elderly patients with severe AS. These findings may provide support for clinical decision making in individuals within this patient group.

Background: HIV-infected patients responding to HAART can show a diverse spectrum of symptoms caused by inflammatory reaction. The pathogenesis of this phenomenon, called immune restoration disease (IRD), is unclear. This study describes the spectrum of IRD and analyses the immunological and clinical parameters that could be related to its development., Methods: In a retrospective, matched case-control study, 17 HIV-infected individuals who developed inflammatory symptoms < 12 months after initiation of HAART were included. HIV-infected controls were matched for age, gender and CDC classification. Factors included in the analysis were: CD4+ and CD8+ cell counts, deltaCD4+ and deltaCD8+, CD4/CD8 ratios, HIV-1-RNA load (VL), AVL and the number of CDC events prior to HAART., Results: The median time after initiation of HAART and developing IRD (n = 17) was 72 days (range 2-319). In nine cases (53%) a mycobacterial infection was identified as the underlying cause. HAART was started at a mean CD4+ count (+/- SD) of 55 x 10(6) /l (+/- 59) and 85 x 10(6) /l (+/- 78.0) for cases and controls, respectively (p = 0.13). After initiation of HAART, the CD4+ count showed a 10.6 fold increase at the onset of IRD in the cases and a 2.7 fold increase in the controls in an equal period of time (p = 0.020). The other parameters analysed did not differ significantly between cases and controls., Conclusion: We conclude that the risk of developing IRD is associated with a high-fold increase in CD4+ lymphocytes. In this study, mycobacteria are the pathogens most frequently associated with IRD.

Background: (1) To assess the prevalence of histologically confirmed cervical intraepithelial neoplasia in patients with cervical smears diagnosed as atypical squamous or glandular cells of undetermined significance. (2) To evaluate the role of colposcopy and the presence of human papillomavirus in detecting underlying cervical intraepithelial neoplasia., Materials and Methods: In this prospective cohort, 148 women with atypical squamous or glandular cells of undetermined significance were evaluated by colposcopy, histological sampling, and human papillomavirus deoxyribonucleic acid testing., Results: Histological diagnosis of >/= cervical intraepithelial neoplasia II was found in 10/148 women. Women with a histological >/= cervical intraepithelial neoplasia II had a higher prevalence of >/= two abnormal quadrants (90% vs. 38%/= cervical intraepithelial neoplasia II.

Background: Literature on the cosmetic results of various surgical methods to close the skin is scarce. We sought to compare the cosmetic results of two different surgical techniques of skin closure after lower midline laparotomy., Materials and Methods: A randomized clinical trial compared a running nylon skin suture to interrupted Donati stitches in 58 patients undergoing gynecological surgery. Scar hypertrophy, scar width, scar color, the presence of cross-hatching marks, and a total scar score were assessed in all patients at 2 weeks, 6 months, and 12 months postoperatively., Results: On average closing the wounds with Donati stitches took 5 min longer than using a running suture (P > 0.001). The Donati sutures caused significantly less cross-hatching at 2 weeks and 6 months postoperatively. At 1 year, the scar color following Donati closure was also significantly less pronounced than in the running suture arm. The total scar score was significantly better in the Donati arm at each of the three time periods of assessment. The difference at 6 months was equal to the difference at 1 year., Conclusions: Closing the skin of lower midline laparotomy wounds with Donati stitches resulted in a cosmetically better scar. Scar cosmetics of lower midline laparotomies could be improved by using interrupted Donati stitches instead of a running suture. The difference was significant at 2 weeks, 6 months, and 12 months postoperatively, but the magnitude of the difference was the same at 6 and at 12 months.

