Alzheimer’s disease (AD) and glaucoma are two distinct multifactorial neurodegenerative diseases, primarily affecting the elderly. Common pathophysiological mechanisms have been elucidated in the past decades. First of all both diseases are progressive, with AD leading to dementia and glaucoma inducing blindness. Pathologically, they all feature synaptic dysfunction with changes of neuronal circuitry, progressive accumulation of protein aggregates such as the beta amyloid (Aβ) and intracellular microtubule inclusions containing hyperphosphorylated tau, which belongs to microtubule associated protein family. During an early phase of degeneration, both diseases are characterized by synaptic dysfunction and changes of mitogen-activated protein kinases (MAPK). Common degenerative mechanisms underlying both diseases are discussed here, along with recent results on the potential use of the visual system as a biomarker for diagnosis and progression of AD. Common neuropathological changes and mechanisms in AD and glaucoma have facilitated the transfer of therapeutic strategies between diseases. In particular, we discuss past and present evidence for neuroprotective effects of brain-derived neurotrophic factor (BDNF). Alzheimer’s disease (AD) is a neurodegenerative progressive disease of the elderly leading to dementia. The world Alzheimer report  of 2015 indicated that 46.8 million people worldwide are living with dementia; this number is expected to double every 20 years  on chromosomes 14 and 1, respectively.Early onset familial alzheimer disease (eFAD). Abnormalities of the amyloid precursor protein (APP) that render it more amyloidogenic, or defects of processing normal APP cause genetic forms of AD. The literature estimates that eFAD accounts for approximately 2% of all people with dementia . SAD is very common in the elderly  followed by inflammatory process, glial reaction, reactive oxygen species production, oxidative stress and mitochondrial abnormalities, propagation of neurodegenerative processes leading to cell death. Both diseases are characterized by common features such as synaptic dysfunction and neuronal cell death at the level of the inner retina  on chromosome 17. Tau is highly expressed in neurons and is abundant in axons , ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF) increase the survival of neurons in animal models of injury and disease (Alqawlaq et al., BDNF level is reduced in the glaucomatous retina (Pease et al., in vivo the use of high BDNF doses should be avoided to circumvent potential undesired effects such as the proconvulsant effects (Heinrich et al., BDNF is important for survival and plasticity of the RGCs in models of ON injury and disease (Peinado-Ramón et al., We reported that several common disease features appear in the AD and glaucoma. Based on common disease features that have been described here, several opportunities exist to develop common therapeutic strategies. A successful example involves neuroprotection by BDNF.All authors listed, have made substantial, direct and intellectual contribution to the work, and approved its final version of the manuscript. LD conceived the review focus, conducted literature review and finalized the manuscript. CC summarized and finalized the manuscript. CF conducted literature review and finalized the manuscript. EC conducted literature review and finalized the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The findings regarding the effects of thiazolidinediones (TZDs) in nonalcoholic steatohepatitis (NASH) patients have been inconsistent, and the assessment of different clinical variables for evaluating the effects of TZDs confound a direct comparison of the results of different randomized clinical trials (RCTs), especially with regard to lifestyle changes. In this paper, we performed a meta-analysis of randomized controlled trials to clarify the effects of TZD treatment with and without lifestyle changes on histological markers of NASH and clinical variables related to insulin resistance (IR), hyperlipidemia, and obesity. We searched the literature using the following MeSH terms: “nonalcoholic steatohepatitis,” “non-alcoholic steatohepatitis,” “thiazolidinedione,” “pioglitazone,” “rosiglitazone,” “randomized,” and “clinical trial.” Five eligible RCTs were selected, in which patients were treated with either pioglitazone or rosiglitazone, with or without lifestyle changes. We compared the effects of TZD treatment on hepatic fibrosis, lobular inflammation, IR improvement, fasting serum insulin, adiposity, and dyslipidemia between the various studies using fixed and random effects models, and heterogeneity in clinical outcomes was assessed. Significant improvement in hepatic fibrosis did not occur among the patients treated with TZDs alone or in those who underwent both lifestyle changes and TZD therapy. Lobular inflammation decreased in NASH patients who received TZD treatment and in those who underwent both TZD therapy and lifestyle changes. Although TZD treatment resulted in no significant improvement in IR, NASH patients who underwent both lifestyle changes and TZD therapy experienced a significantly greater reduction in their fasting insulin level than that observed in the control patients, whereas patients treated with TZDs alone did not. Although TZD-treated patients experienced significantly greater weight gain than the control patients, TZD treatment had no significant impact on body-mass index, percentage of body fat, or serum levels of cholesterol and triglyceride. Our findings indicate that additional variables should be assessed to obtain a more comprehensive evaluation of the effects of TZD treatment on IR and comorbidity risk factors in NASH patients, and suggest that including lifestyle changes and additional insulin-sensitizing agents in TZD regimens might improve the benefits of TZD therapy for NASH. A number of different mechanisms in hepatocytes are known to contribute to fatty degeneration of the liver in the development of NAFLD, including increased lipogenesis, decreased lipid excretion, and reduced oxidation of free fatty acids (FFAs).–8 Although the factors contributing to NASH pathogenesis and its progression to fibrosis and cirrhosis are less clear, lipid peroxidation in hepatocytes and proinflammatory cytokines and adipokines are thought to play important roles.–8Nonalcoholic steatohepatitis (NASH) is a histologically severe form of nonalcoholic fatty liver disease (NAFLD) that can progress to hepatic fibrosis and cirhosis.–11 and it is rapidly becoming the leading indicator for liver transplantation.,12 The incidence of NASH in China has also increased recently. Increased risks of insulin resistance (IR), cardiovascular disease (CVD), and metabolic syndrome (MetS) are associated with NASH.–18 The development of IR increases the serum level of FFAs, which increases hepatocyte uptake of FFAs, leading to mitochondrial β-oxidation overload, the net effect of which can contribute to hepatic steatosis and NAFLD progression.,19 Hyperinsulinemia due to IR increases the levels of FFAs and triglycerides in hepatocytes by increasing glycolysis and decreasing the production of apolipoprotein B-100.The link between hepatic steatosis and IR suggests the importance of using treatment regimens that have beneficial effects on both NASH and IR.In recent years, NASH has become the most prevalent form of liver disease in industrialized nations,,20–22 Diet control and exercise have also been shown to improve both IR and NASH when combined with TZD drug therapy in clinical trials.,24 However, the findings regarding the effects of TZDs on NASH have been somewhat inconsistent, due to differences in intervention strategies, histological scoring, and reporting methods. In addition, the use of different assessment variables and reporting methods for evaluating the effects of TZDs on insulin sensitivity in NASH patients confound a direct comparison of the therapeutic effects of TZDs and lifestyle changes on IR. We performed a meta-analysis of randomized controlled trials (RCTs) to clarify the effects of TZD treatment with and without lifestyle changes on glycemic control, serum lipids, obesity-related characteristics, and NASH-related histological variables.The thiazolidinediones (TZDs), pioglitazone and rosiglitazone, modulate insulin sensitivity in a variety of tissues via peroxisome proliferator activated receptor-γ signaling, and have been shown to improve blood glucose control, as well as NASH-related parameters in clinical studies.22.1 and this report was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We searched the MEDLINE, EMBASE, EBSCO, Springer, Ovid, and Cochrane Library databases for published reports of RCTs published in English that evaluated the effects of TZDs on NASH clinical outcomes. The following keywords were used for the literature search: “nonalcoholic steatohepatitis,” “non-alcoholic steatohepatitis,” “thiazolidinedione,” “pioglitazone,” “rosiglitazone,” “randomized,” and “clinical trial.” We used a date range for our search ending in 2015. Our study was approved by the Research Ethics Committee at our institution.Our meta-analysis was performed according to the recommendations of the Cochrane Handbook,2.2 and fasting serum insulin level. Changes in the following patient characteristics and serum lipid levels were monitored to assess potential adverse effects of TZD treatment: body weight, body mass index (BMI), percentage body fat, total serum cholesterol, and serum triglyceride.Two reviewers (XL and LH) independently reviewed the full-text versions of all the articles retrieved in the