Polygenic contributions to performance on the Balloon Analogue Risk Task.

Risky decision-making is a common, heritable endophenotype seen across many psychiatric disorders. Its underlying genetic architecture is incompletely explored. We examined behavior in the Balloon Analogue Risk Task (BART), which tests risky decision-making, in two independent samples of European ancestry. One sample (n = 1138) comprised healthy participants and some psychiatric patients (53 schizophrenia, 42 bipolar disorder, 47 ADHD); the other (n = 911) excluded for recent treatment of various psychiatric disorders but not ADHD. Participants provided DNA and performed the BART, indexed by mean adjusted pumps. We constructed a polygenic risk score (PRS) for discovery in each dataset and tested it in the other as replication. Subsequently, a genome-wide MEGA-analysis, combining both samples, tested genetic correlation with risk-taking self-report in the UK Biobank sample and psychiatric phenotypes characterized by risk-taking (ADHD, Bipolar Disorder, Alcohol Use Disorder, prior cannabis use) in the Psychiatric Genomics Consortium. The PRS for BART performance in one dataset predicted task performance in the replication sample (r = 0.13, p = 0.000012, pFDR = 0.000052), as did the reciprocal analysis (r = 0.09, p = 0.0083, pFDR=0.04). Excluding participants with psychiatric diagnoses produced similar results. The MEGA-GWAS identified a single SNP (rs12023073; p = 3.24 × 10-8) near IGSF21, a protein involved in inhibitory brain synapses; replication samples are needed to validate this result. A PRS for self-reported cannabis use (p = 0.00047, pFDR = 0.0053), but not self-reported risk-taking or psychiatric disorder status, predicted behavior on the BART in our MEGA-GWAS sample. The findings reveal polygenic architecture of risky decision-making as measured by the BART and highlight its overlap with cannabis use.

LUCAS Device Use Associated with Prolonged Pauses during Application and Long Chest Compression Intervals.

BACKGROUND: Tenets of high-quality out-of-hospital cardiac arrest (OHCA) resuscitation include early recognition and treatment of shockable rhythms, and minimizing interruptions in compressions. Little is known about how use of a mechanical compression device affects these elements. We hypothesize that use of such a device is associated with prolonged pauses in compressions to apply the device, and long compression intervals overall. METHODS: We systematically abstracted CPR metrics from 4 months of adult non-traumatic OHCA cases, each of which had at least 10 minutes of resuscitation, used a LUCAS device, and had a valid monitor file attached to the patient care report. Our primary outcomes of interest were the duration of each pause in compressions and the duration of compressions between pauses, stratified by whether or not the LUCAS device was used/applied during the segment. Each pause was further evaluated for a possible associated procedure based on pre-defined criteria. Descriptive statistics, chi-square, and Kruskal-Wallis tests were used as appropriate. RESULTS: Fifty-eight cases were included, median age 62.5 years (IQR 49.3-70.8), 47% female, 66% nonwhite. Overall, 633 compression-pause segments were analyzed (517 with and 116 without LUCAS applied). Spacing of pauses was significantly longer with the LUCAS than without [median (IQR) 133 (82-213) seconds vs. 38 (18-62) seconds, p < 0.05]. When using a LUCAS, compressions were continuous for at least 3 min in 166/517 segments, at least 4 min in 89/517 segments, and at least 5 min in 56/517 segments. Without a LUCAS, compressions were longer than 3 min in 7/116 segments. Pauses exceeded 10 s more frequently with LUCAS application (32/38) than airway management or defibrillation (27/80, p < 0.05). Peri-LUCAS pauses exceeded 30 s in 6/38 cases. CONCLUSION: LUCAS use was associated with long compression intervals without identifiable pauses to assess for pulse or cardiac rhythm, and device application was associated with longer pauses than airway management or defibrillation. The clinical significance and effect on patient outcomes remain uncertain and require further study.

Challenges in αCD38-chimeric antigen receptor (CAR)-expressing natural killer (NK) cell-based immunotherapy in multiple myeloma: Harnessing the CD38dim phenotype of cytokine-stimulated NK cells as a strategy to prevent fratricide.

