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Major depressive disorder (MDD) is a leading cause of disease burden worldwide, with lifetime prevalence in the United States of 17%. Here we present the results of the first prospective, large-scale, patient- and rater-blind, randomized controlled trial evaluating the clinical importance of achieving congruence between combinatorial pharmacogenomic (PGx) testing and medication selection for MDD.
1,167 outpatients diagnosed with MDD and an inadequate response to ≥1 psychotropic medications were enrolled and randomized 1:1 to a Treatment as Usual (TAU) arm or PGx-guided care arm. Combinatorial PGx testing categorized medications in three groups based on the level of gene-drug interactions: use as directed, use with caution, or use with increased caution and more frequent monitoring. Patient assessments were performed at weeks 0 (baseline), 4, 8, 12 and 24. Patients, site raters, and central raters were blinded in both arms until after week 8. In the guided-care arm, physicians had access to the combinatorial PGx test result to guide medication selection. Primary outcomes utilized the Hamilton Depression Rating Scale (HAM-D17) and included symptom improvement (percent change in HAM-D17 from baseline), response (50% decrease in HAM-D17 from baseline), and remission (HAM-D17<7) at the fully blinded week 8 time point. The durability of patient outcomes was assessed at week 24. Medications were considered congruent with PGx test results if they were in the ‘use as directed’ or ‘use with caution’ report categories while medications in the ‘use with increased caution and more frequent monitoring’ were considered incongruent. Patients who started on incongruent medications were analyzed separately according to whether they changed to congruent medications by week8.
At week 8, symptom improvement for individuals in the guided-care arm was not significantly different than TAU (27.2% versus 24.4%, p=0.11). However, individuals in the guided-care arm were more likely than those in TAU to achieve remission (15% versus 10%; p<0.01) and response (26% versus 20%; p=0.01). Remission rates, response rates, and symptom reductions continued to improve in the guided-treatment arm until the 24week time point. Congruent prescribing increased to 91% in the guided-care arm by week 8. Among patients who were taking one or more incongruent medication at baseline, those who changed to congruent medications by week 8 demonstrated significantly greater symptom improvement (p<0.01), response (p=0.04), and remission rates (p<0.01) compared to those who persisted on incongruent medications.
Combinatorial PGx testing improves short- and long-term response and remission rates for MDD compared to standard of care. In addition, prescribing congruency with PGx-guided medication recommendations is important for achieving symptom improvement, response, and remission for MDD patients.
Funding Acknowledgements: This study was supported by Assurex Health, Inc.
Ample amount of data suggests role of REM sleep deprivation as the cause and effect of mania. In the present model, we have tried to implement behavioral sensitization to sleep deprivation, conditions mimicking natural circumstances, so as to produce an animal model with symptomatology resembling very close to human mania. Pre-clinical and clinical studies have shown that mania is often co-morbid with multiple sclerosis, therefore we sought to find out whether myelin integrity is disrupted and if lithium could protect against such damage.
(1) To analyse mania-like behavior after REM sleep deprivation. (2) To analyse any damage to myelin under TEM.
We wanted to see if there could be any damage to myelin after behavioral sensitization to stress.
Rats were sleep deprived by classical flowerpot or platform method. OFT was performed to assess behavior of rats. The analysis was performed over 5 min, separated into 5 bins of 1 min each. Behavioral scores included total square entries, inner square entries, time spent in center, rearing frequency, time spent rearing, number of grooming bouts, time spent grooming defecation and time spent still. TEM was performed to study changes in myelination in two distinct regions of brain, DG and VTA.
It was observed that the REM sleep deprived rats had mania like symptoms. REM sleep deprivation lead to demyelination in DG and VTA. Lithium treatment restored myelination per se.
The result suggests the involvement of myelin damage in the pathogenesis of mania, Li offers protection against such damage.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Accelerated aging is associated with major depressive disorder (MDD) and studies of yoga and meditation based lifestyle intervention (YMLI) on biomarkers of cellular aging are lacking.
Aim and objectives
To investigate the peripheral blood biomarkers of cellular aging in MDD patients after short term YMLI. Biomarkers include DNA damage, oxidative stress (OS), telomere attrition, and nutrition sensing assessed respectively by 8-hydroxy 2’- deoxyguanosine (8-OHdG); reactive oxygen species (ROS) and total antioxidant capacity (TAC); telomere length and telomerase activity; and sirtuin-1.
