Survival analysis with delayed entry in selected families with application to human longevity

In the field of aging research, family-based sampling study designs are commonly used to study the lifespans of long-lived family members. However, the specific sampling procedure should be carefully taken into account in order to avoid biases. This work is motivated by the Leiden Longevity Study, a family-based cohort of long-lived siblings. Families were invited to participate in the study if at least two siblings were ‘long-lived’, where ‘long-lived’ meant being older than 89 years for men or older than 91 years for women. As a result, more than 400 families were included in the study and followed for around 10 years. For estimation of marker-specific survival probabilities and correlations among life times of family members, delayed entry due to outcome-dependent sampling mechanisms has to be taken into account. We consider shared frailty models to model left-truncated correlated survival data. The treatment of left truncation in shared frailty models is still an open issue and the literature on this topic is scarce. We show that the current approaches provide, in general, biased estimates and we propose a new method to tackle this selection problem by applying a correction on the likelihood estimation by means of inverse probability weighting at the family level

Neutralising effects of small molecule toxin inhibitors on nanofractionated coagulopathic Crotalinae snake venoms

Repurposing small molecule drugs and drug candidates is considered as a promising approach to revolutionise the treatment of snakebite envenoming. In this study, we investigated the inhibiting effects of the small molecules varespladib (nonspecific phospholipase A2 inhibitor), marimastat (broad spectrum matrix metalloprotease inhibitor) and dimercaprol (metal ion chelator) against coagulopathic toxins found in Crotalinae (pit vipers) snake venoms. Venoms from Bothrops asper, Bothrops jararaca, Calloselasma rhodostoma and Deinagkistrodon acutus were separated by liquid chromatography, followed by nanofractionation and mass spectrometry identification undertaken in parallel. Nanofractions of the venom toxins were then subjected to a high-throughput coagulation assay in the presence of different concentrations of the small molecules under study. Anticoagulant venom toxins were mostly identified as phospholipases A2, while procoagulant venom activities were mainly associated with snake venom metalloproteinases and snake venom serine proteases. Varespladib was found to effectively inhibit most anticoagulant venom effects, and also showed some inhibition against procoagulant toxins. Contrastingly, marimastat and dimercaprol were both effective inhibitors of procoagulant venom activities but showed little inhibitory capability against anticoagulant toxins. The information obtained from this study aids our understanding of the mechanisms of action of toxin inhibitor drug candidates, and highlights their potential as future snakebite treatments

Negotiating ADHD: pragmatic medicalization and creolization in urban India

Although a growing number of studies have demonstrated differences in responses to ADHD-like behaviours, very few studies have focused on theorizing diversity in the way ADHD is framed and approached globally. To contribute to the study of medicalization in a global context, this study examines the discursive field in which care professionals explain and treat ADHD among children in metropolitan India and addresses the need for an analytic framework to grasp the variations in the way ADHD is understood and approached. Building on the concepts of pragmatic medicalization and creolization, we study ADHD discourses in India asking ‘What is at stake’ and ‘What matters most’? In this mixed methods study, 64 care professionals regularly involved in assessing ADHD-like behaviour completed an online Q-sort, and 21 professionals participated in face-to-face interviews. The Q-data were subjected to factor analysis. The interviews were analyzed using qualitative content analyses. Our study identified six distinct ADHD discourses, which showed that care professionals combine explanatory and treatment models. Professionals adapt their explanations and treatments of ADHD to parents’ worries regarding academic performance, family prestige, stigma and side effects of allopathic medicine. Our findings indicate that an awareness of local concerns and adjustments to structural opportunities can diversify how ADHD-like behaviour is framed and responded to. This study demonstrates that medicalization operates between the emerging institutions of care and the everyday concerns of families and care professionals and reveals the need to examine conflicting stakes as drivers of diverse responses to ADHD diagnosis and treatment in India and the rest of the world.Prevention, Population and Disease management (PrePoD)Public Health and primary car

Handgrip strength at midlife and familial longevity

Low handgrip strength has been linked with premature mortality in diverse samples of middle-aged and elderly subjects. The value of handgrip strength as marker of "exceptional" human longevity has not been previously explored. We postulated that the genetic influence on extreme survival might also be involved in the muscular strength determination pathway. Therefore, the objective of this study was to assess the muscle strength in a sample of middle-aged adults who are genetically enriched for exceptional survival and comparing them to a control group. We included 336 offspring of the nonagenarian from the Leiden Longevity Study who were enriched for heritable exceptional longevity, and 336 of their partners were used as controls. The Leiden Longevity study was a prospective follow up study of long-living siblings pairs together with their offspring and their partners. Handgrip strength was used as a proxy for overall muscle strength. No significant difference in handgrip strength was seen between the offspring of the nonagenarian and their partners after adjustment for potential confounders including body compositions, sum score of comorbidities, medication use, smoking and alcohol history. The main determinants of midlife handgrip strength were age, gender, total body percentage fat and relative appendicular lean mass. Although midlife handgrip strength has previously been shown to be an important prognostic indicator of survival, it is not a marker of exceptional familial longevity in middleaged adults. This finding suggests that genetic component of susceptibility to extreme survival is likely to be separate from that of muscular strength

Antivenom Neutralization of Coagulopathic Snake Venom Toxins Assessed by Bioactivity Profiling Using Nanofractionation Analytics

Venomous snakebite is one of the world’s most lethal neglected tropical diseases. Animal-derived antivenoms are the only standardized specific therapies currently available for treating snakebite envenoming, but due to venom variation, often this treatment is not effective in counteracting all clinical symptoms caused by the multitude of injected toxins. In this study, the coagulopathic toxicities of venoms from the medically relevant snake species Bothrops asper, Calloselasma rhodostoma, Deinagkistrodon acutus, Daboia russelii, Echis carinatus and Echis ocellatus were assessed. The venoms were separated by liquid chromatography (LC) followed by nanofractionation and parallel mass spectrometry (MS). A recently developed high-throughput coagulation assay was employed to assess both the pro- and anticoagulant activity of separated venom toxins. The neutralization capacity of antivenoms on separated venom components was assessed and the coagulopathic venom peptides and enzymes that were either neutralized or remained active in the presence of antivenom were identified by correlating bioassay results with the MS data and with off-line generated proteomics data. The results showed that most snake venoms analyzed contained both procoagulants and anticoagulants. Most anticoagulants were identified as phospholipases A2s (PLA2s) and most procoagulants correlated with snake venom metalloproteinases (SVMPs) and serine proteases (SVSPs). This information can be used to better understand antivenom neutralization and can aid in the development of next-generation antivenom treatments

Replication of LDL SWAs hits in PROSPER/PHASE as validation for future (pharmaco)genetic analyses

<p><b>Background:</b> The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.</p> <p><b>Methods:</b> The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.</p> <p><b>Results:</b> Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.</p> <p><b>Conclusion:</b> With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.</p&gt