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Indoleamine-2, 3-dioxygenase is responsible for tryptophan catabolism; IFN-β is a treatment for multiple sclerosis (MS) and it has been associated with depression. IDO activation might play a role in IFN-β induction of depressive symptoms. Depressive symptoms associated with MS illness and IFN-β treatment have been treated with pharmacological and non-pharmacological intervention.
Evaluation of the kynurenine pathway, IDO activation and neurotoxic agents, serum BDNF in MS patients during IFN-β intervention.
14 study subjects, aged 18-64 years with major depressive disorder and MS treated with IFN-β, before and after pharmacologic and non-pharmacologic intervention, and 34 age matched healthy controls were enrolled at the University of Rome "La Sapienza" and at the at the University of Antwerp. Depressed participants were randomized to sertraline-treatment or interpersonal psychodynamic psychotherapy.
There were significant improvements in both depression and anxiety symptoms with medication and psychotherapy groups, although the effect with sertraline was more robust. Sertraline treatment was associated with a decline in serotonin. In the psychotherapy group, a significant increase in 3-hydroxyanthranilic acid (HAA) was observed after 4 months treatment (p= .04) with a significant decrease in tryptophan levels at 6 weeks (p= .02) and a trend towards a significant decrease in BDNF after 6 wks (p=0.06), neither of which were seen in the medication condition.
The increase in HAA among the psychotherapy-treated patients raises the possibility of a neurodegenerative challenge for patients with multiple sclerosis during treatment with IFN-β which appeared to be prevented with pharmacological treatment.
Two randomized, controlled trials of L-methylfolate augmentation of SSRIs for major depressive disorder (MDD) were conducted using a novel study design (sequential parallel comparison design- SPCD).
To evaluate the efficacy of L-methylfolate augmentation using the Hamilton Depression Rating Scale.
In study one (TRD-1), 148 outpatients with SSRI-resistant MDD were enrolled in a 60-day, SPCD study, divided into two 30-day periods (phases 1 and 2). Patients were randomized 2:3:3 to receive L-methylfolate (7.5mg/d in phase 1, 15mg/d in phase 2), placebo in phase 1 followed by L-methylfolate 7.5mg/d in phase 2, or placebo for both phases. Study two (TRD-2) involved 75 patients and was identical in design to TRD-1 except for the dose of L-methylfolate (15mg only).
In the TRD-1 Study, L-methylfolate 7.5 mg/d was not found to be more effective than placebo. In phase 1 of the TRD-2 Study, 37% of patients on L-methylfolate 15mg/d responded and 18% of placebo patients responded, while in phase 2 among placebo non-responders, the response rates were 28% on L-methylfolate 15mg/d and 9.5% on placebo. When phases 1 and 2 were pooled according to the SPCD model, the difference in response rates was statistically significant in favor of L-methylfolate (p = 0.0399). The rates of spontaneously reported AEs and rates of study discontinuation appear r comparable between L-methylfolate and placebo in both studies. Rates of study discontinuation were also comparable
These studies suggest that L-methylfolate 15 mg/d may be a safe and effective augmentation strategy for inadequate response to SSRIs.
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.
Immune system markers may predict affective disorder treatment response, but whether an overall immune system marker predicts bipolar disorder treatment effect is unclear.
Bipolar CHOICE (N = 482) and LiTMUS (N = 283) were similar comparative effectiveness trials treating patients with bipolar disorder for 24 weeks with four different treatment arms (standard-dose lithium, quetiapine, moderate-dose lithium plus optimised personalised treatment (OPT) and OPT without lithium). We performed secondary mixed effects linear regression analyses adjusted for age, gender, smoking and body mass index to investigate relationships between pre-treatment white blood cell (WBC) levels and clinical global impression scale (CGI) response.
Compared to participants with WBC counts of 4.5–10 × 109/l, participants with WBC < 4.5 or WBC ≥ 10 showed similar improvement within each specific treatment arm and in gender-stratified analyses.
An overall immune system marker did not predict differential treatment response to four different treatment approaches for bipolar disorder all lasting 24 weeks.
Environmental rights, also known as the human rights or constitutional rights that are used for the protection of the environment, have proliferated over the last forty-five years. However, the precise levels of protection that they represent has since been a major question associated with this phenomenon. Environmental Rights: The Development of Standards systematically investigates this question by analyzing the emerging standards of environmental protection that are associated with such rights and the way that those associations are becoming formalized. It covers all of the relevant human rights treaties to illustrate how environmental rights standards are emerging in this dynamic area. Bringing together an elite group of scholars, this book discusses significant new insights into the way that environmental rights are developing, the standards of protection that they confer, and the way that standards in the field of environmental rights can potentially be further developed in the future.