We consecutively enrolled 33 MDD patients and 40 healthy subjects; 30 MDD patients were followed up with 12- week YMLI. Biomarkers of cellular aging in peripheral blood were measured with assay kits. All patients were evaluated by examining the correlation between cellular aging markers and Montgomery–Asberg Depression Rating Scale (MADRS) scores.
The levels of DNA damage, OS, and telomere attrition in MDD patients were significantly higher than healthy subjects (all P = 0.005). The MADRS scores had a significantly positive association with 8-OHdG and ROS levels and negative association with TAC, telomerase and sirtuin-1 levels (all P < 0.01).
Peripheral blood biomarker levels in our results suggest significant cellular aging in MDD patients compared to healthy subjects. There was strong correlation between the changes in biomarkers of cellular aging and clinical improvement in MDD. Our study is the first to show significant increase in sirtuin-1 levels in MDD patients after yoga and meditation. Therefore, biomarkers of cellular aging might be indicators of MDD severity and clinical remission after YMLI.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Large-scale studies evaluating risk factors for Clostridium difficile infection (CDI), a leading cause of infectious diarrhea among patients undergoing stem cell transplantation (SCT), are lacking. We have evaluated risk factors for CDI among both autologous SCT (auto-SCT), and allogeneic SCT (allo-SCT) recipients using the National Inpatient Sample (NIS) database provided by the Healthcare Cost and Utilization Project (HCUP).
We used patient data obtained from the NIS database for all adult patients admitted for auto- and allo-SCTs from January 2001 to December 2010. We performed multivariate logistic regression analyses to evaluate risk factors of CDI in auto- and allo-SCT patients.
Auto-SCTs constituted 61.5% of all SCTs performed during the study period. Of the 53,072 auto-SCT patients, 5.8% had CDI, whereas 8.5% of 33,189 allo-SCT patients had CDI. Univariate analyses identified age, gender, indication for SCT, radiation as part of the conditioning regimen, respiratory failure, septicemia, lengthy hospital stay, and multiple comorbidities as risk factors for CDI in both subsets. On multivariate analyses for auto-SCT, there was significant correlation between age and the indication for transplant (P=.003), but the indication for either auto- or allo-SCT was not associated with CDI on multivariate analyses. The following factors were found to be associated with CDI: septicemia (auto-SCT odds ratio [OR],=1.64; 95% confidence interval [CI], 1.35–2; and allo-SCT OR, 1.69; 95% CI, 1.36–2.1), male gender (auto-SCT OR, 1.29; 95% CI, 1.09–1.53; and allo-SCT OR, 1.36; 95% CI, 1.18–1.57), lengthy hospital stay (auto-SCT OR, 2.81; 95% CI, 2.29–3.45; and allo-SCT OR, 2.63; 95% CI, 2.15–3.22), and presence of multiple comorbidities (auto-SCT OR, 1.32; 95% CI, 1.11–1.57; and allo-SCT OR, 1.18; 95% CI, 1.0–1.4).
The prevalence of CDI was higher among patients undergoing allo-SCT. CDI was significantly associated with longer hospital stay, septicemia, and male gender for auto- and allo-SCT recipients. While this analysis did not permit us to directly ascribe the associations to be causative for CDI, it identifies the more vulnerable population for CDI and provides a rationale for the development of more effective approaches to preventing CDI.
A hand operated benchtop stamping press was developed to conduct research on microscale hole fabrication in polymer membranes for applications as scaffolds in tissue engineering. A biocompatible and biodegradable polymer, poly(ε-caprolactone), was selected for micropunching. Membranes between 30 μm and 50 μm thick were fabricated by hot melt extrusion, but could not be stamped with a 200 μm circular punch at room temperature, regardless of die clearance due to excessive strain to fracture. This problem was overcome by cooling the membrane and die sets with liquid nitrogen to take advantage of induced brittle behavior below the polymer’s glass transition temperature. While cooled, 203 μm hole patterns were successfully punched in 33 μm thick poly(ε-caprolactone) membranes with 11% die clearance, achieving 71% porosity.
To examine barriers to initiation and continuation of mental health treatment among individuals with common mental disorders.
