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Depression is among the most prevalent mental disorders worldwide, and a substantial proportion of patients do not respond adequately to standard antidepressants. Our understanding of the pathophysiology of depression is no longer limited to the chemical imbalance of neurotransmitters, but also involves the interplay of proinflammatory modulators in the central nervous system, as well as folate metabolism. Additional factors such as stress and metabolic disorders also may contribute. Multiple inflammatory, metabolic, and genetic markers have been identified and may provide critical information to help clinicians individualize treatments for patients to achieve optimal outcomes. Recent advancements in research have clarified underlying causes of depression and have led to possible new avenues for adjunctive treatment. Among these is L-methylfolate, a medical food that is thought to enhance synthesis of monoamines (serotonin, norepinephrine, and dopamine), suppress inflammation, and promote neural health. Clinical studies that assessed supplemental use of L-methylfolate in patients with usual care-resistant depression found that it resulted in improved outcomes. Patients with selective serotonin reuptake inhibitor-resistant depression, and particularly subgroups with biomarkers of inflammation or metabolic disorders or folate metabolism-related genetic polymorphisms (or ≥2 of these factors), had the best responses. Considering this, the goals of this review are to 1) highlight recent advances in the pathophysiology of major depressive disorder as it pertains to folate and associated biomarkers and 2) establish the profiles of patients with depression who could benefit most from supplemental use of L-methylfolate.
Sheath blight caused by soil borne necrotrophic fungus Rhizoctonia solani [teleomorph-Thanatephorus cucumeris (Frank) Donk.] is a major disease of rice. The disease is increasing over the year in India and cause up to 69% yield loss under favourable conditions. A total of 67 accessions of Oryza nivara were screened to identify resistance against sheath blight during 2015. Out of these, 16 accessions were found moderately resistant (MR) which were further evaluated during the year 2016 and 2017. After three years of screening, 12 of them were found to have a consistent moderate resistant reaction whereas four of the O. nivara accessions namely, IRGC81941, IRGC102463C, CR100097 and CR100110A have shown moderately susceptible to susceptible reaction against sheath blight. A correlation study revealed that different disease variables measured were significantly (P < 0.05) correlated. All the genotypes and genotype × environment interaction had a significant (P < 0.001) effect on all the disease variables. Cluster analysis showed that all the accessions were clustered into four groups which showed resistant, MR, moderately susceptible and susceptible reactions. Among all the O. nivara accessions IRGC81941A showed the maximum potential against sheath blight due to a least relative lesion height of 22.80%. None of the accession had complete resistance to the disease. The identified promising accessions such as IRGC81835, IRGC81941A, CR100008 and CR100111B can be utilized in a sheath blight resistance breeding program.
One of the challenges with initiating long-acting injectable (LAI) antipsychotic regimens is achieving relevant drug levels quickly. After first injection of the LAI antipsychotic aripiprazole lauroxil (AL), the lag to reaching relevant plasma aripiprazole levels was initially addressed using supplemental oral aripiprazole for 21 days. A 1-day AL initiation regimen using a NanoCrystal® Dispersion formulation of AL (ALNCD; Aristada Initio®) combined with a single 30 mg dose of oral aripiprazole has been developed as an alternative approach. We compared the 1-day AL initiation regimen (ALNCD + 30 mg oral aripiprazole for 1 day) with the 21-day AL initiation regimen (AL + 15 mg/day of oral aripiprazole for 21 days) using kinetic modeling. Observed and modeled data demonstrate that the 1-day AL initiation regimen provides continuous aripiprazole exposure comparable to the 21-day AL initiation regimen. Each component of the 1-day AL initiation regimen (30 mg oral aripiprazole, ALNCD, and AL) contributes to aripiprazole plasma levels at different times, with oral aripiprazole predominating in the first week, then ALNCD and AL over time. In a double-blind, placebo-controlled, phase 1 study in patients with schizophrenia, the 1-day initiation regimen resulted in rapid achievement of relevant plasma aripiprazole levels comparable to those from the 21-day initiation regimen. Safety and tolerability of the 1-day regimen were consistent with the known profile of aripiprazole. Each part of the 1-day initiation regimen, together with AL, is necessary for continuous aripiprazole exposure from treatment initiation until the next regularly scheduled AL injection is administered.