literature search to identify eligible studies. Conflicts were resolved by a third reviewer (ZY). The following inclusion criteria were used for study selection: RCT in which a TZD was used to treat NASH, included a control or placebo group for comparison, patients received a diagnosis of NASH on the basis of histological examination of liver biopsy, and all patients were ≥18 years of age. The exclusion criteria were as follows: no randomization; patients were treated with a combination of TZDs and other drugs; and included patients diagnosed with NAFLD without NASH, other severe liver diseases, any malignancy, heart failure, or kidney failure. No limitations were made on the basis of sex or language. We analyzed the following primary outcomes: Histological response to treatment based on changes in steatosis grade and lobular inflammation score, change in IR based on the homeostasis model assessment (HOMA-IR),2.3Quality assessment was based on the following domains: randomization, allocation concealment, and blinding of participants and outcome assessors. The following data were extracted by a single investigator (LW): general information, including the study title, authors, and publication date; study features, including study design, outcomes assessed, bias prevention, outcomes reported, management of withdrawals, and adverse effects reported; and treatment details, including TZD dosage, duration of treatment, and length of follow-up. Categorical variables were recorded as incidences, and continuous variables were recorded as the mean and standard deviation (SD) of changes from baseline.2.4http://tech.cochrane.org/revman/download). Heterogeneity in the datasets was assessed on the basis of the I statistic, with I2 >50% indicating significant heterogeneity. Random and fixed effects regression models were used to evaluate the effects of treatment for comparisons in which significant heterogeneity in the dataset was or was not detected, respectively. The results of the random and fixed effects models with P < 0.05 were considered to represent statistically significant differences. The histological assessments were treated as dichotomous categorical variables, for which the treatment effects were evaluated on the basis of the odds ratio (OR) and 95% confidence interval (95% CI). The body characteristics and serum biochemical variables were treated as dichotomous continuous variables. The mean difference (MD) and 95% CI were calculated for continuous variables if the measurement scales were identical in the studies compared. If the measurement scales were not identical, the standardized MD (SMD) and 95% CI were calculated. Forest plots were constructed to present the comparisons of the treatment effects between the RCTs.All statistics were computed using the RevMan, version 5.3.5, program provided by the Cochrane Collaboration website . In our overall analysis of the 5 selected RCTs, the fixed effects model showed that patients who received treatment that included TZD therapy experienced a significantly greater reduction in fibrosis than that in their corresponding placebo and control groups . In the overall analysis of lobular inflammation in 4 of the selected RCTs, the fixed effects model showed that patients treated with a TZD experienced a significantly greater reduction in lobular inflammation, than that in the corresponding placebo groups . The random effects model showed no significant difference between the change in HOMA-IR for patients treated with a TZD and that of their corresponding control group . The random effects model showed that patients treated with a TZD experienced a significantly greater reduction in their fasting insulin level, than that of patients in their corresponding control group . The fixed effects model showed no significant difference in the change in BMI between the TZD-treated patients and the control patients . The fixed effects model showed a significantly greater increase in body weight occurred among the TZD-treated patients, than that in the control groups . The fixed effects model showed that the increase in the percentage of body fat among the TZD-treated patients was not significantly greater than that in the control or placebo groups . The random effects model showed that the increase in the level of serum cholesterol in TZD-treated patients was not significantly different than the change in serum cholesterol in the corresponding control patients . The fixed effects model showed that the change in the serum triglyceride level in TZD-treated patients was not significantly different than that in the corresponding control groups . Our overall and subgroup analyses of changes in HOMA-IR found no significant improvement in IR in any of the TZD treatment groups. However, our subgroup analyses showed that NASH patients who underwent both lifestyle changes and TZD therapy experienced a significantly greater reduction in fasting insulin level than that in the control patients, whereas patients treated with TZDs alone did not experience a significantly greater reduction in fasting insulin level than that in patients who received a placebo. These results indicate that additional markers of IR should be analyzed in RCTs of TZD treatments for NASH, and warrant future investigations of the effects of diet control, exercise, and TZD combination therapy on IR in nondiabetic NASH patients to determine whether such treatment regimens can reduce the risk of T2DM. Our findings also suggest that the inclusion of additional glucose-lowering medications in NASH treatment regimens may be beneficial for reducing the risk and severity of IR.The development of IR contributes to the progression of fatty liver degeneration from simple steatosis to NASH because it stimulates de novo lipogenesis in hepatocytes, and is associated with the development of fibrosis.,39 which may be the result of partial activation of PPARα by pioglitazone. However, we found that TZD therapy had no significant impact on the serum levels of total cholesterol and triglyceride. Previous studies have shown that TZD can increase the serum level of adiponectin, which is known to be associated with an increased risk of MetS and CVD. Our results suggest the need for additional assessments of risk factors for T2DM, CVD, and MetS in clinical studies of TZD treatment for NAFLD or NASH.To assess the safety of TZD therapy, we also analyzed the incidence of adverse effects of TZD treatment that are known to be risk factors for T2DM, CVD, and MetS. Although patients treated with TZDs experienced significantly greater weight gain than that which occurred in the control patients, they did not experience a significantly greater increase in BMI or percentage of body fat. Therefore, the underlying mechanism of the weight gain observed was unlikely to involve an increase in adipogenesis. Although both rosiglitazone and pioglitazone are peroxisome-proliferator activated receptor γ (PPARγ) agonists, pioglitazone has been shown to be more effective than rosiglitazone for managing low-density lipoprotein cholesterol and triglyceride levels,In conclusion, our meta-analysis of RCTs of TZD therapy for NASH revealed no significant improvement in liver fibrosis or IR. However, our analysis of fasting insulin levels indicated that additional clinical variables should be assessed to obtain a more comprehensive evaluation of the effects of TZD treatment on insulin sensitivity in NASH patients, and suggested that including diet control, exercise, and additional insulin-sensitizing drugs in TZD treatment regimens may be beneficial for reducing IR in NASH patients. Our analyses of adiposity and dyslipidemia-related adverse effects indicated that additional clinical variables and serum biochemical markers should be assessed in TZD-treated NASH patients to identify the mechanism through which TZDs contribute to weight gain, and to determine whether TZD-induced weight gain is clinically relevant to the risk of T2DM, CVD, and MetS in NASH patients. The relatively small numbers of studies included in our meta-analysis and subgroup analyses reduce the statistical power of our investigation, and thereby serve to limit the interpretation of our findings.


Schizophrenia is a severe disorder affecting approximately 1% of the population. The disorder is associated with symptoms such as false perceptions and beliefs and disturbances in affect and language production. In 2004 the total direct healthcare and non-healthcare cost in Canada was estimated at $2 billion, with an additional productivity loss estimated at $5 billion.I will present a program of research into disease-specific and genetic risk factors associated with structural and functional brain abnormalities, including morphology (amount of grey matter), structural connectivity (amount of white matter integrity), and brain functioning (amount of brain activity) in individuals with schizophrenia, their family members, and community controls using magnetic resonance imaging. As healthy relatives share genes with their affected family member, but do not share the disease process, abnormalities present in relatives are likely associated with the genes for schizophrenia.Evidence was found for disease-specific, genetic risk and compensatory brain mechanisms associated with schizophrenia that were complementary between the results from brain morphology, structural connectivity, and brain functioning.Isolating the biological and genetic basis of these deficits could ultimately aid in developing novel psychosocial and pharmacological treatments to facilitate improved day-to-day functioning in schizophrenia.


