The association of adolescents' smoking with the physical activity levels of their friends.

BACKGROUND: Smoking is inversely related to people's Physical Activity Level (PAL). As the behavior of friends may affect the choices and behavior of adolescents, having friends with a high PAL may potentially protect against adolescent smoking. This study aims to assess whether adolescents' smoking is associated with the PAL of their friends. METHODS: SILNE-R survey data of 11.918 adolescents from 55 different schools in 7 European cities was used to determine weekly smoking, individual PAL, PAL of friends, school PAL, and smoking of friends. Multilevel, multivariable logistic regression analysis were used to assess the association between the PAL of friends and weekly smoking. Several socio-demographic variables were included as covariates in the analysis. RESULTS: Our results indicated that 10.8% of the respondents was smoking weekly. Weekly smoking was most common among adolescents whose friends had a PAL of 0-42.0 min per day (14.5%). Respondents were significantly more likely to be smoking weekly if their friends were on average 0-42 min vs. 80-180 min physically active (OR 1.27 [95% CI 1.04-1.55]). This association existed independently of the individual PAL of respondents. Stratification for smoking of friends yielded equal results, although the association appeared to be somewhat stronger for those with smoking friends (OR 1.38 [95% CI 1.06-1.82]). CONCLUSION: Adolescents are less likely to smoke weekly if they associate with friends who spend >80 min per day on physical activity. Initiatives aimed at the prevention of smoking among adolescents may benefit from organizing group-based physical activity programs.

The impact of smoke-free policies on smoking at outdoor sports clubs: a qualitative study.

OBJECTIVES: Smoking may still occur at sports clubs with an outdoor smoke-free policy (SFP). This study aims to map the occurrence of smoking at various sports clubs in the Netherlands and to understand why smoking occurs at some clubs but not at others. STUDY DESIGN: This was a qualitative design in the form of semistructured interviews. METHODS: Semistructured interviews (n = 34) were held online with smoking and non-smoking members of 17 Dutch outdoor sports clubs (in field hockey, korfball, football, and tennis) with an outdoor SFP. Data were analyzed using content analysis. RESULTS: We identified four situations where smoking still occurred: (1) directly at the entrance, (2) at some distance from the entrance, (3) in particular places on the premises, and (4) in various places or on occasions when alcohol is consumed. Smoking directly at the entrance was most often perceived as a bothersome situation that was difficult to avoid. The occurrence of these situations differed per sports club depending on the scope of the SFP (the comprehensiveness of the SFP and the presence or absence of a smoking area) and factors influencing policy compliance (physical characteristics of the sports club's premises, the presence or absence of children, and several enforcement difficulties). CONCLUSION: In some sports clubs, smoking remained common on the premises despite an outdoor SFP. Exposure to second-hand smoke might be reduced by formulating a comprehensive SFP, improving policy compliance also in situations where children are absent, and organizing the enforcement of the policy.

Evaluation of a nationwide Dutch guideline to detect Lynch syndrome in patients with endometrial cancer.

OBJECTIVE: In the Netherlands a nationwide guideline was introduced in 2016, which recommended routine Lynch syndrome screening (LSS) for all women with endometrial cancer (EC) <70 years of age. LSS consists of immunohistochemical (IHC) staining for loss of mismatch repair (MMR) protein expression, supplemented with MLH1 methylation analysis if indicated. Test results are evaluated by the treating gynaecologist, who refers eligible patients to a clinical geneticist. We evaluated the implementation of this guideline. METHODS: From the nation-wide pathology database we selected all women diagnosed with EC < 70 years of age, treated from 1.6.2016-1.6.2017 in 14 hospitals. We collected data on the results of LSS and follow up of cases with suspected LS. RESULTS: In 183 out of 204 tumours (90%) LSS was performed. In 41 cases (22%) MMR protein expression was lost, in 25 cases due to hypermethylation of the MLH1 promotor. One patient was known with a pathogenic MLH1 variant. The option of genetic counselling was discussed with 12 of the 15 remaining patients, of whom three declined. After counselling by the genetic counsellor nine patients underwent germline testing. In two no pathogenic germline variant was detected, two were diagnosed with a pathogenic PMS2 variant, and five with a pathogenic MSH6 variant, in concordance with the IHC profiles. CONCLUSION: Coverage of LSS was high (90%), though referral for genetic counselling could be improved. Gynaecologists ought to be aware of the benefits and possible drawbacks of knowing mutational status, and require training in discussing this with their patients.