Whereas genetic susceptibility increases the risk for major depressive disorder (MDD), non-genetic protective factors may mitigate this risk. In a large-scale prospective study of US Army soldiers, we examined whether trait resilience and/or unit cohesion could protect against the onset of MDD following combat deployment, even in soldiers at high polygenic risk.
Data were analyzed from 3079 soldiers of European ancestry assessed before and after their deployment to Afghanistan. Incident MDD was defined as no MDD episode at pre-deployment, followed by a MDD episode following deployment. Polygenic risk scores were constructed from a large-scale genome-wide association study of major depression. We first examined the main effects of the MDD PRS and each protective factor on incident MDD. We then tested the effects of each protective factor on incident MDD across strata of polygenic risk.
Polygenic risk showed a dose–response relationship to depression, such that soldiers at high polygenic risk had greatest odds for incident MDD. Both unit cohesion and trait resilience were prospectively associated with reduced risk for incident MDD. Notably, the protective effect of unit cohesion persisted even in soldiers at highest polygenic risk.
Polygenic risk was associated with new-onset MDD in deployed soldiers. However, unit cohesion – an index of perceived support and morale – was protective against incident MDD even among those at highest genetic risk, and may represent a potent target for promoting resilience in vulnerable soldiers. Findings illustrate the value of combining genomic and environmental data in a prospective design to identify robust protective factors for mental health.
Slow release is a fundamental feature of long-acting injectable (LAI) antipsychotics. This property allows continuous drug exposure between dosing intervals. However, there can be a significant delay between giving the first LAI dose and achievement of efficacious plasma concentrations. This time period requires additional pharmacologic intervention. Until now, this delay was addressed with one of two strategies: 1) continuing with supplemental oral antipsychotic, or 2) giving more LAI up front (e.g. loading dose). A third strategy has now been developed to reduce the time needed for oral supplementation when starting the LAI aripiprazole lauroxil (AL) from 21days to 1day. A nano-crystalline milled dispersion of AL (ALNCD; brand name ARISTADA INITIO™) was formulated by reducing the AL particle diameter from micron-size particles to nanometer- sized particles. ALNCD has faster dissolution and a shorter half-life than AL and is designed to be used as a single injection along with a single oral aripiprazole dose of 30mg as a 1-day alternative to the 21days of oral aripiprazole supplementation. Here we provide an overview of the new 1-day initiation regimen for starting AL treatment, and demonstrate the relative contributions of each of its components.
A blinded, randomized, phase 1, pharmacokinetic (PK), and safety study compared the 1-day initiation regimen with the 21-day oral aripiprazole regimen. A combination of observed data, and population pharmacokinetic model–based simulations were used to plot plasma aripiprazole concentrations of single doses of ALNCD, 30mg oral aripiprazole, and AL, individually, and all three combined.
The PK profiles of the 1-day and 21-day initiation regimens (both in conjunction with either 441mg or 882mg doses of AL) were comparable, with therapeutically relevant aripiprazole levels achieved within 4days of treatment initiation. The safety profile of the 1-day initiation regimen was similar to the 21-day initiation regimen, and consistent with that of AL. Aripiprazole concentration–time profiles demonstrated that each component delivered aripiprazole to the systemic circulation at different time periods, with the 30mg dose of oral aripiprazole predominant in the first week, followed by ALNCD, and then AL.
The 1-day initiation regimen is well-tolerated and a suitable alternative to 21days of oral aripiprazole supplementation for starting AL. Each component of the 1-day initiation regimen, together with AL, is necessary to provide continuous coverage from treatment initiation until the next regularly scheduled AL injection.
Funding Acknowledgements: This study was funded by Alkermes Inc.
