Environmental factors shaping the gut microbiome in a Dutch population.

The gut microbiome is associated with diverse diseases1-3, but a universal signature of a healthy or unhealthy microbiome has not been identified, and there is a need to understand how genetics, exposome, lifestyle and diet shape the microbiome in health and disease. Here we profiled bacterial composition, function, antibiotic resistance and virulence factors in the gut microbiomes of 8,208 Dutch individuals from a three-generational cohort comprising 2,756 families. We correlated these to 241 host and environmental factors, including physical and mental health, use of medication, diet, socioeconomic factors and childhood and current exposome. We identify that the microbiome is shaped primarily by the environment and cohabitation. Only around 6.6% of taxa are heritable, whereas the variance of around 48.6% of taxa is significantly explained by cohabitation. By identifying 2,856 associations between the microbiome and health, we find that seemingly unrelated diseases share a common microbiome signature that is independent of comorbidities. Furthermore, we identify 7,519 associations between microbiome features and diet, socioeconomics and early life and current exposome, with numerous early-life and current factors being significantly associated with microbiome function and composition. Overall, this study provides a comprehensive overview of gut microbiome and the underlying impact of heritability and exposures that will facilitate future development of microbiome-targeted therapies.

Seizure-related complication rate in a residential population with epilepsy and intellectual disability (ECOMRAID-trial).

INTRODUCTION: The aim of the ECOMRAID trial (Epileptic seizure related Complication RAte in residential population of persons with epilepsy and Intellectual Disability) was to study seizure-related complications (status epilepticus, respiratory complications, or other severe complications) in people with epilepsy and intellectual disability living in a residential setting. The results of the present study are a prerequisite for performing a prospective study into the effectiveness of nocturnal surveillance patients with high risk for Sudden unexpected death in epilepsy (SUDEP). MATERIAL AND METHODS: A retrospective study was conducted in three general residential care institutions and one residential specialized epilepsy clinic. In this 5-year cohort, we collected the following data: age (at inclusion and in case of death), sex, type of residential care, different types of complications, rescue/emergency medication administration, transfers to another department (internal midcare / monitoring unit or general hospital) and a self-designed SUDEP risk score. Our primary research questions were to assess the number of patients who experienced seizure-related complications and their individual complication rates. The secondary research questions were to document the relationship of these complications with the SUDEP risk score, with the type of residential living, and with the frequency of interventions by caregivers. RESULTS: We included 370 patients (1790 patient-years) and in 135 of them, we found 717 seizure-related complications. The following complication rates were found: all complications: at 36%, status epilepticus: at 13%, respiratory complications: at 5%, and other complications at 26%. In residential care institutions, we found fewer patients with complications compared to the specialized epilepsy clinic (all complications 24% vs 42%, OR 0.44, p < 0.01; status epilepticus 5% vs 17%, OR 0.27, p < 0.01; other: complications 19% vs 30%, OR 0.56, p < 0.05). In residential care institutions, we found more "other complications" than in the specialized epilepsy clinic (89% vs 71%, OR 3.13, p < 0.0001). The annual frequency of all complications together was higher in residential care institutions (range 0 to 21 vs 0 to 10, p < 0.05). Rescue medication was given to 75% of the patients, but more often in the specialized epilepsy clinic (median 2.6 vs 0.5 times/patient/year, p < 0.001). In the specialized epilepsy clinic, more patients were transferred to a midcare / monitoring unit or general hospital (56% vs 9%, OR 13.44, p < 0.0001) with higher yearly frequencies (median 0.2 vs 0.0, p < 0.001). There were no reported cases of SUDEP. The median SUDEP risk score was higher in the specialized epilepsy clinic (5 vs 4, p < 0.05) and was weakly correlated with the status epilepticus (ρ = 0.20, p < 0.001) and (total) complication rate (ρ = 0.18, p < 0.001). CONCLUSION: We found seizure-related complications in more than one-third of the patients with epilepsy and intellectual disability living in a residential setting over a period of 5 years. The data also quantify seizure-related complications in patients with epilepsy and intellectual disability.