BACKGROUND AIMS: Adoptive cell therapy with chimeric antigen receptor (CAR)-expressing natural killer (NK) cells is an emerging approach that holds promise in multiple myeloma (MM). However, the generation of CAR-NK cells targeting CD38 is met with obstacles due to the expression of CD38 on NK cells. Knock-out of CD38 is currently explored as a strategy, although the consequences of the lack of CD38 expression with regards to engraftment and activity in the bone marrow microenvironment are not fully elucidated. Here, we present an alternative approach by harnessing the CD38dim phenotype occurring during long-term cytokine stimulation of primary NK cells. METHODS: Primary NK cells were expanded from peripheral blood mononuclear cells by long-term IL-2 stimulation. During expansion, the CD38 expression was monitored in order to identify a time point when introduction of a novel affinity-optimized αCD38-CAR confered optimal viability, i.e. prevented fratricide. CD38dim NK cells were trasduced with retroviral vectors encoding for the CAR trasngene and their functionality was assessed in in vitro activation and cytotoxicity assays. RESULTS: We verified the functionality of the αCD38-CAR-NK cells against CD38+ cell lines and primary MM cells. Importantly, we demonstrated that αCD38-CAR-NK cells derived from patients with MM have increased activity against autologous MM samples ex vivo. CONCLUSIONS: Overall, our results highlight that incorporation of a functional αCD38-CAR construct into a suitable NK-cell expansion and activation protocol results in a potent and feasible immunotherapeutic strategy for the treatment of patients with MM.

Co-designed weight management intervention for women recovering from oestrogen-receptor positive breast cancer.

BACKGROUND: Weight gain is commonly observed during and after breast cancer treatment and is associated with poorer survival outcomes, particularly in women with oestrogen receptor-positive (ER +) disease. The aim of this study was to co-design (with patients) a programme of tailored, personalised support (intervention), including high-quality support materials, to help female breast cancer patients (BCPs) with ER + disease to develop the skills and confidence needed for sustainable weight loss.  METHODS: ER + BCPs were recruited from two UK National Health Service (NHS) Trusts. The selection criteria included (i) recent experience of breast cancer treatment (within 36 months of completing primary treatment); (ii) participation in a recent focus group study investigating weight management perceptions and experiences; (iii) willingness to share experiences and contribute to discussions on the support structures needed for sustainable dietary and physical activity behaviour change. Co-design workshops included presentations and interactive activities and were facilitated by an experienced co-design researcher (HH), assisted by other members of the research team (KP, SW and JS). RESULTS: Two groups of BCPs from the North of England (N = 4) and South Yorkshire (N = 5) participated in a two-stage co-design process. The stage 1 and stage 2 co-design workshops were held two weeks apart and took place between Jan-March 2019, with each workshop being approximately 2 h in duration. Guided by the Behaviour Change Wheel, a theoretically-informed weight management intervention was developed on the basis of co-designed strategies to overcome physical and emotional barriers to dietary and physical activity behaviour change. BCPs were instrumental in designing all key features of the intervention, in terms of Capability (e.g., evidence-based information, peer-support and shared experiences), Opportunity (e.g., flexible approach to weight management based on core principles) and Motivation (e.g., appropriate use of goal-setting and high-quality resources, including motivational factsheets) for behaviour change. CONCLUSION: This co-design approach enabled the development of a theoretically-informed intervention with a content, structure and delivery model that has the potential to address the weight management challenges faced by BCPs diagnosed with ER + disease. Future research is required to evaluate the effectiveness of the intervention for eliciting clinically-important and sustainable weight loss in this population.

Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial.

BACKGROUND: Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously. PATIENTS AND METHODS: Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer. RESULTS: In the OSP (n = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n = 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1∗28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1∗1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n = 1/11; 9.1% ORR). CONCLUSIONS: SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.

The art and science of priority-setting: assessing the value of Public Health England's Prioritization Framework.

