Sex differences in pain catastrophizing and its relation to the transition from acute pain to chronic pain.

BACKGROUND AND IMPORTANCE: Differences exist between sexes in pain and pain-related outcomes, such as development of chronic pain. Previous studies suggested a higher risk for pain chronification in female patients. Furthermore, pain catastrophizing is an important risk factor for chronification of pain. However, it is unclear whether sex differences in catastrophic thinking could explain the sex differences in pain chronification. OBJECTIVES: The aim of this study was to examine sex differences in pain catastrophizing. Additionally, we investigated pain catastrophizing as a potential mediator of sex differences in the transition of acute to chronic pain. DESIGN, SETTINGS AND PARTICIPANTS: Adults visiting one of the 15 participating emergency departments in the Netherlands with acute pain-related complaints. Subjects had to meet inclusion criteria and complete questionnaires about their health and pain. OUTCOMES MEASURE AND ANALYSIS: The outcomes in this prospective cohort study were pain catastrophizing (short form pain catastrophizing) and pain chronification at 90 days (Numeric Rating Scale ≥ 1). Data was analysed using univariate and multivariable logistic regression models. Finally, stratified regression analyses were conducted to assess whether differences in pain catastrophizing accounted for observed differences in pain chronification between sexes. MAIN RESULTS: In total 1,906 patients were included. Females catastrophized pain significantly more than males (p < 0.001). Multiple regression analyses suggested that pain catastrophizing is associated with pain chronification in both sexes. CONCLUSIONS: This study reported differences between sexes in catastrophic cognitions in the development of chronic pain. This is possibly of clinical importance to identify high-risk patients and ensure an early intervention to prevent the transition from acute to chronic pain.

Head and neck exam practices of dental professionals.

OBJECTIVE: Periodic examination of the head and neck includes screening for oral cancer, which is largely performed in dental offices by vigilant oral healthcare providers. The aim of this study was to assess practice patterns among Virginia dentists in performing head and neck exams and the referral rates of biopsies after completion of head and neck exams. We hypothesized that not all dentists perform head and neck exams and there is a difference between dentists who refer patients for a biopsy and those that perform biopsies. METHODS: General dentists and dental specialists who are members of the Virginia Dental Association were invited to participate in a cross-sectional survey study through REDCap to self-report their head and neck exam protocols. RESULTS: A total of 224 providers completed the survey. The majority of respondents were general dentists with more than 20 years in practice, who practice in a private setting, and see more than 10 patients in a day. All respondents stated they perform intraoral examinations, but 10 respondents stated they do not perform extraoral examinations. Nearly a third of respondents reported doing their own biopsies. CONCLUSIONS: Although only 8.5% of oral healthcare providers in Virginia responded to our survey, respondents are following the 2017 ADA good practice statement by providing their patients with head and neck exams to screen for oral cancer. Additional education pertaining to extraoral anatomy, malignant transformation of oral potentially malignant disorders, and pathology procedures may be helpful to clinicians.

Valaciclovir for Epstein-Barr Virus Suppression in Moderate-to-Severe COPD: A Randomized Double-Blind Placebo-Controlled Trial.