Background: Only a small proportion of cervical cancer recurrences is detected during routine follow-up. We investigated which percentage of recurrences is detected during follow-up, which diagnostic tools are helpful to detect recurrent disease and which factors are of prognostic significance once recurrent disease has been established in patients treated for cervical cancer stage IB-IVA., Methods: Characteristics of the primary tumor, characteristics of recurrent disease and follow-up were collected retrospectively from clinical records of 277 patients who achieved a complete remission of at least 3 months after primary treatment for cervical cancer in 1992, 1993 and 1994 in three university hospitals in the Netherlands., Results: Of 277 patients, 47 (17%) developed recurrent disease; this was most often detected after self-referral (45%), and in 32% during routine follow-up. Survival did not differ significantly between these two groups. The presence of symptoms (87%) was the most important first abnormal test result leading to diagnosis of recurrence. In univariate analysis, disease-free interval (DFI) and treatment modality were significant prognostic factors for crude survival of recurrence. However, treatment modality varied considerably and the subgroups were small. Therefore, multivariate analysis was not feasible and clinically valid conclusions could not be drawn., Conclusions: In only 32% of all cases, recurrence was detected during a scheduled follow-up visit. In the majority of patients, recurrent cervical cancer was detected by symptoms (87%). In recurrent disease, DFI was a prognostic factor for survival.

The U-shaped serial position curve (SPC) of single-trial free recall is a well-established empirical fact, and there is ample evidence that it is the result of two different memory functions. However, it is insufficiently clear whether the same holds true for the SPC of multi-trial free recall. Free recall test measurements of two large heterogeneous groups of psychiatric patients were subjected to factor extraction using Principal Components Analysis and oblique rotation in two studies. The results of these two experiments show that the SPCs of single- and multi-trial free recall arise from the same two functions i.e. one function underlies the recency part, the other the primacy and middle (prerecency) part. Possible theoretical interpretations are discussed.

Umbilical cord blood (UCB), bone marrow (BM) and mobilized peripheral blood (mPB) are used as sources of hematopoietic stem cells for transplantation. The NOD/SCID mouse model was used to compare the lineage-specific repopulating potential of CD34(+) cells derived from these sources. Six to 8 weeks after transplantation, blood, BM, spleen, liver and thymus, were harvested, and analyzed by flow cytometry using CD34, CD45, myeloid, and lymphoid lineage-specific antibodies. Fifty percent engraftment of human cells in bone marrow of mice was estimated to be reached with 0.55 x 10(6) CD34(+) UCB cells or with 7.9 x 10(6) CD34(+) cells from adult sources, illustrating a 10-fold superiority of UCB CD34(+) cells to engraft NOD/SCID mice. Lineage-specific characterization of engrafted human cells showed that the high engraftment potential of CD34(+) cells from UCB was due to a preferential B cell development (2-81%). In contrast, comparable percentages of myeloid cells were found following transplantation of CD34(+) cells from UCB, BM and mPB (1-38%), and occurred at significant levels only at relatively high doses. Since the CD34 content of UCB transplants is usually at least one log lower than of transplant from adult sources, these results correspond to the clinical findings with UCB transplantation showing a relatively high overall engraftment, but delayed myeloid recovery.

Celiprolol, a novel beta blocker, may be more effective than propranolol in unstable angina pectoris because of both its beta-1-receptor selectivity and its vasodilator property. In the present report 53 patients with angiographic coronary artery disease but uncompromised left ventricular function and with electrocardiographically documented recurrent angina pectoris in spite of bed rest, aspirin, and repeated sublingual administration of nitroglycerin were studied. They were randomized for treatment with equipotent doses of either the nonselective beta blocker propranolol (80 mg/day) or the selective beta blocker with beta-2-agonistic property, celiprolol (200 mg/day) during one week. Angina frequency was higher in the propranolol group (P < 0.01), whereas myocardial oxygen demand as estimated by the double product (DP = SBP x HR, systolic blood pressure x heart rate) was equally reduced by the two beta blockers. Forearm blood flow was essentially higher in the celiprolol group (P < 0.001). A stepwise logistic regression analysis showed that the beneficial effects of the beta blockers were largely dependent on their effect on peripheral flow, in addition to reduction of the double product. The authors conclude that (1) Both celiprolol and propranolol largely reduce angina pectoris frequency in unstable angina pectoris. (2) Celiprolol contributes to nearly complete relief in three times as many patients as propranolol; after adjustment for double product or for systolic blood pressure plus heart rate it performs even eight times better. (3) The similar effects of the two compounds on the double product and the essentially different effects on peripheral flow support the conclusion that celiprolol exerts its beneficial effect to a large extent through its vasodilator property.