Background: The Choosing Wisely campaign aims to reduce unnecessary testing. Over testing for urinary tract infections and concomitant overtreatment of asymptomatic bacteriuria is a target of this campaign, aiming to decrease healthcare costs and the risks of side effects such as Clostridium difficile infection, adverse reactions, and antimicrobial resistance. During the study baseline (2017), 95 urine cultures (UC) were sent for every 1000 ED visits (9.5%). Of these, fewer than 20% were positive. Aim Statement: The aim of this improvement initiative was to reduce UC testing in the ED, by 50%, from a baseline average of nearly 100 cultures per 1000 ED patients visits, to 50 cultures per 1000 visits, by May 31st, 2018. Measures & Design: This was an interrupted time series study, analyzed using Statistical Process Control (SPC) methodology. Root cause analysis was performed using an Ishikawa diagram. A Pareto chart was completed via multi-voting. A Driver Diagram was developed using the highest ranked items from the Pareto chart to identify locally relevant and feasible interventions. Interventions 1) Medical directives were modified; Routine paired sending of UC with urinalysis by nurses was removed. 2) Physician Education and implementation of a clinical decision aid (CDA); A CDA was created using PDSA methodology, using an iterative approach from development through implementation. Outcome measure: rate of Urine Cultures sent per 1000 ED patient visits Process measure: percent of positive cultures Balancing measures: rate of 14-day ED return visits and hospital admission for patients diagnosed with UTI/Urosepsis/Pyelonephritis. Evalution/Results: At the study's conclusion, there was a decrease in UC rate, from 95 per 1000 ED visits, to 59 per 1000 ED visits (RR 38%, AR 3.6%) There was evidence of special cause variation on the SPC chart. Positive cultures increased from 19% to 34%. There was no increase in the rate of ED 14-day return visits or hospital admission for patients with a diagnosis of UTI, urosepsis or pyelonephritis. Discussion/Impact: The study interventions of uncoupling routine sending of UA and UC, and physician education and use of a clinical decision aid, effectively decreased the rate of UC testing during the study period. A reduction in inappropriate UC testing is important to limit avoidable patient morbidity and reduce unnecessary health care spending. Further studies are indicated to target interventions on patient subgroups and to reduce unnecessary antibiotic prescriptions.
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.
Excessive rainfall and dam failures resulted in floodwater contaminating our public water supply. The endotoxin risk in the contaminated water created challenges in recovery of sterile processing for our surgical equipment. Recovery plans should include a potable water source and a method to connect it to the required location. We share our solution of plumbing our sterile processing equipment to tanker-transported potable water sources. (Disaster Med Public Health Preparedness. 2018; 12: 415–418)
A scalable approach for synthesis of ultra-thin (<10 nm) transition metal dichalcogenides (TMD) films on stretchable polymeric materials is presented. Specifically, magnetron sputtering from pure TMD targets, such as MoS2 and WS2, was used for growth of amorphous precursor films at room temperature on polydimethylsiloxane substrates. Stacks of different TMD films were grown upon each other and integrated with optically transparent insulating layers such as boron nitride. These precursor films were subsequently laser annealed to form high quality, few-layer crystalline TMDs. This combination of sputtering and laser annealing is commercially scalable and lends itself well to patterning. Analysis by Raman spectroscopy, scanning probe, optical, and transmission electron microscopy, and x-ray photoelectron spectroscopy confirm our assertions and illustrate annealing mechanisms. Electrical properties of simple devices built on flexible substrates are correlated to annealing processes. This new approach is a significant step toward commercial-scale stretchable 2D heterostructured nanoelectronic devices.
We studied the effect of a cross-conjugated bridging group (χC) on charge-transfer in a push-pull chromophore system. The hyperpolarizability of such molecules was found to be comparable to that of a fully π-conjugated molecule (πC) with the same donor and acceptor. The cross-conjugated moiety was then applied as a pendant to a fully π-conjugated chromophore containing a tricyanopyrroline acceptor (TCP). The addition of a χC moiety did not alter the intrinsic hyperpolarizability and provides an avenue for extending and aiding πC systems. The molecules were examined by X-ray diffraction (XRD), hyper-Raleigh scattering (HRS) and UV-visible (UV-vis) spectroscopy. Experimental results were compared with the predictions of density functional theory (DFT). Cross-conjugated molecules have comparable β values, relative to πC molecules, due to reduced spatial overlap between the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). Thus, the χC architecture could facilitate independent modification of donor and acceptor strengths while minimizing unfavorable effects on electronic transitions and dipole moments.