BACKGROUND: Epstein-Barr virus (EBV) frequently is measured at high levels in COPD using sputum quantitative polymerase chain reaction, whereas airway immunohistochemistry analysis has shown EBV detection to be common in severe disease. RESEARCH QUESTION: Is valaciclovir safe and effective for EBV suppression in COPD? STUDY DESIGN AND METHODS: The Epstein-Barr Virus Suppression in COPD (EViSCO) trial was a randomized double-blind placebo-controlled trial conducted at the Mater Hospital Belfast, Northern Ireland. Eligible patients had stable moderate-to-severe COPD and sputum EBV (measured using quantitative polymerase chain reaction) and were assigned randomly (1:1) to valaciclovir (1 g tid) or matching placebo for 8 weeks. The primary efficacy outcome was sputum EBV suppression (defined as ≥ 90% sputum viral load reduction) at week 8. The primary safety outcome was the incidence of serious adverse reactions. Secondary outcome measures were FEV1 and drug tolerability. Exploratory outcomes included changes in quality of life, sputum cell counts, and cytokines. RESULTS: From November 2, 2018, through March 12, 2020, 84 patients were assigned randomly (n = 43 to valaciclovir). Eighty-one patients completed trial follow-up and were included in the intention-to-treat analysis of the primary outcome. A greater number of participants in the valaciclovir group achieved EBV suppression (n = 36 [87.8%] vs n = 17 [42.5%]; P < .001). Valaciclovir was associated with a significant reduction in sputum EBV titer compared with placebo (-90,404 copies/mL [interquartile range, -298,000 to -15,200 copies/mL] vs -3,940 copies/mL [interquartile range, -114,400 to 50,150 copies/mL]; P = .002). A statistically nonsignificant 24-mL numerical FEV1 increase was shown in the valaciclovir group (difference, -44 mL [95% CI, -150 to 62 mL]; P = .41). However, a reduction in sputum white cell count was noted in the valaciclovir group compared with the placebo group (difference, 2.89 [95% CI, 1.5 × 106-7.4 × 106]; P = .003). INTERPRETATION: Valaciclovir is safe and effective for EBV suppression in COPD and may attenuate the sputum inflammatory cell infiltrate. The findings from the current study provide support for a larger trial to evaluate long-term clinical outcomes. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03699904; URL: www. CLINICALTRIALS: gov.

Resting-State Functional Connectivity Differences Following Experimental Manipulation of the Orbitofrontal Cortex in Two Directions via Theta-Burst Stimulation.

Compulsive behaviors (CBs) have been linked to orbitofrontal cortex (OFC) function in animal and human studies. However, brain regions function not in isolation but as components of widely distributed brain networks-such as those indexed via resting-state functional connectivity (RSFC). Sixty-nine individuals with CB disorders were randomized to receive a single session of neuromodulation targeting the left OFC-intermittent theta-burst stimulation (iTBS) or continuous TBS (cTBS)-followed immediately by computer-based behavioral "habit override" training. OFC seeds were used to quantify RSFC following iTBS and following cTBS. Relative to cTBS, iTBS showed increased RSFC between right OFC (Brodmann's area 47) and other areas, including dorsomedial prefrontal cortex (dmPFC), occipital cortex, and a priori dorsal and ventral striatal regions. RSFC connectivity effects were correlated with OFC/frontopolar target engagement and with subjective difficulty during habit-override training. Findings help reveal neural network-level impacts of neuromodulation paired with a specific behavioral context, informing mechanistic intervention development.

Anxiety as a disorder of uncertainty: implications for understanding maladaptive anxiety, anxious avoidance, and exposure therapy.

In cognitive-behavioral conceptualizations of anxiety, exaggerated threat expectancies underlie maladaptive anxiety. This view has led to successful treatments, notably exposure therapy, but is not consistent with the empirical literature on learning and choice alterations in anxiety. Empirically, anxiety is better described as a disorder of uncertainty learning. How disruptions in uncertainty lead to impairing avoidance and are treated with exposure-based methods, however, is unclear. Here, we integrate concepts from neurocomputational learning models with clinical literature on exposure therapy to propose a new framework for understanding maladaptive uncertainty functioning in anxiety. Specifically, we propose that anxiety disorders are fundamentally disorders of uncertainty learning and that successful treatments, particularly exposure therapy, work by remediating maladaptive avoidance from dysfunctional explore/exploit decisions in uncertain, potentially aversive situations. This framework reconciles several inconsistencies in the literature and provides a path forward to better understand and treat anxiety.

Pain severity at emergency department discharge as a predictor for chronification of pain.