Work can be an important etiologic factor in the genesis of some mental disordersincluding cognitive disability. Occupational neuropsychology constitutes anintriguing new but neglected area of research and clinical practice which dealswith the neurocognitive consequences of the work environment and work habits.Neuropsychological knowledge is fundamental to understand cognitive requirementsof work competence. Work can impact sleep patterns and mental energy, which inturn can cause neuropsychological symptoms. This report presents relevantevidence to illustrate the relationship between work and cognitivedysfunction. Occupationalneuropsychology encompasses and supports several medical specialties, includingoccupational psychiatry whose recent revival is due to the increasing number ofmental disorders in work activities and new laws protecting employeehealth.5 coupled with the granting of social security benefits forthose insured under Social Security ("psychoneuroses" ranks first among the causesof temporary disability and second and third among the causes of permanentdisability6) show the importance of occupational psychiatry and occupationalneuropsychology.4 The weight of statistics, plus theefforts of researchers, has led to legal recognition of the relationship betweenmental health and work, by Decree No. 3.048/99, from the Brazilian Ministry ofSocial Security, which deals with Work-Related Mental Disorders.The high incidence of mental disorders among workers - around 30% for minor mentaldisorders and 5%-10% for severe mental disordersIn this brief review, we present relevant evidence that illustrates and highlightsthe relationship between work and mental (including cognitive) function anddysfunction, contributing to structure knowledge in this field. Occupationalneuropsychology is presented according to its most characteristic and structuralaspects. In the present aggregated review of the literature, a search of thedatabases SciELO and MEDLINE was conducted using the key words "occupational health""and" "cognition". The most representative articles on the subject were selected,dedicating special attention to the contributions of internationally renownedinvestigators. Reference books that were pertinent under the framework of thisreview article were also consulted.trapalium ("work") means athree-piece instrument which was used both as an agricultural tool and an instrumentof torture. The theoretical understanding of the underlying health of workers isbased on a body of knowledge from different disciplines such as Social Medicine,Public Health, Internal Medicine, Labor Medicine, Sociology, Social Epidemiology andEngineering among many others. This understanding, allied with the knowledge of theworker at their workstation and experiences of burden, represents a new approach tounderstanding the relationship between health and work and proposes a new practiceof healthcare professionals and intervention in the workplace.7 Occupational diseases are easilyrecognized as an effect of en vironmental hazards to which workers are exposed,whereas the relationship between mental disorders and work are less recognized,i.e., the so-called psychosocial risks that include phenomena of aneurophysiological, cognitive, psychological, social and organizationalnature.8The knowledge that work can cause illness is ancient. The very origin of the meaningof "work" alludes to its dual status as an activity that involves suffering andachievement, since the Latin word 9The multiple and complex aspects involved in the workplace, work environment,economic issues, work relationships and workers health, including mental health,define the need for government involvement in the provision of laws, economicincentives - policies, in short - to attenuate the effects of work distress onworkers' mental health, as reported by some researchers.11 shift work12 and particularly the presence of psychiatricsymptoms.13 The success oflabor is typically conceptualized in two main dimensions: an extrinsic dimension(objective) and an intrinsic dimension (subjective).14 The extrinsic dimension refers to measurablevariables, such as salary, promotions, career and quality of work scrutinized byothers. The intrinsic dimension refers to the self-assessment of levels ofsatisfaction related to job performance.15 This evaluation process is intrinsically related to theconcept of work ability.16According to some authors17 the"ability to work" is defined as the self-assessment the worker makes regarding theirwell-being now and in the near future and the ability to ensure their work in termsof its requirements, health and available psychological resources.There are several factors affecting the ability to work. Among these are theinfluence of age,18 Theconcept includes a set of higher-order cognitive functions, which are instrumentalin self-regulation of human behavior,19 such as abstract reasoning and problem solving;20 planning, organizing andself-monitoring of actions that target a specific goal;21 and inhibition of irrelevant behaviors as well asmental flexibility.19 In thissense, a lack of integrity or impairment of executive functions may impair effectivework performance, including the ability to work.18Over recent years in the neuropsychological field, there has been growing interest inthe concept and assessment of executive cognitive functions and how these functionsrelate to health and adaptive behaviors, indispensable for personal, social andprofessional well-being.15 may be mediated ormoderated by certain personality traits. According to other authors,22 high levels of neuroticism have anegative influence on the levels of decision-making and consequent injury at work,while high levels of extroversion and conscientiousness positively influence bothexecutive functioning and the ability to work. The characterization of thesevariables, and understanding how they interrelate, is crucial for the implementationof techniques and preventive strategies to promote health among workers,contributing to an improvement in their ability to work and their executivefunctioning, favoring the development of a better quality of life.The relationship between work ability and executive cognitive functions, according tosome authors,23 have reportedelements that act as triggers of the process of cognitive malfunctioning at work,namely: lack of time control at work ; requirement for high levels of attention and concentration to perform tasks;occupational exposure . However, theestablishment of a causal link with work is complex, since the morbidity process hasan element of specificity and involves multiple aspects of the subject.Some authors24 Empirical data from a study25 correlating accidents among interns and sleepdeprivation on duties and night-shift work determined that each extended work shiftscheduled during a month increased the monthly risk of a motor vehicle crash by 9.1percent  and increased themonthly risk of a crash during the commute from work by 16.2 percent . On months in which interns worked five ormore extended shifts, the risk of falling asleep at the wheel while driving or whilestationary in traffic was significantly increased .Reduced sleep is a frequent effect of suboptimal work schedules or shift work. On theother hand, sleep deprivation results in significant impairments in cognitive andmotor performance which increase for instance the risk of motor vehicle crashes andwork-related injuries and fatal accidents.25Sleep and cognition are temporally regulated by a homeostatic process generatingpressure for sleep as a function of sleep/wake history, and a circadian processgenerating pressure for wakefulness as a function of time of day. Under normalnocturnal sleep conditions, these two processes are aligned in such a manner as toprovide optimal daytime performance and consolidated nighttime sleep. However, underconditions of sleep deprivation, shift work or trans-meridian travel, the twoprocesses become misaligned, resulting in fatigue and cognitive deficits.26 investigated simpleand high-order cognitive performance change after one night of sleep deprivation(SD) and recovery after 7 h of normal recovery sleep opportunity over three recoverydays. According to these authors, performance on simple tasks such as addition orshort-term memory, was not reduced after SD and was poorest on the baseline day,improving gradually thereafter. High-order cognitive performances were at theirlowest on the post-vigil day and needed 2 recovery sleep opportunities to return tobaseline levels.Some authors27 Along the same line of investigation, Rollinson etal. studied interns working nights in an emergency department and showed asignificant reduction in visual memory capacity during the night shift.28Other authors report that short-term memory appears to decline after day andovernight shifts, based on data collected from a study involving attending emergencyphysicians before and after day and overnight shifts.30 Fatigue resultingfrom several days of a long work schedule affects behavioral or psychological test performances.29For over a century, it has been recognized that long working hours can lead to agreater perception of fatigue by workers and to a reduction in worker efficiency.The role of fatigue in worker health and safety, measured in terms of accident andabsenteeism rates, as a result of longer workdays has also been examined, and someauthors have explored the effects of acute or short-term fatigue  on job performance.30 Mental fatigueis reflected by a failure to complete mental tasks that require self-motivation andinternal cues, in the absence of demonstrable cognitive failure or motor weakness.Lieberman31 suggests useof cognitive tests that assess vigilance, ability to sustain attention, and choicereaction time for the assessment of mental energy and fatigue. Someauthors32 have shown thatcompared to a non-fatigued group, fatigued participants displayed more perseverationon the Wisconsin Card Sorting Test and showed prolonged planningtime on the Tower of London task. Fatigue did not however, affectperformance on a simple memory task. These authors concluded by highlightingcompromised