The association between leptin concentration and blood coagulation: Results from the NEO study.

BACKGROUND: The adipocyte-derived hormone leptin has been associated with altered blood coagulation in in vitro studies. However, it is unclear whether this association is relevant in vivo and to what extent this association is influenced by total body fat. Therefore, we aimed to examine the association between serum leptin and blood coagulation while taking total body fat into account in a population-based cohort study. METHODS: We performed a cross-sectional analysis with baseline measurements of 5797 participants of the Netherlands Epidemiology of Obesity (NEO) study, a population-based cohort of middle-aged men and women. We examined associations between serum leptin concentration and coagulation factor concentrations and parameters of platelet activation in linear regression analyses. All analyses were adjusted for multiple covariates, including total body fat. RESULTS: In multivariable adjusted analyses a 1 µg/L higher serum leptin concentration was associated with a 0.22 IU/dL (95% CI: 0.11, 0.32) higher FVIII concentration and a 0.20 IU/dL (95% CI: 0.14, 0.27) higher FIX concentration (3.5 IU/dL FVIII and 3.2 IU/dL FIX per SD leptin). Serum leptin concentration was not associated with FXI, fibrinogen, platelet count, mean platelet volume and platelet distribution width in multivariable adjusted analyses. DISCUSSION: This study showed that serum leptin concentration was associated with higher concentrations of FVIII and FIX in an observational study, which could be clinically relevant.

High-sensitivity C-reactive protein, low-grade systemic inflammation and type 2 diabetes mellitus: A two-sample Mendelian randomization study.

BACKGROUND AND AIMS: The role of inflammation in type 2 diabetes mellitus (T2D) remains unclear. We investigated the associations of high sensitivity C-reactive protein (hsCRP) concentration with T2D and glycemic traits using two-sample Mendelian Randomization. METHODS AND RESULTS: We used publically available summary-statistics data from genome-wide association studies on T2D (DIAGRAM: 12 171 cases; 56 862 controls) and glycemic traits (MAGIC: 46 186 participants without diabetes mellitus). We combined the effects of the genetic instrumental variables through inverse-variance weighting (IVW), and MR-Egger regression and weighted-median estimation as sensitivity analyses which take into account potential violations (e.g., directional pleiotropy) of the assumptions of instrumental variable analyses. Analyses were conducted using 15 known hsCRP genetic instruments among which 6 instruments are hsCRP specific and not involved in inflammatory processes beyond hsCRP concentration regulation. Though we found no association between the combined effect of the genetic instrumental variables for hsCRP and T2D with IVW (odds ratio per 1 ln [hsCRP in mg/L]: 1.15; 95% confidence interval: 0.93, 1.42), we found associations for T2D with MR-Egger regression and weighted-median estimation (odds ratio with 95% confidence interval per 1 ln [hsCRP in mg/L], MR-Egger regression: 1.29; 1.08, 1.49; weighted-median estimator: 1.21; 1.02, 1.39). We found no association with T2D for the combination of hsCRP-specific genetic instruments nor did we found associations with glycemic traits in any of the analyses. CONCLUSION: Evidence was provided for a potential causal association between hsCRP and T2D, but only after considering directional pleiotropy. However, hsCRP was not causally associated with glycemic traits.

A critical appraisal of pharmacogenetic inference.