BACKGROUND: Findings are presented from the evaluation of Public Health England's (PHE) Prioritization Framework (PF) aimed to assist local authority commissioners with their public health investment and disinvestment decisions. The study explored the take up of the PF in three early adopter local authority settings. METHODS: Semi-structured interviews (n = 30) across three local authorities supplemented by participant observation of workshops. RESULTS: Participants acknowledged that the PF provided a systematic means of guiding priority-setting and one that encouraged transparency over investment and disinvestment decisions. The role performed by PHE and its regional teams in facilitating the process was especially welcomed and considered critical to the adoption process. However, uptake of the PF required a significant investment of time and commitment from public health teams at a time when resources were stretched. The impact of the political environment in the local government was a major factor determining the likely uptake of the PF. Ensuring committed leadership and engagement from senior politicians and officers was regarded as critical to success. CONCLUSIONS: The study assessed the value and impact of PHE's PF tool in three early adopter local authorities. Further research could explore the value of the tool in aiding investment and disinvestment decisions and its impact on spending.

Hemocytic sarcoma of the body wall in a California king crab Paralithodes californiensis.

Neoplasia is rarely reported in decapod crustaceans, and sarcoma has not been previously reported in any crab species. A California king crab Paralithodes californiensis with a recent history of autotomy (4 legs lost) and anorexia was found dead. Grossly, the crab had a pigmented ulcer on the right cheliped merus. Necropsy tissue samples were placed in 10% neutral buffered formalin and processed routinely for histology. Both histochemical (i.e. Brown and Brenn Gram, Fite-Faraco acid fast, Fontana-Masson, Giemsa, hematoxylin and eosin, Masson's trichrome, periodic acid-Schiff [PAS], phosphotungstic acid-hematoxylin, and von Kossa) and immunohistochemical (i.e. cytokeratin, vimentin, and lysozyme) stains were performed. The body wall (presumably of the right cheliped merus) was ulcerated and subtended by a densely cellular, unencapsulated, invasive neoplasm composed of spindle cells arranged in intersecting streams and bundles embedded in a small to moderate amount of fibromatous stroma. Neoplastic cells were oval to elongate with fibrillar, pale eosinophilic cytoplasm that occasionally contained moderate numbers of small, spherical, brightly eosinophilic granules that were highlighted with PAS and Giemsa stains. Neoplastic cells had mild atypia and no evident mitoses. Immunohistochemical stains were noncontributory. This neoplasm is consistent with hemocytic sarcoma of semi-granulocytic origin. Decapod crustaceans have 3 types of hemocytes: hyalinocytes, granulocytes, and semi-granulocytes. Neoplastic cells had PAS- and Giemsa-positive granules, which are present in both semi-granulocytes and granulocytes. Semi-granulocytes can elongate and are associated with deposition of extracellular matrix during some immune responses. Neoplastic cells were elongate and associated with deposition of matrix. These findings suggest neoplastic cells were of semi-granulocytic origin.

Patient preferences of chemotherapy treatment options and tolerance of chemotherapy side effects in advanced stage lung cancer.

BACKGROUND: In the U.S., lung cancer accounts for 14% of cancer diagnoses and 28% of cancer deaths annually. Since no cure exists for advanced lung cancer, the main treatment goal is to prolong survival. Chemotherapy regimens produce side effects with different profiles. Coupling this with individual patient's preferred side effects could result in patient-centered choices leading to better treatment outcomes. There are apparently no previous studies of or tools for assessing and utilizing patient chemotherapy preferences in clinical settings. The long-term goal of the study was to facilitate patients' treatment choices for advanced-stage lung cancer. A primary aim was to determine how preferences for chemotherapy side effects relate to chemotherapy choices. METHODS: An observational, longitudinal, open cohort study of patients with advanced-stage non-small cell lung cancer (NSCLC) was conducted. Data sources included patient medical records and from one to three interviews per subject. Data were analyzed using Chi-square, Fisher's Exact and McNamara's test, and logistic regression. RESULTS: Patients identified the top three chemotherapy side effects that they would most like to avoid: shortness of breath, bleeding, and fatigue. These side effects were similar between first and last interviews, although the rank order changed after patients experienced chemotherapy. CONCLUSIONS: Patients ranked drug side effects that they would most like to avoid. Patient-centered clinical care and patient-centered outcomes research are feasible and may be enhanced by stakeholder commitment. The study results are limited to patients with advanced NSCLC. Most of the subjects were White, since patients were drawn from the U.S. Midwest, a predominantly White population.