executive control under fatigue, which may explain the typical errorsand sub-optimal performance often found in fatigued individuals.32Prolonged cognitive load associated with some professions can cause fatigue, which,in turn, can dramatically impact cognitive functions by decreasing mentalenergy.33 The phenomenon of burnout has a chronic nature andexhibits remarkable stability over time regardless of sample makeup, culturalcontext, and length of time of follow-up survey.34 Oosterholt et al.35 suggested that burnout leads to permanent cognitivedeficits, that subjective burnout complaints reduce faster than deficits incognitive test performance, or that cognitive deficits are a cause rather than aconsequence of burnout.Burnout is an important concept relevant to the present issue. This refers to a worksyndrome first described in physicians characterized as a unique affectivemultidimensional response to stress, the core components of which are emotionalexhaustion, physical fatigue, and cognitive weariness.36(CBI) and the Maslach Burnout Inventory.37 Despite the importance of the burnout phenomenon, fewsystematic investigation assessing work as a cause of burnout are available,although more attention has been dedicated to burnout as a consequence of disease.Systematic approaches to burnout as a consequence of work that go beyond the care ofpatients can shed light on the condition and help its prevention.At least two available instruments have been designed for assessing work burnout: theCopenhagen Burnout Inventory36 haveinvestigated the relationship among commercial airline pilots' amount of sleep,subjective fatigue, and sustained attention before and after international flightsusing a 5 min PalmPilot-based psychomotor vigilance task and self-rating of level offatigue using the Samn-Perelli Fatigue Checklist. A significant main effect of stageof flight was found for self-rated fatigue and mean response speed.International commercial airline pilots may experience heightened fatigue due toirregular sleep schedules, long duty days, night flying, and multiple time zonechanges. Some authors29 examined whetherincreased overtime work among automotive workers predicted impairment in cognitiveperformance in the domains of attention and executive function. These researchersfound that overtime work affects cognitive function as measured byneuropsychological testing, with impairments observed in tasks requiring attentionand executive function skills.Proctor et al.Conclusions. Occupational neuropsychology constitutes an intriguing newbut neglected area of research and clinical practice which deals with theneurocognitive consequences of the work environment and work habits.Neuropsychological knowledge is fundamental to understand cognitive requirements ofwork competence. Work can impact sleep patterns and mental energy, which in turn cancause neuropsychological symptoms. Recognition that increased overtime work affectscognitive function in certain functional areas and, by extension, may affect workerperformance, has important implications for the health and safety of workers as wellas for the economic management of the workplace. In addition, better understandingof neuropsychological implications of these work dysfunctions, and theirrelationships with work ability and workers' mental health, will allow assessmentand preventive programs to be devised as well as more specific and efficienttherapeutic tools for managing the mental distress triggered, exacerbated or causedby work.


Significant resources are being invested into eHealth technology to improve health care. Few resources have focused on evaluating the impact of use on patient outcomes A standardized set of metrics used across health systems and research will enable aggregation of data to inform improved implementation, clinical practice, and ultimately health outcomes associated with use of patient-facing eHealth technologies.The objective of this project was to conduct a systematic review to (1) identify existing instruments for eHealth research and implementation evaluation from the patient’s point of view, (2) characterize measurement components, and (3) assess psychometrics.Concepts from existing models and published studies of technology use and adoption were identified and used to inform a search strategy. Search terms were broadly categorized as platforms , measurement , function/information use , health care occupations , and eHealth/telemedicine . A computerized database search was conducted through June 2014. Included articles (1) described development of an instrument, or (2) used an instrument that could be traced back to its original publication, or (3) modified an instrument, and (4) with full text in English language, and (5) focused on the patient perspective on technology, including patient preferences and satisfaction, engagement with technology, usability, competency and fluency with technology, computer literacy, and trust in and acceptance of technology. The review was limited to instruments that reported at least one psychometric property. Excluded were investigator-developed measures, disease-specific assessments delivered via technology or telephone , and measures focused primarily on clinician use .The search strategy yielded 47,320 articles. Following elimination of duplicates and non-English language publications  and books (n=27), another 31,647 articles were excluded through review of titles. Following a review of the abstracts of the remaining 1096 articles, 68 were retained for full-text review. Of these, 16 described an instrument and six used an instrument; one instrument was drawn from the GEM database, resulting in 23 articles for inclusion. None included a complete psychometric evaluation. The most frequently assessed property was internal consistency . Testing for aspects of validity ranged from 48% (11/23) to 78% (18/23). Approximately half  reported how to score the instrument. Only six (26%) assessed the readability of the instrument for end users, although all the measures rely on self-report.Although most measures identified in this review were published after the year 2000, rapidly changing technology makes instrument development challenging. Platform-agnostic measures need to be developed that focus on concepts important for use of any type of eHealth innovation. At present, there are important gaps in the availability of psychometrically sound measures to evaluate eHealth technologies. Patient-facing eHealth is a multidisciplinary field focused on the delivery or enhancement of health information and health services through information and communication technologies . eHealthThis paper focuses on patient use of eHealth, which includes personal health records and patient portals accessed via computers or mobile devices, and other telehealth devices designed for use primarily by patients and caregivers, even though some patient-facing technologies  are also used by clinicians . SeveralAlthough studies using eHealth technologies may include measures that attempt to quantify the characteristics or effect of eHealth interventions, to date, there are no uniform, widely agreed-on measures. More rigorous measurement is needed to determine the full benefit(s) of an eHealth-delivered intervention to both patients and the health care system . ScientiSimilarly, the Patient-Reported Outcomes Measurement System (PROMIS) was developed by the National Institutes of Health in an effort to develop, validate, and standardize items that may be used to measure patient-reported outcomes common across medical conditions . PROMIS Both PROMIS and GEM promote use of standardized measures and data analysis across multiple studies and conditions. Although these measures can be an important component of studies focused on use of eHealth technologies, the items and instruments contained in these compendiums do not specifically focus on issues surrounding use of eHealth technology with and by patients. For example, although GEM or PROMIS may include instruments or items that measure patient satisfaction with communication with a physician, they do not include items specific to physician-patient communication when using telehealth or secure messaging, nor do they specifically address technology usability issues. Recent efforts to summarize measures related specifically to technology use include a compendium of health information technology-related survey tools developed by the Agency for Healthcare Research and Quality (AHRQ). The AHRQ compendium includes a wide variety of measures, but the website does not provide detailed information on psychometric properties. Thus, although work is in progress to develop and identify measures that may address eHealth evaluation needs, more work is needed.Implementation research focuses on structural and organizational characteristics of the environment where an innovation is being or will be used. Within this environment are individuals  with various characteristics that may hinder or facilitate adoption of the innovation within the particular environment. In this review, we focus on the innovation  and how features of this innovation will impact implementation. Consistent and well-validated measures will contribute to determining the true benefit of eHealth interventions across studies and over time. Consistently used measures will enable the health care system to collect uniform data on (1) the likelihood of adoption of an eHealth technology; (2) patient, organizational, or health care system barriers and facilitators to adoption; (3) user attitudes toward and/or satisfaction with a technology; (4) the degree to which meaningful user characteristics  mediate the relationship between technology use and improved health outcomes , and (5) the return on investment of eHealth technology to assess value.The objective of this project was to conduct a systematic review to (1) identify existing instruments for eHealth research and implementation evaluation, (2) characterize measurement components, and (3) assess psychometrics. Additionally, this study seeks to highlight current limitations of this body of research.Through a series