Introduction: Inadequate pain management remains a problem in the emergency department (ED) and might increase the risk of chronic pain. Previous studies suggested that pain intensity is associated with pain chronification in specific patient groups. This study aims to study the association between pain intensity {[verbal] numeric rating scale ([V]NRS) ≥ 7} at discharge from the ED and pain chronification in the general population. Objective: To assess whether a high pain score at discharge from the ED increases the risk of chronic pain development. Methods: Adults who visited the ED with pain as their main complaint, and who were not hospitalized, were eligible for inclusion. Chronic pain was defined as pain with an (V)NRS score ≥1 90 days after the ED visit and with a similar location to the acute pain. Results: We included 1906 patients, of whom 825 participants completed 90 days of follow-up. Approximately 34.1% left the ED with an (V)NRS score ≥7, and 67.8% reported an (V)NRS score of ≥1 90 at days. Of all patients leaving the ED with an (V)NRS score ≥7, 76.5% developed chronic pain vs 63.2% of patients with (V)NRS score <7 (P < 0.01). After correction, this difference was borderline statistically significant with an odds ratio of 1.45 (95% confidence interval: 0.99-2.13, P = 0.054). Various sensitivity analyses using a different (V)NRS at discharge and different definitions of chronic pain at 90 days showed a significant difference in the chronification of pain. Conclusion: This study suggests that pain intensity at discharge from the ED, regardless of the localization or cause of pain, increased the risk of developing chronic pain. By distinguishing patients at risk and providing an effective treatment, chronic pain and the associated burden of disease might be preventable.

Clinical Trial Readiness for Spinal Muscular Atrophy: Experience of an International Educational-Training Initiative.

Several successful clinical trials have been conducted in spinal muscular atrophy (SMA) over recent years which have led to the approval of splicing modifiers and gene transfer therapies. With an increasing number of other agents progressing through pre-clinical and clinical development, increasing worldwide clinical trial readiness is becoming essential.SMA Europe initiated a clinical trial readiness project, which included the development of a pilot face-to-face educational-training initiative for clinical specialists and physiotherapists involved in SMA, with an emphasis on the patient perspective. Participants were selected through two surveys and, ahead of the meeting, a mock protocol with specific questions was provided. The initiative involved a series of presentations, role-play and interactive exercises. We describe here our experience and evaluation of this educational-training initiative, emphasising scientific aspects, psychosocial implications and level of satisfaction.From a participant, patient and industry perspective, such training was considered successful and met the objective, which was to improve clinical trial readiness in emerging sites. Resource planning, ethical considerations and communication with patients were identified as three important topics for future training. This initiative highlights the need to develop a training programme to achieve clinical trial readiness across Europe and showcases a collaborative effort with different stakeholders, clinicians, patient advocacy groups and sponsors to address an important issue.

Humans adaptively resolve the explore-exploit dilemma under cognitive constraints: Evidence from a multi-armed bandit task.

When navigating uncertain worlds, humans must balance exploring new options versus exploiting known rewards. Longer horizons and spatially structured option values encourage humans to explore, but the impact of real-world cognitive constraints such as environment size and memory demands on explore-exploit decisions is unclear. In the present study, humans chose between options varying in uncertainty during a multi-armed bandit task with varying environment size and memory demands. Regression and cognitive computational models of choice behavior showed that with a lower cognitive load, humans are more exploratory than a simulated value-maximizing learner, but under cognitive constraints, they adaptively scale down exploration to maintain exploitation. Thus, while humans are curious, cognitive constraints force people to decrease their strategic exploration in a resource-rational-like manner to focus on harvesting known rewards.

Relationship between inflammatory status and microbial composition in severe asthma and during exacerbation.

BACKGROUND: In T2-mediated severe asthma, biologic therapies, such as mepolizumab, are increasingly used to control disease. Current biomarkers can indicate adequate suppression of T2 inflammation, but it is unclear whether they provide information about airway microbial composition. We investigated the relationships between current T2 biomarkers and microbial profiles, characteristics associated with a ProteobacteriaHIGH microbial profile and the effects of mepolizumab on airway ecology. METHODS: Microbiota sequencing was performed on sputum samples obtained at stable and exacerbation state from 140 subjects with severe asthma participating in two clinical trials. Inflammatory subgroups were compared on the basis of biomarkers, including FeNO and sputum and blood eosinophils. ProteobacteriaHIGH subjects were identified by Proteobacteria to Firmicutes ratio ≥0.485. Where paired sputum from stable visits was available, we compared microbial composition at baseline and following ≥12 weeks of mepolizumab. RESULTS: Microbial composition was not related to inflammatory subgroup based on sputum or blood eosinophils. FeNO ≥50 ppb when stable and at exacerbation indicated a group with less dispersed microbial profiles characterised by high alpha-diversity and low Proteobacteria. ProteobacteriaHIGH subjects were neutrophilic and had a longer time from asthma diagnosis than ProteobacteriaLOW subjects. In those studied, mepolizumab did not alter airway bacterial load or lead to increased Proteobacteria. CONCLUSION: High FeNO could indicate a subgroup of severe asthma less likely to benefit from antimicrobial strategies at exacerbation or in the context of poor control. Where FeNO is <50 ppb, biomarkers of microbial composition are required to identify those likely to respond to microbiome-directed strategies. We found no evidence that mepolizumab alters airway microbial composition.

