Implementing multifactorial psychotherapy research in online virtual environments (IMPROVE-2): study protocol for a phase III trial of the MOST randomized component selection method for internet cognitive-behavioural therapy for depression.

BACKGROUND: Depression is a global health challenge. Although there are effective psychological and pharmaceutical interventions, our best treatments achieve remission rates less than 1/3 and limited sustained recovery. Underpinning this efficacy gap is limited understanding of how complex psychological interventions for depression work. Recent reviews have argued that the active ingredients of therapy need to be identified so that therapy can be made briefer, more potent, and to improve scalability. This in turn requires the use of rigorous study designs that test the presence or absence of individual therapeutic elements, rather than standard comparative randomised controlled trials. One such approach is the Multiphase Optimization Strategy, which uses efficient experimentation such as factorial designs to identify active factors in complex interventions. This approach has been successfully applied to behavioural health but not yet to mental health interventions. METHODS/DESIGN: A Phase III randomised, single-blind balanced fractional factorial trial, based in England and conducted on the internet, randomized at the level of the patient, will investigate the active ingredients of internet cognitive-behavioural therapy (CBT) for depression. Adults with depression (operationalized as PHQ-9 score ≥ 10), recruited directly from the internet and from an UK National Health Service Improving Access to Psychological Therapies service, will be randomized across seven experimental factors, each reflecting the presence versus absence of specific treatment components (activity scheduling, functional analysis, thought challenging, relaxation, concreteness training, absorption, self-compassion training) using a 32-condition balanced fractional factorial design (2IV(7-2)). The primary outcome is symptoms of depression (PHQ-9) at 12 weeks. Secondary outcomes include symptoms of anxiety and process measures related to hypothesized mechanisms. DISCUSSION: Better understanding of the active ingredients of efficacious therapies, such as CBT, is necessary in order to improve and further disseminate these interventions. This study is the first application of a component selection experiment to psychological interventions in depression and will enable us to determine the main effect of each treatment component and its relative efficacy, and cast light on underlying mechanisms, so that we can systematically enhance internet CBT. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24117387 . Registered 26 August 2014.Funding for this trial is provided by grants from the Cornwall NHS Foundation Trust and South West Peninsula Academic Health Research Network to EW. LC is supported by United States National Institutes of Health grants P50DA039838, P01CA180945, R01DK097364, and R01AA022931

Daily relationships among maternal rumination, mood and bonding with infant

This is the final version. Available on open access from Elsevier via the DOI in this recordData availability: The authors do not have permission to share data.There is little research examining the association between maternal maladaptive emotion regulation strategies such as rumination and perceived maternal bonding and mood. This study investigated the concurrent and prospective relationship of both trait and daily rumination with daily perceived maternal bonding and mood. Ninety-three mothers of infants aged between 3 and 14 months completed a ten-day diary study investigating the relationship between daily and trait ruminative self-focus, negative affect and perceived maternal bonding, or her perceived feelings of closeness with her infant. The majority of mothers reported mild to moderate depressive symptoms. The data were analysed using Hierarchical Linear Modelling. Baseline depressive symptoms and trait rumination were each positively associated with mean levels of daily ruminative self-focus and mood over the ten-day sampling period. Bonding with infant at baseline was not associated with mean levels of daily rumination, mood or bonding over the sampling period. Concurrently, daily rumination and daily bonding were negatively correlated, after accounting for daily mood. Prospectively, lower levels of daily bonding predicted increases in daily rumination and depressive mood on the subsequent day. Interestingly, daily rumination did not predict increases in depressive mood or bonding on the subsequent day, suggesting that rumination occurred in response to perceived disruptions in feelings of closeness with the infant, but did not lead to prospective decreases in these feelings of closeness. These findings hold important implications for understanding the relationship between the mother-infant relationship, and maternal rumination and depressive mood, suggesting that disruptions in the way mothers perceive they are bonding to their infants may contribute to depressongenic processes.University of Exete

Investigation of active ingredients within internet cognitive-behavioral therapy for depression: a randomized optimization trial

