Tailoring the Implementation of New Biomarkers Based on Their Added Predictive Value in Subgroups of Individuals

Background\ud The value of new biomarkers or imaging tests, when added to a prediction model, is currently evaluated using reclassification measures, such as the net reclassification improvement (NRI). However, these measures only provide an estimate of improved reclassification at population level. We present a straightforward approach to characterize subgroups of reclassified individuals in order to tailor implementation of a new prediction model to individuals expected to benefit from it.\ud \ud Methods\ud In a large Dutch population cohort (n = 21,992) we classified individuals to low (<5%) and high (≥5%) fatal cardiovascular disease risk by the Framingham risk score (FRS) and reclassified them based on the systematic coronary risk evaluation (SCORE). Subsequently, we characterized the reclassified individuals and, in case of heterogeneity, applied cluster analysis to identify and characterize subgroups. These characterizations were used to select individuals expected to benefit from implementation of SCORE.\ud \ud Results\ud Reclassification after applying SCORE in all individuals resulted in an NRI of 5.00% (95% CI [-0.53%; 11.50%]) within the events, 0.06% (95% CI [-0.08%; 0.22%]) within the nonevents, and a total NRI of 0.051 (95% CI [-0.004; 0.116]). Among the correctly downward reclassified individuals cluster analysis identified three subgroups. Using the characterizations of the typically correctly reclassified individuals, implementing SCORE only in individuals expected to benefit (n = 2,707,12.3%) improved the NRI to 5.32% (95% CI [-0.13%; 12.06%]) within the events, 0.24% (95% CI [0.10%; 0.36%]) within the nonevents, and a total NRI of 0.055 (95% CI [0.001; 0.123]). Overall, the risk levels for individuals reclassified by tailored implementation of SCORE were more accurate.\ud \ud Discussion\ud In our empirical example the presented approach successfully characterized subgroups of reclassified individuals that could be used to improve reclassification and reduce implementation burden. In particular when newly added biomarkers or imaging tests are costly or burdensome such a tailored implementation strategy may save resources and improve (cost-)effectivenes

Lower striatal dopamine D2/3 receptor availability in obese compared with non-obese subjects

Background: Obesity is a result of a relative excess in energy intake over energy expenditure. These processes are controlled by genetic, environmental, psychological and biological factors. One of the factors involved in the regulation of food intake and satiety is dopaminergic signalling. A small number of studies have reported that striatal dopamine D-2/D-3 receptor [D2/3R] availability is lower in morbidly obese subjects. Methods: To confirm the role of D2/3R in obesity, we measured striatal D2/3R availability, using [I-123]IBZM SPECT, in 15 obese women and 15 non-obese controls. Results: Striatal D2/3R availability was 23% (p = 0.028) lower in obese compared with non-obese women. Conclusion: This study is an independent replication of the finding that severely obese subjects have lower striatal D2/3R availability. Our findings invigorate the evidence for lower striatal D2/3R availability in obesity and confirm the role of the striatal dopaminergic reward system in obesit

Genotyping of Giardia in Dutch patients and animals: a phylogenetic analysis of human and animal isolates.

Giardia duodenalis (syn. Giardia lamblia, Giardia intestinalis) is a protozoan organism that can infect the intestinal tract of many animal species including mammals. Genetic heterogeneity of G. duodenalis is well described but the zoonotic potential is still not clear. In this study, we analysed 100 Giardia DNA samples directly isolated from human stool specimens, to get more insight in the different G. duodenalis assemblages present in the Dutch human population. Results showed that these human isolates could be divided into two main Assemblages A and B within the G. duodenalis group on the basis of PCR assays specific for the Assemblages A and B and the DNA sequences of 18S ribosomal RNA and the glutamate dehydrogenase (gdh) genes. Genotyping results showed that G. duodenalis isolates originating from Dutch human patients belonged in 35% of the cases to Assemblage A (34/98) and in 65% of the cases to Assemblage B (64/98) whereas two human cases remained negative in all assays tested. In addition, we compared these human samples with animal samples from the Netherlands and human and animal samples from other countries. A phylogenetic analysis was carried out on the DNA sequences obtained from these Giardia and those available in GenBank. Using gdh DNA sequence analysis, human and animal Assemblage A and B Giardia isolates could be identified. However, phylogenetic analysis revealed different sub-clustering for human and animal isolates where host-species-specific assemblages (C, D, E, F and G) could be identified. The geographic origin of the human and animal samples was not a discriminating factor