Retrospective analysis of endocarditis patients to investigate the eligibility for oral antibiotic treatment in routine daily practice.

BACKGROUND: According to the current guidelines of the European Society of Cardiology, patients with left-sided infective endocarditis are treated with intravenous antibiotics for 4-6 weeks, leading to extensive hospital stay and high costs. Recently, the Partial Oral Treatment of Endocarditis (POET) trial suggested that partial oral treatment is effective and safe in selected patients. Here, we investigated if such patients are seen in our daily clinical practice. METHODS: We enrolled 119 adult patients diagnosed with left-sided infective endocarditis in a retrospective, observational study. We identified those that would be eligible for switching to partial oral antibiotic treatment as defined in the POET trial (e.g. stable clinical condition without signs of infection). Secondary objectives were to provide insight into the time until each patient was eligible for partial oral treatment, and to determine parameters of longer hospital stay and/or need for extended intravenous antibiotic treatment. RESULTS: Applying the POET selection criteria, the condition of 38 patients (32%) was stable enough to switch them to partial oral treatment, of which 18 (47.3%), 8 (21.1%), 9 (23.7%) and 3 patients (7.9%) were eligible for switching after 10, 14, 21 days or 28 days of intravenous treatment, respectively. CONCLUSION: One-third of patients who presented with left-sided endocarditis in routine clinical practice were possible candidates for switching to partial oral treatment. This could have major implications for both the patient's quality of life and healthcare costs. These results offer an interesting perspective for implementation of such a strategy, which should be accompanied by a prospective cost-effectiveness analysis.

Recommendation for supportive care in patients receiving concurrent chemotherapy and radiotherapy for lung cancer.

Concurrent chemotherapy and radiotherapy (CCRT) followed by durvalumab immune therapy in appropriate patients is considered to be the standard of care in most fit stage III non-small-cell lung cancer (NSCLC) patients. However, CCRT is a toxic treatment that affects all organ systems and may cause acute and permanent side effects, some of which may be lethal. Supportive care is therefore of utmost importance in this clinical setting. A group of experts from the European Society for Therapeutic Radiology and Oncology (ESTRO) and the European Society of Medical Oncology (ESMO) identified the following items of importance for further improvement of supportive care: smoking cessation; nutrition before and during CCRT (including treatment and prevention of anorexia); physical exercise before and during CCRT; prevention and treatment of acute esophagitis and dysphagia; treatment of cough and dyspnea; treatment of skin reactions; treatment of fatigue; prophylaxis of nausea and emesis; prevention, diagnosis, and treatment of cardiac disease and damage; and optimization of radiotherapy techniques and chemotherapy adjustments to reduce toxicity in the era of immune therapy. The resulting recommendations are summarized in this manuscript and knowledge gaps identified, in which future investments are needed to improve supportive care and hence quality of life and survival for our stage III NSCLC patients.

Metacognitive reflection and insight therapy (MERIT) for patients with schizophrenia.

BACKGROUND: Impaired metacognition is associated with difficulties in the daily functioning of people with psychosis. Metacognition can be divided into four domains: Self-Reflection, Understanding the Other's Mind, Decentration, and Mastery. This study investigated whether Metacognitive Reflection and Insight Therapy (MERIT) can be used to improve metacognition. METHODS: This study is a randomized controlled trial. Patients in the active condition (n = 35) received forty MERIT sessions, the control group (n = 35) received treatment as usual. Multilevel intention-to-treat and completers analyses were performed for metacognition and secondary outcomes (psychotic symptomatology, cognitive insight, Theory of Mind, empathy, depression, self-stigma, quality of life, social functioning, and work readiness). RESULTS: Eighteen out of 35 participants finished treatment, half the drop-out stemmed from therapist attrition (N = 5) or before the first session (N = 4). Intention-to-treat analysis demonstrated that in both groups metacognition improved between pre- and post-measurements, with no significant differences between the groups. Patients who received MERIT continued to improve, while the control group returned to baseline, leading to significant differences at follow-up. Completers analysis (18/35) showed improvements on the Metacognition Assessment Scale (MAS-A) scales Self Reflectivity and metacognitive Mastery at follow-up. No effects were found on secondary outcomes. CONCLUSIONS: On average, participants in the MERIT group were, based on MAS-A scores, at follow-up more likely to recognize their thoughts as changeable rather than as facts. MERIT might be useful for patients whose self-reflection is too limited to benefit from other therapies. Given how no changes were found in secondary measures, further research is needed. Limitations and suggestions for future research are discussed.

