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Pharmacogenomic testing has emerged to aid medication selection for patients with major depressive disorder (MDD) by identifying potential gene-drug interactions (GDI). Many pharmacogenomic tests are available with varying levels of supporting evidence, including direct-to-consumer and physician-ordered tests. We retrospectively evaluated the safety of using a physician-ordered combinatorial pharmacogenomic test (GeneSight) to guide medication selection for patients with MDD in a large, randomized, controlled trial (GUIDED).
Materials and Methods
Patients diagnosed with MDD who had an inadequate response to ≥1 psychotropic medication were randomized to treatment as usual (TAU) or combinatorial pharmacogenomic test-guided care (guided-care). All received combinatorial pharmacogenomic testing and medications were categorized by predicted GDI (no, moderate, or significant GDI). Patients and raters were blinded to study arm, and physicians were blinded to test results for patients in TAU, through week 8. Measures included adverse events (AEs, present/absent), worsening suicidal ideation (increase of ≥1 on the corresponding HAM-D17 question), or symptom worsening (HAM-D17 increase of ≥1). These measures were evaluated based on medication changes [add only, drop only, switch (add and drop), any, and none] and study arm, as well as baseline medication GDI.
Most patients had a medication change between baseline and week 8 (938/1,166; 80.5%), including 269 (23.1%) who added only, 80 (6.9%) who dropped only, and 589 (50.5%) who switched medications. In the full cohort, changing medications resulted in an increased relative risk (RR) of experiencing AEs at both week 4 and 8 [RR 2.00 (95% CI 1.41–2.83) and RR 2.25 (95% CI 1.39–3.65), respectively]. This was true regardless of arm, with no significant difference observed between guided-care and TAU, though the RRs for guided-care were lower than for TAU. Medication change was not associated with increased suicidal ideation or symptom worsening, regardless of study arm or type of medication change. Special attention was focused on patients who entered the study taking medications identified by pharmacogenomic testing as likely having significant GDI; those who were only taking medications subject to no or moderate GDI at week 8 were significantly less likely to experience AEs than those who were still taking at least one medication subject to significant GDI (RR 0.39, 95% CI 0.15–0.99, p=0.048). No other significant differences in risk were observed at week 8.
These data indicate that patient safety in the combinatorial pharmacogenomic test-guided care arm was no worse than TAU in the GUIDED trial. Moreover, combinatorial pharmacogenomic-guided medication selection may reduce some safety concerns. Collectively, these data demonstrate that combinatorial pharmacogenomic testing can be adopted safely into clinical practice without risking symptom degradation among patients.
Shape-memory abnormalities are seen in some nitinol atrial septal occluders. Variably described as cobra-head, tulip, and others, their incidence, mechanisms, clinical impact, and outcome have not been systematically analysed.
We retrospectively reviewed all consecutive device closures in the last 6 years for deformations. Type and size of the occluder, deployment technique, size, and angulation/kinking of the delivery sheath were analysed. Procedural success, duration, and other complications were studied.
A total of 112 devices (11.8%) among 950 occluders used in 936 patients showed deformities. Fourteen of 936 received 2 devices. Deformities were transient and self-correcting in 40%. Multivariate analysis showed significant associations with oversized sheaths (p = 0.004), kinked/angulated sheaths (p < 0.001), special deployment techniques (p < 0.001), and twist in the device waist (p = 0.011). Despite more frequent deformities with Figulla (15.6%) and Amplatzer (13.9%) occluders than Cera occluders (6.6%) and larger devices (>24 mm – 14.6%) than smaller devices (less than or equal to 24 mm – 9.7%), they were not significant on multivariate analysis. In vivo manipulations corrected most deformities; nineteen needed in vitro reformations and four needed a change of device. Despite prolongation of the procedure, repeated attempts (mean 2.76 ± 1.7 attempts, with a range from 1 to 9 attempts), and supraventricular tachycardia in two patients, there were no serious adverse effects.
Deformations were frequent in 11.8% of atrial septal occluders on a targeted search. Oversized and angulated/kinked sheaths, special techniques like pulmonary vein deployment and twist in device waist during procedure predisposed to deformities. While most deformities were corrected with manipulations, removal of the device was infrequently needed and change of device was rarely required. Long procedural time and multiple attempts for deployment did not affect procedural success.
Ductal stents, right ventricular outflow tract stents, and aortopulmonary shunts are used to palliate newborns and infants with reduced pulmonary blood flow. Current long-term outcomes of these palliations from resource-restricted countries are unknown.
This single-centre, retrospective, observational study analysed the technical success, immediate and late mortality, re-interventions, and length of palliation in infants ≤5 kg who underwent aortopulmonary shunts, ductal, and pulmonary outflow stents. Patients were grouped by their anatomy.
There were 69 infants who underwent one of the palliations. Technical success was 90% for aortopulmonary shunts (n = 10), 91% for pulmonary outflow stents (n = 11) and 100% for ductal stents (n = 48). Early mortality within 30 days in 12/69 patients was observed in 20% after shunts, 9% after pulmonary outflow stents, and 19% after ductal stents. Late mortality in 11 patients was seen in 20% after shunts, 18% after outflow stents, and 15% after ductal stents. Seven patients needed re-interventions; two following shunts, one following outflow stent, and four following ductal stents for hypoxia. Among the anatomical groups, 10/12 patients with pulmonary atresia, intact ventricular septum survived after valvotomy and ductal stenting. Survival to Glenn shunt after ductal stent for pulmonary atresia, intact ventricular septum and diminutive right ventricle was very low in two out of eight patients, but very good (100%) for other univentricular hearts. Among 35 patients with biventricular lesions, 22 survived to the next stage.
