Noncognitive Behavioral Changes Associated With Alzheimer's Disease: Implications of Neuroimaging Findings.

Alzheimer's disease (AD) is commonly associated with noncognitive behavioral changes (NCBCs). The authors systematically reviewed whether neuroimaging has helped with understanding the pathophysiology, diagnosis, or management of NCBCs associated with AD, including depression, aggression or agitation, anxiety, apathy, psychosis, and sleep disorder. The authors identified dissociable neural substrates with multimodal imaging: depression implicates the lateral and superior prefrontal cortex; apathy and agitation implicate the dorsal anterior cingulate; psychosis implicates right lateralized frontal and medial temporal areas; and anxiety implicates mesial temporal regions. Frontal white matter changes appear to underlie many NCBCs, emphasizing the preventative management of vascular risk factors. Further delineation of underlying neurocircuitry and pathophysiology in larger data sets might lead to biomarker identification for diagnosis and optimizing treatment targets.

Defining a staged-based process for economic and financial evaluations of mHealth programs.

Mobile and wireless technology for health (mHealth) has the potential to improve health outcomes by addressing critical health systems constraints that impede coverage, utilization, and effectiveness of health services. To date, few mHealth programs have been implemented at scale and there remains a paucity of evidence on their effectiveness and value for money. This paper aims to improve understanding among mHealth program managers and key stakeholders of how to select methods for economic evaluation (comparative analysis for determining value for money) and financial evaluation (determination of the cost of implementing an intervention, estimation of costs for sustaining or expanding an intervention, and assessment of its affordability). We outline a 6 stage-based process for selecting and integrating economic and financial evaluation methods into the monitoring and evaluation of mHealth solutions including (1) defining the program strategy and linkages with key outcomes, (2) assessment of effectiveness, (3) full economic evaluation or partial evaluation, (4) sub-group analyses, (5) estimating resource requirements for expansion, (6) affordability assessment and identification of models for financial sustainability. While application of these stages optimally occurs linearly, finite resources, limited technical expertise, and the timing of evaluation initiation may impede this. We recommend that analysts prioritize economic and financial evaluation methods based on programmatic linkages with health outcomes; alignment with an mHealth solution's broader stage of maturity and stage of evaluation; overarching monitoring and evaluation activities; stakeholder evidence needs; time point of initiation; and available resources for evaluations.

Cost-effectiveness analysis of the diarrhea alleviation through zinc and oral rehydration therapy (DAZT) program in rural Gujarat India: an application of the net-benefit regression framework.

BACKGROUND: This study evaluates the cost-effectiveness of the DAZT program for scaling up treatment of acute child diarrhea in Gujarat India using a net-benefit regression framework. METHODS: Costs were calculated from societal and caregivers' perspectives and effectiveness was assessed in terms of coverage of zinc and both zinc and Oral Rehydration Salt. Regression models were tested in simple linear regression, with a specified set of covariates, and with a specified set of covariates and interaction terms using linear regression with endogenous treatment effects was used as the reference case. RESULTS: The DAZT program was cost-effective with over 95% certainty above $5.50 and $7.50 per appropriately treated child in the unadjusted and adjusted models respectively, with specifications including interaction terms being cost-effective with 85-97% certainty. DISCUSSION: Findings from this study should be combined with other evidence when considering decisions to scale up programs such as the DAZT program to promote the use of ORS and zinc to treat child diarrhea.

Economic evaluation of neonatal care packages in a cluster-randomized controlled trial in Sylhet, Bangladesh.