Struggling with nutrition in patients with advanced cancer: nutrition and nourishment-focusing on metabolism and supportive care.

Patients with advanced cancer are at high risk of losing vital body resources resulting in malnutrition, immunodeficiency, impaired quality of life and worse clinical outcome. Prominent among the diverse factors contributing to this complex condition are metabolic derangements characterized by systemic inflammation, catabolism and accumulating changes in body composition. Because cure in advanced cancer still remains elusive, optimal supportive and integrated palliative care are required to allow patients to tolerate aggressive or long-term anticancer treatments, to maintain an adequate quality of life or to stay the course of advancing disease. Support needs to address and focus on all physical, psychological and social problems interfering with food intake, digestion and anabolism to maintaining adequate body resources and functions. Reliable screening for malnutrition, adequate assessment of the nutritional and metabolic status, and individualized multimodal care require the establishment of dedicated operating procedures involving experts and standardized pathways for communication among all participants involved in clinical cancer care. Therapeutic options include counseling, enriching foods, oral nutritional supplements, enteral and parenteral nutrition, metabolic modulation, exercise training, supportive care to enable and improve the intake of adequate amounts of food, as well as psycho-oncology and social support. Finally, to enable this new level of nutritional and metabolic patient care it appears necessary to establish common definitions and grading systems allowing not only for efficient treatment but allocating adequate medical resources to reach this goal.

Struggling with nutrition in patients with advanced cancer: nutrition and nourishment-focusing on metabolism and supportive care.

Patients with advanced cancer are at high risk of losing vital body resources resulting in malnutrition, immunodeficiency, impaired quality of life and worse clinical outcome. Prominent among the diverse factors contributing to this complex condition are metabolic derangements characterized by systemic inflammation, catabolism and accumulating changes in body composition. Because cure in advanced cancer still remains elusive, optimal supportive and integrated palliative care are required to allow patients to tolerate aggressive or long-term anticancer treatments, to maintain an adequate quality of life or to stay the course of advancing disease. Support needs to address and focus on all physical, psychological and social problems interfering with food intake, digestion and anabolism to maintaining adequate body resources and functions. Reliable screening for malnutrition, adequate assessment of the nutritional and metabolic status, and individualized multimodal care require the establishment of dedicated operating procedures involving experts and standardized pathways for communication among all participants involved in clinical cancer care. Therapeutic options include counseling, enriching foods, oral nutritional supplements, enteral and parenteral nutrition, metabolic modulation, exercise training, supportive care to enable and improve the intake of adequate amounts of food, as well as psycho-oncology and social support. Finally, to enable this new level of nutritional and metabolic patient care it appears necessary to establish common definitions and grading systems allowing not only for efficient treatment but allocating adequate medical resources to reach this goal.

Systematic review and meta-analysis of the evidence for oral nutritional intervention on nutritional and clinical outcomes during chemo(radio)therapy: current evidence and guidance for design of future trials.