In essence, pharmacogenetic research is aimed at discovering variants of importance to gene-treatment interaction. However, epidemiological studies are rarely set up with this goal in mind. It is therefore of great importance that researchers clearly communicate which assumptions they have had to make, and which inherent limitations apply to the interpretation of their results. This review discusses considerations of, and the underlying assumptions for, utilizing different response phenotypes and study designs popular in pharmacogenetic research to infer gene-treatment interaction effects, with a special focus on those dealing with of clinical effects of drug treatment.

Optimising the ISAR-HP to screen efficiently for functional decline in older patients.

INTRODUCTION: The Identification of Seniors At Risk-Hospitalised Patients (ISAR-HP) has recently been included in guidelines as a frailty indicator to identify patients for comprehensive geriatric assessment. Previous studies showed that the conventional cut-off score incorrectly classifies a high percentage of patients as high risk. We aimed to optimise the predictive value of ISAR-HP by using different cut-offs in older acutely hospitalised patients. METHODS: A prospective follow-up study was performed in two Dutch hospitals. Acutely hospitalised patients aged ≥ 70 years were included. Demographics, illness severity parameters, geriatric measurements and the ISAR-HP scores were obtained at baseline. The primary outcome was a combined end point of functional decline or mortality during 90-day follow-up. RESULTS: In total 765 acutely hospitalised older patients were included, with a median age of 79 years, of whom 276 (36.1%) experienced functional decline or mortality. The conventional ISAR-HP cut-off of ≥ 2 assigned 432/765 patients (56.5%) as high risk, with a positive predictive value (PPV) of 0.49 (95%CI 0.45-0.54) and a negative predictive value of 0.81 (95%CI 0.76-0.85). Thus, 51% of those whom the ISAR-HP denoted as high risk did not experience the outcome of interest. Raising the cut-off to ≥ 4 assigned 205/765 patients (26.8%) as high risk, with a marginally increased PPV to 0.55 (95%CI 0.48-0.62). CONCLUSION: The ISAR-HP with the conventional cut-off of ≥ 2 incorrectly identifies a large group of patients at high risk for functional decline or mortality and raising the cut-off to 4 only marginally improved performance. Caution is warranted to ensure efficient screening and follow-up interventions.

Non-response to (statin) therapy: the importance of distinguishing non-responders from non-adherers in pharmacogenetic studies.

PURPOSE: In pharmacogenetic research, genetic variation in non-responders and high responders is compared with the aim to identify the genetic loci responsible for this variation in response. However, an important question is whether the non-responders are truly biologically non-responsive or actually non-adherent? Therefore, the aim of this study was to describe, within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), characteristics of both non-responders and high responders of statin treatment in order to possibly discriminate non-responders from non-adherers. METHODS: Baseline characteristics of non-responders to statin therapy (≤10 % LDL-C reduction) were compared with those of high responders (>40 % LDL-C reduction) through a linear regression analysis. In addition, pharmacogenetic candidate gene analysis was performed to show the effect of excluding non-responders from the analysis. RESULTS: Non-responders to statin therapy were younger (p = 0.001), more often smoked (p < 0.001), had a higher alcohol consumption (p < 0.001), had lower LDL cholesterol levels (p < 0.001), had a lower prevalence of hypertension (p < 0.001), and had lower cognitive function (p = 0.035) compared to subjects who highly responded to pravastatin treatment. Moreover, excluding non-responders from pharmacogenetic studies yielded more robust results, as standard errors decreased. CONCLUSION: Our results suggest that non-responders to statin therapy are more likely to actually be non-adherers, since they have more characteristics that are viewed as indicators of high self-perceived health and low disease awareness, possibly making the subjects less adherent to study medication. We suggest that in pharmacogenetic research, extreme non-responders should be excluded to overcome the problem that non-adherence is investigated instead of non-responsiveness.

Using genetic variation for establishing causality of cardiovascular risk factors: overcoming confounding and reverse causality.

Cardiovascular disease (CVD) remains the leading cause of death in developed countries, despite the decline of CVD mortality over the last two decades. From observational, predictive research, efforts have been made to find causal risk factors for CVD. However, in recent years, some of these findings have been shown to be mistaken. Possible explanations for the discrepant findings are confounding and reverse causation. Genetic epidemiology has tried to address these problems through the use of Mendelian randomisation. In this paper, we discuss the promise and limitations of using genetic variation for establishing causality of cardiovascular risk factors.