Background: Reversible splenial lesion syndrome (RESLES) is a rare clinico-radiological entity associated with multiple etiologies including infection, metabolic, and epileptic disorders. We describe the case of a child with a reversible splenial lesion who presented with encephalopathy and prior history of episodic ataxia. Methods: A 3-year-old girl presented to the Stollery Children’s hospital with three days of respiratory symptoms followed by acute onset ataxia and encephalopathy. Blood, respiratory samples, and cerebral spinal fluid (CSF) were drawn to investigate for infectious, autoimmune, and metabolic causes. Magnetic resonance imaging (MRI) brain was done and repeated. Results: A respiratory panel tested positive for respiratory syncytial virus (RSV), enterovirus, and rhinovirus. CSF analysis revealed elevated white blood cell count (283). MRI brain demonstrated diffusion restriction involving the posterior body and splenium of the corpus callosum and bilateral middle cerebral peduncles, which resolved nine days later. The patient received high-dose steroids with gradual improvement in the encephalopathy and ataxia. Conclusions: This report contributes to the complexities in clinical understanding of RESLES, as it highlights a novel presentation with ataxia and encephalopathy. The patient’s diagnosis was complicated by previous ataxic episodes of unknown etiology, which allows further consideration of a metabolic or genetic ataxic syndrome and its relationship to encephalopathy.
In this work, the deformation mechanisms underlying the room temperature deformation of the pseudomorphic body centered cubic (BCC) Mg phase in Mg/Nb nanolayered composites are studied. Nanolayered composites comprised of 50% volume fraction of Mg and Nb were synthesized using physical vapor deposition with the individual layer thicknesses h of 5, 6.7, and 50 nm. At the lower layer thicknesses of h = 5 and 6.7 nm, Mg has undergone a phase transition from HCP to BCC such that it formed a coherent interface with the adjoining Nb phase. Micropillar compression testing normal and parallel to the interface plane shows that the BCC Mg nanolayered composite is much stronger and can sustain higher strains to failure than the HCP Mg nanolayered composite. A crystal plasticity model incorporating confined layer slip is presented and applied to link the observed anisotropy and hardening in the deformation response to the underlying slip mechanisms.
GLP-1 (abnormal germline proliferation) is a Notch-like receptor protein that plays an essential role in pharyngeal development. In this study, an orthologue of Caenorhabditis elegans glp-1 was identified in Meloidogyne incognita. A computational analysis revealed that the orthologue contained almost all the domains present in the C. elegans gene: specifically, the LIN-12/Notch repeat, the ankyrin repeat, a transmembrane domain and different ligand-binding motifs were present in orthologue, but the epidermal growth factor-like motif was not observed. An expression analysis showed differential expression of glp-1 throughout the life cycle of M. incognita, with relatively higher expression in the egg stage. To evaluate the silencing efficacy of Mi-glp-1, transgenic Arabidopsis plants carrying double-stranded RNA constructs of glp-1 were generated, and infection of these plants with M. incognita resulted in a 47–50% reduction in the numbers of galls, females and egg masses. Females obtained from the transgenic RNAi lines exhibited 40–60% reductions in the transcript levels of the targeted glp-1 gene compared with females isolated from the control plants. Second-generation juveniles (J2s), which were descendants of the infected females from the transgenic lines, showed aberrant phenotypes. These J2s exhibited a significant decrease in the overall distance from the stylet to the metacorpus region, and this effect was accompanied by disruption around the metacorporeal bulb of the pharynx. The present study suggests a role for this gene in organ (pharynx) development during embryogenesis in M. incognita and its potential use as a target in the management of nematode infestations in plants.
We examined vancomycin-resistant enterococci (VRE)-directed antimicrobial use and VRE bacteremia in a cohort of allogeneic hematopoietic cell transplantation patients from a center where VRE screening is standard prior to transplant. In this cohort, VRE bacteremia (VREB) was infrequent. In patients without VREB, colonized patients received VRE therapy more often than noncolonized patients.
We study 30 solar flare events associated with coronal mass ejections (CMEs) that produced geomagnetic storms as measured in Dst index. Our study reveals that the magnitude of Dst index is significantly associated with maximum solar wind speed, peak of Bz component of the IMF and the product of peak Bz and solar wind speed (minimum and maximum). From our investigations, it can be inferred that CMEs travel with higher speed in the beginning and their speed reduces as they reach L1 location.
