Edwin R. van den Heuvel

Social relationships and risk of dementia: A systematic review and meta-analysis of longitudinal cohort studies

It is unclear to what extent poor social relationships are related to the development of dementia. A comprehensive systematic literature search identified 19 longitudinal cohort studies investigating the association between various social relationship factors and incident dementia in the general population. Relative risks (RRs) with 95% confidence intervals (CIs) were pooled using random-effects meta-analysis. Low social participation (RR: 1.41 (95% CI: 1.13-1.75)), less frequent social contact (RR: 1.57 (95% CI: 1.32-1.85)), and more loneliness (RR: 1.58 (95% CI: 1.19-2.09)) were statistically significant associated with incident dementia. The results of the association between social network size and dementia were inconsistent. No statistically significant association was found for low satisfaction with social network and the onset of dementia (RR: 1.25 (95% CI: 0.96-1.62). We conclude that social relationship factors that represent a lack of social interaction are associated with incident dementia. The strength of the associations between poor social interaction and incident dementia is comparable with other well-established risk factors for dementia, including low education attainment, physical inactivity, and late-life depression.

NTCP models for patient-rated xerostomia and sticky saliva after treatment with intensity modulated radiotherapy for head and neck cancer: The role of dosimetric and clinical factors

PURPOSE The purpose of this multicentre prospective study was to develop multivariable logistic regression models to make valid predictions about the risk of moderate-to-severe patient-rated xerostomia (XER(M6)) and sticky saliva 6 months (STIC(M6)) after primary treatment with intensity modulated radiotherapy (IMRT) with or without chemotherapy for head and neck cancer (HNC). METHODS AND MATERIALS The study population was composed of 178 consecutive HNC patients treated with IMRT. All patients were included in a standard follow up programme in which acute and late side effects and quality of life were prospectively assessed, prior to, during and after treatment. The primary endpoints were XER(M6) and STIC(M6) as assessed by the EORTC QLQ-H&N35 after completing IMRT. Organs at risk (OARs) potentially involved in salivary function were delineated on planning-CT, including the parotid, submandibular and sublingual glands and the minor glands in the soft palate, cheeks and lips. Patients with moderate-to-severe xerostomia or sticky saliva, respectively, at baseline were excluded. The optimal number of variables for a multivariate logistic regression model was determined using a bootstrapping method. RESULTS Eventually, 51.6% of the cases suffered from XER(M6). The multivariate analysis showed that the mean contralateral parotid gland dose and baseline xerostomia (none vs. a bit) were the most important predictors for XER(M6). For the multivariate NTCP model, the area under the receiver operating curve (AUC) was 0.68 (95% CI 0.60-0.76) and the discrimination slope was 0.10, respectively. Calibration was good with a calibration slope of 1.0. At 6 months after IMRT, 35.6% of the cases reported STIC(M6). The mean contralateral submandibular gland dose, the mean sublingual dose and the mean dose to the minor salivary glands located in the soft palate were most predictive for STIC(M6). For this model, the AUC was 0.70 (95% CI 0.61-0.78) and the discrimination slope was 0.12. Calibration was good with a calibration slope of 1.0. CONCLUSIONS The multivariable NTCP models presented in this paper can be used to predict patient-rated xerostomia and sticky saliva. The dose volume parameters included in the models can be used to further optimise IMRT treatment.

Effectiveness of seasonal influenza vaccine in community-dwelling elderly people: a meta-analysis of test-negative design case-control studies