The importance of disease prevalence in clinical decision making: a real practice study on COVID-19 antigen test in Curacao.

The performance of a test can be suboptimal, but in appropriate setting such a test is still useful for clinical decision making. We investigated the role of Antigen Rapid Diagnostic Test (Ag-RDT) for clinical decision making in an Emergency Department (ED) in Curacao during peak of COVID-19 pandemic. Ag-RDT was performed in the naso- and oropharynx-swabs from patients with respiratory insufficiency presented to the ED. Ag-RDT was performed in 153 patients, of which 64 (41.8%) showed positive results. Comparing Ag-RDT results with molecular tests, its sensitivity was 68.8% (95% CI 57.4 to 78.7), and specificity of 94.6% (95% CI 84.9 to 98.9). The positive and negative predictive value were 95.1% (95% CI 86.5 to 98.3) and 66.3 (95% CI 58.6 to 73.3), respectively. All patients with Ag-RDT positive test were admitted to the cohorted COVD-19 department of the hospital. By using Ag-RDT, 35.9% of rapid PCR tests (that are more costly and laborious to perform) could be avoided at cost of 5.8% patients with false positive result. In conclusion, in real practice, disease prevalence is as important as test's performance for clinical decision making. The conclusion may also be applicable for other diagnostic tests than COVID-19 diagnostic.

Airway remodelling rather than cellular infiltration characterizes both type2 cytokine biomarker-high and -low severe asthma.

BACKGROUND: The most recognizable phenotype of severe asthma comprises people who are blood eosinophil and FeNO-high, driven by type 2 (T2) cytokine biology, which responds to targeted biological therapies. However, in many people with severe asthma, these T2 biomarkers are suppressed but poorly controlled asthma persists. The mechanisms driving asthma in the absence of T2 biology are poorly understood. OBJECTIVES: To explore airway pathology in T2 biomarker-high and -low severe asthma. METHODS: T2 biomarker-high severe asthma (T2-high, n = 17) was compared with biomarker-intermediate (T2-intermediate, n = 21) and biomarker-low (T2-low, n = 20) severe asthma and healthy controls (n = 28). Bronchoscopy samples were processed for immunohistochemistry, and sputum for cytokines, PGD2 and LTE4 measurements. RESULTS: Tissue eosinophil, neutrophil and mast cell counts were similar across severe asthma phenotypes and not increased when compared to healthy controls. In contrast, the remodelling features of airway smooth muscle mass and MUC5AC expression were increased in all asthma groups compared with health, but similar across asthma subgroups. Submucosal glands were increased in T2-intermediate and T2-low asthma. In spite of similar tissue cellular inflammation, sputum IL-4, IL-5 and CCL26 were increased in T2-high versus T2-low asthma, and several further T2-associated cytokines, PGD2 and LTE4 , were increased in T2-high and T2-intermediate asthma compared with healthy controls. CONCLUSIONS: Eosinophilic tissue inflammation within proximal airways is suppressed in T2 biomarker-high and T2-low severe asthma, but inflammatory and structural cell activation is present, with sputum T2-associated cytokines highest in T2 biomarker-high patients. Airway remodelling persists and may be important for residual disease expression beyond eosinophilic exacerbations. Registered at ClincialTrials.gov: NCT02883530.

A double-blind study assessing the impact of orbitofrontal theta burst stimulation on goal-directed behavior.