This is the author accepted manuscript. The final version is available from the American Medical Association via the DOI in this recordIMPORTANCE: There is limited understanding of how complex evidence-based psychological interventions such as cognitive behavioral therapy (CBT) for depression work. Identifying active ingredients may help to make therapy more potent, brief, and scalable. OBJECTIVE: To test the individual main effects and interactions of 7 treatment components within internet-delivered CBT for depression to investigate its active ingredients. DESIGN, SETTING, AND PARTICIPANTS: This randomized optimization trial using a 32-condition, balanced, fractional factorial optimization experiment (IMPROVE-2) recruited adults with depression (Patient Health Questionnaire-9 [PHQ-9] score ≥10) from internet advertising and the UK National Health Service Improving Access to Psychological Therapies service. Participants were randomized from July 7, 2015, to March 29, 2017, with follow-up for 6 months after treatment until December 29, 2017. Data were analyzed from July 2018 to April 2023. INTERVENTIONS: Participants were randomized with equal probability to 7 experimental factors within the internet CBT platform, each reflecting the presence vs absence of specific treatment components (activity scheduling, functional analysis, thought challenging, relaxation, concreteness training, absorption, and self-compassion training). MAIN OUTCOMES AND MEASURES: The primary outcome was depression symptoms (PHQ-9 score). Secondary outcomes include anxiety symptoms and work, home, and social functioning. RESULTS: Among 767 participants (mean age [SD] age, 38.5 [11.62] years; range, 18-76 years; 635 women [82.8%]), 506 (66%) completed the 6-month posttreatment follow-up. On average, participants receiving internet-delivered CBT had reduced depression (pre-to-posttreatment difference in PHQ-9 score, -7.79 [90% CI, -8.21 to -7.37]; 6-month follow-up difference in PHQ-9 score, -8.63 [90% CI, -9.04 to -8.22]). A baseline score-adjusted analysis of covariance model using effect-coded intervention variables (-1 or +1) found no main effect on depression symptoms for the presence vs absence of activity scheduling, functional analysis, thought challenging, relaxation, concreteness training, or self-compassion training (posttreatment: largest difference in PHQ-9 score [functional analysis], -0.09 [90% CI, -0.56 to 0.39]; 6-month follow-up: largest difference in PHQ-9 score [relaxation], -0.18 [90% CI, -0.61 to 0.25]). Only absorption training had a significant main effect on depressive symptoms at 6-month follow-up (posttreatment difference in PHQ-9 score, 0.21 [90% CI, -0.27 to 0.68]; 6-month follow-up difference in PHQ-9 score, -0.54, [90% CI, -0.97 to -0.11]). CONCLUSIONS AND RELEVANCE: In this randomized optimization trial, all components of internet-delivered CBT except absorption training did not significantly reduce depression symptoms relative to their absence despite an overall average reduction in symptoms. The findings suggest that treatment benefit from internet-delivered CBT probably accrues from spontaneous remission, factors common to all CBT components (eg, structure, making active plans), and nonspecific therapy factors (eg, positive expectancy), with the possible exception of absorption focused on enhancing direct contact with positive reinforcers. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN24117387.Cornwall Partnership NHS Foundation TrustSouth West Academic Health Science Networ

Validation of a 5-item Tool to Measure Patient Assessment of Clinician Compassion in the Emergency Department.

BACKGROUND: To test if the 5-item compassion measure (a tool previously validated in the outpatient setting to measure patient assessment of clinician compassion) is a valid and reliable tool to quantify a distinct construct (i.e. clinical compassion) among patients evaluated in the emergency department (ED). METHODS: Cross-sectional study conducted in three academic emergency departments in the U.S. between November 2018 and April 2019. We enrolled adult patients who were evaluated in the EDs of the participating institutions and administered the 5-item compassion measure after completion of care in the ED. Validity testing was performed using confirmatory factor analysis. Cronbach\u27s alpha was used to test reliability. Convergent validity with patient assessment of overall satisfaction questions was tested using Spearman correlation coefficients and we tested if the 5-item compassion measure assessed a construct distinct from overall patient satisfaction using confirmatory factor analysis. RESULTS: We analyzed 866 patient responses. Confirmatory factor analysis found all five items loaded well on a single construct and our model was found to have good fit. Reliability was excellent (Cronbach\u27s alpha = 0.93) among the entire cohort. These results remained consistent on sub-analyses stratified by individual institutions. The 5-item compassion measure had moderate correlation with overall patient satisfaction (r = 0.66) and patient recommendation of the ED to friends and family (r = 0.57), but reflected a patient experience domain (i.e. compassionate care) distinctly different from patient satisfaction. CONCLUSIONS: The 5-item compassion measure is a valid and reliable tool to measure patient assessment of clinical compassion in the ED

Transplantation of canine olfactory ensheathing cells producing chondroitinase ABC promotes chondroitin sulphate proteoglycan digestion and axonal sprouting following spinal cord injury