Translational profiling of stress-induced neuroplasticity in the CA3 pyramidal neurons of BDNF Val66Met mice.

Genetic susceptibility and environmental factors (such as stress) can interact to affect the likelihood of developing a mood disorder. Stress-induced changes in the hippocampus have been implicated in mood disorders, and mutations in several genes have now been associated with increased risk, such as brain-derived neurotrophic factor (BDNF). The hippocampus has important anatomical subdivisions, and pyramidal neurons of the vulnerable CA3 region show significant remodeling after chronic stress, but the mechanisms underlying their unique plasticity remain unknown. This study characterizes stress-induced changes in the in vivo translating mRNA of this cell population using a CA3-specific enhanced green fluorescent protein (EGFP) reporter fused to the L10a large ribosomal subunit (EGFPL10a). RNA-sequencing after isolation of polysome-bound mRNAs allows for cell-type-specific, genome-wide characterization of translational changes after stress. The data demonstrate that acute and chronic stress produce unique translational profiles and that the stress history of the animal can alter future reactivity of CA3 neurons. CA3-specific EGFPL10a mice were then crossed to the stress-susceptible BDNF Val66Met mouse line to characterize how a known genetic susceptibility alters both baseline translational profiles and the reactivity of CA3 neurons to stress. Not only do Met allele carriers exhibit distinct levels of baseline translation in genes implicated in ion channel function and cytoskeletal regulation, but they also activate a stress response profile that is highly dissimilar from wild-type mice. Closer examination of genes implicated in the mechanisms of neuroplasticity, such as the NMDA and AMPA subunits and the BDNF pathway, reveal how wild-type mice upregulate many of these genes in response to stress, but Met allele carriers fail to do so. These profiles provide a roadmap of stress-induced changes in a genetically homogenous population of hippocampal neurons and illustrate the profound effects of gene-environment interactions on the translational profile of these cells.

Host identification in unfed ticks from stable isotope compositions (δ13 C and δ15 N).

Determination of the ratios of natural stable isotopes (13 C/12 C and 15 N/14 N) in unfed Ixodes ricinus nymphs and adults, which, in their previous stage, fed on captive wild rodents (Apodemus sylvaticus and Myodes glareolus), wild birds (Parus major and Cyanistes caeruleus) or domestic ruminants (Ovis aries and Bos taurus), demonstrated that it is possible to identify each host category with confidence. First, the tick-blood spacing, which is the difference between values obtained from ticks and the blood of hosts that they had fed on in the previous stage, was consistent (152 spacings investigated from 15 host individuals in total). Second, potential confounding factors (tick age and sex) did not affect the discriminatory power of the isotope patterns, nor did different rearing conditions (room temperature vs. 4 °C) or the duration of development (maximum of 430 days). The findings that the tick-blood isotope spacings, across a diverse range of hosts, were similar and predictable, and that confounders had little or no effect on this, strongly support the usage of the isotope approach. Because each of the host categories has a different role in the population dynamics of I. ricinus and in tick-borne pathogen ecology, the method described here has great potential for the clarification of tick and tick-borne pathogen ecology in the field.

Establishing gold standards for System-Level Measures: a modified Delphi consensus process.