OBJECTIVE: To evaluate and compare the cost-effectiveness of two strategies for neonatal care in Sylhet division, Bangladesh. METHODS: In a cluster-randomized controlled trial, two strategies for neonatal care--known as home care and community care--were compared with existing services. For each study arm, economic costs were estimated from a societal perspective, inclusive of programme costs, provider costs and household out-of-pocket payments on care-seeking. Neonatal mortality in each study arm was determined through household surveys. The incremental cost-effectiveness of each strategy--compared with that of the pre-existing levels of maternal and neonatal care--was then estimated. The levels of uncertainty in our estimates were quantified through probabilistic sensitivity analysis. FINDINGS: The incremental programme costs of implementing the home-care package were 2939 (95% confidence interval, CI: 1833-7616) United States dollars (US$) per neonatal death averted and US$ 103.49 (95% CI: 64.72-265.93) per disability-adjusted life year (DALY) averted. The corresponding total societal costs were US$ 2971 (95% CI: 1844-7628) and US$ 104.62 (95% CI: 65.15-266.60), respectively. The home-care package was cost-effective--with 95% certainty--if healthy life years were valued above US$ 214 per DALY averted. In contrast, implementation of the community-care strategy led to no reduction in neonatal mortality and did not appear to be cost-effective. CONCLUSION: The home-care package represents a highly cost-effective intervention strategy that should be considered for replication and scale-up in Bangladesh and similar settings elsewhere.

Cost-effectiveness of inguinal hernia surgery in northwestern Ecuador.

BACKGROUND: Cost-effectiveness of tension-free inguinal hernia repair at a private 20-bed rural hospital in Esmeraldas Province, Ecuador, was calculated relative to no treatment. METHODS: Lichtenstein repair using mosquito net or polypropylene commercial mesh was provided to patients with inguinal hernia by surgeons from Europe and North America. Prospective data were collected from provider, patient, and societal perspectives, with component costs collected on site and from local supply companies or published literature. Patient outcomes were forecasted using disability adjusted life years (DALYs) averted. Uncertainty in patient-level data was evaluated with Monte-Carlo simulation. RESULTS: Surgery was provided to 102 patients with inguinal hernias of various sizes. Local anesthesia was used for 80 % of operations during the first mission, and spinal anesthesia was used for 89 % in the second mission. Few complications were observed. An average 6.39 DALYs (3,0) were averted per patient (95 % confidence interval: 6.22-6.84). The average cost per patient was US$499.33 (95 % CI: US$490.19-$526.03) from a provider perspective, US$118.79 (95 % CI: US$110.28-$143.72) from a patient perspective, and US$615.46 (95 % CI: US$603.39-$650.40) from a societal perspective. Mean cost-effectiveness from a provider perspective was US$78.18/DALY averted (95 % CI: US$75.86-$85.78) according to DALYs (3,0) averted using the West Life Table level 26, well below the Ecuadorian per-capita Gross National Income (US$3,850). Results were robust to all sensitivity analyses. CONCLUSIONS: Inguinal hernia repair was cost-effective in western Ecuador through international collaboration.

Cost-effectiveness of the introduction of a pre-erythrocytic malaria vaccine into the expanded program on immunization in sub-Saharan Africa: analysis of uncertainties using a stochastic individual-based simulation model of Plasmodium falciparum malaria.

OBJECTIVE: To evaluate the cost-effectiveness of introducing the RTS,S malaria vaccine into the Expanded Programme on Immunization (EPI) in Sub-Saharan Africa (SSA), the contributions of different sources of uncertainty, and the associated expected value of perfect information (EVPI). METHODS: Vaccination was simulated in populations of 100,000 people at 10 different entomological inoculation rates (EIRs), using an existing stochastic model and a 10-year time horizon. Incremental cost-effectiveness ratios (ICERs) and EVPI were computed from weighted averages of outputs using two different assignments of the EIR distribution in 2007. Uncertainty was evaluated by resampling of epidemiological, vaccination, and health systems model parameters. RESULTS: Health benefits were predicted consistently only at low transmission, and program costs always substantially exceeded case management savings. Optimal cost-effectiveness was at EIR of about 10 infectious bites per annum (ibpa). Main contributors to ICER uncertainty were uncertainty in transmission intensity, price per vaccine dose, decay rate of the vaccine effect, degree of homogeneity in host response, and some epidemiological model parameters. Other health system costs were unimportant. With a ceiling ratio of 207 international dollars per disability-adjusted life-year averted, 52.4% of parameterizations predicted cost-effectiveness in the primary analysis. CONCLUSIONS: Cost-effectiveness of RTS,S will be maximal in low endemicity settings (EIR 2-20 ibpa). Widespread deployment of other transmission-reducing interventions will thus improve cost-effectiveness, suggesting a selective introduction strategy. EVPI is substantial. Accrual of up-to-date information on local endemicity to guide deployment decisions would be highly efficient.