[Cognition problems during rehabilitation of stroke patients in a nursing home]. / Cognitieve problematiek bij revalidatie van CVA-patiënten in het verpleeghuis.

In many regions in the Netherlands the care for stroke patients is organised in a coordinated stroke service. Within these stroke services, each year more patients are referred to nursing homes for a period of rehabilitation. A stroke leads to lasting cognitive and emotional consequences in more than half of the stroke patients. These consequences interfere with the daily life of the patients and their caregivers. Due to the nature and severity of these problems specific care is needed in the nursing home. In the present article a procedure for cognitive screening in a nursing home is described and data of a large group of patients are presented. These data clearly show the magnitude of the cognitive problems: high percentages of impairments are found in many cognitive domains. In the discussion therefore arguments are given for specialised care - assessment as well as treatment - in the nursing home for stroke patients with cognitive deficits.

Routine pelvic lymphadenectomy in apparently early stage endometrial cancer.

AIMS: Controversial issues with respect to the treatment of patients with endometrial cancer include indications for lymphadenectomy and adjuvant radiotherapy. PATIENT AND METHODS: Between 1998 and 2004 all women with endometrial cancer stage I were included (n = 335). They all underwent total abdominal hysterectomy and bilateral salpingo-oöphorectomy. Two hundred and thirty-seven women also had a pelvic lymphadenectomy. When pelvic lymphadenectomy was performed, radiotherapy was administered only to patients with lymph-node metastases. Otherwise, adjuvant radiotherapy was based on the presence of risk factors. RESULTS: Eleven patients had lymph-node metastases. The overall absolute and relative survival-estimate at 5 years was 85.0 and 93.7%, respectively. Loco-regional recurrence was 8.5%. In the group with pelvic lymphadenectomy and negative lymph nodes these rates were 88.2, 93.9 and 5.6%, respectively. In 58 patients without any of the risk factors tumour grade III, deep myometrial invasion, or age > or =60 years, no lymph-node metastases were found. CONCLUSION: In patients with endometrial cancer FIGO stage I without risk-factors, a phenomenon which occurs in about 25% of patients with clinical stage I endometrial cancer, a lymphadenectomy can be omitted. In other patients, the debate regarding the optimal treatment will remain.

Isolation of rat intestinal crypt cells.

A technique is presented which yields single cells and intact crypts in suspension from unfixed rat intestinal mucosal epithelium. Everted lengths of intestine were digested by 27 mM sodium citrate in phosphate-buffered saline (pH = 7.3) at 37 degrees C. Mucosal cells were dislodged by vibratory stress (hand vortexing) following incubation for prescribed intervals at 37 degrees C in 1.5 mM ethylenediamine tetraacetic acid (EDTA) and 0.5 mM dithiothreitol (dtt). Alkaline phosphatase determinations, phase microscopy, and in vivo and in vitro evaluations of tritiated thymidine ([3H]TdR) incorporation were performed on isolated intestinal cells. Data indicate that cells were sequentially derived from villus tip to crypt base as judged by cellular morphology, alkaline phosphatase activity/mg protein and radioactivity per microgram protein. Upon completion of the intestinal cell isolation assay, scanning electron microscopy of the remaining intestine revealed that approximately 95% of the crypt openings were vacant; the villi were totally denuded; the supporting structures, including the lamina propria, appeared intact. In vitro radiolabelling of intestinal cell fractions enriched with crypts revealed a linear incorporation of [3H]TdR from 0-60 min which was strongly influenced by the presence of foetal calf serum (FCS). Measurements of the compensatory response of the mucosa to resection of 70% of the small bowel indicated that the mucosal cell separation is capable of detecting alterations in crypt cell proliferation. Previously, such alterations were monitored by other methods utilizing microdissection procedures or stathmokinetic agents.