OBJECTIVE: To establish aspirational 'gold standards' for a suite of System-Level Measures (SLMs) being used by Counties Manukau Health (CM Health), a New Zealand (NZ) District Health Board. DESIGN: This study employed a multi-stage, multi-method modified Delphi consensus process. SETTING: The Delphi consensus process involved virtual (email) communication between participants (Round 1) and a structured face-to-face meeting (Round 2) held in Auckland, NZ. PARTICIPANTS: Participants comprised of health professionals, managers, academics and quality improvement experts with an interest in the use of SLMs. INTERVENTIONS: Participants in the first round received a letter requesting their participation in an anonymous Delphi. The second round involved national and international health system experts taking part in a structured, facilitated face-to-face meeting. Participants reviewed 15 SLMs in total. The SLMs all related to the three domains of the Triple Aim: Population Health, e.g. life expectancy at birth; Patient Experience of Care, e.g. rate of adverse events; and Cost and Productivity, e.g. healthcare expenditure per capita. MAIN OUTCOME MEASURES: For a proposed gold standard to be agreed and established for each SLM. RESULTS: Twelve participants took part in Round 1, with 19 participating in Round 2. The process established agreement on a gold standard for each of the 15 reviewed SLMs. CONCLUSION: We demonstrated that the Delphi consensus process can be used to establish gold standards for a suite of SLMs used by a NZ Health Board (CM Health).

Age and Alzheimer's disease gene expression profiles reversed by the glutamate modulator riluzole.

Alzheimer's disease (AD) and age-related cognitive decline represent a growing health burden and involve the hippocampus, a vulnerable brain region implicated in learning and memory. To understand the molecular effects of aging on the hippocampus, this study characterized the gene expression changes associated with aging in rodents using RNA-sequencing (RNA-seq). The glutamate modulator, riluzole, which was recently shown to improve memory performance in aged rats, prevented many of the hippocampal age-related gene expression changes. A comparison of the effects of riluzole in rats against human AD data sets revealed that many of the gene changes in AD are reversed by riluzole. Expression changes identified by RNA-Seq were validated by qRT-PCR open arrays. Riluzole is known to increase the glutamate transporter EAAT2's ability to scavenge excess glutamate, regulating synaptic transmission. RNA-seq and immunohistochemistry confirmed an increase in EAAT2 expression in hippocampus, identifying a possible mechanism underlying the improved memory function after riluzole treatment.

Improving medication safety for home nursing clients: A prospective observational study of a novel clinical pharmacy service-The Visiting Pharmacist (ViP) study.

WHAT IS KNOWN AND OBJECTIVE: Polypharmacy, medication errors and adverse events are common in older people receiving home nursing medication management support. Access to clinical pharmacists is limited. In Australia, few home nursing clients receive a general practitioner (GP)-initiated pharmacist-led Home Medicines Review, despite their eligibility and community nurses' (CN) efforts to facilitate this. An integrated home nursing clinical pharmacy service, in which CNs directly referred clients to a pharmacist, was therefore developed and piloted. The aim was to explore the number and type of medication-related problems (MRPs) and medication treatment authorization (medication order) discrepancies identified and addressed by clinical pharmacists. METHODS: Two part-time clinical pharmacists were employed. They reviewed and reconciled clients' medications, educated clients/carers about their medicines, provided advice and support to CNs and worked with clients' GPs and other prescribers to optimize medication regimens and revise/update nurses' medication treatment authorizations. Evaluation involved review of clients' medicines data, including treatment authorizations and pharmacist medication review reports. RESULTS AND DISCUSSION: Eighty-four clients (median 86 years, 6 health conditions, 13 medications) were reviewed. The pharmacists identified 334 MRPs (median 4 per client) and 307 medication discrepancies in treatment authorizations (median 2 per client). The pharmacists made 282 recommendations to prescribers to address MRPs; 148 (52.5%) recommendations were acted on, resulting in 190 medication changes for 60 (71.4%) clients (median 2 per client). The pharmacists prepared, or assisted GPs to update, treatment authorizations for 68 (81%) clients. WHAT IS NEW AND CONCLUSION: Integrating pharmacists into a home nursing service identified and addressed MRPs and medication treatment authorization discrepancies, hence contributing to enhanced medication safety.

Randomized feasibility trial of high-intensity interval training before elective abdominal aortic aneurysm repair.