Olfactory ensheathing cell (OEC) transplantation is a promising strategy for treating spinal cord injury (SCI), as has been demonstrated in experimental SCI models and naturally occurring SCI in dogs. However, the presence of chondroitin sulphate proteoglycans within the extracellular matrix of the glial scar can inhibit efficient axonal repair and limit the therapeutic potential of OECs. Here we have used lentiviral vectors to genetically modify canine OECs to continuously deliver mammalian chondroitinase ABC at the lesion site in order to degrade the inhibitory chondroitin sulphate proteoglycans in a rodent model of spinal cord injury. We demonstrate that these chondroitinase producing canine OECs survived at 4 weeks following transplantation into the spinal cord lesion and effectively digested chondroitin sulphate proteoglycans at the site of injury. There was evidence of sprouting within the corticospinal tract rostral to the lesion and an increase in the number of corticospinal axons caudal to the lesion, suggestive of axonal regeneration. Our results indicate that delivery of the chondroitinase enzyme can be achieved with the genetically modified OECs to increase axon growth following SCI. The combination of these two promising approaches is a potential strategy for promoting neural regeneration following SCI in veterinary practice and human patients

Integral elastic, electronic-state, ionization, and total cross sections for electron scattering with furfural

We report absolute experimental integral cross sections (ICSs) for electron impact excitation of bands of electronic-states in furfural, for incident electron energies in the range 20-250 eV. Wherever possible, those results are compared to corresponding excitation cross sections in the structurally similar species furan, as previously reported by da Costa et al. [Phys. Rev. A 85, 062706 (2012)] and Regeta and Allan [Phys. Rev. A 91, 012707 (2015)]. Generally, very good agreement is found. In addition, ICSs calculated with our independent atom model (IAM) with screening corrected additivity rule (SCAR) formalism, extended to account for interference (I) terms that arise due to the multi-centre nature of the scattering problem, are also reported. The sum of those ICSs gives the IAM-SCAR+I total cross section for electron-furfural scattering. Where possible, those calculated IAM-SCAR+I ICS results are compared against corresponding results from the present measurements with an acceptable level of accord being obtained. Similarly, but only for the band I and band II excited electronic states, we also present results from our Schwinger multichannel method with pseudopotentials calculations. Those results are found to be in good qualitative accord with the present experimental ICSs. Finally, with a view to assembling a complete cross section data base for furfural, some binary-encounter-Bethe-level total ionization cross sections for this collision system are presented. (C) 2016 AIP Publishing LLC

Results from an 18 country cross-sectional study examining experiences of nature for people with common mental health disorders

This is the final version. Available on open access from Nature Research via the DOI in this recordExposure to natural environments is associated with a lower risk of common mental health disorders (CMDs), such as depression and anxiety, but we know little about nature-related motivations, practices and experiences of those already experiencing CMDs. We used data from an 18-country survey to explore these issues (n = 18,838), taking self-reported doctor-prescribed medication for depression and/or anxiety as an indicator of a CMD (n = 2698, 14%). Intrinsic motivation for visiting nature was high for all, though slightly lower for those with CMDs. Most individuals with a CMD reported visiting nature ≥ once a week. Although perceived social pressure to visit nature was associated with higher visit likelihood, it was also associated with lower intrinsic motivation, lower visit happiness and higher visit anxiety. Individuals with CMDs seem to be using nature for self-management, but ‘green prescription’ programmes need to be sensitive, and avoid undermining intrinsic motivation and nature-based experiences.European Union Horizon 202

hERG1a N-terminal eag domain–containing polypeptides regulate homomeric hERG1b and heteromeric hERG1a/hERG1b channels: A possible mechanism for long QT syndrome