of investigator meetings, we identified key concepts from existing models, published studies of technology use and adoption, and sociotechnical perspectives on health information technology implementation and evaluation -23. UsinWe conducted a systematic search of the literature using the selected search terms. Based on guidance from our health sciences librarian, databases used included MEDLINE, Scopus, PsychInfo, CINAHL, Health and Psychosocial Instruments (HAPI) for articles published through June 2014. Each database was searched using terms included in Our search strategy also included review of currently funded research projects within the health services research arm of the Veterans Health Administration (VA) system focused on eHealth (n=56), and existing instrument/measure compendiums . All search results were transferred to a reference management software database (EndNote); duplicates, articles where the text was not in English, and books were eliminated.Our article inclusion criteria were broad to identify the full extent of instruments designed for eHealth research and implementation evaluation. We focused explicitly on instruments that assessed an eHealth-specific construct from the patient’s point of view. Articles were selected if they (1) described development of an instrument, or (2) used an instrument in an evaluation of an eHealth technology that could be traced back to an original publication describing its development, or (3) modified an instrument, and (4) with full text in English language. The review was limited to instruments that reported at least one psychometric property. Excluded were investigator-developed measures or sets of questions without psychometric evaluation, disease-specific assessments delivered via technology or telephone , and measures focused primarily on clinician use . We limited our review to articles that reported at least one established psychometric property  independently reviewed 100 article titles followed by an in-depth discussion to establish agreement on inclusion of articles. Next, the review was repeated two times using an additional 100 article titles each time, until agreement was reached on articles to include for further review. All article titles were then reviewed to exclude ineligible articles. The abstracts of the remaining articles were reviewed by a pair of investigators  following an independent review of 20 articles to establish interrater consistency. The remaining abstracts were then independently reviewed and discrepancies between reviewers were resolved by discussion and consensus. Articles that did not meet criteria were excluded , and remaining articles were retained for full-text review. Articles were then classified as describing the development and testing of an instrument or as using an instrument. For articles using an instrument, reference lists were reviewed to identify citations for the original instrument development.A data extraction form with definitions for each item was developed by the study team  24]. To. To24]. The search strategy yielded 47,320 articles . Following elimination of duplicates and full text not in English language publications  and books (n=27), most articles were excluded through review of titles . Following a review of the abstracts of the remaining 1096 articles, 68 were retained for full-text review. Of these, 16 described an instrument and six used an instrument; one instrument was drawn from the GEM database, resulting in 23 articles for inclusion in the review . Of thesWe identified common conceptual threads across the 23 instruments. We reviewed the literature to identify salient concepts and constructs from existing technology use models -22,25. MThe 23 articles included in this review were mapped to the 12 identified concepts based on whether the instrument encompassed the concept. The most common constructs addressed by this set of measures were effectiveness, efficiency, hardware and software, perceived ease of use, satisfaction, and usability -23 Tabl and 3. INo instrument included a complete psychometric evaluation . The mosEarly instruments (prior to the year 2000) ,37-42 foOf the 23 articles reviewed, no instrument included a complete psychometric evaluation. The most frequently assessed property was internal consistency. Testing for aspects of validity ranged from 48% (11/23) to 78% (18/23). Approximately half  reported how to score the instrument. Only six (26%) assessed the readability of the instrument for end users, although all the measures rely on self-report.Common theoretical concepts addressed in the instruments were effectiveness, efficiency, hardware/software, perceived ease of use, and satisfaction. A notable exception is that only three instruments focused on communication. Conversely, we identified some concepts addressed in the instruments that have not been included in current theoretical models, including stress, esthetics, eHealth literacy, comfort, and decision-making autonomy. Current instruments require fuller evaluation of psychometric properties.Measures that can be applied consistently across technologies and platforms are needed so that distinct platforms that serve the same purpose can be compared. For example, evaluation of an intervention to treat depression could utilize a standard measure of usability, regardless of whether it was a mobile app or Web-based , regardless of the platform used to deliver the intervention . Using these types of measures, investigators and others implementing eHealth technologies can compare technologies and use this information when selecting a technology.Our review expands on the AHRQ compendium, which lists available measures but provides less detail about their other attributes. We also investigated whether the psychometric properties of the measures had been established, which is a critical information need when selecting a measure for research or evaluation. However, although most would agree that instruments with psychometric properties are very helpful, there may also be a role for using self-developed questions that may more clearly and directly get at the target construct or a specific patient behavior. The AHRQ compendium is populated with many such instruments and future researchers should carefully consider the trade-offs of using investigator-developed question sets that may specifically address their question of interest versus a more validated instrument that may also need to be modified to fit an eHealth evaluation. Furthermore, investigators may want to consider instruments listed in the AHRQ compendium for further development and psychometric evaluation.Implementation of eHealth technologies can involve substantial investment in terms of costs and effort. Research on eHealth has also increased dramatically over the past several years, yet studies rarely utilize common methods and/or instruments. The results of this project provide critical insights regarding existing eHealth instruments and identify gaps for which new instruments are needed. Use of common and psychometrically sound instruments can inform future studies so that the results from multiple studies can be compared and synthesized.Although most the instruments identified in this review were published after the year 2000, rapidly changing technology makes instrument development challenging. Platform-agnostic measures need to be developed that focus on concepts important for use of any type of eHealth innovation. Instrument development as a research enterprise is typically undervalued, relative to more direct practice-relevant research. Instrument development can also be a complex and lengthy process. Thus, funding agencies should consider addressing this gap, given the persistent and expected growth in the deployment of technology to improve care processes and patient outcomes.We did not conduct a comprehensive search for all published uses of the identified instruments as it was beyond the scope of this study. The grey literature  were not included in our review. Furthermore, the review potentially missed some published as well as unpublished measures based on keyword choice and/or elimination of articles through review of title or abstract. Finally, our choice of theoretical models used to analyze the selected articles may impose limitations on our findings.Based on our review, we highlight some of the more useful measures that we believe could be useful in most technology studies. These include the eHealth literacy scale (eHEALS) , the ComDevelopment of a standard measure of the intuitiveness of the user interface would allow platform-agnostic comparisons between user interfaces . Finally, given the explosion of new technologies in the market focused on health behaviors, a standard measure of the relative advantage of a new technology feature when compared to prior methods and/or a standard measure of the degree to which new technology facilitates a target behavior  could provide important insights to inform technology adoption strategies.Advances in eHealth offer tremendous potential to improve access to care, efficiency of care delivery processes, and overall quality. Significant resources are being invested in eHealth technologies, driven in part by meaningful use requirements. Consumer behavioral health interventions are increasingly being made available via multiple platforms . Identification of useful and valid measures to evaluate these interventions has important potential to contribute to improved implementation, clinical practice, and ultimately population health since insights gleaned from standardized measurement can directly inform system improvements and optimal implementation strategies. In addition, having better measures to evaluate implementation of eHealth technologies will help improve consumers’ experiences with technologies and assess whether use of these technologies is making a measurable difference in quality of care or the patient experience. More longitudinal research will be needed to develop measures that more comprehensively address the wider frame of concepts important for the meaningful implementation of eHealth technologies.