Patients with disorders of compulsivity show impairments in goal-directed behavior, which have been linked to orbitofrontal cortex (OFC) dysfunction. We recently showed that continuous theta burst stimulation (cTBS), which reduces OFC activity, had a beneficial effect on compulsive behaviors both immediately and at 1 week follow-up compared with inhibitory TBS (iTBS). In this same sample, we investigated whether two behavioral measures of goal-directed control (devaluation success on a habit override task; model-based planning on the two-step task) were also affected by acute modulation of OFC activity. Overall, model-based planning and devaluation success were significantly related to each other and (for devaluation success) to symptoms in our transdiagnostic clinical sample. These measures were moderately to highly stable across time. In individuals with low levels of model-based planning, active cTBS improved devaluation success. Analogous to previously reported clinical effects, this effect was specific to cTBS and not iTBS. Overall, results suggested that measures of goal directed behavior are reliable but less affected by cTBS than clinical self-report. Future research should continue to examine longitudinal changes in behavioral measures to determine their temporal relationship with symptom improvement after treatment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Multimodal Prehabilitation During Neoadjuvant Therapy Prior to Esophagogastric Cancer Resection: Effect on Cardiopulmonary Exercise Test Performance, Muscle Mass and Quality of Life-A Pilot Randomized Clinical Trial.

BACKGROUND: Neoadjuvant therapy reduces fitness, muscle mass, and quality of life (QOL). For patients undergoing chemotherapy and surgery for esophagogastric cancer, maintenance of fitness is paramount. This study investigated the effect of exercise and psychological prehabilitation on anaerobic threshold (AT) at cardiopulmonary exercise testing (CPET). Secondary endpoints included peak oxygen uptake (peak VO2), skeletal muscle mass, QOL, and neoadjuvant therapy completion. METHODS: This parallel-arm randomized controlled trial assigned patients with locally advanced esophagogastric cancer to receive prehabilitation or usual care. The 15-week program comprised twice-weekly supervised exercises, thrice-weekly home exercises, and psychological coaching. CPET was performed at baseline, 2 weeks after neoadjuvant therapy, and 1 week preoperatively. Skeletal muscle cross-sectional area at L3 was analyzed on staging and restaging computed tomography. QOL questionnaires were completed at baseline, mid-neoadjuvant therapy, at restaging laparoscopy, and postoperatively at 2 weeks, 6 weeks and 6 months. RESULTS: Fifty-four participants were randomized (prehabilitation group, n = 26; control group, n = 28). No difference in AT between groups was observed post-neoadjuvant therapy. Prehabilitation resulted in an attenuated peak VO2 decline {-0.4 [95% confidence interval (CI) -0.8 to 0.1] vs. -2.5 [95% CI -2.8 to -2.2] mL/kg/min; p = 0.022}, less muscle loss [-11.6 (95% CI -14.2 to -9.0) vs. -15.6 (95% CI -18.7 to -15.4) cm2/m2; p = 0.049], and improved QOL. More prehabilitation patients completed neoadjuvant therapy at full dose [prehabilitation group, 18 (75%) vs. control group, 13 (46%); p = 0.036]. No adverse events were reported. CONCLUSIONS: This study has demonstrated some retention of cardiopulmonary fitness (peak VO2), muscle, and QOL in prehabilitation subjects. Further large-scale trials will help determine whether these promising findings translate into improved clinical and oncological outcomes. Trial Registration ClinicalTrials.gov NCT02950324.

Delay discounting in suicidal behavior: Myopic preference or inconsistent valuation?

Prior studies sought to explain the predisposition to suicidal behavior in terms of myopic preference for immediate versus delayed reward, generating mixed evidence. Data from gambling and bandit tasks, however, suggest that suboptimal decisions in suicidal individuals are explained by inconsistent valuation rather than myopic preferences. We tested these two alternative hypotheses using a delay discounting task in 622 adults (suicide attempters with depression, suicide ideators with depression, nonsuicidal participants with depression, and healthy controls) recruited across three sites through inpatient psychiatric units, mood disorders clinics, primary care, and advertisements. Multilevel models revealed group differences in valuation consistencies in all three samples, with high-lethality suicide attempters exhibiting less consistent valuation than all other groups in Samples 1 and 3 and less consistent valuation than the healthy controls or participants with depression in Sample 2. In contrast, group differences in preference for immediate versus delayed reward were observed only in Sample 1 and were due to the high-lethality suicide attempters displaying a weaker preference for immediate reward than low-lethality suicide attempters. The findings were robust to confounds such as cognitive functioning and comorbidities. Seemingly impulsive choices in suicidal behavior are explained by inconsistent reward valuation rather than a true preference for immediate reward. In a suicidal crisis, this inconsistency may result in a misestimation of the value of suicide relative to constructive alternatives and deterrents. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The importance of disease prevalence in clinical decision making: a real practice study on COVID-19 antigen test in Curacao