Background: Driven by reduced nutritional intakes and metabolic alterations, malnutrition in cancer patients adversely affects quality of life, treatment tolerance and survival. We examined evidence for oral nutritional interventions during chemo(radio)therapy. Design: We carried out a systematic review of randomized controlled trials (RCT) with either dietary counseling (DC), high-energy oral nutritional supplements (ONS) aiming at improving intakes or ONS enriched with protein and n-3 polyunsaturated fatty acids (PUFA) additionally aiming for modulation of cancer-related metabolic alterations. Meta-analyses were carried out on body weight (BW) response to nutritional interventions, with subgroup analyses for DC and/or high-energy ONS or high-protein n-3 PUFA-enriched ONS. Results: Eleven studies were identified. Meta-analysis showed overall benefit of interventions on BW during chemo(radio)therapy (+1.31 kg, 95% CI 0.24-2.38, P = 0.02, heterogeneity Q = 21.1, P = 0.007). Subgroup analysis showed no effect of DC and/or high-energy ONS (+0.80 kg, 95% CI -1.14 to 2.74, P = 0.32; Q = 10.5, P = 0.03), possibly due to limited compliance and intakes falling short of intake goals. A significant effect was observed for high-protein n-3 PUFA-enriched intervention compared with isocaloric controls (+1.89 kg, 95% CI 0.51-3.27, P = 0.02; Q = 3.1 P = 0.37). High-protein, n-3 PUFA-enriched ONS studies showed attenuation of lean body mass loss (N = 2 studies) and improvement of some quality of life domains (N = 3 studies). Overall, studies were limited in number, heterogeneous, and inadequately powered to show effects on treatment toxicity or survival. Conclusion: This systematic review suggests an overall positive effect of nutritional interventions during chemo(radio)therapy on BW. Subgroup analyses showed effects were driven by high-protein n-3 PUFA-enriched ONS, suggesting the benefit of targeting metabolic alterations. DC and/or high-energy ONS were less effective, likely due to cumulative caloric deficits despite interventions. We highlight the need and provide recommendations for well-designed RCT to determine the effect of nutritional interventions on clinical outcomes, with specific focus on reaching nutritional goals and providing the right nutrients, as part of an integral supportive care approach.

Elucidating vancomycin-resistant Enterococcus faecium outbreaks: the role of clonal spread and movement of mobile genetic elements.

Background: Vancomycin-resistant Enterococcus faecium (VREfm) has emerged as a nosocomial pathogen worldwide. The dissemination of VREfm is due to both clonal spread and spread of mobile genetic elements (MGEs) such as transposons. Objectives: We aimed to combine vanB-carrying transposon data with core-genome MLST (cgMLST) typing and epidemiological data to understand the pathways of transmission in nosocomial outbreaks. Methods: Retrospectively, 36 VREfm isolates obtained from 34 patients from seven VREfm outbreak investigations in 2014 were analysed. Isolates were sequenced on a MiSeq and a MinION instrument. De novo assembly was performed in CLC Genomics Workbench and the hybrid assemblies were obtained through Unicycler v0.4.1. Ridom SeqSphere+ was used to extract MLST and cgMLST data. Detailed analysis of each transposon and their integration points was performed using the Artemis Comparison Tool (ACT) and multiple blast analyses. Results: Four different vanB transposons were found among the isolates. cgMLST divided ST80 isolates into three cluster types (CTs); CT16, CT104 and CT106. ST117 isolates were divided into CT24, CT103 and CT105. Within VREfm isolates belonging to CT103, two different vanB transposons were found. In contrast, VREfm isolates belonging to CT104 and CT106 harboured an identical vanB transposon. Conclusions: cgMLST provides a high discriminatory power for the epidemiological analysis of VREfm. However, additional transposon analysis is needed to detect horizontal gene transfer. Combining these two methods allows investigation of both clonal spread as well as the spread of MGEs. This leads to new insights and thereby better understanding of the complex transmission routes in VREfm outbreaks.

Management of drug interactions with direct-acting antivirals in Dutch HIV/hepatitis C virus-coinfected patients: adequate but not perfect.