Background: Celiprolol, a novel beta-blocker, may be more effective than propranolol in unstable angina pectoris because of both its beta 1-receptor selectivity and its vasodilatory property., Methods: Fifty-three patients with angiographic coronary artery disease but uncompromised left ventricular function and with recurrent angina pectoris in spite of bed rest, aspirin, and repeated sublingual administration of nitroglycerin were randomized for 1 week of treatment with equipotent doses of either the nonselective beta-blocker propranolol (80 mg/day) or celiprolol (200 mg/day)., Results: Angina frequency was higher in the propranolol group (p < 0.01), whereas myocardial oxygen demand as estimated by the double product (systolic blood pressure x heart rate) was equally reduced by the two beta-blockers. Forearm blood flow was higher in the celiprolol group (p < 0.001). A stepwise logistic regression analysis showed that the beneficial effects of the beta-blockers were largely dependent on their effect on peripheral flow, in addition to reduction of the double product., Conclusions: Both celiprolol and propranolol largely reduce angina pectoris frequency in unstable angina pectoris. Celiprolol contributes to nearly complete relief in three times as many patients as propranolol; after adjustment for double product, it did so in eight times as many patients. The similar effects of the two compounds on the double product, and the essentially different effects on peripheral flow, support the theory that celiprolol exerts its beneficial effect to a large extent through its vasodilatory property.

Heart rate variability at rest, during deep breathing, or standing up and with the Valsalva manoeuvre did not differ significantly between 67 patients with idiopathic Parkinson's disease (PD) and 31 healthy age matched controls. Blood pressure (BP) responses to standing up and sustained handgrip revealed diminished autonomic function in the PD group. In a preliminary analysis of the PD group older age, anti-Parkinson medication and higher Hoehn and Yahr (HY) stages were each associated with poor autonomic responsiveness. Disease duration was only related to the systolic BP fall on standing up. Multiple stepwise regression analysis showed that older age explained most of the variance of heart rate variability (up to 36%), and the only significant PD related factor was the use of medication, which explained less than 7%. The HY stage accounted for 12.7% of the variance in the standing up BP test, and the use of medication explained 10.6% of the variance of the systolic BP change in the sustained hand grip test. The unmedicated PD subgroup (n = 33), who had mild disease of short duration, showed no evidence of autonomic dysfunction. Cardiovascular autonomic dysfunction in PD is mild, mainly affects blood pressure responses, and occurs only in advanced cases.

A case-control study was conducted to examine the presence of psychosocial factors before, during, and after acute myocardial infarction (AMI) in Dutch men under sixty years of age. The study included 42 AMI patients and 48 individuals in an age-adjusted sampled control group. The psychological factors included high level of psychological stress, of social isolation, type A1 and A2 behavior, and mental depression. They were assessed by means of the Health Insurance Questionnaire of Greater New York. Univariate analysis indicated that the presence of psychological factors was common at the onset of the myocardial infarction (MI). It clearly diminished, however, after the MI had taken place. In a stepwise logistic regression analysis after adjustment for the independent variables hypertension, cholesterol, and smoking, the following three characteristics were independently related to the risk of MI: no talking (item of social isolation, P = 0.008), need to excel (item of type A1 behavior, P = 0.04), and blue feeling (item of mental depression, P = 0.09). The authors conclude that in men under 60 with AMI, the presence of psychosocial characteristics is common and that this group is going to change its life-style soon after the MI, even without any psychosocial rehabilitation therapy. Follow-up studies investigating the influence of psychological factors on survival and reinfarction should be adjusted for these changes in life-style.