ABSTRACT The performance of a test can be suboptimal, but in appropriate setting such a test is still useful for clinical decision making. We investigated the role of Antigen Rapid Diagnostic Test (Ag-RDT) for clinical decision making in an Emergency Department (ED) in Curacao during peak of COVID-19 pandemic. Ag-RDT was performed in the naso- and oropharynxswabs from patients with respiratory insufficiency presented to the ED. Ag-RDT was performed in 153 patients, of which 64 (41.8%) showed positive results. Comparing Ag-RDT results with molecular tests, its sensitivity was 68.8% (95% CI 57.4 to 78.7), and specificity of 94.6% (95% CI 84.9 to 98.9). The positive and negative predictive value were 95.1% (95% CI 86.5 to 98.3) and 66.3 (95% CI 58.6 to 73.3), respectively. All patients with Ag-RDT positive test were admitted to the cohorted COVD-19 department of the hospital. By using Ag-RDT, 35.9% of rapid PCR tests (that are more costly and laborious to perform) could be avoided at cost of 5.8% patients with false positive result. In conclusion, in real practice, disease prevalence is as important as test's performance for clinical decision making. The conclusion may also be applicable for other diagnostic tests than COVID-19 diagnostic.

A global review of seed enhancement technology use to inform improved applications in restoration.

Seed-based restoration often experiences poor success due to a range of edaphic and biotic issues. Seed enhancement technologies (SETs) are a novel approach that can alleviate these pressures and improve restoration success. Broadly, SETs have been reviewed for agricultural and horticultural purposes, for specific types of SETs such as coating or priming, or for focal ecosystems. However, information is lacking for SETs within a restoration focused context, and how they are being used to alleviate certain barriers. This review aimed to synthesise the current literature on SETs to understand what SETs are being tested, in which sectors and locations they are being tested, what issues are faced within restoration using SETs, and how SETs are being used to approach these issues. Priming was highlighted as the main SET investigated. Inoculation, pesticide application and magnetic fields were also commonly tested (SETs we termed 'prospective techniques'). SET research mainly occurred in the agricultural sector. More recently, other sectors, such as restoration and rangeland management, have increased efforts into SET research. The restoration sector has focused on extruded pelleting and coating (with activated carbon), in combination with herbicide application, to overcome invasive species, and coating with certain additives to alleviate edaphic issues. Other sectors outside restoration were largely focused on evaluating priming for overcoming these barriers. The majority of priming research has been completed on crop species and differences between these species and ecosystems must be considered in future restoration efforts that focus on native seed use. Generally, SETs require further refinement, including identifying ideal additives and their optimum concentrations to target certain issues, refining formulations for coating and extruded pelleting and developing flash flaming. A bet-hedging approach using multiple SETs and/or combinations of SETs may be advantageous in overcoming a wide range of barriers in seed-based restoration.

Reinforcement Learning Disruptions in Individuals With Depression and Sensitivity to Symptom Change Following Cognitive Behavioral Therapy.