OBJECTIVES: Direct-acting antivirals (DAAs) for treatment of chronic hepatitis C virus (HCV) infection can cause drug-drug interactions (DDIs) with combination antiretroviral therapy (cART) and non-cART co-medication. We mapped how physicians manage DDIs between DAAs and co-medication and analysed treatment outcomes. METHODS: Data were prospectively collected as part of the ATHENA HIV observational cohort and retrospectively analysed. Dutch patients with HIV/HCV coinfection who initiated treatment with DAAs between January 2015 and May 2016 were included. Co-medication 3 months prior to and during DAA therapy was identified. Potential DDIs with the DAAs were checked using http://hep-druginteractions.org. DDIs were categorized as: (1) no interaction expected; (2) potential interaction; (3) contra-indication; (4) no recommendation. These categories were used to determine which patients switched or had a DDI during DAA therapy with co-medication. RESULTS: A total of 423 patients were treated with DAAs, of whom 418 (99%) used cART and 251 (59%) used non-cART co-medication. Before commencing DAA treatment, in 17 of 84 (20%) patients the non-cART co-medication which could result in a category 2/3 DDI was discontinued before DAA initiation, including two of six (33%) prescriptions of category 3 drugs. A total of 196 of 418 (47%) patients had a category 2/3 DDI between their DAA regimen and cART. Category 2/3 DDIs were prevented by switching cART in 78 of 147 (53%) and 47 of 49 (98%) patients. Overall, 367 of 423 (87%) patients have achieved a sustained virological response (33 in follow-up). CONCLUSIONS: Prescription patterns suggest that physicians are aware of potential DDIs between co-medication and DAAs, in particular potential DDIs with cART. Greater awareness is needed concerning category 3 interactions between non-cART co-medication and DAAs.

The benefits of hepatitis C virus cure: Every rose has thorns.

To examine mid-term benefits on hepatic complications, extrahepatic clinical syndromes and quality of life associated with HCV cure; to review the few safety issues linked to oral direct-acting antivirals (DAAs); and to discuss the potential population benefits of reducing the burden of HCV infection. DAAs cure HCV infection in more than 95% of patients. The halting of liver inflammation and fibrosis progression translates into both hepatic and extrahepatic benefits and reduces the need for liver transplantation. A reduction in the frequency of extrahepatic manifestations such as mixed cryoglobulinaemia and vasculitis and improvements in quality of life and fatigue have also been described. A few safety issues linked to DAAs such as the potential recurrence of aggressive HCC, the flares of hepatitis B virus in patients with overt or occult HBV infection are been discussed. Curing HCV infection also has a high potential to reduce the burden of HCV infection at the population level. With widespread scaling up of HCV treatment, several modeling studies suggest that major reductions in HCV prevalence and incidence are possible, and that elimination of viral hepatitis is an achievable target by 2030.

Greater carotid intima media thickness at a younger age in HIV-infected patients compared with reference values for an uninfected cohort.

OBJECTIVES: In contrast to the general population, no decline in cardiovascular disease (CVD) has been noted in HIV-infected patients over the last 10 years. We compared the carotid artery intima media thickness (CIMT) of HIV-infected patients to that of age- and gender-matched reference values and determined the relationship between CVD risk factors and CIMT. METHODS: A total of 292 HIV-infected patients were enrolled in the study. Data collected included vascular screening data, data obtained using a questionnaire, data obtained from laboratory assessments and CIMT measurement. Using linear regression (adjusted for age/gender/known HIV), the association between HIV-specific and classical cardiovascular risk factors and CIMT was evaluated. RESULTS: The cohort comprised for 91% of male patients, aged 49.4 ± 10.5 years, with a known duration of HIV infection of 8.8 ± 6.7 years. The mean with standard deviation (mean ± SD) CIMT was 0.77 ± 0.19 mm, compared with 0.58 ± 0.05 mm in the controls. A steeper increase of CIMT per age was seen in the HIV-infected patients. A significant relationship between CIMT and hypertension, diabetes mellitus, smoking, systolic blood pressure, HbA1c (glycated hemoglobin) and ankle brachial index was found. Of the HIV-specific variables, only a relationship between CIMT and length of cART use and between CIMT and (inversely) current cART use was seen. CONCLUSIONS: A greater CIMT was found in HIV-infected patients compared with controls. In contrast to HIV-specific variables, classical CVD risk factors were associated with a greater CIMT and should therefore be the focus of preventive measures.

Review of functional MRI in HIV: effects of aging and medication.