Solid fuel use is the major source of household air pollution (HAP) and accounts for a substantial burden of morbidity and mortality in low and middle income countries. To evaluate and compare childhood mortality attributable to HAP in four South Asian countries.A series of Demographic and Health Survey (DHS) datasets for Bangladesh, India, Nepal and Pakistan were used for analysis. Estimates of relative risk and exposure prevalence relating to use of cooking fuel and under-five mortality were used to calculate population attributable fractions (PAFs) for each country. Potential impact fractions (PIFs) were also calculated assessing theoretical scenarios based on published interventions aiming to reduce exposure prevalence.P = 0.007). Combined PAF estimates for South Asia found that 66% (95% CI: 43.1–81.5%) of the 13,290 estimated cases of under-five mortality was attributable to HAP. Joint PIF estimates (assuming achievable reductions in HAP reported in intervention studies conducted in South Asia) indicates 47% of neonatal and 43% of under-five mortality cases associated with HAP could be avoidable in the four South Asian countries studied.There are an increased risk of under-five mortality in those exposed to cooking fuel compared to those not exposed in the four South Asian countries  could reduce substantially under-five mortality in South Asian countries. Household air pollution (HAP) from unprocessed fuels traditionally used for cooking is a key public health hazard and one of the leading environmental causes of disability worldwide, predominantly due to respiratory illness and deaths among children under-five years of age in low and lower-middle-income countries –3. In loSouth Asia is home to a large, fast-growing population with a substantial proportion of the population living in poverty, and a region of the world with the highest population density . There iIt is well documented from studies in South Asian countries –26 that http://www.dhsprogram.com). All existing datasets  with available information on HAP were used in the analysis. The DHS program is responsible for collecting, summarizing and publishing nationally representative data on health and population in developing countries. This program is implemented by ICF international of Calverton, Maryland, USA and financial support from the United States Agency for International Development (USAID). Demographic and heath data of urban and rural areas were collected by interviewing ever-married women and men using a stratified sample of households based on a two-stage cluster design with an average response rate of more than 90% in South Asia. An index period of five years was used for each survey to minimize recall bias of child birth and death information which was self-reported by the mother. A total of 221,745 singleton live-born children from Bangladesh, India, Nepal and Pakistan were obtained in this study, of which 13,290 died within 5-years prior to the mother being interviewed.Nationally representative and publicly available Demographic and Health Survey (DHS) datasets for four South Asian countries such as Bangladesh, India, Nepal and Pakistan were focused in this study, collected with approval from the DHS program . The analyses were also carried out for neonatal mortality , as most of the deaths occurred in the first month of life of children in these study countries. Outcome variables were considered dichotomous for the analysis.The main exposure of interest was the type of cooking fuel used in the household. The respondents were asked, “What type of fuel does your household mainly use for cooking?” The reported fuels were categorised into “clean fuels” , natural gas and biogas) and “polluting fuels”  in the analysis. Previous studies reporting the adverse effects of exposure to kerosene fuel has raised questions about the magnitude of the effect of HAP on under-five mortality or respiratory illness when kerosene has been categorized as a clean fuel , 29, 30.For investigating the association between use of cooking fuel and under-five mortality, a number of potential confounding factors were defined for each study country comprising place of residence, wealth index of household, mother’s age, mother’s education, mother’s working status, breastfeeding status of mother, sex of child, location of kitchen, type of house and wall and floor material of household. These socio-economic, individual and behavioural factors have previously been identified as potential confounders for the association between HAP and under-five mortality in developing countries , 35–41. Incidence proportions of neonatal and under-five mortality were calculated by following the similar method provided in the guideline of the DHS program . PrevaleThe population attributable fraction (PAF) was used to measure the proportion of neonatal and under-five mortality in South Asia that could theoretically be prevented by eliminating HAP from the use of cooking fuels in households, assuming the other risk factors remain unchanged. The PAF was calculated by using the following formula , 48,\docp is the prevalence of exposure from use of cooking fuel and RR is the adjusted relative risk estimated from DHS datasets for Bangladesh, India, Nepal and Pakistan. A joint PAF across four South Asian countries was also calculated by using the following formula [Where  formula , 49,\docr denotes each individual risk factor. PAF assumes that risk factors are independent and uncorrelated and has been reduced by the use of relative risks that has been adjusted for potential confounders.Where However, PAF provides estimates based on the unrealistic counterfactual scenario of the elimination of an exposure from a given population  . This espc is the proportion of the neonatal and under-five children in a given exposure category c, RRc is the adjusted relative risk for that category estimated from the DHS datasets and pc* is the estimated proportion in category c after the intervention. In the analysis for this present study, the estimated effect of interventions was based on previously published intervention studies in South Asia [Where uth Asia , 28. Theuth Asia . A seconMonte-Carlo simulation models were used to estimate the 95% confidence intervals (CI) for PAF and PIF estimates, to account for the uncertainty around the exposure prevalence and relative risk estimates using the Ersatz Software1.31 in MS Excel . A beta P = 0.007) and neonatal mortality  , natural gas and biogas) from polluting fuels could reduce more than 65% of cases of under-five mortality. However, in practice, not all poor rural and urban communities could feasibly eliminate their use of solid fuels , 55–57. Another sustainable alternative of this problem is to use improved cooking stoves with chimney installation  proposed in previous intervention reports and studies , 58–60. Women’s empowerment is another important factor for decreasing under-five mortality, as women are responsible for cooking in most of the South Asian countries , 59, 62.This present study has a number of limitations and strengths. Firstly, categorising study participants into exposed and non-exposed to cooking fuel may lead to misclassification bias, for example, some households use a combination of clean and polluting fuels even where clean fuels are available to cut down their fuel expenditure using solid fuels which are cheap and affordable option in South Asian context , 64–66. Despite these methodological limitations, this study incorporated large, nationally representative datasets from Bangladesh, India, Nepal and Pakistan with a very high response rate (approximately 90%) from participants. A number of international studies from many countries including GBD study , 67–69 uThe burden of under-five mortality associated with HAP in South Asia remains a significant and preventable public health problem. The wider implementation of programs targeting the modifiable exposure of cooking fuel, through improvements in house design, behavioural intervention, health system policies and continued economic development particularly rural and low income urban communities has the potential to substantially reduce child mortality burden in South Asia.


Neurocognitive deficits are associated with many serious mental illnesses (SMI), including schizophrenia, bipolar disorder, and major depressive disorder, and have been found to negatively impact social and occupational outcomes, clinical prognosis, and overall quality of life. These deficits have also been observed in people in earlier phases of schizophrenia, specifically in young people at clinical high risk (CHR) of psychosis. In these youth, neurocognitive deficits present at a level intermediate to healthy controls and those with early psychosis, indicating that mild impairments in neurocognitive functioning may be early markers of illness development. It is possible that neurocognitive deficits may be present in young people at risk of a range of SMI beyond the psychosis-spectrum, including affective and anxiety disorders. The aim of this study was to compare neurocognitive functioning in a sample of youth at risk of SMI across the different clinical stages described by McGorry and colleagues and compare them to healthy controls (HCs). It was hypothesized that participants in the later stages of risk, characterized by the presence of subthreshold psychiatric symptoms or attenuated syndromes, would exhibit impairments in neurocognitive performance compared to HCs and asymptomatic youth at familial high risk.This was an observational, cross-sectional study of 243 male and female individuals between the ages of 12–26. The sample consists of participants in the Canadian Psychiatric Risk and Outcome Study (PROCAN) and included: asymptomatic participants at familial high risk for SMI ; youth with early mood or anxiety symptoms ; youth with attenuated psychotic or affective syndromes and distress ; and HCs (n=42). The neurocognitive battery included the WRAT-4 reading task, WASI Vocabulary and WASI Matrix Reasoning tasks, and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB). All neurocognitive tasks were administered at baseline. Group differences in neurocognitive performance were analyzed using MANCOVA/ANCOVA analyses. Covariates included age and sex.Subjects in Stage 0 and Stage 1a did not significantly differ from any group. Subjects in Stage 1b (attenuated syndromes) had significantly lower neurocognitive scores in the domains of speed of processing, working memory, attention/vigilance and reasoning and problem solving, and on composite scores of neurocognitive performance and full-scale IQ compared to HCs. A secondary analysis demonstrated that subjects in Stage 1b who met CHR status according to Criteria of Psychosis-risk Syndromes (n=83) had lower scores in the domains of working memory, verbal learning, and reasoning and problem solving and on the overall composite score than the other participants in Stage 1b who did not meet CHR criteria.This study provides evidence for a growing literature which suggests that neurocognitive deficits may be markers of susceptibility for SMI development. It also increases what is known about neurocognitive performance associated with different stages of risk for SMI. Identification of such impairments could aid with detection of early mental health problems prior to illness onset.