BACKGROUND: This study assessed the feasibility of a preoperative high-intensity interval training (HIT) programme in patients awaiting elective abdominal aortic aneurysm repair. METHODS: In this feasibility trial, participants were allocated by minimization to preoperative HIT or usual care. Patients in the HIT group were offered three exercise sessions per week for 4 weeks, and weekly maintenance sessions if surgery was delayed. Feasibility and acceptability outcomes were: rates of screening, eligibility, recruitment, retention, outcome completion, adverse events and adherence to exercise. Data on exercise enjoyment (Physical Activity Enjoyment Scale, PACES), cardiorespiratory fitness (anaerobic threshold and peak oxygen uptake), quality of life, postoperative morbidity and mortality, duration of hospital stay and healthcare utilization were also collected. RESULTS: Twenty-seven patients were allocated to HIT and 26 to usual care (controls). Screening, eligibility, recruitment, retention and outcome completion rates were 100 per cent (556 of 556), 43·2 per cent (240 of 556), 22·1 per cent (53 of 240), 91 per cent (48 of 53) and 79-92 per cent respectively. The overall exercise session attendance rate was 75·8 per cent (276 of 364), and the mean(s.d.) PACES score after the programme was 98(19) ('enjoyable'); however, the intensity of exercise was generally lower than intended. The mean anaerobic threshold after exercise training (adjusted for baseline score and minimization variables) was 11·7 ml per kg per min in the exercise group and 11·4 ml per kg per min in controls (difference 0·3 (95 per cent c.i. -0·4 to 1·1) ml per kg per min). There were trivial-to-small differences in postoperative clinical and patient-reported outcomes between the exercise and control groups. CONCLUSION: Despite the intensity of exercise being generally lower than intended, the findings support the feasibility and acceptability of both preoperative HIT and the trial procedures. A definitive trial is warranted. Registration number: ISRCTN09433624 ( https://www.isrctn.com/).

Representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering therapies in Type 2 diabetes.

AIMS: Our aim was to investigate the proportional representation of people of South Asian origin in cardiovascular outcome trials of glucose-lowering drugs or strategies in Type 2 diabetes, noting that these are among the most significant pieces of evidence used to formulate the guidelines on which clinical practice is largely based. METHODS: We searched for cardiovascular outcome trials in Type 2 diabetes published before January 2015, and extracted data on the ethnicity of participants. These were compared against expected values for proportional representation of South Asian individuals, based on population data from the USA, from the UK, and globally. RESULTS: Twelve studies met our inclusion criteria and, of these, eight presented a sufficiently detailed breakdown of participant ethnicity to permit numerical analysis. In general, people of South Asian origin were found to be under-represented in trials compared with UK and global expectations and over-represented compared with US expectations. Among the eight trials for which South Asian representation could be reliably estimated, seven under-represented this group relative to the 11.2% of the UK diabetes population estimated to be South Asian, with the representation in these trials ranging from 0.0% to 10.0%. CONCLUSIONS: Clinicians should exercise caution when generalizing the results of trials to their own practice, with regard to the ethnicity of individuals. Efforts should be made to improve reporting of ethnicity and improve diversity in trial recruitment, although we acknowledge that there are challenges that must be overcome to make this a reality.

Clinical effectiveness and cost-effectiveness of foot orthoses for people with established rheumatoid arthritis: an exploratory clinical trial.

