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The purpose of the present study was to evaluate the efficacy and safety of (-)-OSU6162 in doses up to 30 mg b.i.d. in patients suffering from mental fatigue following stroke or traumatic brain injury (TBI).
This 4+4 weeks double blind randomised cross-over study included 30 patients afflicted with mental fatigue following a stroke or head trauma occurring at least twelve months earlier. Efficacy was assessed using the Mental Fatigue Scale (MFS), the Self-rating Scale for Affective Syndromes (CPRS), the Frenchay Activity Index (FAI), and a battery of neuropsychological tests. Safety was evaluated by recording spontaneously reported adverse events.
There were significant differences on the patients’ total FAI scores (p=0.0097), the subscale FAI outdoor scores (p=0.0243), and on the trail making test (TMT-B) (p=0.0325) in favour of (-)-OSU6162 treatment. Principal component analysis showed a clear overall positive treatment effect in 10 of 28 patients; those who responded best to treatment had their greatest improvements on the MFS. Reported adverse events were mild or moderate in severity and did not differ between the (-)-OSU6162 and the placebo period.
The most obvious beneficial effects of (-)-OSU6162 was on the patients’ activity level, illustrated by the improvement on the FAI scale. Moreover, a subgroup of patients showed substantial improvements on the Mental Fatigue Scale. Based on these observed therapeutic effects, in conjunction with the good tolerability of (-)-OSU6162, this compound may offer promise for treating at least part of the symptomatology in patients suffering from stroke- or TBI-induced mental fatigue.
Although lignin has been negatively correlated with neutral detergent fibre (NDF) digestibility (NDFD) in ruminants and used to predict potential extent of NDF digestion of forages, selection of an analysis, Klason lignin (KL) or acid detergent lignin (ADL), to describe the nutritionally relevant lignin has not been resolved. Dismissed as an artifact is the difference between KL and ADL (∆L). A question is whether ∆L influences digestibility of NDF. We evaluated the relationships of ∆L, KL, and ADL with NDFD in order to determine the nutritionally homogeneous or heterogeneous nature of KL. Data sets from 2 laboratories (DS1, DS2) were used that included ADL, KL, and in vitro NDFD at 48 h (NDFD48). DS1 contained 7 C3 grasses, 17 C4 maize forages and 19 alfalfas, and DS2 had 15 C3 grasses, 8 C4 forages, and 6 alfalfas. Mean ∆L was greater than ADL in C3 and C4 samples, and less in alfalfas. Within forage type and laboratory, ∆L was not correlated with NDFD48 (r = -0.34 to 0.49; all P>0.17). ADL was more consistently correlated with NDFD48 (r = -0.47 to -0.95; P <0.01-0.21) than was KL (r = 0.03 to -0.91; P <0.01-0.94). ∆L as a proportion of KL was correlated with NDFD48 in C3 and C4 samples (r = 0.44 to 0.76; P <0.01-0.08). The differing behaviors of ∆L and ADL relative to NDFD48 indicate that KL is a nutritionally heterogeneous fraction, the behavior of which may vary by forage type and ratios of ADL and ∆L present.
Increased fruit and vegetable (FV) intake is associated with reduced blood pressure. However, it is not clear whether the effect of FV on blood pressure depends on the type of FV consumed. Furthermore, there is limited research regarding the comparative effect of juices or whole FV on blood pressure. Baseline data from a prospective cohort study examined the cross-sectional association between total FV intake, but also specific types of FV and blood pressure in France and Northern Ireland. A total of 10660 men aged 50–59 years were recruited from 1991 to 1994. Blood pressure was measured in a clinic setting, and dietary intake was assessed by food-frequency questionnaire (FFQ). After adjusting for potential confounders, both systolic (SBP) and diastolic blood pressure (DBP) were significantly inversely associated with total fruit, vegetable and fruit juice intake however when results were examined according to the sub-type of fruit or vegetable (citrus fruit, other fruit, fruit juices, cooked vegetables and raw vegetables), only the other fruit and raw vegetable categories were consistently associated with reduced SBP and DBP. In relation to the risk of hypertension based on systolic blood pressure >140 mmHg, the odds ratio for total fruit, vegetable and fruit juice intake (per fourth) was 0.95 (95 % CI 0.91, 1.00), with the same estimates being 0.98 (CI % 0.94, 1.02) for citrus fruit intake (per fourth), 1.02 (CI % 0.98, 1.06) for fruit juice intake (per fourth), 0.93 (CI % 0.89, 0.98) for other fruit intake (per fourth), 1.05 (CI % 0.99, 1.10) for cooked vegetable intake (per fourth) and 0.86 (CI % 0.80, 0.91) for raw vegetable intake (per fourth). Similar results were obtained for DBP. In conclusion, a high overall intake of fruit, vegetables and fruit juice was inversely associated with SBP and DBP and risk of hypertension, but that this association differs by FV sub-type, suggesting that the strength of the association between these FV sub-types and blood pressure might be related to the type consumed, or to processing or cooking-related factors.