Background: Clozapine is the antipsychotic of choice for treatment-resistant schizophrenia and has minimal risk for extrapyramidal symptoms. Therapeutic benefits, however, are accompanied by a myriad of cardiometabolic side-effects. The specific reasons for clozapine's high propensity to cause adverse cardiometabolic events remain unknown, but it is believed that autonomic dysfunction may play a role in many of these.Objective: This systematic review summarizes the literature on autonomic dysfunction and related cardiovascular side effects associated with clozapine treatment.Method: A search of the EMBASE, MEDLINE, and EBM Cochrane databases was conducted using the search terms antipsychotic agents, antipsychotic drug*, antipsychotic*, schizophrenia, schizophren*, psychos*, psychotic*, mental ill*, mental disorder*, neuroleptic*, cardiovascular*, cardiovascular diseases, clozapine*, clozaril*, autonomic*, sympathetic*, catecholamine*, norepinephrine, noradrenaline, epinephrine, adrenaline.Results: The search yielded 37 studies that were reviewed, of which only 16 studies have used interventions to manage cardiovascular side effects. Side effects reported in the studies include myocarditis, orthostatic hypotension and tachycardia. These were attributed to sympathetic hyperactivity, decreased vagal contribution, blockade of cholinergic and adrenergic receptors, reduced heart rate variability and elevated catecholamines with clozapine use. Autonomic neuropathy was identified by monitoring blood pressure and heart rate changes in response to stimuli and by spectral analysis of heart rate variability. Metoprolol, lorazepam, atenolol, propranolol, amlodipine, vasopressin and norepinephrine infusion were used to treat tachycardia and fluctuations in blood pressure, yet results were limited to case reports.Conclusion: The results indicate there is a lack of clinical studies investigating autonomic dysfunction and a limited use of interventions to manage cardiovascular side effects associated with clozapine. As there is often no alternative treatment for refractory schizophrenia, the current review highlights the need for better designed studies, use of autonomic tests for prevention of cardiovascular disease and development of novel interventions for clozapine-induced side effects. Case reports, animal studies and clinical studies published in English were included. Additional records were identified from reference lists and independent searches. Human studies were excluded if subjects were under 18 years of age. The primary author conducted all screening and extraction of relevant articles from the search. Due to the mixed nature and amount of articles identified, the authors conducted a systematic review instead of a meta-analysis for better representation of the available literature.n = 180 from Embase, n = 13 from MEDLINE and n = 15 from EBM Cochrane). Additional records were identified from other sources (gray literature and reference lists) (n = 33) and 11 duplicates were found. Twenty-one studies were excluded due to publication in a language other than English and 147 studies were excluded for irrelevance based on screening of abstracts and titles. The remaining 66 full-text articles were assessed and 29 full-text articles were excluded with reasons . The final 37 articles comprised of case reports and studies evaluating the effects of CLZ on autonomic function. See Table The literature search identified 208 studies as outlined in Figure Various tests have been developed to assess autonomic function and screen for autonomic neuropathies  is a noninvasive, beat-to-beat analysis of fluctuations in HR  to those treated with haloperidol  or olanzapine  and found CLZ induced tachycardia while significantly lowering the total variability of HR. They also found an increased LF/HF ratio in CLZ-treated patients, indicative of increased sympathetic activity associated with CLZ  to those with low affinity (LMA), with CLZ belonging to the HMA group  and OLA (n = 18). The authors had previously found that PRV yielded results comparable to HRV, with parameters calculated from finger pulses instead of electrocardiograms for the PRV  was further investigated in a study comparing CLZ  or skin conductance is another widely used measure for sympathetic activity. Arousal of the SNS is directly correlated to sweat gland activity, as measured by electrical conductivity in the skin. There is evidence of both extremes of the EDA spectrum in patients with schizophrenia, known as non-responders (hypoactivity) and responders (hyperactivity), respectively Ohman, . EDA is Due to accessibility issues and invasiveness of measuring direct neuronal activity in humans, sampling of the major catecholamines norepinephrine (NE), epinephrine (E), and dopamine in plasma or urine has become increasingly popular for assessing sympathetic activity in health and disease , dihydroxyphenylacetic acid (DOPAC), 3,4-dihydroxyphenylglycol (DHPG) were analyzed to reflect adrenergic action. A significant surge in plasma NE was evident in the CLZ group, which was statistically correlated with an increase in dopa , a product of dopamine metabolism, in the first 5 days of treatment  or bipolar disorder (n = 20) were given placebo (n = 24) or melatonin  for 8 weeks and anthropometric variables were measured prior to and after the trial. All subjects were previously on SGA medication  for ≤3 months before recruitment. Although melatonin lowered DBP in all patients, the decrease was not statistically different from that of the placebo group in patients with schizophrenia. Metabolic measures also did not improve with melatonin use in patients with schizophrenia, while patients with bipolar disorder showed favorable outcome. The lack of therapeutic benefits for the schizophrenia patients is perhaps due to pooling data from 4 SGAs with varying risk for adverse cardiometabolic side effects instead of assessing the neuroleptics individually  of the included studies have used interventions that have successfully attenuated CLZ-induced cardiovascular complications. These interventions include metoprolol, lorazepam, atenolol, PRO, amlodipine, vasopressin and NE infusion   and myocardial damage (troponin I or T) markers in routine blood work for signs of myocarditis. As the onset of myocarditis is typically within 14 – 22 days of the start of CLZ treatment, it is critical to closely monitor patients for fever, troponin I or T and CRP levels for the first 28 days of treatment (Ronaldson et al., Reduced HRV, elevated catecholamines, tachycardia and hypotension are known effects of CLZ treatment. Yet there is a lack of controlled trials to confirm that these autonomic abnormalities are caused specifically by CLZ. Future studies should incorporate both mechanistic relationships as well as interventions to minimize CLZ's adverse effects on cardiovascular function, such as different dosing strategies (Procyshyn et al., JY performed the systematic search and wrote the manuscript, in collaboration with AB. All other authors assisted with the review and contributed to the final draft of the manuscript.in silico, Lundbeck, Otsuka, Roche, and Eli Lilly, and received honoraria from Rush University, University of Calgary, University of Hong Kong, Massachusetts General Hospital, British Columbia Health Authorities, the British Association for Psychopharmacology and the Canadian Psychiatric Association. RP has been a member of the following advisory boards in the past 3 years: Janssen, Lundbeck, and Otsuka. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.AB has received grants from Bristol-Myers Squibb. WH has received consulting fees or sat on paid advisory boards for


