Parental Age and Offspring Childhood Mental Health: A Multi-Cohort, Population-Based Investigation.

To examine the contributions of maternal and paternal age on offspring externalizing and internalizing problems, this study analyzed problem behaviors at age 10-12 years from four Dutch population-based cohorts (N = 32,892) by a multiple informant design. Bayesian evidence synthesis was used to combine results across cohorts with 50% of the data analyzed for discovery and 50% for confirmation. There was evidence of a robust negative linear relation between parental age and externalizing problems as reported by parents. In teacher-reports, this relation was largely explained by parental socio-economic status. Parental age had limited to no association with internalizing problems. Thus, in this large population-based study, either a beneficial or no effect of advanced parenthood on child problem behavior was observed.

Inflammation and Monocyte Recruitment due to Aging and Mechanical Stretch in Alveolar Epithelium are Inhibited by the Molecular Chaperone 4-phenylbutyrate.

INTRODUCTION: Ventilator-Induced lung injury (VILI) is a form of acute lung injury that is initiated or exacerbated by mechanical ventilation. The aging lung is also more susceptible to injury. Harmful mechanical stretch of the alveolar epithelium is a recognized mechanism of VILI, yet little is known about how mechanical stretch affects aged epithelial cells. Disruption to Endoplasmic Reticulum (ER) homeostasis results in a condition known as ER stress that leads to disruption of cellular homeostasis, apoptosis, and inflammation. ER stress is increased with aging and other pathological stimuli. We hypothesized that age and mechanical stretch increase alveolar epithelial cells' proinflammatory responses that are mediated by ER stress. Furthermore, we believed that inhibition of this upstream mechanism with 4PBA, an ER stress reducer, alleviates subsequent inflammation and monocyte recruitment. METHODS: Type II alveolar epithelial cells (ATII) were harvested from C57Bl6/J mice 2 months (young) and 20 months (old) of age. The cells were cyclically stretched at 15% change in surface area for up to 24 hours. Prior to stretch, groups were administered 4PBA or vehicle as a control. RESULTS: Mechanical stretch and age upregulated ER stress and proinflammatory MCP-1/CCL2 and MIP-1ß/CCL4 chemokine expression in ATIIs. Age-matched and mismatched monocyte recruitment by ATII conditioned media was also quantified. CONCLUSIONS: Age increases susceptibility to stretch-induced ER stress and downstream inflammatory gene expression in a primary ATII epithelial cell model. Administration of 4PBA attenuated the increased ER stress and proinflammatory responses from stretch and/or age and significantly reduced monocyte migration to ATII conditioned media.

THE GAP BETWEEN ECONOMIC EVALUATIONS AND CLINICAL PRACTICE: A SYSTEMATIC REVIEW OF ECONOMIC EVALUATIONS ON DABIGATRAN FOR ATRIAL FIBRILLATION.

OBJECTIVES: As model-based economic evaluations (MBEEs) are widely used to make decisions in the context of policy, it is imperative that they represent clinical practice. Here, we assess the relevance of MBEEs on dabigatran for the prevention of stroke in patients with atrial fibrillation (AF). METHODS: We performed a systematic review on the basis of a developed questionnaire, tailored to oral anticoagulation in patients with AF. Included studies had a full body text in English, compared dabigatran with a vitamin K antagonist, were not dedicated to one or more subgroup(s), and yielded an incremental cost-effectiveness ratio. The relevance of all MBEEs was assessed on the basis of ten context-independent factors, which encompassed clinical outcomes and treatment duration. The MBEEs performed for the United States were assessed on the basis of seventeen context-dependent factors, which were related to the country's target population and clinical environment. RESULTS: The search yielded twenty-nine MBEEs, of which six were performed for the United States. On average, 54 percent of the context-independent factors were included per study, and 37 percent of the seventeen context-dependent factors in the U.S. STUDIES: The share of relevant factors per study did not increase over time. CONCLUSIONS: MBEEs on dabigatran leave out several relevant factors, limiting their usefulness to decision makers. We strongly urge health economic researchers to improve the relevance of their MBEEs by including context-independent relevance factors, and modeling context-dependent factors befitting the decision context concerned.

Combining value of information analysis and ethical argumentation in decisions on participation of vulnerable patients in clinical research.