Cost-effectiveness of skin-barrier-enhancing emollients among preterm infants in Bangladesh.

OBJECTIVE: To evaluate the cost-effectiveness of topical emollients, sunflower seed oil (SSO) and synthetic Aquaphor, versus no treatment, in preventing mortality among hospitalized preterm infants (< 33 weeks gestation) at a tertiary hospital in Bangladesh. METHODS: Evidence from a randomized controlled efficacy trial was evaluated using standard Monte Carlo simulation. Programme costs were obtained from a retrospective review of activities. Patient costs were collected from patient records. Health outcomes were calculated as deaths averted and discounted years of life lost (YLLs) averted. Results were deemed cost-effective if they fell below a ceiling ratio based on the per capita gross national income of Bangladesh (United States dollars, US$ 470). FINDINGS: Aquaphor and SSO were both highly cost-effective relative to control, reducing neonatal mortality by 26% and 32%, respectively. SSO cost US$ 61 per death averted and US$ 2.15 per YLL averted (I$ 6.39, international dollars, per YLL averted). Aquaphor cost US$ 162 per death averted and US$ 5.74 per YLL averted (I$ 17.09 per YLL averted). Results were robust to sensitivity analysis. Aquaphor was cost-effective relative to SSO with 77% certainty: it cost an incremental US$ 26 more per patient treated, but averted 1.25 YLLs (US$ 20.74 per YLL averted). CONCLUSION: Topical therapy with SSO or Aquaphor was highly cost-effective in reducing deaths from infection among the preterm neonates studied. The choice of emollient should be made taking into account budgetary limitations and ease of supply. Further research is warranted on additional locally available emollients, use of emollients in community-based settings and generalizability to other geographic regions.

Psychopharmacological neuroprotection in neurodegenerative disease: heuristic clinical applications.

In Part I of this report, the authors reviewed preclinical and clinical evidence of neuroprotection by psychotropics and proposed criteria to predict translational neuroprotection. Here, the authors review a broad array of neuroprotective mechanisms and, based on evidence reviewed in Part I, consider agents with pharmacodynamic mechanisms of action that may be associated with neuroprotection. The neuroprotective potential of the pharmacodynamic mechanisms discussed here are held in common with drugs that evidenced neuroprotective potential in Part I. The agents examined here have symptomatic utility in neurodegenerative disease neuropsychiatric disorders and combine the most promising pharmacodynamic mechanisms yet have received insufficient research to date. Modafinil, duloxetine, ziprasidone, s-zopiclone, and ramelteon are evaluated in terms of their putative neuropsychiatric symptomatic and heuristic neuroprotective disease-modifying potentials. The authors review these agents in terms of their potential for clinical neuroprotection and suggest a criterion-based research agenda for future studies of their neuroprotective potential. Further research is needed with regard to the 10 translational neuroprotective candidate criteria, neuroprotective clinical trials, the correlation of psychotropic pharmacodynamic mechanisms with neuroprotective actions, and the translational predictive utility of the proposed candidate criteria.

Psychopharmacological neuroprotection in neurodegenerative disease: assessing the preclinical data.