In contrast to many countries where rabies has been well controlled in humans and livestock, even in wildlife, rabies is still endemic in almost regions of China. In Northwest China, rabies transmitted by stray dogs and wild foxes has caused heavy economic losses to local herdsmen, as well as causing numbers of human cases. In this study, as part of an investigation of ways to prevent rabies epidemics in livestock, we report an analysis of domestic cattle and camel rabies cases in Ningxia Hui (NHAR) and Inner Mongolia Autonomous Region (IMAR) and the immune efficacy of canine inactivated rabies vaccines in these animals. We found that rabies viruses from these animals are closely related to dog-hosted China I and fox-associated China III lineages, respectively, indicating that the infections originated from two different sources (dogs and wild foxes). As well as the previously reported Arctic and Arctic-related China IV lineage in IMAR, at least three separate phylogenetic groups of rabies virus consistently exist and spread throughout Northwest China. Since there is no licensed oral vaccine for wild foxes and no inactivated vaccine for large livestock, local canine inactivated vaccine products were used for emergency immunization of beef and milk cattle and bactrian (two-humped) camels in local farms. Compared with a single injection with one (low-efficacy) or three doses (high-cost), a single injection of a double dose of canine vaccine provided low-price and convenience for local veterinarians while inducing levels of virus neutralizing antibodies indicative of protection against rabies for at least 1 year in the cattle and camels. However, licensed vaccines for wildlife and large domestic animals are still needed in China. Rabies virus continues to cross carnivorous species and to infect humans and livestock in China. Rabies vaccination of the principal reservoir animals is even now being neglected in most regions of China, resulting in continuous expansion of rabies epidemics. Since there is no oral vaccine for stray dogs and wild animals and no inactivated vaccine for large domestic animals, rabies is not currently controlled in this country. We report rabies outbreaks caused by bites of dogs and wild foxes and the long-term effects on protection against rabies using canine inactivated vaccines in domestic camels and cattle. Our results indicate that at least three separate phylogenetic groups of rabies virus consistently exist and spread throughout Northwest China. Local canine vaccine products can be used to induce levels of virus neutralizing antibodies indicative of protection against rabies in cattle and camels; however, licensed oral and inactivated vaccines for reservoir carnivores and large domestic animals are urgently needed for elimination of rabies in China. Rabies has been a continuous and serious threat to Chinese public health with three large epidemic waves since 1949 . HoweverIn northwestern China, rabies transmitted by stray dogs and wild foxes has caused heavy economic losses to local herdsmen following infection of domestic animals such as cattle, camels, goats and horses ,5, yet phttp://ec.europa.eu/food/animals/pet-movement/approved-labs/index_en.htm). No human patient-derived clinical materials and non-human primates were used in the completion of these studies.All animal brain sampling was post-mortem. All animal experiments described in this paper have been conducted according to the Guidelines on the Humane Treatment of Laboratory Animals stipulated by the Ministry of Science and Technology of the People’s Republic of China and approved (license no. 2009–045) by the Animal Welfare Committee of the Military Veterinary Research Institute, Changchun, China. Rabies serological testing in our laboratory has been annually approved by ANSES-Nancy Laboratory (France) since 2013  and dairy cows (10 samples) were collected by our group from two farms in Urat Front Banner, Bayannur city, IMAR. Fifteen brain tissue samples of clinically suspect and dead camels were collected from a bactrian (two-humped) camel farm in Shahu Lake district, Yinchuan city, NHAR and sent to our laboratory for rabies diagnosis by the local Center for Animal Disease Control and Prevention. All brain samples were tested in our laboratory using the direct immunofluorescence assay (FDA), performed using LIGHT DIAGNOSTICS Rabies FITC-globulin conjugate  as described previously . The comA phylogenetic tree was constructed using the Maximum Likelihood method in MEGA 7.0.14 , in whicFor emergency prophylaxis to prevent future outbreaks of rabies in the local farms, 300 adult cattle (270 beef cattle and 30 dairy cows) and 330 adult bactrian camels were randomly divided into 9 groups  and 30 camels from the tail vein of cattle and the jugular vein of camels. Sera were separated by centrifugation following incubation at ambient temperature for 3h. Rabies virus neutralizing antibody (RVNA) was assayed using the standard FAVN method ,12 beforThe new N gene sequences in this study were submitted to GenBank, with accession numbers KM016901, KM016899, KU928249 and KU928250.According to the results of FDA and RT-PCR, all brain samples collected from 11 beef cattle, 15 camels and 10 dairy cows were diagnosed positive for rabies in our laboratory and the sequences of the viral N gene were absolutely identical to each other in individual farms.Rabies in wild foxes was sporadically recorded in the early 1980s in the Xinjiang Uyghur Autonomous Region (XUAR) and IMAR, China . In the In NHAR, no human case was reported before 2011, in which year there were 2 recorded rabies cases . FollowiPhylogenetic analysis of the isolated viruses is an alternative way to track rabies transmission. Although all the collected samples were positive for rabies, the sequences of the rabies virus isolates from individual farms were absolutely identical to each other. Only one sequence from each farm was used in phylogenetic analysis. As shown in p < 0.05) in RVNA titers between the one-dose groups and multi-dose groups by one-way ANOVA, and no significant difference (p > 0.05) between two-dose groups and three-dose groups. Levels of RVNA indicative of protection in all tested animals vaccinated with two or three doses lasted more than one year (p > 0.05), possibly due to genetic differences in the two animals. According to the local veterinary clinical records, no overt clinical reactions, such as allergic reactions, mortality, anorexia, pyrexia, rumination, changes in behaviour, weight gain, milk production, male and female fertility, occurred during the three-month period following immunization.The cut-off value of rabies RVNA titer, 0.50 IU/mL, is defined as the minimum antibody level affording complete protection . No deteone year ; howeverThe ‘One health’ concept has been proposed as an effective way to successfully eliminate human rabies cases worldwide by 2030 . In ChinMolecular epidemiological studies on rabies viruses isolated in China indicate that the viruses can be divided into 6 lineages (China I–VI) , in whicMost livestock cases occurring in China as spillover from rabid carnivores have been reported as accidents in which vaccination of livestock was not performed to prevent re-emergence of rabies ,17. HoweCurrently, six local brands and four imported brands of canine inactivated vaccines have been approved by the Ministry of Agriculture of China, with sufficient production levels for rabies vaccination of domestic dogs. However, oral vaccines for stray dogs and wildlife remain at the laboratory-research level and for certain technical and official reasons, are not expected to be approved in China for production for another 5–10 years. In addition, as noted above, most large livestock cases occurring in China have been treated as occasional accidents in situations where inactivated vaccine for large animals is rarely used. There is no demand, with the result that inactivated rabies vaccine for large animals has not so far been developed and produced in China. Therefore, to control rabies in domestic animals, only one type of vaccine, i.e., canine inactivated vaccine, can be used to immunize via the intramuscular injection route. To be accepted by local veterinarians and farmers, the vaccine must be low-cost and easy to use. In this study, a single vaccination of two doses of canine vaccine has been shown to induce levels of virus neutralizing antibodies indicative of protection against rabies in cattle and camels; however, licensed vaccines for large domestic animals are still needed for use in pasture farms in China.in vivo is complex, in which RVNA is only a partial contributor. It remains a challenge to determine how accurately the FAVN test, which utilizes in vitro neutralization for assaying RVNA, measures the protective level in vivo [in vitro method for absolute proof of in vivo protection.In endemic countries, the duration of immunity resulting from vaccination should be determined in the target animals and, according to the OIE recommendation , vaccine in vivo . Therefoin vivo and surveillance in vitro remain so far unknown, our data show that the current vaccine can confer protective immunity in camels for at least 1 year.Camel rabies outbreaks have occurred mainly in the Middle East in the past few decades –20; howeIn conclusion, since vaccination and serological test programs for reservoir animals are the basic and effective approaches to prevent established and imported rabies in China, more research should be devoted to the development of oral vaccines for dogs and foxes. In addition, regular surveillance of cross-border transmission between China and neighbouring countries is required for wildlife rabies control.S1 FigRed dots indicate the location of rabies virus strains isolated from wild fox and cattle in the present study in IMAR. The green dot identifies camel rabies in the present study in NHAR. The black dots represent fox-associated rabies cases reported previously during the recent outbreaks in XUAR and IMAR.(TIF)Click here for additional data file.S1 Table(DOC)Click here for additional data file.