Data were from the World Health Organization (WHO) World Mental Health (WMH) surveys. Representative household samples were interviewed face to face in 24 countries. Reasons to initiate and continue treatment were examined in a subsample (n = 636 78) and analyzed at different levels of clinical severity.
Among those with a DSM-IV disorder in the past 12 months, low perceived need was the most common reason for not initiating treatment and more common among moderate and mild than severe cases. Women and younger people with disorders were more likely to recognize a need for treatment. A desire to handle the problem on one's own was the most common barrier among respondents with a disorder who perceived a need for treatment (63.8%). Attitudinal barriers were much more important than structural barriers to both initiating and continuing treatment. However, attitudinal barriers dominated for mild-moderate cases and structural barriers for severe cases. Perceived ineffectiveness of treatment was the most commonly reported reason for treatment drop-out (39.3%), followed by negative experiences with treatment providers (26.9% of respondents with severe disorders).
Low perceived need and attitudinal barriers are the major barriers to seeking and staying in treatment among individuals with common mental disorders worldwide. Apart from targeting structural barriers, mainly in countries with poor resources, increasing population mental health literacy is an important endeavor worldwide.
Conventional medical therapies for ulcerative colitis (UC) are still limited due to the adverse side effects like dose-dependent diarrhoea and insufficient potency to keep in remission for long-term periods. So, new alternatives that provide more effective and safe therapies for ulcerative colitis are constantly being sought. In the present study, probiotic LaBb Dahi was selected for investigation of its therapeutic effect on DSS-induced colitis model in mice. LaBb Dahi was prepared by co-culturing Dahi culture of Lactococci along with selected strain of Lactobacillus acidophilus LaVK2 and Bifidobacterium bifidum BbVK3 in buffalo milk. Four groups of mice (12 each) were fed for 17 d with buffalo milk (normal control), buffalo milk plus DSS (Colitis control), Dahi plus DSS, and LaBb Dahi plus DSS, respectively, with basal diet. The disease activity scores, weight loss, organ weight, colon length, myeloperoxidase (MPO) and β-glucoronidase activity was assessed, and the histopathological picture of the colon of mice was studied. All colitis control mice evidenced significant increase in MPO, β-glucoronidase activity and showed high disease activity scores along with histological damage to colonic tissue. Feeding with LaBb Dahi offered significant reduction in MPO activity, β-glucoronidase activity and improved disease activity scores. We found significant decline in length of colon, organ weight and body weight in colitis induced controls which were improved significantly by feeding LaBb Dahi. The present study suggests that LaBb Dahi can be used as a potential nutraceutical intervention to combat UC related changes and may offer effective adjunctive treatment for management of UC.
In this global study we sought to estimate the degree to which a family member might feel embarrassed when a close relative is suffering from an alcohol, drug, or mental health condition (ADMC) versus a general medical condition (GMC). To date, most studies have considered embarrassment and stigma in society and internalized by the afflicted individual but have not assessed family embarrassment in a large-scale study.
In 16 sites of the World Mental Health Surveys (WMHS), standardized assessments were completed including items on family embarrassment. Site matching was used to constrain local socially shared determinants of stigma-related feelings, enabling a conditional logistic regression model that estimates the embarrassment close relatives may hold in relation to family members affected by an ADMC, a GMC, or both conditions.
There was a statistically robust association such that subgroups with an ADMC-affected relative were more likely to feel embarrassed compared to subgroups with a relative affected by a GMC (p < 0.001), even with covariate adjustments for age and sex.
The pattern of evidence from this research is consistent with conceptual models for interventions that target individual- and family-level stigma-related feelings of embarrassment as possible obstacles to effective early intervention and treatment for an ADMC. Macro-level interventions are under way but micro-level interventions may also be required among family members, along with care for each person with an ADMC.
A retrospective case–case control study was conducted, including 60 cases with daptomycin-nonsusceptible vancomycin-resistant enterococci (DNS-VRE) matched to cases with daptomycin-susceptible VRE and to uninfected controls (1:1:3 ratio). Immunosuppression, presence of comorbid conditions, and prior exposure to antimicrobials were independent predictors of DNS-VRE, although prior daptomycin exposure occurred rarely. In summary, a case–case control study identified independent risk factors for the isolation of DNS-VRE: immunosuppression, multiple comorbid conditions, and prior exposures to cephalosporines and metronidazole.
Suicide is a leading cause of death worldwide; however, little
information is available about the treatment of suicidal people, or about
barriers to treatment.