This manuscript reviews the preclinical in vitro, ex vivo, and nonhuman in vivo effects of psychopharmacological agents in clinical use on cell physiology with a view toward identifying agents with neuroprotective properties in neurodegenerative disease. These agents are routinely used in the symptomatic treatment of neurodegenerative disease. Each agent is reviewed in terms of its effects on pathogenic proteins, proteasomal function, mitochondrial viability, mitochondrial function and metabolism, mitochondrial permeability transition pore development, cellular viability, and apoptosis. Effects on the metabolism of the neurodegenerative disease pathogenic proteins alpha-synuclein, beta-amyloid, and tau, including tau phosphorylation, are particularly addressed, with application to Alzheimer's and Parkinson's diseases. Limitations of the current data are detailed and predictive criteria for translational clinical neuroprotection are proposed and discussed. Drugs that warrant further study for neuroprotection in neurodegenerative disease include pramipexole, thioridazine, risperidone, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, fluoxetine, buspirone, clonazepam, diphenhydramine, and melatonin. Those with multiple neuroprotective mechanisms include pramipexole, thioridazine, olanzapine, quetiapine, lithium, valproate, desipramine, maprotiline, clonazepam, and melatonin. Those best viewed circumspectly in neurodegenerative disease until clinical disease course outcomes data become available, include several antipsychotics, lithium, oxcarbazepine, valproate, several tricyclic antidepressants, certain SSRIs, diazepam, and possibly diphenhydramine. A search for clinical studies of neuroprotection revealed only a single study demonstrating putatively positive results for ropinirole. An agenda for research on potentially neuroprotective agent is provided.

Thrombin stimulates mitogenesis in pig cerebrovascular smooth muscle cells involving activation of pro-matrix metalloproteinase-2.

Generation of thrombin is associated with vascular remodeling that involves proliferation of vascular smooth muscle cells (SMCs) and activation of pro-matrix metalloproteinases (pro-MMPs). The present study was to investigate whether thrombin would induce mitogenesis and activation of pro-MMPs in cerebrovascular SMCs (CSMCs), and if so, whether MMP activity would contribute to the CSMC mitogenesis. CSMCs were cultured from pig middle cerebral arteries and stimulated with thrombin. Thrombin (0.1-5U/ml), in a dose-dependent fashion, stimulated mitogenesis in CSMCs as detected by bromo-2'-deoxy-uridine (BrdU) incorporation. Additionally, zymographic analyses showed that thrombin stimulated the appearance of the active form of MMP-2 (MMP-2) in a concentration-dependent manner, but not the release of pro-MMP-2. Thrombin did not affect expression of cell-associated pro-MMP-2 protein as evaluated by Western blot analysis. Treatment with the synthetic MMP inhibitor GM6001 or antibodies to MMP-2 significantly reduced thrombin-induced BrdU incorporation in CSMCs. In conclusion, thrombin activates pro-MMP-2 in the absence of elevated pro-MMP-2 expression and secretion in CSMCs, and thrombin induces CSMC mitogenesis involving its action on MMP-2. These findings suggest that thrombin may have relevance in cerebrovascular remodeling associated with brain atherosclerosis and atherothrombotic ischemic stroke through a mechanism involving MMP-dependent CSMC mitogenesis.

Neuroanatomy of pathological laughing and crying: a report of the American Neuropsychiatric Association Committee on Research.

Pathological laughing and crying (PLC) is a clinical condition that occurs in patients with various neurological disorders. It is characterized by the presence of episodic and contextually inappropriate or merely exaggerated outbursts of laughter and/or crying without commensurate feelings. This review provides an in depth analysis of the neuroanatomy of lesions seen in patients with this clinical condition, discusses the relevant functional neuroimaging and electrophysiological stimulation studies in human subjects, and summarizes the current treatment options. It concludes with a presentation of the remaining questions and directions for future research.

Public health and policy issues of hernia surgery in Africa.

Inguinal hernia repair has been overlooked as a public health priority in Africa, with its high prevalence largely unrecognized, and traditional public health viewpoints assuming that not enough infrastructure, human resources, or financing capacity are available for effective service provision. Emerging evidence suggests that inguinal hernias in Ghana are approximately ten times as prevalent as in high-income countries, are much more long-standing and severe, and can be repaired with low-cost techniques using mosquito net mesh through international collaboration. Outcomes from surgery are comparable to published literature, and potential exists for scaling up capacity. Special attention must be paid to creating financing systems that encourage eventual local self-sustainability.

Economic costs to caregivers of diarrhoea treatment among children below 5 in rural Gujarat India: findings from an external evaluation of the DAZT programme.