BACKGROUND: The participation of vulnerable patients in clinical research poses apparent ethical dilemmas. Depending on the nature of the vulnerability, their participation may challenge the ethical principles of autonomy, non-maleficence, or justice. On the other hand, non-participation may preclude the building of a knowledge base that is a prerequisite for defining the optimal clinical management of vulnerable patients. Such clinical uncertainty may also incur substantial economic costs. MAIN TEXT: We present the participation of pre-menopausal women with atrial fibrillation in trials of novel oral anticoagulant drugs as a case study. Due to their non-participation in pivotal trials, it is uncertain whether for them, the risks that are associated with these drugs are outweighed by the advantages compared with conventional treatment. We addressed the question whether research of this new class of drugs in this subgroup would be appropriate from both, an ethical as well an economic perspective. We used the method of specifying norms as a wider framework to resolve the apparent ethical dilemma, while incorporating the question whether research of oral anticoagulants in premenopausal women with atrial fibrillation can be justified on economic grounds. For the latter, the results of a value-of-information analysis were used. CONCLUSIONS: Further clinical research on NOACs in premenopausal women with atrial fibrillation can be justified on both, ethical and economic grounds. Addressing apparent ethical dilemmas by invoking a method such as specifying norms can improve the quality of public practical reasoning. As such, the method should also prove valuable to committees that have formally been granted the authority to review trial protocols and proposals for scientific research.

Uncertainty on the effectiveness and safety of rivaroxaban in premenopausal women with atrial fibrillation: empirical evidence needed.

BACKGROUND: Novel anticoagulations (NOACs) are increasingly prescribed for the prevention of stroke in premenopausal women with atrial fibrillation. Small studies suggest NOACs are associated with a higher risk of abnormal uterine bleeds than vitamin K antagonists (VKAs). Because there is no direct empirical evidence on the benefit/risk profile of rivaroxaban compared to VKAs in this subgroup, we synthesize available indirect evidence, estimate decision uncertainty on the treatments, and assess whether further research in premenopausal women is warranted. METHODS: A Markov model with annual cycles and a lifetime horizon was developed comparing rivaroxaban (the most frequently prescribed NOAC in this population) and VKAs. Clinical event rates, associated quality adjusted life years, and health care costs were obtained from different sources and adjusted for gender, age, and history of stroke. A Monte Carlo simulation with 10,000 iterations was then performed for a hypothetical cohort of premenopausal women, estimated to be reflective of the population of premenopausal women with AF in The Netherlands. RESULTS: In the simulation, rivaroxaban is the better treatment option for the prevention of ischemic strokes in premenopausal women in 61% of the iterations. Similarly, this is 98% for intracranial hemorrhages, 24% for major abnormal uterine bleeds, 1% for minor abnormal uterine bleeds, 9% for other major extracranial hemorrhages, and 23% for other minor extracranial hemorrhages. There is a 78% chance that rivaroxaban offers the most quality-adjusted life years. The expected value of perfect information in The Netherlands equals 122 quality-adjusted life years and 22 million Euros. CONCLUSIONS: There is a 22% risk that rivaroxaban offers a worse rather than a better benefit/risk profile than vitamin K antagonists in premenopausal women. Although rivaroxaban is preferred over VKAs in this population, further research is warranted, and should preferably take the shape of an internationally coordinated registry study including other NOACs.

Practice points in gynecardiology: Abnormal uterine bleeding in premenopausal women taking oral anticoagulant or antiplatelet therapy.

A growing number of premenopausal women are currently using antithrombotic and/or (dual) antiplatelet therapy for various cardiovascular indications. These may induce or exacerbate abnormal uterine bleeding and more awareness and knowledge among prescribers is required. Heavy and irregular menstrual bleeding is common in women in their forties and may have a variety of underlying causes that require different treatment options. Thus using anticoagulants in premenopausal women demands specific expertise and close collaboration between cardiovascular physicians and gynecologists. In this article we summarize the scope of the problem and provide practical recommendations for the care for young women taking anticoagulants and/or (dual) antiplatelet therapy. We also recommend that more safety data on uterine bleeding with novel anticoagulants in premenopausal women should be obtained.

Changes in health care expenditure after the loss of a spouse: data on 6,487 older widows and widowers in the Netherlands.

BACKGROUND: In ageing populations, informal care holds great potential to limit rising health care expenditure. The majority of informal care is delivered by spouses. The loss of informal care due to the death of the spouse could therefore increase expenditure levels for formal care. OBJECTIVE: To investigate the impact of the death of the spouse on health care expenditure by older people through time. Additionally, to examine whether the impact differs between socio-demographic groups, and what health services are affected most. DESIGN: Longitudinal data on health care expenditure (from July 2007 through 2010) from a regional Dutch health care insurer was matched with data on marital status (2004-2011) from the Central Bureau of Statistics. Linear mixed models with log transformed health care expenditure, generalized linear models and two-part models were used to retrieve standardized levels of monthly health care expenditure of 6,487 older widowed subjects in the 42 months before and after the loss of the spouse. RESULTS: Mean monthly health care expenditure in married subjects was € 502 in the 42 months before the death of the spouse, and expenditure levels rose by € 239 (48%) in the 42 months after the death of the spouse. The increase in expenditure after the death of the spouse was highest for men (€ 319; 59%) and the oldest old (€ 553; 82%). Expenditure levels showed the highest increase for hospital and home care services (together € 166). CONCLUSIONS: The loss of the spouse is associated with an increase in health care expenditure. The relatively high rise in long-term care expenses suggests that the loss of informal care is an important determinant of this rise.