Cyanotic infants, despite undergoing technically successful palliation had a high inter-stage mortality irrespective of the type of palliation. Duct stenting in univentricular hearts and in pulmonary atresia with an intact ventricular septum and adequate sized right ventricle tended to have low mortality and better long-term outcome. Completion of biventricular repair after palliation was achieved only in 63% of patients, reflecting unique challenges in developing countries despite advances in intensive care and interventions.
Headache is a common complaint among adolescents and is associated with several comorbid conditions particularly anxiety and depression. Transdiagnostic cognitive behavior therapy (TCBT) is an alternative approach to third wave CBT. It attempts to address multiple diagnoses at the same time while focusing on shared pathology and common processes (McEvoy et al., 2009).
To develop a group transdiagnostic cognitive behavior therapy intervention module for adolescents with comorbid headache and anxiety disorder and to evaluate the module in terms of feasibility, acceptance and efficacy.
A TCBT intervention module for headache and anxiety disorder for use with adolescents was developed. Fifteen adolescents diagnosed with comorbid headache and anxiety disorder were recruited from the outpatient psychiatric clinic at AIIMS, New Delhi. Baseline, mid-and post- intervention assessments was done on Youth Self Report, M.I.N.I KID, Anxiety Disorders Interview Schedule, STAI – Y, CDI – 2, Headache Diary, Headache Impact Test (HIT) and Global Assessment Scale for Children (CGAS). TCBT was carried out over a period of 12 weeks with one group session per week for each of the three groups.
85% participants showed clinically significant improvement as rated on scores on STAI-Y, HIT and CGAS. Qualitative interpretation of headache diary showed significant decrease in the frequency, intensity and duration of headache for all participants.
TCBT module was found to be feasible, acceptable and efficacious leading to significant symptom reduction.
Possible benefits of TCBT as pertaining to the Indian context along with barriers are further discussed.
Despite the strong evidence for its effectiveness for depression in adolescence, cognitive behavior therapy (CBT) remains difficult to access in India. Computerized CBT offers a substantive contribution to the delivery of effective care improving accessibility of treatment. The present study is an endeavor to assess the felt needs of adolescents vis-à -vis the difficulties and stressors experienced by them. Another objective of the study has been to develop and test a culturally relevant computer assisted CBT program called 'smartteen'. The presentation will discuss the results of the pilot test of the effectiveness of the intervention on a sample of 20 participants in reducing depressive symptoms.
In this pre and post research design, 20 depressed adolescents seeking treatment from the Department of Psychiatry at a premier institute in India, are being randomly assigned to intervention (n=10) and treatment as usual (n=10). Three assessments will be carried out at pre, mid (6 weeks of intervention) and post intervention (3 months of intervention) by a blind assessor. The primary outcome is recovery from depression and analysis will be done by intent to treat.
Results and Discussion
The study is ongoing and results will be presented at the time of presentation.
The Genomics Used to Improve DEpresssion Decisions (GUIDED) trial assessed outcomes associated with combinatorial pharmacogenomic (PGx) testing in patients with major depressive disorder (MDD). Analyses used the 17-item Hamilton Depression (HAM-D17) rating scale; however, studies demonstrate that the abbreviated, core depression symptom-focused, HAM-D6 rating scale may have greater sensitivity toward detecting differences between treatment and placebo. However, the sensitivity of HAM-D6 has not been tested for two active treatment arms. Here, we evaluated the sensitivity of the HAM-D6 scale, relative to the HAM-D17 scale, when assessing outcomes for actively treated patients in the GUIDED trial.
Outpatients (N=1,298) diagnosed with MDD and an inadequate treatment response to >1 psychotropic medication were randomized into treatment as usual (TAU) or combinatorial PGx-guided (guided-care) arms. Combinatorial PGx testing was performed on all patients, though test reports were only available to the guided-care arm. All patients and raters were blinded to study arm until after week 8. Medications on the combinatorial PGx test report were categorized based on the level of predicted gene-drug interactions: ‘use as directed’, ‘moderate gene-drug interactions’, or ‘significant gene-drug interactions.’ Patient outcomes were assessed by arm at week 8 using HAM-D6 and HAM-D17 rating scales, including symptom improvement (percent change in scale), response (≥50% decrease in scale), and remission (HAM-D6 ≤4 and HAM-D17 ≤7).
At week 8, the guided-care arm demonstrated statistically significant symptom improvement over TAU using HAM-D6 scale (Δ=4.4%, p=0.023), but not using the HAM-D17 scale (Δ=3.2%, p=0.069). The response rate increased significantly for guided-care compared with TAU using both HAM-D6 (Δ=7.0%, p=0.004) and HAM-D17 (Δ=6.3%, p=0.007). Remission rates were also significantly greater for guided-care versus TAU using both scales (HAM-D6 Δ=4.6%, p=0.031; HAM-D17 Δ=5.5%, p=0.005). Patients taking medication(s) predicted to have gene-drug interactions at baseline showed further increased benefit over TAU at week 8 using HAM-D6 for symptom improvement (Δ=7.3%, p=0.004) response (Δ=10.0%, p=0.001) and remission (Δ=7.9%, p=0.005). Comparatively, the magnitude of the differences in outcomes between arms at week 8 was lower using HAM-D17 (symptom improvement Δ=5.0%, p=0.029; response Δ=8.0%, p=0.008; remission Δ=7.5%, p=0.003).
Combinatorial PGx-guided care achieved significantly better patient outcomes compared with TAU when assessed using the HAM-D6 scale. These findings suggest that the HAM-D6 scale is better suited than is the HAM-D17 for evaluating change in randomized, controlled trials comparing active treatment arms.
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.
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.
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.