INTRODUCTION: Diarrhoea is a leading cause of mortality among young children in India although few receive the recommended treatment. The diarrhoea alleviation through zinc and oral rehydration salts (ORS) therapy (DAZT) team initiated a programme in Gujarat from 2011 to 2013 to increase coverage of these interventions through public and private providers at scale. This study evaluates the economic impact of diarrhoea to caregivers before and after the introduction of zinc and ORS at scale through the DAZT programme. METHODS: The DAZT programme evaluation took a before-and-after study design using a two-stage clustered cross-sectional survey. Factors associated with the odds of caregivers incurring economic costs and their amounts were evaluated in a two-part modelling approach. RESULTS: The DAZT programme lowered unadjusted economic costs to caregivers of treating a diarrhoeal episode from $4.04 to $2.49 in 2 years. Controlling for covariates, analysis showed no association between the programme and a change in odds of incurring an economic cost but did show an association with a reduction in economic cost of $2.15 (95% confidence interval (CI) $1.20-$3.11) per diarrhoea episode. A more than 4-fold increase in care-seeking from public community health workers, reduction in care-seeking from higher levels of the health system and reduced spending on drugs besides ORS and zinc may explain these results. DISCUSSION: This study found an association between zinc introduction and a reduction in economic burden of diarrhoea treatment to caregivers in underserved rural areas of Gujarat through more efficient patterns of care-seeking and content of care.

Angiotensin II induces proliferation of human cerebral artery smooth muscle cells through a basic fibroblast growth factor (bFGF) dependent mechanism.

Remodeling of cerebral arteries in hypertension produces thickened vessel walls associated with atherosclerotic plaque formation. In both thickening and plaque formation, proliferation of vascular smooth muscle cells is a hallmark. Genetically hypertensive rats treated with an angiotensin II (Ang II) AT1 receptor antagonist inhibited thickening of cerebral arteries suggesting a mitogenic action of Ang II on cerebral arterial VSMC (CVSMC). However, in studies using smooth muscle cells cultured from peripheral arteries, Ang II causes cell hypertrophy, but not proliferation. We determined the effect of Ang II on proliferation of cultured human CVSMC. CVSMC were cultured from the basilar artery obtained at autopsy. Ang II (10(-7) M) stimulated proliferation determined by counting cells and mitochondrial activity assay. Synthesis and release of basic fibroblast growth factor (bFGF) was essential for Ang II-stimulated proliferation. These findings are consistent with the notion that Ang II stimulates CVSMC proliferation thereby contributing to vessel remodeling.

Phenotypic diversity of smooth muscle cells isolated from human intracranial basilar artery.

The present work examined heterogeneity of vascular smooth muscle cells cultured from human cerebral arteries that has not been previously reported. Primary smooth muscle cell cultures were isolated from human intracranial basilar arteries. Using a ring isolation method, multiple clones were generated from the cell cultures. These clones had two distinctly different morphologies: (1) fusiform; and (2) stellate. At confluence the fusiform-shaped clones grew in compact clusters with overlapping cells while the stellate-shaped clones were contact-inhibited growing in a monolayered pattern. The smooth muscle differentiation markers, alpha-smooth muscle-actin, calponin and smooth muscle-myosin heavy chains were expressed in all these clones. In response to serum stimulation, the stellate-shaped clones had a higher growth rate than the fusiform clones. This study reports that smooth muscle cells derived from human basilar arteries are heterogeneous.

Protocol for the economic evaluation of the diarrhea alleviation through zinc and oral rehydration salt therapy at scale through private and public providers in rural Gujarat and Uttar Pradesh, India.