HIV-associated neurocognitive disorder (HAND) is a frequently occurring comorbidity of HIV infection. Evidence suggests this condition starts subclinical before a progression to a symptomatic stage. Blood oxygenated level dependent (BOLD) fMRI has shown to be a sensitive tool to detect abnormal brain function in an early stage and might therefore be useful to evaluate the effect of HIV infection on brain function. An extensive literature search was performed in June 2015. Eligibility criteria for included studies were as follows: (1) conducting with HIV-positive patients, (2) using BOLD fMRI, and (3) including a HIV-negative control group. A total of 19 studies were included in the review including 931 participants. Differences in activation between HIV-positive and -negative participants were found when testing multiple domains, i.e., attention, (working) memory, and especially executive functioning. Overall, HIV-positive patients showed hyperactivation in task-related brain regions despite equal performances as controls. Task performance was degraded only for the most complex tasks. A few studies investigated the effect of aging on fMRI, and most of them found no interaction with HIV infection. Only three studies evaluated the effect of combination antiretroviral therapy (cART) on functional data suggesting an increase in activation with the use of cART. fMRI is a sensitive instrument to detect subtle cognitive changes in HIV patients. Open questions remain regarding the effects of cART on fMRI and the effects of aging on fMRI.

Cardiovascular risk prediction in HIV-infected patients: comparing the Framingham, atherosclerotic cardiovascular disease risk score (ASCVD), Systematic Coronary Risk Evaluation for the Netherlands (SCORE-NL) and Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) risk prediction models.

OBJECTIVES: The aim of the study was to compare the predictions of five popular cardiovascular disease (CVD) risk prediction models, namely the Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) model, the Framingham Heart Study (FHS) coronary heart disease (FHS-CHD) and general CVD (FHS-CVD) models, the American Heart Association (AHA) atherosclerotic cardiovascular disease risk score (ASCVD) model and the Systematic Coronary Risk Evaluation for the Netherlands (SCORE-NL) model. METHODS: A cross-sectional design was used to compare the cumulative CVD risk predictions of the models. Furthermore, the predictions of the general CVD models were compared with those of the HIV-specific D:A:D model using three categories (< 10%, 10-20% and > 20%) to categorize the risk and to determine the degree to which patients were categorized similarly or in a higher/lower category. RESULTS: A total of 997 HIV-infected patients were included in the study: 81% were male and they had a median age of 46 [interquartile range (IQR) 40-52] years, a known duration of HIV infection of 6.8 (IQR 3.7-10.9) years, and a median time on ART of 6.4 (IQR 3.0-11.5) years. The D:A:D, ASCVD and SCORE-NL models gave a lower cumulative CVD risk, compared with that of the FHS-CVD and FHS-CHD models. Comparing the general CVD models with the D:A:D model, the FHS-CVD and FHS-CHD models only classified 65% and 79% of patients, respectively, in the same category as did the D:A:D model. However, for the ASCVD and SCORE-NL models, this percentage was 89% and 87%, respectively. Furthermore, FHS-CVD and FHS-CHD attributed a higher CVD risk to 33% and 16% of patients, respectively, while this percentage was < 6% for ASCVD and SCORE-NL. CONCLUSIONS: When using FHS-CVD and FHS-CHD, a higher overall CVD risk was attributed to the HIV-infected patients than when using the D:A:D, ASCVD and SCORE-NL models. This could have consequences regarding overtreatment, drug-related adverse events and drug-drug interactions.

[Metacognition in psychotic disorders: from concepts to intervention]. / Metacognitie bij psychotische stoornissen: van concept naar interventie.

BACKGROUND: Persons with a psychotic disorder commonly experience difficulties with what is considered to be metacognitive capacity. In this article we discuss several definitions of this concept, the measurement instruments involved and the clinical interventions that target this concept. AIM: To present a review of various frequently used definitions of metacognition and related concepts and to describe the measurement instruments involved and the treatment options available for improving the metacognitive capacity of persons with a psychotic disorder. METHOD: We present an overview of several definitions of metacognition in psychotic disorders and we discuss frequently used measurement instruments and treatment options. The article focuses on recent developments in a model devised by Semerari et al. The measurement instrument involved (Metacognition Assessment Scale - A) is discussed in terms of it being an addition to existing methods. RESULTS: On the basis of the literature it appears that metacognition and related concepts are measurable constructs, although definitions and instruments vary considerably. The new conceptualisation of social information processing also leads to the development of a new form of psychotherapy that aims to help patients suffering from psychotic disorders to improve metacognitive capacity. CONCLUSION: There seems to be evidence that metacognitive abilities are a possible target for treatment, but further research is needed.