Variation in the costs of dying and the role of different health services, socio-demographic characteristics, and preceding health care expenses.

The health care costs of population ageing are for an important part attributable to higher mortality rates in combination with high costs of dying. This paper answers three questions that remain unanswered regarding the costs of dying: (1) contributions of different health services to the costs of dying; (2) variation in the costs of dying; and (3) the influence of preceding health care expenses on the costs of dying. We retrieved data on 61,495 Dutch subjects aged 65 and older from July 2007 through 2010 from a regional health care insurer. We included all deceased subjects of whom health care expenses were known for 26 months prior to death (n=2833). Costs of dying were defined as health care expenses made in the last six months before death. Lorenz curves, generalized linear models and a two-part model were used for our analyses. (1) The average costs of dying are €25,919. Medical care contributes to 57% of this total, and long-term care 43%. The costs of dying mainly relate to hospital care (40%). (2) In the costs of dying, 75% is attributable to the costliest half of the population. For medical care, this distribution figure is 86%, and for long-term care 92%. Age and preceding expenses are significant determinants of this variation in the costs of dying. (3) Overall, higher preceding health care expenses are associated with higher costs of dying, indicating that the costs of dying are higher for those with a longer patient history. To summarize, there is not a large variation in the costs of dying, but there are large differences in the nature of these costs. Before death, the oldest old utilize more long-term care while their younger counterparts visit hospitals more often. To curb the health care costs of population ageing, a further understanding of the costs of dying is crucial.

Old age mortality and macroeconomic cycles.

BACKGROUND: As mortality is more and more concentrated at old age, it becomes critical to identify the determinants of old age mortality. It has counter-intuitively been found that mortality rates at all ages are higher during short-term increases in economic growth. Work-stress is found to be a contributing factor to this association, but cannot explain the association for the older, retired population. METHODS: Historical figures of gross domestic product (Angus Maddison) were compared with mortality rates (Human Mortality Database) of middle aged (40-44 years) and older people (70-74 years) in 19 developed countries for the period 1950-2008. Regressions were performed on the de-trended data, accounting for autocorrelation and aggregated using random effects models. RESULTS: Most countries show pro-cyclical associations between the economy and mortality, especially with regard to male mortality rates. On average, for every 1% increase in gross domestic product, mortality increases with 0.36% for 70-year-old to 74-year-old men (p<0.001) and 0.38% for 40-year-old to 44-year-old men (p<0.001). The effect for women is 0.18% for 70-year-olds to 74-year-olds (p=0.012) and 0.15% for 40-year-olds to 44-year-olds (p=0.118). CONCLUSIONS: In developed countries, mortality rates increase during upward cycles in the economy, and decrease during downward cycles. This effect is similar for the older and middle-aged population. Traditional explanations as work-stress and traffic accidents cannot explain our findings. Lower levels of social support and informal care by the working population during good economic times can play an important role, but this remains to be formally investigated.

Relationship between social anxiety and perceived trustworthiness.

Four different patterns of biased ratings of facial expressions of emotions have been found in socially anxious participants: higher negative ratings of (1) negative, (2) neutral, and (3) positive facial expressions than nonanxious controls. As a fourth pattern, some studies have found no group differences in ratings of facial expressions of emotion. However, these studies usually employed valence and arousal ratings that arguably may be less able to reflect processing of social information. We examined the relationship between social anxiety and face ratings for perceived trustworthiness given that trustworthiness is an inherently socially relevant construct. Improving on earlier analytical strategies, we evaluated the four previously found result patterns using a Bayesian approach. Ninety-eight undergraduates rated 198 face stimuli on perceived trustworthiness. Subsequently, participants completed social anxiety questionnaires to assess the severity of social fears. Bayesian modeling indicated that the probability that social anxiety did not influence judgments of trustworthiness had at least three times more empirical support in our sample than assuming any kind of negative interpretation bias in social anxiety. We concluded that the deviant interpretation of facial trustworthiness is not a relevant aspect in social anxiety.

Incorporation of historical data in the analysis of randomized therapeutic trials.