We analyze Sun-as-a-star observations spanning over solar cycles 22 – 24 from the ground-based network BiSON and solar cycles 23 – 24 collected by the space-based VIRGO and GOLF instruments on board the SoHO satellite. Using simultaneous observations from all three instruments, our analysis suggests that the structural and magnetic changes responsible for modifying the frequencies remained comparable between cycle 23 and cycle 24 but differ from cycle 22. Thus we infer that the magnetic layer of the Sun has become thinner since the beginning of cycle 23 and continues during the current cycle.
Using continuous observations for 22 years from ground-based network GONG and space-borne instruments MDI onboard SoHO and HMI onboard SDO, we report both global and local properties of the convection zone and their variations with time.
Predictions of sunspot cycle are important due to their space weather effects. Bhatt et al. (2009) predicted sunspot cycle 24 (Maximum amplitude: 92.8±19.6; Timing:October 2012±4 months) using relative sunspot number (International Sunspot Number), and average geomagnetic activity index aa considering 2008 as the year of sunspot minimum. Owing to the extended solar minimum till 2009, we re-examine our prediction model. Also, the newly calibrated international sunspot number reduces many discrepancies in the old dataset and is available from Solar Influences Data Center (SIDC) website. Considering 2009 as sunspot minimum year and newly calibrated international sunspot number, (i) The annual maximum amplitude of cycle 24 = 118.5±24.4 (observed = 113.3±0.1), (ii) A smoothed monthly mean sunspot number maximum in January 2014±4 months (observed in February 2014). Our prediction method appears to be a reliable indicator for the predictability of cycle 25.
The temporal correlation between neutron and hard X-ray (HXR) emissions from a hundred joules plasma focus device (PF-400J) was studied. A method, time history analysis, to estimate the time of origin of neutrons with respect to HXRs is applied. In most of the discharges, it was found that neutrons are originated before HXRs in the axial direction and after HXRs in the radial direction. In some discharges, the time difference between HXRs and neutrons origin was found large enough, so that it can be interpreted that those neutrons would have been originated before the pinch. A qualitative discussion is conjectured to explain the experimental observations.
Investigations of drinking behavior across military deployment cycles are scarce, and few prospective studies have examined risk factors for post-deployment alcohol misuse.
Prevalence of alcohol misuse was estimated among 4645 US Army soldiers who participated in a longitudinal survey. Assessment occurred 1–2 months before soldiers deployed to Afghanistan in 2012 (T0), upon their return to the USA (T1), 3 months later (T2), and 9 months later (T3). Weights-adjusted logistic regression was used to evaluate associations of hypothesized risk factors with post-deployment incidence and persistence of heavy drinking (HD) (consuming 5 + alcoholic drinks at least 1–2×/week) and alcohol or substance use disorder (AUD/SUD).
Prevalence of past-month HD at T0, T2, and T3 was 23.3% (s.e. = 0.7%), 26.1% (s.e. = 0.8%), and 22.3% (s.e. = 0.7%); corresponding estimates for any binge drinking (BD) were 52.5% (s.e. = 1.0%), 52.5% (s.e. = 1.0%), and 41.3% (s.e. = 0.9%). Greater personal life stress during deployment (e.g., relationship, family, or financial problems) – but not combat stress – was associated with new onset of HD at T2 [per standard score increase: adjusted odds ratio (AOR) = 1.20, 95% CI 1.06–1.35, p = 0.003]; incidence of AUD/SUD at T2 (AOR = 1.54, 95% CI 1.25–1.89, p < 0.0005); and persistence of AUD/SUD at T2 and T3 (AOR = 1.30, 95% CI 1.08–1.56, p = 0.005). Any BD pre-deployment was associated with post-deployment onset of HD (AOR = 3.21, 95% CI 2.57–4.02, p < 0.0005) and AUD/SUD (AOR = 1.85, 95% CI 1.27–2.70, p = 0.001).
Alcohol misuse is common during the months preceding and following deployment. Timely intervention aimed at alleviating/managing personal stressors or curbing risky drinking might reduce risk of alcohol-related problems post-deployment.
To evaluate the short- to medium-term effectiveness of potassium titanyl phosphate (KTP) laser Dermastat in patients with recurrent anterior epistaxis.