Presence of bile acids in human follicular fluid and their relation with embryo development in modified natural cycle IVF.

STUDY QUESTION: Are bile acids (BA) and their respective subspecies present in human follicular fluid (FF) and do they relate to embryo quality in modified natural cycle IVF (MNC-IVF)? SUMMARY ANSWER: BA concentrations are 2-fold higher in follicular fluid than in serum and ursodeoxycholic acid (UDCA) derivatives were associated with development of top quality embryos on Day 3 after fertilization. WHAT IS KNOWN ALREADY: Granulosa cells are capable of synthesizing BA, but a potential correlation with oocyte and embryo quality as well as information on the presence and role of BA subspecies in follicular fluid have yet to be investigated. STUDY DESIGN, SIZE, DURATION: Between January 2001 and June 2004, follicular fluid and serum samples were collected from 303 patients treated in a single academic centre that was involved in a multicentre cohort study on the effectiveness of MNC-IVF. PARTICIPANTS/MATERIALS, SETTING, METHODS: Material from patients who underwent a first cycle of MNC-IVF was used. Serum was not stored from all patients, and the available material comprised 156 follicular fluid and 116 matching serum samples. Total BA and BA subspecies were measured in follicular fluid and in matching serum by enzymatic fluorimetric assay and liquid chromatography-mass spectrometry, respectively. The association of BA in follicular fluid with oocyte and embryo quality parameters, such as fertilization rate and cell number, presence of multinucleated blastomeres and percentage of fragmentation on Day 3, was analysed. MAIN RESULTS AND THE ROLE OF CHANCE: Embryos with eight cells on Day 3 after oocyte retrieval were more likely to originate from follicles with a higher level of UDCA derivatives than those with fewer than eight cells (P < 0.05). Furthermore, follicular fluid levels of chenodeoxycholic derivatives were higher and deoxycholic derivatives were lower in the group of embryos with fragmentation compared with those without (each P < 0.05). Levels of total BA were 2-fold higher in follicular fluid compared with serum (P < 0.001), but had no predictive value for oocyte and embryo quality. LIMITATIONS, REASONS FOR CAUTION: Only samples originating from first cycle MNC-IVF were used, which resulted in 14 samples only from women with an ongoing pregnancy, therefore further prospective studies are required to confirm the association of UDCA with IVF pregnancy outcomes. The inter-cycle variability of BA levels in follicular fluid within individuals has yet to be investigated. We checked for macroscopic signs of contamination of follicular fluid by blood but the possibility that small traces of blood were present within the follicular fluid remains. Finally, although BA are considered stable when stored at -20°C, there was a time lag of 10 years between the collection and analysis of follicular fluid and serum samples. WIDER IMPLICATIONS OF THE FINDINGS: The favourable relation between UDCA derivatives in follicular fluid and good embryo development and quality deserves further prospective research, with live birth rates as the end-point. STUDY FUNDING/COMPETING INTERESTS: This work was supported by a grant from the Netherlands Organisation for Scientific Research (VIDI Grant 917-56-358 to U.J.F.T.). No competing interests are reported.

Low serum hyaluronic acid levels associated with spontaneous HBsAg clearance.