Suicide is a leading cause of mortality in youth, yet the course of suicide attempts is poorly documented. We explored the vulnerable transition from adolescence to emerging adulthood to identify group trajectories and risk factors.
The National Longitudinal Survey of Children and Youth is a prospective representative cohort of Canadian children. We followed participants aged 7–11 years in 1994–95 to age 23 (2008–09). We modelled self-reported past-year suicide attempts (ages 12 to 23 years) using growth mixture models. We analysed risk factors from self- and parent-report questionnaires at pre-adolescence (ages 10–11) and early adolescence (ages 12–13) using multinomial logistic regressions. Analyses were adjusted for sample non-response and attrition.
In 2233 participants answering questions on teen and adult suicide attempts, we identified three trajectories: never attempted (96.0%), adolescence-limited (2.0%) and persisting into adulthood (2.0%). Adolescent girls aged 12–13 with depression/anxiety symptoms, and with mothers experiencing depression had higher risks of adolescence-limited than never-attempted [relative risk RR 9.27 (95% confidence interval: 1.73–49.82); 2.03 (1.02–3.32), for each standard deviation increase; 1.07 (1.00–1.15); respectively]. Preteen ADHD symptoms increased the risk of attempts persisting into adulthood as compared to never-attempted [RR 2.05 (1.29–3.28) for each standard deviation increase]. Suicide death of schoolmate/acquaintance increased risks of an adulthood trajectory as compared to never-attempted and adolescence-limited [RR 8.41 (3.04–23.27) and 6.63 (1.29–34.06), respectively].
In half the participants attempting suicide, attempts continued into adulthood. We stress the need for preventive strategies in early adolescence and differential clinical/educational interventions as identified for each trajectory.
The Pediatric Heart Network Normal Echocardiogram Database Study had unanticipated challenges. We sought to describe these challenges and lessons learned to improve the design of future studies.
Challenges were divided into three categories: enrolment, echocardiographic imaging, and protocol violations. Memoranda, Core Lab reports, and adjudication logs were reviewed. A centre-level questionnaire provided information regarding local processes for data collection. Descriptive statistics were used, and chi-square tests determined differences in imaging quality.
For the 19 participating centres, challenges with enrolment included variations in Institutional Review Board definitions of “retrospective” eligibility, overestimation of non-White participants, centre categorisation of Hispanic participants that differed from National Institutes of Health definitions, and exclusion of potential participants due to missing demographic data. Institutional Review Board amendments resolved many of these challenges. There was an unanticipated burden imposed on centres due to high numbers of echocardiograms that were reviewed but failed to meet submission criteria. Additionally, image transfer software malfunctions delayed Core Lab image review and feedback. Between the early and late study periods, the proportion of unacceptable echocardiograms submitted to the Core Lab decreased (14 versus 7%, p < 0.01). Most protocol violations were from eligibility violations and inadvertent protected health information disclosure (overall 2.5%). Adjudication committee reviews led to protocol changes.
Numerous challenges encountered during the Normal Echocardiogram Database Study prolonged study enrolment. The retrospective design and flaws in image transfer software were key impediments to study completion and should be considered when designing future studies collecting echocardiographic images as a primary outcome.