Historical studies provide a valuable source of information for the motivation and design of later trials. Bayesian techniques offer possibilities for the quantitative inclusion of prior knowledge within the analysis of current trial data. Combining information from previous studies into an informative prior distribution is, however, a delicate case. The power prior distribution is a tool to estimate the effect of an intervention in a current study sample, while accounting for the information provided by previous research. In this study we evaluate the use of the power prior distribution, illustrated with data from a large randomized clinical trial on the effect of ST-wave analysis in intrapartum fetal monitoring. We advocate the use of a power prior distribution with pre-specified fixed study weights based on differences in study characteristics. We propose obtaining a ranking of the historical studies via expert elicitation, based on relevance for the current study, and specify study weights accordingly.

The effect of zinc bacitracin and roxarsone on performance of broiler chickens when fed in combination with narasin.

Six trials were conducted at various locations to determine the response of broiler chickens to combinations of zinc bacitracin and roxarsone when fed in the presence of narasin. The addition of zinc bacitracin at 55 mg per kg significantly improved growth rate and feed utilization when data from all locations were combined. There was no effect of roxarsone fed at 50 mg per kg on BW or feed utilization, nor was there an interaction of roxarsone and zinc bacitracin on BW. There was a significant interaction of roxarsone and zinc bacitracin for feed utilization; addition of zinc bacitracin significantly improved feed utilization both in the presence and absence of roxarsone, but the improvement was greater in the absence of roxarsone.

Evidence for association-activation effects in reactions of papain from studies on its reactivity towards isomeric two-protonic-state reactivity probes.

4-(N-Aminoethyl 4-pyridyl disulphide)-7-nitrobenzo-2-oxa-1,3-diazole was synthesized and evaluted as a two-protonic-state reactivity probe by kinetic study of its reactions with papain (EC 3.4.22.2) and with benzimidazol-2-ylmethanethiol. Evidence is presented to suggest that: (i) both this probe molecule and its 2-pyridyl isomer bind to papain; (ii) the binding is followed by a change in the environment of the thiol group of cysteine-25; (iii) the striking rate maximum in neutral media observed in the reaction of papain with the 2-pyridyl isomer but not with the 4-pyridyl isomer arises from association of the 2-pyridyl leaving group with the imidazolium ion of histidine-159.

A reporter group delivery system with both absolute and selective specificity for thiol groups and an improved fluorescent probe containing the 7-nitrobenzo-2-oxa-1,3-diazole moiety.

1. 4-(N-2-Aminoethyl2'-pyridyl disulphide)-7-nitrobenzo-2-oxa-1,3-diazole (compound I) was synthesized and evaluated as a fluorescent labelling reagent for thiol groups. 2. The design of compound (I) as one example of a general type of reporter group delivery reagent (2-pyridyl-S-S-X, where X contains an environmentally sensitive spectroscopic probe) is discussed. 3. The electronic absorption spectrum of compound (I) was determined over a wide range of pH and the spectral changes that accompany its reaction with low-molecular-weight thiols, e.g. L-cysteine, and with papain (EC 3.4.22.2) and bovine serum albumin are discussed. 4. A new value of epsilon343 for 2-thiopyridone (Py-2-SH) was determined as 8.08 X 10(3) +/- 0.08 X 10(3)M-1-cm-1. 5. Spectral analysis of the reactions of compound (I) with L-cysteine and with papain (in the pH range 3.5-8.0) showed that even under equimolar conditions the reaction (thiol-disulphide interchange to release Py-2-SH) is essentially stoicheimoetric and probably proceeds by specific attack at the sulphur atom distal from the pyridyl ring of compound (I). 6. The fluorescence-emission spectra of compound (I) and of the products of its reaction with papain and with ficin (EC 3.4.22.3) were determined. Compound (I) is highly fluorescent in aqueous solution. Excitation within the intense visible absorption band (lambda max. 481 nm, epsilon max. 2.52 X 10(4)M-1-cm-1) provides green fluorescence with an emission maximum at 540 nm. Both papain and ficin labelled by reaction with compound (I) are characterized by fluorescence-emission maxima (535 nm and 530 nm respectively) of even higher intensity. The fluorescence emission of the product of the reaction of papain with compound (I) was shown to be 25 times more intense than that of the product of the reaction of papain with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (Nbd chloride). 7. The second-order rate constants (k2) for the reactions of compound (I) and of Nbd chloride with GSH, papain, albumin, ficin, 2-benzimidazolylmethanethiol and 2-benzimidazolylethanethiol were determined at 25.0 degrees C and various pH values. At pH4 the values of k2(compound I)/k2(Nbd chloride) are: GSH, 288; albumin, 36; papain 3 X 10(3); ficin, 3 X 10(4). 8. The pH-k2 profiles for the reactions of compound (I) and of Nbd chloride with the two 2-benzimidazolylalkanethiols were determined. Of the four profiles only that for the reaction of compound (I) with 2-benzimidazolylmethanethiol is characterized by a striking rate maximum in acidic media.