PURPOSE: The pathophysiological underlying mechanism of spontaneous HBsAg clearance in hepatitis B virus (HBV) infected patients is largely unknown. However, serum hyaluronic acid (sHA) plays a role in liver fibrosis progression and reversely could serve as a potential biomarker for HBsAg clearance. This study investigates whether low sHA is associated with HBsAg loss in non-Asian HBV patients. METHODS: Non-Asian women living in Amsterdam with known chronic HBV infection between 1990-2003 were invited for a single follow-up visit at the Municipal Health Service Amsterdam between September 2011 to May 2012. Serum hyaluronic acid and liver stiffness measurement together with clinical evaluation, biochemical and virologic blood tests were performed. RESULTS: Of the 160 women, HBsAg loss occurred in 38 (23 %) patients between diagnosis and follow-up. sHA levels were lower in HBsAg negative patients compared to HBsAg positive patients (14.5 [9.4-27.2] ng/mL vs 25.0 [12.3-42.5] ng/mL, p <0.01). A similar distinction in sHA between low and high HBV DNA was noted. sHA had a significant discriminatory ability to differentiate between HBsAg positive and HBsAg negative patients, (AUC 0.65 [95 % CI 0.55-0.75], p < 0.01). In multivariable analysis only sHA level was associated with HBsAg loss (OR 0.4 [0.2-0.9]). Finally, F3-F4 fibrosis (cut-off >8.1 kPa) was diagnosed in 3 % in HBsAg negative patients compared to 10 % in HBsAg positive patients (p = 0.15). CONCLUSION: Serum HA levels are lower in patients who experience spontaneous HBsAg loss compared to HBsAg positive patients.

Changes in the frequency of benign focal spikes accompany changes in central information processing speed: a prospective 2-year follow-up study.

We prospectively examined whether changes in the frequency of benign focal spikes accompany changes in cognition. Twenty-six children with benign focal spikes (19 with Rolandic epilepsy) and learning difficulties were examined with repeated 24-hour EEG recordings, three cognitive tests on central information processing speed (CIPS), and questionnaires on cognition and behavior at baseline, 6months, and 2years. Antiepileptic drug changes were allowed when estimated necessary by the treating physician. At baseline, a lower CIPS was correlated with a higher frequency of diurnal interictal epileptiform discharges (IEDs) and with worse academic achievement. At follow-up, there was a significant correlation between changes in CIPS and EEG changes in wakefulness (in the same direction) when the EEG outcome was dichotomized in IED frequency "increased" or "not increased". Behavioral problems were more often observed in patients with higher frequency of IEDs in sleep at baseline and in those with ongoing IEDs compared with those with EEG remission (without or with sporadic IEDs in the recording) at the end of the study period. No changes were observed in the results of the questionnaires. A lower diurnal IED frequency at baseline, lack of serial IEDs, and occurrence of only unilateral IEDs were correlated with a higher chance of EEG remission at 2-year follow-up. Electroencephalography remission could not be predicted from other epilepsy variables except from seizure freedom in the last six months. Our results confirm the nonbenign character of 'benign' focal spikes. Whether an early and stable EEG remission can be achieved through antiepileptic treatment and whether this is of benefit for cognitive development should be examined in prospective placebo-controlled randomized trials.

[Cost-effectiveness in Dutch mental health care: future because of ROM?]. / Doelmatigheid in de ggz: toekomst dankzij ROM?

BACKGROUND: The document reporting Dutch mental health care negotiations for 2014-2017 calls for a cost decrease based on cost-effectiveness. Thanks to ROM, the Dutch mental health care seems well prepared for cost-effectiveness research. AIM: Evaluate how valid cost-effectiveness research should be established in mental health care and the role of rom therein. METHOD: Evaluation of requirements of cost-effectiveness research, trends, and a translation to Dutch mental health care. RESULTS: Valid cost-effectiveness research in mental health care requires the application of a societal perspective, a long time-horizon and an adequate evaluation of quality of life of patients. Healthcare consumption, outcome of care and characterisation of the patient population should be measured systematically and continuously. Currently, rom-data are not suitable to serve as a basis for cost-effectiveness research, although a proper basis is present. Further development of rom could lead to a situation in which mental health care is purchased on the basis of cost-effectiveness. However, cost-effectiveness will only really be improved if quality of care is rewarded, rather than rewarding activities that are not always related to outcome of care. CONCLUSION: Cost-effectiveness research in mental health care should focus on societal costs and benefits, quality of life and a long time-horizon. If developed further, rom has the potential to be a basis for cost-effectiveness research in the future.