Human ether-á-go-go–related gene (hERG) potassium channels are critical for cardiac action potential repolarization. Cardiac hERG channels comprise two primary isoforms: hERG1a, which has a regulatory N-terminal Per-Arnt-Sim (PAS) domain, and hERG1b, which does not. Isolated, PAS-containing hERG1a N-terminal regions (NTRs) directly regulate NTR-deleted hERG1a channels; however, it is unclear whether hERG1b isoforms contain sufficient machinery to support regulation by hERG1a NTRs. To test this, we constructed a series of PAS domain–containing hERG1a NTRs (encoding amino acids 1–181, 1–228, 1–319, and 1–365). The NTRs were also predicted to form from truncation mutations that were linked to type 2 long QT syndrome (LQTS), a cardiac arrhythmia disorder associated with mutations in the hERG gene. All of the hERG1a NTRs markedly regulated heteromeric hERG1a/hERG1b channels and homomeric hERG1b channels by decreasing the magnitude of the current–voltage relationship and slowing the kinetics of channel closing (deactivation). In contrast, NTRs did not measurably regulate hERG1a channels. A short NTR (encoding amino acids 1–135) composed primarily of the PAS domain was sufficient to regulate hERG1b. These results suggest that isolated hERG1a NTRs directly interact with hERG1b subunits. Our results demonstrate that deactivation is faster in hERG1a/hERG1b channels compared to hERG1a channels because of fewer PAS domains, not because of an inhibitory effect of the unique hERG1b NTR. A decrease in outward current density of hERG1a/hERG1b channels by hERG1a NTRs may be a mechanism for LQTS

Effect of supplemental Ca2+ on NaCl-stressed castor plants (Ricinus communis L.)

Greenhouse experiments were conducted to assess the effects of supplemental Ca2+ in salinised soil on germination and plant growth response of castor plant (Ricinus communis L. Var. Avani-31, Euphorbiaceae). NaCl amounting to 390 g was thoroughly mixed with soil of seven lots, of 100 kg each, to give electrical conductivity of 4.1 dS m–1. Further, Ca(NO3)2 × 4H20 to the quantity of 97.5, 195, 292.5, 390, 487.5, and 585 g was separately mixed with soil of six lots to give 1:0.25, 1:0.50, 1:0.75, 1:1, 1:1.25, and 1:1.50 Na+/Ca2+ ratios, respectively. The soil of the seventh lot contained only NaCl and its Na+/Ca2+ ratio was 1:0. Soil without addition of NaCl and Ca (NO3)2 × 4H20 served as control, with a 0:0 Na+/Ca2+ ratio. Salinity significantly retarded seed germination and plant growth, but the deleterious effects of NaCl on seed germination were ameliorated and plant growth was restored with Ca2+ supply at the critical level (1:0.25 Na+/Ca2+ ratio) to salinised soil. Supply of Ca2+ above the critical level further retarded seed germination and plant growth due to the increased soil salinity. Salt stress reduced N, P, K+ and Ca2+ content in plant tissues, but these nutrients were restored by addition of Ca2+ at the critical level to saline soil. In contrast, Na+ content in plant tissues significantly increased in response to salinity, but significantly decreased with increasing Ca2+ supply to saline soil. The results are discussed in terms of the beneficial effects of Ca2+ supply on the plant growth of Ricinus communis grown under saline conditions

Stable Cytotoxic T Cell Escape Mutation in Hepatitis C Virus Is Linked to Maintenance of Viral Fitness

Mechanisms by which hepatitis C virus (HCV) evades cellular immunity to establish persistence in chronically infected individuals are not clear. Mutations in human leukocyte antigen (HLA) class I-restricted epitopes targeted by CD8+ T cells are associated with persistence, but the extent to which these mutations affect viral fitness is not fully understood. Previous work showed that the HCV quasispecies in a persistently infected chimpanzee accumulated multiple mutations in numerous class I epitopes over a period of 7 years. During the acute phase of infection, one representative epitope in the C-terminal region of the NS3/4A helicase, NS31629-1637, displayed multiple serial amino acid substitutions in major histocompatibility complex (MHC) anchor and T cell receptor (TCR) contact residues. Only one of these amino acid substitutions at position 9 (P9) of the epitope was stable in the quasispecies. We therefore assessed the effect of each mutation observed during in vivo infection on viral fitness and T cell responses using an HCV subgenomic replicon system and a recently developed in vitro infectious virus cell culture model. Mutation of a position 7 (P7) TCR-contact residue, I1635T, expectedly ablated the T cell response without affecting viral RNA replication or virion production. In contrast, two mutations at the P9 MHC-anchor residue abrogated antigen-specific T cell responses, but additionally decreased viral RNA replication and virion production. The first escape mutation, L1637P, detected in vivo only transiently at 3 mo after infection, decreased viral production, and reverted to the parental sequence in vitro. The second P9 variant, L1637S, which was stable in vivo through 7 years of follow-up, evaded the antigen-specific T cell response and did not revert in vitro despite being less optimal in virion production compared to the parental virus. These studies suggest that HCV escape mutants emerging early in infection are not necessarily stable, but are eventually replaced with variants that achieve a balance between immune evasion and fitness for replication