Importance: Major depressive disorder is prevalent and impairing. Parsing neurocomputational substrates of reinforcement learning in individuals with depression may facilitate a mechanistic understanding of the disorder and suggest new cognitive therapeutic targets. Objective: To determine associations among computational model-derived reinforcement learning parameters, depression symptoms, and symptom changes after treatment. Design, Setting, and Participants: In this mixed cross-sectional-cohort study, individuals performed reward and loss variants of a probabilistic learning task during functional magnetic resonance imaging at baseline and follow-up. A volunteer sample with and without a depression diagnosis was recruited from the community. Participants were assessed from July 2011 to February 2017, and data were analyzed from May 2017 to May 2021. Main Outcomes and Measures: Computational model-based analyses of participants' choices assessed a priori hypotheses about associations between components of reward-based and loss-based learning with depression symptoms. Changes in both learning parameters and symptoms were then assessed in a subset of participants who received cognitive behavioral therapy (CBT). Results: Of 101 included adults, 69 (68.3%) were female, and the mean (SD) age was 34.4 (11.2) years. A total of 69 participants with a depression diagnosis and 32 participants without a depression diagnosis were included at baseline; 48 participants (28 with depression who received CBT and 20 without depression) were included at follow-up (mean [SD] of 115.1 [15.6] days). Computational model-based analyses of behavioral choices and neural data identified associations of learning with symptoms during reward learning and loss learning, respectively. During reward learning only, anhedonia (and not negative affect or arousal) was associated with model-derived learning parameters (learning rate: posterior mean regression ß = -0.14; 95% credible interval [CrI], -0.12 to -0.03; outcome sensitivity: posterior mean regression ß = 0.18; 95% CrI, 0.02 to 0.37) and neural learning signals (moderation of association between striatal prediction error and expected value signals: t97 = -2.10; P = .04). During loss learning only, negative affect (and not anhedonia or arousal) was associated with learning parameters (outcome shift: posterior mean regression ß = -0.11; 95% CrI, -0.20 to -0.01) and disrupted neural encoding of learning signals (association with subgenual anterior cingulate prediction error signals: r = -0.28; P = .005). Symptom improvement following CBT was associated with normalization of learning parameters that were disrupted at baseline (reward learning rate: posterior mean regression ß = 0.15; 90% CrI, 0.001 to 0.41; loss outcome shift: posterior mean regression ß = 0.42; 90% CrI, 0.09 to 0.77). Conclusions and Relevance: In this study, the mapping of reinforcement learning components to symptoms of major depression revealed mechanistic features associated with these symptoms and points to possible learning-based therapeutic processes and targets.

The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational study.