BACKGROUND: Child diarrhea persists as a leading public health problem in India despite evidence supporting zinc and low osmolarity oral rehydration salts as effective treatments. Across 2 years in 2010-2013, the Diarrhea Alleviation using Zinc and Oral Rehydration Salts Therapy (DAZT) program was implemented to operationalize delivery of these interventions at scale through private and public sector providers in rural Gujarat and Uttar Pradesh, India. METHODS/DESIGN: This study evaluates the cost-effectiveness of DAZT program activities relative to status quo conditions existing before the study, comparing a Monte Carlo simulation method with net-benefit regression, discussing the strengths and weaknesses of each approach. A control group was not included in the 'before and after' study design as zinc has proven effectiveness for diarrhea treatment. Costs will be calculated using a societal perspective including program implementation and household out-of-pocket payments for care seeking, as well as estimates of wages lost. Outcomes will be measured in terms of episodes averted in net-benefit regression and in terms of the years of life lost component of disability-adjusted life years in the method based on Monte Carlo simulation. The Lives Saved Tool will be used to model anticipated changes in mortality over time and deaths averted based on incremental changes in coverage of oral rehydration salts and zinc. Data will derive from cross-sectional surveys at the start, midpoint, and endpoint of the program. In addition, Lives Saved Tool (LiST) projections will be used to define the reference case value for the ceiling ratio in terms of natural units. DISCUSSION: This study will be useful both in its application to an economic evaluation of a public health program in its implementation phase but also in its comparison of two methodological approaches to cost-effectiveness analysis. Both policy recommendations and methodological lessons learned will be discussed, recognizing the limitations in drawing strong policy conclusions due to the uncontrolled study design. It is expected that this protocol will be useful to researchers planning what method to use for the evaluation of similar before and after studies.

Forecasting burden of long-term disability from neonatal conditions: results from the Projahnmo I trial, Sylhet, Bangladesh.

INTRODUCTION: The burden of disease resulting from neonatal conditions is substantial in developing countries. From 2003 to 2005, the Projahnmo I programme delivered community-based interventions for maternal and newborn health in Sylhet, Bangladesh. This analysis quantifies burden of disability and incorporates non-fatal outcomes into cost-effectiveness analysis of interventions delivered in the Projahnmo I programme. METHODS: A decision tree model was created to predict disability resulting from preterm birth, neonatal meningitis and intrapartum-related hypoxia ('birth asphyxia'). Outcomes were defined as the years lost to disability (YLD) component of disability-adjusted life years (DALYs). Calculations were based on data from the Projahnmo I trial, supplemented with values from published literature and expert opinion where data were absent. RESULTS: 195 YLD per 1000 neonates [95% confidence interval (CI): 157-241] were predicted in the main calculation, sensitive to different DALY assumptions, disability weights and alternative model structures. The Projahnmo I home care intervention may have averted 2.0 (1.3-2.8) YLD per 1000 neonates. Compared with calculations based on reductions in mortality alone, the cost-effectiveness ratio decreased by only 0.6% from $105.23 to $104.62 ($65.15-$266.60) when YLD were included, with 0.6% more DALYs averted [total 338/1000 (95% CI: 131-542)]. DISCUSSION: A significant burden of disability results from neonatal conditions in Sylhet, Bangladesh. Adding YLD has very little impact on recommendations based on cost-effectiveness, even at the margin of programme adoption. This model provides guidance for collecting data on disabilities in new settings.

Role of melatonin in mood disorders and the antidepressant effects of agomelatine.

INTRODUCTION: Disturbances of circadian rhythms and sleep play an important role in various types of mood disorders like major depressive disorder (MDD), bipolar depressive disorder (BPD) and seasonal affective disorder (SAD). Malfunctioning of the SCN-pineal-melatonin link has been suggested as the main cause for these disorders. As a rhythm-regulating factor and as a hormone involved in the regulation of sleep, melatonin is essential for the control of mood and behavior. AREAS COVERED: Melatonin's involvement in various mood disorders is reviewed based on studies undertaken in patients with MDD, BPD and SAD. The chemistry and metabolism of the newly introduced antidepressant, agomelatine, a MT1/MT2 melatonin receptor agonist and 5-HT2c antagonist in brain areas involved in mood regulation are also discussed. Its clinical role in mood regulation, agomelatine's efficacy, safety and tolerability are also reviewed. EXPERT OPINION: Agomelatine, a melatonergic antidepressant with a rapid onset of action, has been shown effective in various types of mood disorders (e.g., MDD, BPD, SAD). Some studies find it superior to other common antidepressants (SSRIs, SNRIs) that are in clinical use today. Agomelatine's efficacy, good tolerability and safety profile suggest that it may become a preferred antidepressant in the near future.