To examine the receipt of mental health treatment and barriers to care
among suicidal people around the world.
Twenty-one nationally representative samples worldwide
(n=55 302; age 18 years and over) from the World
Health Organization's World Mental Health Surveys were interviewed
regarding past-year suicidal behaviour and past-year healthcare use.
Suicidal respondents who had not used services in the past year were
asked why they had not sought care.
Two-fifths of the suicidal respondents had received treatment (from 17%
in low-income countries to 56% in high-income countries), mostly from a
general medical practitioner (22%), psychiatrist (15%) or
non-psychiatrist (15%). Those who had actually attempted suicide were
more likely to receive care. Low perceived need was the most important
reason for not seeking help (58%), followed by attitudinal barriers such
as the wish to handle the problem alone (40%) and structural barriers
such as financial concerns (15%). Only 7% of respondents endorsed stigma
as a reason for not seeking treatment.
Most people with suicide ideation, plans and attempts receive no
treatment. This is a consistent and pervasive finding, especially in
low-income countries. Improving the receipt of treatment worldwide will
have to take into account culture-specific factors that may influence the
process of help-seeking.
Glioblastoma multiforme, because of its invasive nature, can be considered a disease of the entire brain. Despite recent advances in surgery, radiotherapy and chemotherapy, current treatment regimens have only a marginal impact on patient survival. A crucial challenge is to deliver drugs effectively to invasive glioma cells residing in a sanctuary within the central nervous system. The blood–brain barrier (BBB) restricts the delivery of many small and large molecules into the brain. Drug delivery to the brain is further restricted by active efflux transporters present at the BBB. Current clinical assessment of drug delivery and hence efficacy is based on the measured drug levels in the bulk tumour mass that is usually removed by surgery. Mounting evidence suggests that the inevitable relapse and lethality of glioblastoma multiforme is due to a failure to effectively treat invasive glioma cells. These invasive cells hide in areas of the brain that are shielded by an intact BBB, where they continue to grow and give rise to the recurrent tumour. Effective delivery of chemotherapeutics to the invasive glioma cells is therefore critical, and long-term efficacy will depend on the ability of a molecularly targeted agent to penetrate an intact and functional BBB throughout the entire brain. This review highlights the various aspects of the BBB, and also the brain–tumour-cell barrier (a barrier due to expression of efflux transporters in tumour cells), that together can significantly influence drug response. It then discusses the challenge of glioma as a disease of the whole brain, which lends emphasis to the need to deliver drugs effectively across the BBB to reach both the central tumour and the invasive glioma cells.
Although significant associations of childhood adversities with adult mental disorders are widely documented, most studies focus on single childhood adversities predicting single disorders.
To examine joint associations of 12 childhood adversities with first onset of 20 DSM–IV disorders in World Mental Health (WMH) Surveys in 21 countries.
Nationally or regionally representative surveys of 51 945 adults assessed childhood adversities and lifetime DSM–IV disorders with the WHO Composite International Diagnostic Interview (CIDI).
Childhood adversities were highly prevalent and interrelated. Childhood adversities associated with maladaptive family functioning (e.g. parental mental illness, child abuse, neglect) were the strongest predictors of disorders. Co-occurring childhood adversities associated with maladaptive family functioning had significant subadditive predictive associations and little specificity across disorders. Childhood adversities account for 29.8% of all disorders across countries.
Childhood adversities have strong associations with all classes of disorders at all life-course stages in all groups of WMH countries. Long-term associations imply the existence of as-yet undetermined mediators.
Burden-of-illness data, which are often used in setting healthcare policy-spending priorities, are unavailable for mental disorders in most countries.
To examine one central aspect of illness burden, the association of serious mental illness with earnings, in the World Health Organization (WHO) World Mental Health (WMH) Surveys.
The WMH Surveys were carried out in 10 high-income and 9 low- and middle-income countries. The associations of personal earnings with serious mental illness were estimated.
Respondents with serious mental illness earned on average a third less than median earnings, with no significant between-country differences (χ2(9) = 5.5–8.1, P = 0.52–0.79). These losses are equivalent to 0.3–0.8% of total national earnings. Reduced earnings among those with earnings and the increased probability of not earning are both important components of these associations.
These results add to a growing body of evidence that mental disorders have high societal costs. Decisions about healthcare resource allocation should take these costs into consideration.