BACKGROUND: Clinical trials with mepolizumab, a humanised monoclonal antibody against interleukin-5, show a 50% reduction in severe asthma exacerbations in people with severe eosinophilic asthma. Exacerbations in patients treated with mepolizumab seem to be different to exacerbations in those given placebo, as patients treated with mepolizumab report fewer symptoms, have a lower sputum eosinophil count, and smaller fall in peak expiratory flow. We aimed to investigate the inflammatory phenotype and physiological characteristics of exacerbation events in patients with severe eosinophilic asthma who were treated with mepolizumab. METHODS: This multicentre, prospective, observational cohort study was carried out at four UK specialist severe asthma centres. Participants were aged 18-80 years, with severe eosinophilic asthma (Global Initiative for Asthma steps 4 and 5), and were eligible for mepolizumab therapy. All participants received mepolizumab 100 mg subcutaneously every 4 weeks, had a scheduled study visit when stable on mepolizumab (≥3 months on treatment), and measured daily peak flow and completed symptoms diaries throughout the course of the study. Participants attended their study centre for unscheduled exacerbation assessment when symptoms worsened outside of their normal daily variation and before commencing rescue treatment. If a participant was unable to attend their study centre for exacerbation or had initiated rescue treatment before the study visit, clinical details of the missed exacerbation were collected by clinical staff. In this exploratory study, the endpoint was 100 clinical assessments at exacerbation completed across all sites for participants on mepolizumab before initiation of rescue treatment. Characteristics of those who had exacerbations on mepolizumab were compared with those who did not, peak flow and symptoms diaries were compared for assessed versus missed exacerbations, and exacerbation phenotypes defined by sputum eosinophil cell count were compared. The utility of fractional exhaled nitric oxide (FeNO) and C-reactive protein in determining exacerbation phenotype on mepolizumab treatment were also assessed. This study is registered with ClinicalTrials.gov, NCT03324230. FINDINGS: Between Nov 30, 2017, and May 29, 2019, 145 participants were enrolled and treated with mepolizumab, five were excluded from the analysis. 172 exacerbations occurred, with 96 (56%) assessed before commencing rescue treatment. Compared with patients who did not exacerbate, patients who exacerbated had a higher exacerbation rate and more emergency department attendances in the year before commencing mepolizumab. The change in peak expiratory flow at nadir in the assessed exacerbation group was mean -40·5 L/min (SD 76·3) versus mean -37·0 L/min (93·0; p=0·84) in the missed exacerbation group, and there was no difference in reported symptom burden. When comparing exacerbations with a high sputum eosinophil count (≥2%; SEHIGH) with exacerbations with a low sputum eosinophil count (<2%; SELOW), the SEHIGH exacerbations were FeNO high (median difference 33 parts per billion [ppb; 95% CI 8 to 87]; p=0·0004), with lower FEV1 percent predicted (mean difference -15·9% [-27·0 to -4·8]; p=0·0075), lower FEV1 to forced vital capacity ratio (mean difference -10·3 [-17·0 to -3·6]; p=0·0043), and higher blood eosinophil counts (median difference 40 cells per µL [20 to 70]; p=0·0009). By contrast, SELOW exacerbations had higher C-reactive protein concentrations (median difference 12·7 mg/L [3·5 to 18·5]; p<0·0001), higher sputum neutrophil counts (median difference 52·7% [34·5 to 59·2]; p<0·0001), and were more likely to be treated with antibiotics (p=0·031). FeNO (≤20 or ≥50 ppb) was the most useful discriminator of inflammatory phenotype at exacerbation. The most common adverse event was hospital admission due to asthma exacerbation (17 [50%] of 34 events), none of the adverse events were study procedure related. INTERPRETATION: Exacerbations on mepolizumab are two distinct entities, which can largely be differentiated using FeNO: non-eosinophilic events are driven by infection with a low FeNO and high C-reactive protein concentration, whereas eosinophilic exacerbations are FeNO high. The results of the MEX study challenge the routine use of oral corticosteroids for the treatment of all asthma exacerbation events on mepolizumab, as well as the switching of biological therapies for treatment failure without profiling the inflammatory phenotype of ongoing asthma exacerbations. The results highlight clinically available tools to enable profiling of these residual exacerbations in patients treated with mepolizumab. FUNDING: UK Medical Research council.

The CAST study protocol: a cluster randomized trial assessing the effect of circumferential casting versus plaster splinting on fracture redisplacement in reduced distal radius fractures in adults.

BACKGROUND: There is no consensus concerning the optimal casting technique for displaced distal radius fractures (DRFs) following closed reduction. This study evaluates whether a splint or a circumferential cast is most optimal to prevent fracture redisplacement in adult patients with a reduced DRF. Additionally, the cost-effectiveness of both cast types will be calculated. METHODS/DESIGN: This multicenter cluster randomized controlled trial will compare initial immobilization with a circumferential below-elbow cast versus a below-elbow plaster splint in reduced DRFs. Randomization will take place on hospital-level (cluster, n = 10) with a cross-over point halfway the inclusion of the needed number of patients per hospital. Inclusion criteria comprise adult patients (≥ 18 years) with a primary displaced DRF which is treated conservatively after closed reduction. Multiple trauma patients (Injury Severity Score ≥ 16), concomitant ulnar fractures (except styloid process fractures) and patients with concomitant injury on the ipsilateral arm or inability to complete study forms will be excluded. Primary study outcome is fracture redisplacement of the initial reduced DRF. Secondary outcomes are patient-reported outcomes assessed with the Disability Arm Shoulder Hand score (DASH) and Patient-Rated Wrist Evaluation score (PRWE), comfort of the cast, quality of life assessed with the EQ-5D-5L questionnaire, analgesics use, cost-effectiveness and (serious) adverse events occurence. In total, 560 patients will be included and followed for 1 year. The estimated time required for inclusion will be 18 months. DISCUSSION: The CAST study will provide evidence whether the type of cast immobilization is of influence on fracture redisplacement in distal radius fractures. Extensive follow-up during one year concerning radiographic, functional and patient reported outcomes will give a broad view on DRF recovery. TRIAL REGISTRATION: Registered in the Dutch Trial Registry on January 14th 2020. Registration number: NL8311 .