Preliminary evidence has suggested that high-fat diets (HFD) enriched with SFA, but not MUFA, promote hyperinsulinaemia and pancreatic hypertrophy with insulin resistance. The objective of this study was to determine whether the substitution of dietary MUFA within a HFD could attenuate the progression of pancreatic islet dysfunction seen with prolonged SFA-HFD. For 32 weeks, C57BL/6J mice were fed either: (1) low-fat diet, (2) SFA-HFD or (3) SFA-HFD for 16 weeks, then switched to MUFA-HFD for 16 weeks (SFA-to-MUFA-HFD). Fasting insulin was assessed throughout the study; islets were isolated following the intervention. Substituting SFA with MUFA-HFD prevented the progression of hyperinsulinaemia observed in SFA-HFD mice (P < 0·001). Glucose-stimulated insulin secretion from isolated islets was reduced by SFA-HFD, yet not fully affected by SFA-to-MUFA-HFD. Markers of β-cell identity (Ins2, Nkx6.1, Ngn3, Rfx6, Pdx1 and Pax6) were reduced, and islet inflammation was increased (IL-1β, 3·0-fold, P = 0·007; CD68, 2·9-fold, P = 0·001; Il-6, 1·1-fold, P = 0·437) in SFA-HFD – effects not seen with SFA-to-MUFA-HFD. Switching to MUFA-HFD can partly attenuate the progression of SFA-HFD-induced hyperinsulinaemia, pancreatic inflammation and impairments in β-cell function. While further work is required from a mechanistic perspective, dietary fat may mediate its effect in an IL-1β–AMP-activated protein kinase α1-dependent fashion. Future work should assess the potential translation of the modulation of metabolic inflammation in man.
The benefit of late window endovascular treatment (EVT) for anterior circulation ischemic stroke has been demonstrated using perfusion-based neuroimaging. We evaluated whether non-contrast CT (NCCT) and CT-angiogram (CTA) alone can select late-presenting patients for EVT.
We performed a retrospective comparison of all patients undergoing EVT at a single comprehensive stroke center from January 2016 to April 2017. Patients planned for EVT were divided into early (<6 hours from onset) and late (≥6 hours from onset or last time seen normal) window groups. Incidence of symptomatic hemorrhagic transformations (sHTs) at 24 hours and 3-month modified Rankin scores (mRSs) were compared.
During the study period, 204 (82%) patients underwent EVT in the early and 44 (18%) in the late window. Median (interquartile range) NIH Stroke Scale Score was similar between groups (early: 18 [15–23] vs. late: 17 [13–21]), as were median ASPECT scores (early: 9 [8–10] vs. late: 9 [7–9]). In the late window, 42 (95%) strokes were of unknown onset. Similar proportions of sHT occurred at 24 hours (early: 12 [6%] vs. late: 4 [9%], p = 0.43). At 3 months, the proportion of patients achieving functional independence (mRS 0–2) were comparable in the early (80/192 [42%]) and late (16/41 [39%]) windows (p = 0.76).
NCCT- and CTA-based patient selection led to similar functional independence outcomes and low proportions of sHT in the early and late windows. In centers without access to perfusion-based neuroimaging, this pragmatic approach could be safe, particularly for strokes of unknown onset.
Little data exists about the methodology of contextualizing version two of the Mental Health Gap Action Programme Intervention Guide (mhGAP-IG) in resource-poor settings. This paper describes the contextualisation and pilot testing of the guide in Kilifi, Kenya.
Contextualisation was conducted as a collaboration between the KEMRI-Wellcome Trust Research Programme (KWTRP) and Kilifi County Government's Department of Health (KCGH) between 2016 and 2018. It adapted a mixed-method design and involved a situational analysis, stakeholder engagement, local adaptation and pilot testing of the adapted guide. Qualitative data were analysed using content analysis to identify key facilitators and barriers to the implementation process. Pre- and post-training scores of the adapted guide were compared using the Wilcoxon signed-rank test.
