Antidepressants demonstrate modest response rates in the treatment of major depressive disorder (MDD). Despite previous genome-wide association studies (GWAS) of antidepressant treatment response, ...the underlying genetic factors are unknown. Using prescription data in a population and family-based cohort (Generation Scotland: Scottish Family Health Study; GS:SFHS), we sought to define a measure of (a) antidepressant treatment resistance and (b) stages of antidepressant resistance by inferring antidepressant switching as non-response to treatment. GWAS were conducted separately for antidepressant treatment resistance in GS:SFHS and the Genome-based Therapeutic Drugs for Depression (GENDEP) study and then meta-analysed (meta-analysis n = 4213, cases = 358). For stages of antidepressant resistance, a GWAS on GS:SFHS only was performed (n = 3452). Additionally, we conducted gene-set enrichment, polygenic risk scoring (PRS) and genetic correlation analysis. We did not identify any significant loci, genes or gene sets associated with antidepressant treatment resistance or stages of resistance. Significant positive genetic correlations of antidepressant treatment resistance and stages of resistance with neuroticism, psychological distress, schizotypy and mood disorder traits were identified. These findings suggest that larger sample sizes are needed to identify the genetic architecture of antidepressant treatment response, and that population-based observational studies may provide a tractable approach to achieving the necessary statistical power.
Medium carbon steels alloyed with two levels each of V and Si were heat treated to form tempered martensite and bainite, followed by nitriding to evaluate their effects on case hardness and residual ...stress. Microstructures were quantitatively characterized with Vickers microhardness testing, scanning electron microscopy (SEM), electron backscatter diffraction (EBSD), X-ray diffraction (XRD), conventional transmission electron microscopy (CTEM), and scanning transmission electron microscopy (STEM). Measurements of subgrain size, cementite size, dislocation density, and volume fractions of nitride precipitates were combined in a strength model to predict the contributions of V and Si to maximum case hardness after nitriding. Higher V contents lead to increases in maximum case hardness by increasing the volume fraction of MX precipitates. Increases in Si content lead to increased maximum case hardness by increasing the volume fraction of amorphous (Si and Mn)-containing nitride precipitates; the presence of Mn in these precipitates has not been previously reported. Higher Si contents also lead to increases in solid solution strengthening because the majority of Si remains in solution in the ferrite matrix. Greater volume fractions of MX and (Si and Mn)-containing nitrides both lead to higher magnitudes of compressive residual stress. The results presented here demonstrate that alloying can improve the properties after nitriding, providing insight into advanced nitriding steel grades and potentially enabling a wider range of steel microstructures to be nitrided without a debit in performance.
Freenet is a distributed information storage system designed to address information privacy and survivability concerns. Freenet operates as a self-organizing P2P network that pools unused disk space ...across potentially hundreds of thousands of desktop computers to create a collaborative virtual file system. Freenet employs a completely decentralized architecture. Given that the P2P environment is inherently untrustworthy and unreliable, we must assume that participants could operate maliciously or fail without warning at any time. Therefore, Freenet implements strategies to protect data integrity and prevent privacy leaks in the former instance, and provide for graceful degradation and redundant data availability in the latter. The system is also designed to adapt to usage patterns, automatically replicating and deleting files to make the most effective use of available storage in response to demand.
Background & AimThe ISCT Process and Product Development (PPD) committee conducted a questionnaire regarding Cost of Goods (COG) topics and activities in Cell & Gene therapy in 2017. They survey's ...questions were around the topics of Product type, Manufacturing, Container, Dose, Storage, Transport, Temperature and Administration.Methods, Results & ConclusionThe ISCT membership was sent the voluntary questionnaire. 51 members filled out the 45-question survey. This poster will release the results and summarize the data from the PPDs COGs questionnaire.A sample of the responses are: respondents were 33% academic vs. private, 93% are working with a therapeutic product, 65% autologous vs. 32% allogenic, T-Cells and MSC represent 68% of cell type used, 54% are seeking US FDA regulation approval and 41% seeking Europe EMEA approval, 31% plan to manufacture at the clinic/hospital, 43% at CMO and 56% internally, 54% plan to use a bag for product delivery and 48% a vial, 44% expect one dose per patient and 31% say it will vary per patient, 56% will store their product at cryogenic temperatures vs 22% fresh, 80% plan to use a DMSO containing cryoprotectant, 34% expect to ship the final product internationally, 74% require thawing of the final product, 56% require a dilution and/or wash, 78% will let the physician determine protocol if any adverse events occur and 50% will offer access to a sponsor review team.The PPD hopes the results of this survey will help further improvements to planning and cost reduction for Cell and Gene therapies.
High‐resolution manometry revolutionized the assessment of esophageal motility disorders and upgraded the classification through the Chicago Classification. A known disadvantage of standard HRM, ...however, is the inability to record esophageal motility function for an extended time interval; therefore, it represents only a more snapshot view of esophageal motor function. In contrast, ambulatory esophageal manometry measures esophageal motility over a prolonged period and detects motor activity during the entire circadian cycle. Furthermore, ambulatory manometry has the ability to measure temporal correlations between symptoms and motor events. This article aimed to review the clinical implications of ambulatory esophageal manometry for various symptoms, covering literature on the manometry catheter, interpretation of findings, and relevance in clinical practice specific to the evaluation of non‐cardiac chest pain, chronic cough, and rumination syndrome.