BACKGROUND The application of test-negative design case-control studies to assess the effectiveness of influenza vaccine has increased substantially in the past few years. The validity of these studies is predicated on the assumption that confounding bias by risk factors is limited by design. We aimed to assess the effectiveness of influenza vaccine in a high-risk group of elderly people. METHODS We searched the Cochrane library, Medline, and Embase up to July 13, 2014, for test-negative design case-control studies that assessed the effectiveness of seasonal influenza vaccine against laboratory confirmed influenza in community-dwelling people aged 60 years or older. We used generalised linear mixed models, adapted for test-negative design case-control studies, to estimate vaccine effectiveness according to vaccine match and epidemic conditions. FINDINGS 35 test-negative design case-control studies with 53 datasets met inclusion criteria. Seasonal influenza vaccine was not significantly effective during local virus activity, irrespective of vaccine match or mismatch to the circulating viruses. Vaccination was significantly effective against laboratory confirmed influenza during sporadic activity (odds ratio [OR] 0·69, 95% CI 0·48-0·99) only when the vaccine matched. Additionally, vaccination was significantly effective during regional (match: OR 0·42, 95% CI 0·30-0·60; mismatch: OR 0·57, 95% CI 0·41-0·79) and widespread (match: 0·54, 0·46-0·62; mismatch: OR 0·72, 95% CI 0·60-0·85) outbreaks. INTERPRETATION Our findings show that in elderly people, irrespective of vaccine match, seasonal influenza vaccination is effective against laboratory confirmed influenza during epidemic seasons. Efforts should be renewed worldwide to further increase uptake of the influenza vaccine in the elderly population. FUNDING None.

Adhesion Forces and Coaggregation between Vaginal Staphylococci and Lactobacilli

Urogenital infections are the most common ailments afflicting women. They are treated with dated antimicrobials whose efficacy is diminishing. The process of infection involves pathogen adhesion and displacement of indigenous Lactobacillus crispatus and Lactobacillus jensenii. An alternative therapeutic approach to antimicrobial therapy is to reestablish lactobacilli in this microbiome through probiotic administration. We hypothesized that lactobacilli displaying strong adhesion forces with pathogens would facilitate coaggregation between the two strains, ultimately explaining the elimination of pathogens seen in vivo. Using atomic force microscopy, we found that adhesion forces between lactobacilli and three virulent toxic shock syndrome toxin 1-producing Staphylococcus aureus strains, were significantly stronger (2.2–6.4 nN) than between staphylococcal pairs (2.2–3.4 nN), especially for the probiotic Lactobacillus reuteri RC-14 (4.0–6.4 nN) after 120 s of bond-strengthening. Moreover, stronger adhesion forces resulted in significantly larger coaggregates. Adhesion between the bacteria occurred instantly upon contact and matured within one to two minutes, demonstrating the potential for rapid anti-pathogen effects using a probiotic. Coaggregation is one of the recognized mechanisms through which lactobacilli can exert their probiotic effects to create a hostile micro-environment around a pathogen. With antimicrobial options fading, it therewith becomes increasingly important to identify lactobacilli that bind strongly with pathogens.

3D Variation in delineation of head and neck organs at risk

BackgroundConsistent delineation of patient anatomy becomes increasingly important with the growing use of highly conformal and adaptive radiotherapy techniques. This study investigates the magnitude and 3D localization of interobserver variability of organs at risk (OARs) in the head and neck area with application of delineation guidelines, to establish measures to reduce current redundant variability in delineation practice.MethodsInterobserver variability among five experienced radiation oncologists was studied in a set of 12 head and neck patient CT scans for the spinal cord, parotid and submandibular glands, thyroid cartilage, and glottic larynx. For all OARs, three endpoints were calculated: the Intraclass Correlation Coefficient (ICC), the Concordance Index (CI) and a 3D measure of variation (3D SD).ResultsAll endpoints showed largest interobserver variability for the glottic larynx (ICC = 0.27, mean CI = 0.37 and 3D SD = 3.9 mm). Better agreement in delineations was observed for the other OARs (range, ICC = 0.32-0.83, mean CI = 0.64-0.71 and 3D SD = 0.9-2.6 mm). Cranial, caudal, and medial regions of the OARs showed largest variations. All endpoints provided support for improvement of delineation practice.ConclusionsVariation in delineation is traced to several regional causes. Measures to reduce this variation can be: (1) guideline development, (2) joint delineation review sessions and (3) application of multimodality imaging. Improvement of delineation practice is needed to standardize patient treatments.