Fifty-eight patients presenting with recurrent anterior epistaxis were treated using potassium titanyl phosphate laser Dermastat. Those with recurrent epistaxis arising from prominent vessels in Little's area, and/or those for whom treatment with silver nitrate cautery failed, were included. The main outcome measure was resolution of epistaxis at two months.
Fifty-eight patients were treated; 27 were under 18 years old. Thirty patients had prominent vessels. Thirty-one patients had undergone previous cautery treatment. Thirty-eight patients had treatment to the left side, 19 to the right and 1 to both. At two months, 74 per cent reported resolution of epistaxis with no complications. This increased to 78 per cent at further follow up.
Our technique is a successful, safe treatment for recurrent anterior epistaxis in an otherwise treatment-resistant group. A single procedure is effective. The handpiece and tip are reusable and sterilisable, resulting in cost-effectiveness.
Introduction: Multiples barriers to appropriate analgesia are reported in the paediatric emergency department (PED), including limited accessibility to effective strategies. Our objective: was to evaluate the improvement in the accessibility of pain and anxiety management strategies in Canadian PEDs, after the creation of a national pediatric pain Quality Improvement Collaborative (QIC), through Pediatric Emergency Research Canada (PERC). Methods: In 2013, the TRAPPED 1 survey was administered to Canadian PEDs, in order to evaluate what resources were in place for pain and anxiety management. A pain QIC was then created to stimulate the implementation of new strategies, through information sharing between PEDs. In 2015, the TRAPPED 2 cross sectional survey was administered. Its focus was to evaluate the improvement in the accessibility of specific strategies reported by each centre, after participating in this QIC, and working to implement change within their own PEDs. Results: All 15/15 Canadian PEDs responded to the TRAPPED 1 survey in 2013 and 11 agreed to participate in the national pain QIC. In-person, phone meetings, follow up surveys and email communications were employed for information sharing. Strategies identified by the QIC to be newly introduced in individual centres were educational initiatives, distraction options, nurse-initiated protocols and intranasal (IN) medications. All 15 PEDs completed the TRAPPED 2 survey. Compared to 2013, an increased number of PEDs used face-based pain scales (14/15 vs 6/15) and behavioural scales (5/15 vs 1/15) for pain assessment in 2015. Use of reminder posters on pain management at triage increased from 4/15 to 6/15 PEDs. Availability of tablets for distraction increased from 4/15 to 10/15 PEDs. Nurse-initiated protocols for topical anesthetic and oral sucrose (for needle procedures) increased from 10/15 to 12/15 sites and from 12/15 to 14/15 sites respectively. Availability of IN medications increased; fentanyl from 9/15 to 14/15 sites and midazolam from 8/15 to 10/15 sites. Ten of the 11 PEDs involved in the QIC strategy reported the implementation of at least one of their own identified strategies. Conclusion: This study suggests that the use of a QIC may improve the introduction of new strategies to reduce pain and anxiety in EDs. QICs may also be helpful to other centres when introducing new strategies.
Forage sorghum is an important component of the fodder supply chain in the arid and semi-arid regions of the world because of its high productivity, ability to utilize water efficiently and adaptability to a wide range of climatic conditions. Identification of high-yielding stable genotypes (G) across environments (E) is challenging because of the complex G × E interactions (GEI). In the present study, the performance of 16 forage sorghum genotypes over seven locations across the rainy seasons of 2010 and 2011 was investigated using GGE biplot analysis. Analysis of variance revealed the existence of significant GEI for fodder yield and all eight associated phenotypic traits. Location accounted for a higher proportion of the variation (0·72–0·91), while genotype contributed only 0·06–0·21 of total variation in different traits. Genotype-by-location interactions contributed 0·02–0·13 of total variation. Promising genotypes for fodder yield and each of the associated traits could be identified effectively using a graphical biplot approach. The majority of test locations were highly correlated. A ‘Which-won-where’ study partitioned the test locations into two mega-environments (MEs): ME1 was represented by five locations with COFS 29 as the best genotype, while ME2 had two locations with S 541 as the best genotype. The existence of two MEs suggested a need for location-specific breeding. Genotype-by-trait biplots indicated that improvement for forage yield could be achieved through indirect selection for plant height, leaf number and early vigour.