Low dose Naltrexone for induction of remission in inflammatory bowel disease patients

Background: Around 30% of patients with inflammatory bowel disease (IBD) are refractory to current IBD drugs or relapse over time. Novel treatments are called for, and low dose Naltrexone (LDN) may provide a safe, easily accessible alternative treatment option for these patients. We investigated the potential of LDN to induce clinical response in therapy refractory IBD patients, and investigated its direct effects on epithelial barrier function. Methods: Patients not in remission and not responding to conventional therapy were offered to initiate LDN as a concomitant treatment. In total 47 IBD patients prescribed LDN were followed prospectively for 12 weeks. Where available, endoscopic remission data, serum and biopsies were collected. Further the effect of Naltrexone on wound healing (scratch assay), cytokine production and endoplasmic reticulum (ER) stress (GRP78 and CHOP western blot analysis, immunohistochemistry) were investigated in HCT116 and CACO2 intestinal epithelial cells, human IBD intestinal organoids and patient samples. Results: Low dose Naltrexone induce

Anti-Malaria Drug Mefloquine Induces Motor Learning Deficits in Humans

Mefloquine (a marketed anti-malaria drug) prophylaxis has a high risk of causing adverse events. Interestingly, animal studies have shown that mefloquine imposes a major deficit in motor learning skills by affecting the connexin 36 gap junctions of the inferior olive. We were therefore interested in assessing whether mefloquine might induce similar effects in humans. The main aim of this study was to investigate the effect of mefloquine on olivary-related motor performance and motor learning tasks in humans. We subjected nine participants to voluntary motor timing (dart throwing task), perceptual timing (rhythm perceptual task) and reflex timing tasks (eye-blink task) before and 24 h after the intake of mefloquine. The influence of mefloquine on motor learning was assessed by subjecting participants with and without mefloquine intake (controls: n = 11 vs mefloquine: n = 8) to an eye-blink conditioning task. Voluntary motor performance, perceptual timing, and reflex blinking were not affected by mefloquine use. However, the influence of mefloquine on motor learning was substantial; both learning speed as well as learning capacity was impaired by mefloquine use. Our data suggest that mefloquine disturbs motor learning skills. This adverse effect can have clinical as well as social clinical implications for mefloquine users. Therefore, this side-effect of mefloquine should be further investigated and recognized by clinicians

Surveillance of zoonotic bacteria in finishing pigs in The Netherlands

In The Netherlands, from 1998 till 2002, a surveillance programme for zoonotic bacteria in finishing pigs was conducted at herd level. In 2000-2002, the prevalence of Salmonella spp. approximated 30%, while a significantly decreasing trend was observed when standardizing data for herdsize, age and quarter of sampling. Serotype discrimination showed the predominance of S. Typhimurium with an increasing role for phage type DT104. Prevalence estimates for Campylobacter spp. were 97% in 1998 (4th quarter only) and 45% in 1999. For STEC O157, prevalence estimates were 2% and 0% in 1998 and 1999, respectively. By using the samples from this study, a comparison study was conducted in which three different selective enrichment media, i.e. RV, MSRV and DIASALM, were compared for the isolation of Salmonella spp. from pig feces. Both MSRV and DIASALM scored significantly better compared to RV. By using logistic regression analysis of farm and herd specific data, potential risk factors for Salmonella spp. in finishing pig herds were identified and quantified

Transmission of MRSA ST398 between pigs during transport from farm to a slaughterhouse and during time spent in the holding area at the slaughterhouse

A distinct clone of MRSA, Multi Locus Sequence Type 398, was found in pigs and people in contact with pigs recently. In The Netherlands, a discrepancy is found between prevalences for MRSA ST398 in individual pigs on slaughterhouses and individual pigs on farms. Four batches of 30 slaughter pigs from 4 MRSA negative farms were selected and sampled before and after transport to the slaughterhouse and after resting time in the slaughterhouse to evaluate the possibility of pigs getting MRSA positive during this short-time period. Additional samples were taken from the environment, i.e. transport lorry and lairage. Pigs that stayed in a contaminated environment, either contaminated lorry or lairage or both, had a higher chance of becoming MRSA positive than pigs that stayed in areas that tested negative for MRSA. It was concluded that transmission of MRSA ST398 takes place in the short-time period of transport to the slaughterhouse and during time spent inlairages