DataSHIELD: taking the analysis to the data, not the data to the analysis

Background: Research in modern biomedicine and social science requires sample sizes so large that they can often only be achieved through a pooled co-analysis of data from several studies. But the pooling of information from individuals in a central database that may be queried by researchers raises important ethico-legal questions and can be controversial. In the UK this has been highlighted by recent debate and controversy relating to the UK’s proposed ‘care.data’ initiative, and these issues reflect important societal and professional concerns about privacy, confidentiality and intellectual property. DataSHIELD provides a novel technological solution that can circumvent some of the most basic challenges in facilitating the access of researchers and other healthcare professionals to individual-level data. Methods: Commands are sent from a central analysis computer (AC) to several data computers (DCs) storing the data to be co-analysed. The data sets are analysed simultaneously but in parallel. The separate parallelized analyses are linked by non-disclosive summary statistics and commands transmitted back and forth between the DCs and the AC. This paper describes the technical implementation of DataSHIELD using a modified R statistical environment linked to an Opal database deployed behind the computer firewall of each DC. Analysis is controlled through a standard R environment at the AC. Results: Based on this Opal/R implementation, DataSHIELD is currently used by the Healthy Obese Project and the Environmental Core Project (BioSHaRE-EU) for the federated analysis of 10 data sets across eight European countries, and this illustrates the opportunities and challenges presented by the DataSHIELD approach. Conclusions: DataSHIELD facilitates important research in settings where: (i) a co-analysis of individual-level data from several studies is scientifically necessary but governance restrictions prohibit the release or sharing of some of the required data, and/or render data access unacceptably slow; (ii) a research group (e.g. in a developing nation) is particularly vulnerable to loss of intellectual property—the researchers want to fully share the information held in their data with national and international collaborators, but do not wish to hand over the physical data themselves; and (iii) a data set is to be included in an individual-level co-analysis but the physical size of the data precludes direct transfer to a new site for analysis.

A systematic review and meta-analysis on the prevalence of Dupuytren disease in the general population of Western countries

Background: Dupuytren disease is a fibroproliferative disease of palmar fascia of the hand. Its prevalence has been the subject of several reviews; however, an accurate description of the prevalence range in the general population—and of the relation between age and disease—is lacking. Methods: Embase and PubMed were searched using database-specific Medical Subject Headings; titles and abstracts were searched for the words “Dupuytren,” “incidence,” and “prevalence.” Two reviewers independently assessed the articles using inclusion and exclusion criteria, and rated the included studies with a quality assessment instrument. In a meta-analysis, the median prevalence, as a function of age by sex, was estimated, accompanied by 95 percent prediction intervals. The observed heterogeneity in prevalence was investigated with respect to study quality and geographic location. Results: Twenty-three of 199 unique identified articles were included. The number of participants ranged from 37 to 97,537, and age ranged from 18 to 100 years. Prevalence varied from 0.6 to 31.6 percent. The quality of studies differed but could not explain the heterogeneity among studies. Mean prevalence was estimated as 12, 21, and 29 percent at ages 55, 65, and 75 years, respectively, based on the relation between age and prevalence determined from 10 studies. Conclusions: The authors describe a prevalence range of Dupuytren disease in the general population of Western countries. The relation between age and prevalence of Dupuytren disease is given according to sex, including 95 percent prediction intervals. It is possible to determine disease prevalence at a certain age for the total population, and for men and women separately.

The effect of a multifaceted educational intervention on medication preparation and administration errors in neonatal intensive care

Objective To examine the effect of a multifaceted educational intervention on the incidence of medication preparation and administration errors in a neonatal intensive care unit (NICU). Design Prospective study with a preintervention and postintervention measurement using direct observation. Setting NICU in a tertiary hospital in the Netherlands. Intervention A multifaceted educational intervention including teaching and self-study. Main outcome measures The incidence of medication preparation and administration errors. Clinical importance was assessed by three experts. Results The incidence of errors decreased from 49% (43–54%) (151 medications with one or more errors of 311 observations) to 31% (87 of 284) (25–36%). Preintervention, 0.3% (0–2%) medications contained severe errors, 26% (21–31%) moderate and 23% (18–28%) minor errors; postintervention, none 0% (0–2%) was severe, 23% (18–28%) moderate and 8% (5–12%) minor. A generalised estimating equations analysis provided an OR of 0.49 (0.29–0.84) for period (p=0.032), (route of administration (p=0.001), observer within period (p=0.036)). Conclusions The multifaceted educational intervention seemed to have contributed to a significant reduction of the preparation and administration error rate, but other measures are needed to improve medication safety further.