OBJECTIVES: Foot orthoses are commonly prescribed as an intervention for people with rheumatoid arthritis (RA). Data relating to the cost-effectiveness of foot orthoses in people with RA are limited. The aim was to evaluate the clinical and cost-effectiveness of two types of foot orthoses in people with established RA. METHOD: A single-blind randomized controlled trial was undertaken to compare custom-made foot orthoses (CMFOs) and simple insoles (SIs) in 41 people with established RA. The Foot Function Index (FFI) was used to measure foot pain, disability, and functional limitation. Costs were estimated from the perspective of the UK National Health Service (NHS), societal (patient and family) perspective, and secondary care resource use in terms of the intervention and staff time. Effects were assessed in terms of health gain expressed as quality-adjusted life years (QALYs). RESULTS: At baseline, 20 participants received a CMFO and 21 participants received an SI. After 16 weeks foot pain improved in both the CMFOs (p = 0.000) and the SIs (p < 0.01). However, disability scores improved for CMFOs (p < 0.001) but not for SIs (p = 0.40). The cost-effectiveness results demonstrated no difference in cost between the arms (CMFOs: £159.10; SIs: £79.10; p = 0.35), with the CMFOs being less effective in terms of cost per QALY gain (p < 0.001). CONCLUSIONS: In people with established RA, semi-rigid customized foot orthoses can improve pain and disability scores in comparison to simple insoles. From a cost-effectiveness perspective, the customized foot orthoses were far more expensive to manufacture, with no significant cost per QALY gain.

Training-Associated Emotional Arousal Shapes Endocannabinoid Modulation of Spatial Memory Retrieval in Rats.

Variations in environmental aversiveness influence emotional memory processes in rats. We have previously shown that cannabinoid effects on memory are dependent on the stress level at the time of training as well as on the aversiveness of the environmental context. Here, we investigated whether the hippocampal endocannabinoid system modulates memory retrieval depending on the training-associated arousal level. Male adult Sprague Dawley rats were trained on a water maze spatial task at two different water temperatures (19°C and 25°C) to elicit either higher or lower stress levels, respectively. Rats trained under the higher stress condition had better memory and higher corticosterone concentrations than rats trained at the lower stress condition. The cannabinoid receptor agonist WIN55212-2 (10-30 ng/side), the 2-arachidonoyl glycerol (2-AG) hydrolysis inhibitor JZL184 (0.1-1 µg/side), and the anandamide (AEA) hydrolysis inhibitor URB597 (10-30 ng/side) were administered bilaterally into the hippocampus 60 min before probe-trial retention testing. WIN55212-2 or JZL184, but not URB597, impaired probe-trial performances only of rats trained at the higher stressful condition. Furthermore, rats trained under higher stress levels displayed an increase in hippocampal 2-AG, but not AEA, levels at the time of retention testing and a decreased affinity of the main 2-AG-degrading enzyme for its substrate. The present findings indicate that the endocannabinoid 2-AG in the hippocampus plays a key role in the selective regulation of spatial memory retrieval of stressful experience, shedding light on the neurobiological mechanisms involved in the impact of stress effects on memory processing. SIGNIFICANCE STATEMENT: Endogenous cannabinoids play a central role in the modulation of memory for emotional events. Here we demonstrate that the endocannabinoid 2-arachidonoylglycerol in the hippocampus, a brain region crucially involved in the regulation of memory processes, selectively modulates spatial memory recall of stressful experiences. Thus, our findings provide evidence that the endocannabinoid 2-arachidonoylglycerol is a key player in mediating the impact of stress on memory retrieval. These findings can pave the way to new potential therapeutic intervention for the treatment of neuropsychiatric disorders, such as post-traumatic stress disorder, where a previous exposure to traumatic events could alter the response to traumatic memory recall leading to mental illness.

Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety.

Corticotropin-releasing hormone (CRH) is a central integrator in the brain of endocrine and behavioral stress responses, whereas activation of the endocannabinoid CB1 receptor suppresses these responses. Although these systems regulate overlapping functions, few studies have investigated whether these systems interact. Here we demonstrate a novel mechanism of CRH-induced anxiety that relies on modulation of endocannabinoids. Specifically, we found that CRH, through activation of the CRH receptor type 1 (CRHR1), evokes a rapid induction of the enzyme fatty acid amide hydrolase (FAAH), which causes a reduction in the endocannabinoid anandamide (AEA), within the amygdala. Similarly, the ability of acute stress to modulate amygdala FAAH and AEA in both rats and mice is also mediated through CRHR1 activation. This interaction occurs specifically in amygdala pyramidal neurons and represents a novel mechanism of endocannabinoid-CRH interactions in regulating amygdala output. Functionally, we found that CRH signaling in the amygdala promotes an anxious phenotype that is prevented by FAAH inhibition. Together, this work suggests that rapid reductions in amygdala AEA signaling following stress may prime the amygdala and facilitate the generation of downstream stress-linked behaviors. Given that endocannabinoid signaling is thought to exert "tonic" regulation on stress and anxiety responses, these data suggest that CRH signaling coordinates a disruption of tonic AEA activity to promote a state of anxiety, which in turn may represent an endogenous mechanism by which stress enhances anxiety. These data suggest that FAAH inhibitors may represent a novel class of anxiolytics that specifically target stress-induced anxiety.