Ambulatory esophageal manometry measures esophageal motility over a prolonged period and detects motor activity during the entire circadian cycle. This article aims to review the clinical implications of ambulatory esophageal manometry for various symptoms, covering literature on the manometry catheter, interpretation of findings and relevance in clinical practice specific to the evaluation of non‐cardiac chest pain, chronic cough and rumination syndrome.
Zika virus (ZIKV) infection causes severe neurological consequences in both gestationally-exposed infants and adults. Sensorial gating deficits strongly correlate to the motor, sensorial and ...cognitive impairments observed in ZIKV-infected patients. However, no startle response or prepulse inhibition (PPI) assessment has been made in patients or animal models. In this study, we identified different outcomes according to the age of infection and sex in mice: neonatally infected animals presented an increase in PPI and delayed startle latency. However, adult-infected male mice presented lower startle amplitude, while a PPI impairment was observed 14 days after infection in both sexes. Our data further the understanding of the functional impacts of ZIKV on the developing and mature nervous system, which could help explain other behavioral and cognitive alterations caused by the virus. With this study, we support the startle reflex testing in ZIKV-exposed patients, especially infants, allowing for early detection of functional neuromotor damage and early intervention.
•ZIKV-infection changes startle response differently according to age and sex.•ZIKV increases startle latency in neonatally infected mice of both sexes.•ZIKV acutely reduces startle amplitude in adult-infected male mice.•ZIKV transiently impair PPI in adult-infected male mice.
Zika virus (ZIKV) infection was historically considered a disease with mild symptoms and no major consequences to human health. However, several long-term, late onset, and chronic neurological ...complications, both in congenitally-exposed babies and in adult patients, have been reported after ZIKV infection, especially after the 2015 epidemics in the American continent. The development or severity of these conditions cannot be fully predicted, but it is possible that genetic, epigenetic, and environmental factors may contribute to determine ZIKV infection outcomes. This reinforces the importance that individuals exposed to ZIKV are submitted to long-term clinical surveillance and highlights the urgent need for the development of therapeutic approaches to reduce or eliminate the neurological burden of infection. Here, we review the epidemiology of ZIKV-associated neurological complications and the role of factors that may influence disease outcome. Moreover, we discuss experimental and clinical evidence of drugs that have shown promising results in vitro or in vitro against viral replication and and/or ZIKV-induced neurotoxicity.
Introduction
Radiotherapy is considered standard of care for adjuvant peri-operative treatment of many spinal tumors, including those with instrumented fusion. Unfortunately, radiation treatment has ...been linked to increased risk of pseudoarthrosis. Newer focused radiotherapy strategies with enhanced conformality could offer improved fusion rates for these patients, but this has not been confirmed.
Methods
We performed a retrospective analysis of patients at three tertiary care academic institutions with primary and secondary spinal malignancies that underwent resection, instrumented fusion, and peri-operative radiotherapy. Two board certified neuro-radiologists used the Lenke fusion score to grade fusion status at 6 and 12-months after surgery. Secondary outcomes included clinical pseudoarthrosis, wound complications, the effect of radiation timing and radiobiological dose delivered, the use of photons versus protons, tumor type, tumor location, and use of autograft on fusion outcomes.
Results
After review of 1252 spinal tumor patients, there were 60 patients with at least 6 months follow-up that were included in our analyses. Twenty-five of these patients received focused radiotherapy, 20 patients received conventional radiotherapy, and 15 patients were treated with protons. There was no significant difference between the groups for covariates such as smoking status, obesity, diabetes, intraoperative use of autograft, and use of peri-operative chemotherapy. There was a significantly higher rate of fusion for patients treated with focused radiotherapy compared to those treated with conventional radiotherapy at 6-months (64.0% versus 30.0%, Odds ratio: 4.15,
p = 0.036
) and 12-months (80.0% versus 42.1%, OR: 5.50,
p = 0.022
). There was a significantly higher rate of clinical pseudoarthrosis in the conventional radiotherapy cohort compared to patients in the focused radiotherapy cohort (19.1% versus 0%,
p = 0.037
). There was no difference in fusion outcomes for any of the secondary outcomes except for use of autograft. The use of intra-operative autograft was associated with an improved fusion at 12-months (66.7% versus 37.5%, OR: 3.33,
p = 0.043
).
Conclusion
Focused radiotherapy may be associated with an improved rate of fusion and clinical pseudoarthrosis when compared to conventional radiation delivery strategies in patients with spinal tumors. Use of autograft at the time of surgery may be associated with improved 12-month fusion rates. Further large-scale prospective and randomized controlled studies are needed to better stratify the effects of radiation delivery modality in these patients.
PDF