Prevalence of Dupuytren disease in The Netherlands

Background: Dupuytren disease is a fibroproliferative disease of palmar fascias of the hand. The prevalence of Dupuytren disease and the association with potential risk factors have been the subject of several studies, although there is a paucity of such data from The Netherlands. Methods: To study the prevalence of Dupuytren disease, the authors drew a random sample of 1360 individuals, stratified by age, from the northern part of The Netherlands. Of this sample, 763 individuals aged 50 to 89 years participated in this cross-sectional study. The authors examined both hands for signs of Dupuytren disease, and a questionnaire was conducted to identify potential risk factors. The effects of these risk factors were investigated using logistic regression analysis. Additional analyses were performed to develop a logistic prediction model for the prevalence of Dupuytren disease. Results: The prevalence of Dupuytren disease was 22.1 percent. Nodules and cords were seen in 17.9 percent, and flexion contractures were present in 4.2 percent of the study population. Prevalence increased with age, from 4.9 percent in participants aged 50 to 55 years to 52.6 percent among those aged 76 to 80 years. Men were more often affected than women; 26.4 percent versus 18.6 percent, respectively (p = 0.007). Other significant risk factors were previous hand injury, excessive alcohol consumption, familial occurrence of Dupuytren disease, and presence of Ledderhose disease. Conclusions: The results show a high prevalence of Dupuytren disease in The Netherlands, particularly the nodular form. Using the developed logistic prediction model, the prevalence of Dupuytren disease can be estimated, based on the presence of significant risk factors. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Magnetic Resonance Imaging Improves Breast Screening Sensitivity in BRCA Mutation Carriers Age ≥ 50 Years: Evidence From an Individual Patient Data Meta-Analysis

PURPOSE There is no consensus on whether magnetic resonance imaging (MRI) should be included in breast screening protocols for women with BRCA1/2 mutations age ≥ 50 years. Therefore, we investigated the evidence on age-related screening accuracy in women with BRCA1/2 mutations using individual patient data (IPD) meta-analysis. PATIENTS AND METHODS IPD were pooled from six high-risk screening trials including women with BRCA1/2 mutations who had completed at least one screening round with both MRI and mammography. A generalized linear mixed model with repeated measurements and a random effect of studies estimated sensitivity and specificity of MRI, mammography, and the combination in all women and specifically in those age ≥ 50 years. RESULTS Pooled analysis showed that in women age ≥ 50 years, screening sensitivity was not different from that in women age < 50 years, whereas screening specificity was. In women age ≥ 50 years, combining MRI and mammography significantly increased screening sensitivity compared with mammography alone (94.1%; 95% CI, 77.7% to 98.7% v 38.1%; 95% CI, 22.4% to 56.7%; P < .001). The combination was not significantly more sensitive than MRI alone (94.1%; 95% CI, 77.7% to 98.7% v 84.4%; 95% CI, 61.8% to 94.8%; P = .28). Combining MRI and mammography in women age ≥ 50 years resulted in sensitivity similar to that in women age < 50 years (94.1%; 95% CI, 77.7% to 98.7% v 93.2%; 95% CI, 79.3% to 98%; P = .79). CONCLUSION Addition of MRI to mammography for screening BRCA1/2 mutation carriers age ≥ 50 years improves screening sensitivity by a magnitude similar to that observed in younger women. Limiting screening MRI in BRCA1/2 carriers age ≥ 50 years should be reconsidered.