We have carried out the B,V and R-band polarimetric and V-band photometric study of the star LO Peg. Our analysis reveal that LO Peg is highly polarized among the sun-like stars. The degree of polarization and polarization position angle are found to be rotationally modulated. The levels of polarization observed in LO Peg could be the result of scattering of an anisotropic stellar radiation field by an optically thin circumstellar envelope or scattering of the stellar radiation by prominence-like structures. The long term photometric observations of LO Peg indicate three independent groups of spots are present on the surface of LO Peg.
Suicide is a leading cause of death worldwide, but the precise effect of childhood adversities as risk factors for the onset and persistence of suicidal behaviour (suicide ideation, plans and attempts) are not well understood.
To examine the associations between childhood adversities as risk factors for the onset and persistence of suicidal behaviour across 21 countries worldwide.
Respondents from nationally representative samples (η = 55 299) were interviewed regarding childhood adversities that occurred before the age of 18 years and lifetime suicidal behaviour.
Childhood adversities were associated with an increased risk of suicide attempt and ideation in both bivariate and multivariate models (odds ratio range 1.2–5.7). The risk increased with the number of adversities experienced, but at a decreasing rate. Sexual and physical abuse were consistently the strongest risk factors for both the onset and persistence of suicidal behaviour, especially during adolescence. Associations remained similar after additional adjustment for respondents' lifetime mental disorder status.
Childhood adversities (especially intrusive or aggressive adversities) are powerful predictors of the onset and persistence of suicidal behaviours.
Gyps vulture populations across the Indian subcontinent collapsed in the 1990s and continue to decline. Repeated population surveys showed that the rate of decline was so rapid that elevated mortality of adult birds must be a key demographic mechanism. Post mortem examination showed that the majority of dead vultures had visceral gout, due to kidney damage. The realisation that diclofenac, a non-steroidal anti-inflammatory drug potentially nephrotoxic to birds, had become a widely used veterinary medicine led to the identification of diclofenac poisoning as the cause of the decline. Surveys of diclofenac contamination of domestic ungulate carcasses, combined with vulture population modelling, show that the level of contamination is sufficient for it to be the sole cause of the decline. Testing on vultures of meloxicam, an alternative NSAID for livestock treatment, showed that it did not harm them at concentrations likely to be encountered by wild birds and would be a safe replacement for diclofenac. The manufacture of diclofenac for veterinary use has been banned, but its sale has not. Consequently, it may be some years before diclofenac is removed from the vultures' food supply. In the meantime, captive populations of three vulture species have been established to provide sources of birds for future reintroduction programmes.
Dry tropical forest communities are among the world's most threatened systems and urgent measures are required to protect and restore them in degraded landscapes. For planning conservation strategies, there is a need to determine the few essential measurable properties, such as number of species and basal area, that best describe the dry forest vegetation and its environment, and to document quantitative relationships among them. This paper examines the relationships between forest basal area and diversity components (number of species and evenness) for a disturbed dry tropical forest of northern India. Data were collected from five sites located in the Vindhyan dry tropical forest of India, selected on the basis of satellite images and field observations to represent the entire range of conditions in terms of canopy cover and disturbance regimes. These sites represented different communities in terms of species composition. The forest was poorer in species richness, and lower in stem density and basal area than wet forests of the tropics. Across sites (communities), the diversity components and tree density were positively related with total tree basal area. Considering basal area as a surrogate of biomass and net production, diversity is found to be positively associated with productivity. A positive relationship between basal area, tree density and species diversity may be an important characteristic of the dry forest, where recurring disturbance does not permit concentration of biomass or stems in only a few strong competitors. However, the relationships of basal area with density, alpha diversity and evenness remain statistically significant only when data from all sites, including the extremely disturbed one, are used in the analysis. In some sites there was a greater coefficient of variation (CV) of basal area than in others, attributed to patchy distribution of stems and resultant blanks. Therefore, to enhance the tree diversity of these forests, the variability in tree basal area must be reduced by regulating local disturbances. Conservation activities, particularly fuelwood plantations near human settlements, deferred grazing and canopy enrichment through multi-species plantations of nursery-raised or wild-collected seedlings of desirable species within the forest patches of low basal area, will be needed to attain restoration goals, but reforestation programmes will have to be made attractive to the forest-dwelling communities.