Human resource for mental health in Kilifi is strained with limited infrastructure and outdated legislation. Barriers to implementation included few specialists for referral, unreliable drug supply, difficulty in translating the guide to Kiswahili language, lack of clarity of the roles of KWTRP and KCGH in the implementation process and the unwillingness of the biomedical practitioners to collaborate with traditional health practitioners to enhance referrals to hospital. In the adaptation process, stakeholders recommended the exclusion of child and adolescent mental and behavioural problems, as well as dementia modules from the final version of the guide. Pilot testing of the adapted guide showed a significant improvement in the post-training scores: 66.3% (95% CI 62.4–70.8) v. 76.6% (95% CI 71.6–79.2) (p < 0.001).
The adapted mhGAP-IG version two can be used across coastal Kenya to train primary healthcare providers. However, successful implementation in Kilifi will require a review of new evidence on the burden of disease, improvements in the mental health system and sustained dialogue among stakeholders.
Insurance benefits which are dependent on the joint mortality of two lives, typically a married couple, form an important part of many insurance portfolios. In this chapter we develop the concepts and models from previous chapters to examine joint life insurance policies. There are also important applications in pension design and valuation, as spousal benefits are a common part of a pension benefit package.
We describe typical benefits offered and introduce standard notation for actuarial functions dependent on two lives. We develop an approach for pricing and valuing these policies, based on the future lifetime random variables, and making the strong assumption that the two lives are independent with respect to mortality.
Next, we show how joint life mortality can be analyzed using multiple state models. This creates a flexible framework to introduce dependence between lives, and we can apply the methods of Chapter 8 to calculate probabilities and value benefits.
In this chapter we represent the future lifetime of an individual as a random variable, and show how probabilities of death or survival can be calculated under this framework. We then define the force of mortality, which is a fundamental quantity in mortality modelling. We introduce some actuarial notation, and discuss properties of the distribution of future lifetime. We introduce the curtate future lifetime random variable, which represents the number of complete years of future life, and is a function of the future lifetime random variable. We explain why this function is useful and derive its probability distribution.
In this chapter we introduce equity-linked insurance contracts. We explore deterministic emerging costs techniques with examples, and demonstrate that deterministic profit testing cannot adequately model these contracts.
We introduce stochastic cash flow analysis, which gives a fuller picture of the characteristics of the equity-linked cash flows, particularly when guarantees are present, and we demonstrate how stochastic cash flow analysis can be used to determine better contract design.
Finally we discuss the use of quantile and conditional tail expectation reserves for equity-linked insurance.
In this chapter we introduce emerging costs, or cash flow analysis for traditional insurance contracts. This is often called profit testing when applied to life insurance.
We introduce profit testing in two stages. First we consider only those cash flows generated by the policy, then we introduce reserves to complete the cash flow analysis.
We define several measures of the profitability of a contract: internal rate of return, expected present value of future profit (net present value), profit margin and discounted payback period. We show how cash flow analysis can be used to set premiums to meet a given measure of profit.
We restrict our attention in this chapter to deterministic profit tests, ignoring uncertainty. We introduce stochastic profit tests in Chapter 15.
In this chapter we introduce some actuarial approaches to estimation and inference used to construct the life tables and survival models that we have been using in previous chapters. We start with a discussion of typical characteristics of lifetime data for actuarial applications. We then show how to use lifetime data to fit survival models, including parametric and non-parametric approaches.
We next move to the Markov models from Chapter 8. Starting with the alive--dead model, and assuming a piecewise constant force of mortality, we derive the maximum likelihood estimator for the force of mortality for each age year. We then extend the methodology to multiple state models with piecewise constant transition intensities.
In this chapter we develop formulae for the valuation of traditional insurance benefits. In particular, we consider whole life, term and endowment insurance. For each of these benefits we identify the random variables representing the present values of the benefits and we derive expressions for moments of these random variables. The functions we develop for traditional benefits will also be useful when we move to modern variable contracts.
We develop valuation functions for benefits based on the continuous future lifetime random variable and the curtate future lifetime random variable from Chapter 2. We introduce a new random variable, the 1/m-thly curtate future lifetime, which we use to value benefits which depend on the number of complete periods of length 1/m years lived by a life age x. We explore relationships between the expected present values of different insurance benefits.
We also introduce the actuarial notation for the expected values of the present value of insurance benefits.