Divergent responses of inflammatory mediators within the amygdala and medial prefrontal cortex to acute psychological stress.

There is now a growing body of literature that indicates that stress can initiate inflammatory processes, both in the periphery and brain; however, the spatiotemporal nature of this response is not well characterized. The aim of this study was to examine the effects of an acute psychological stress on changes in mRNA and protein levels of a wide range of inflammatory mediators across a broad temporal range, in key corticolimbic brain regions involved in the regulation of the stress response (amygdala, hippocampus, hypothalamus, medial prefrontal cortex). mRNA levels of inflammatory mediators were analyzed immediately following 30min or 120min of acute restraint stress and protein levels were examined 0h through 24h post-termination of 120min of acute restraint stress using both multiplex and ELISA methods. Our data demonstrate, for the first time, that exposure to acute psychological stress results in an increase in the protein level of several inflammatory mediators in the amygdala while concomitantly producing a decrease in the protein level of multiple inflammatory mediators within the medial prefrontal cortex. This pattern of changes seemed largely restricted to the amygdala and medial prefrontal cortex, with stress producing few changes in the mRNA or protein levels of inflammatory mediators within the hippocampus or hypothalamus. Consistent with previous research, stress resulted in a general elevation in multiple inflammatory mediators within the circulation. These data indicate that neuroinflammatory responses to stress do not appear to be generalized across brain structures and exhibit a high degree of spatiotemporal specificity. Given the impact of inflammatory signaling on neural excitability and emotional behavior, these data may provide a platform with which to explore the importance of inflammatory signaling within the prefrontocortical-amygdala circuit in the regulation of the neurobehavioral responses to stress.

Deficient adolescent social behavior following early-life inflammation is ameliorated by augmentation of anandamide signaling.

Early-life inflammation has been shown to exert profound effects on brain development and behavior, including altered emotional behavior, stress responsivity and neurochemical/neuropeptide receptor expression and function. The current study extends this research by examining the impact of inflammation, triggered with the bacterial compound lipopolysaccharide (LPS) on postnatal day (P) 14, on social behavior during adolescence. We investigated the role that the endocannabinoid (eCB) system plays in sociability after early-life LPS. To test this, multiple cohorts of Sprague Dawley rats were injected with LPS on P14. In adolescence, rats were subjected to behavioral testing in a reciprocal social interaction paradigm as well as the open field. We quantified eCB levels in the amygdala of P14 and adolescent animals (anandamide and 2-arachidonoylglycerol) as well as adolescent amygdaloid cannabinoid receptor 1 (CB1) binding site density and the hydrolytic activity of the enzyme fatty acid amide hydrolase (FAAH), which metabolizes the eCB anandamide. Additionally, we examined the impact of FAAH inhibition on alterations in social behavior. Our results indicate that P14 LPS decreases adolescent social behavior (play and social non-play) in males and females at P40. This behavioral alteration is accompanied by decreased CB1 binding, increased anandamide levels and increased FAAH activity. Oral administration of the FAAH inhibitor PF-04457845 (1mg/kg) prior to the social interaction task normalizes LPS-induced alterations in social behavior, while not affecting social behavior in the control group. Infusion of 10ng PF-04457845 into the basolateral amygdala normalized social behavior in LPS injected females. These data suggest that alterations in eCB signaling following postnatal inflammation contribute to impairments in social behavior during adolescence and that inhibition of FAAH could be a novel target for disorders involving social deficits such as social anxiety disorders or autism.