A new ground level neutron monitor for space weather assessment.

We report on a new ground-level neutron monitor design for studying cosmic rays and fluxes of solar energetic particles at the Earth's surface. The first-of-its-kind instrument, named the NM-2023 after the year it was standardised and following convention, will be installed at a United Kingdom Meteorological Office observatory (expected completion mid 2024) and will reintroduce such monitoring in the UK for the first time since ca. 1984. Monte Carlo radiation transport code is used for the development and application of parameterised models to investigate alternative neutron detectors, their location and bulk material geometry in a realistic cosmic ray neutron field. Benchmarked against a model of the current and most widespread design standardised in 1964 (the NM-64), two main parameterisation studies are conducted; a simplified standard model and a concept slab parameterisation. We show that the NM-64 standard is well optimised for the intended large-diameter boron trifluoride (BF 3 ) proportional counters but not for multiple smaller diameter counters. The new design (based on a novel slab arrangement) produces comparable counting efficiencies to an NM-64 with six BF 3 counters and has the added advantage of being more compact, lower cost and avoids the use of highly toxic BF 3 .

Systematic pulmonary embolism follow-up increases diagnostic rates of chronic thromboembolic pulmonary hypertension and identifies less severe disease: results from the ASPIRE Registry.

BACKGROUND: Diagnostic rates and risk factors for the subsequent development of chronic thromboembolic pulmonary hypertension (CTEPH) following pulmonary embolism (PE) are not well defined. METHODS: Over a 10-year period (2010-2020), consecutive patients attending a PE follow-up clinic in Sheffield, UK (population 554 600) and all patients diagnosed with CTEPH at a pulmonary hypertension (PH) referral centre in Sheffield (referral population estimated 15-20 million) were included. RESULTS: Of 1956 patients attending the Sheffield PE clinic 3 months following a diagnosis of acute PE, 41 were diagnosed with CTEPH with a cumulative incidence of 2.10%, with 1.89% diagnosed within 2 years. Of 809 patients presenting with pulmonary hypertension (PH) and diagnosed with CTEPH, 32 were Sheffield residents and 777 were non-Sheffield residents. Patients diagnosed with CTEPH at the PE follow-up clinic had shorter symptom duration (p<0.01), better exercise capacity (p<0.05) and less severe pulmonary haemodynamics (p<0.01) compared with patients referred with suspected PH. Patients with no major transient risk factors present at the time of acute PE had a significantly higher risk of CTEPH compared with patients with major transient risk factors (OR 3.6, 95% CI 1.11-11.91; p=0.03). The presence of three computed tomography (CT) features of PH in combination with two or more out of four features of chronic thromboembolic pulmonary disease at the index PE was found in 19% of patients who developed CTEPH and in 0% of patients who did not. Diagnostic rates and pulmonary endarterectomy (PEA) rates were higher at 13.2 and 3.6 per million per year, respectively, for Sheffield residents compared with 3.9-5.2 and 1.7-2.3 per million per year, respectively, for non-Sheffield residents. CONCLUSIONS: In the real-world setting a dedicated PE follow-up pathway identifies patients with less severe CTEPH and increases population-based CTEPH diagnostic and PEA rates. At the time of acute PE diagnosis the absence of major transient risk factors, CT features of PH and chronic thromboembolism are risk factors for a subsequent diagnosis of CTEPH.

Modelling electrified railway signalling misoperations during extreme space weather events in the UK.

Space weather has the potential to impact ground-based technologies on Earth, affecting many systems including railway signalling. This study uses a recently developed model to analyse the impact of geomagnetically induced currents on railway signalling systems in the United Kingdom during the March 1989 and October 2003 geomagnetic storms. The March 1989 storm is also scaled to estimate a 1-in-100 year and a 1-in-200 year extreme storm. Both the Glasgow to Edinburgh line, and the Preston to Lancaster section of the West Coast Main Line are modelled. No "right side" failures (when unoccupied sections appear occupied) are suggested to have occurred during either storm, and the total number of potential "wrong side" failures (when occupied sections appear clear) is low. However, the modelling indicates "right side" and "wrong side" failures are possible on both routes during the 1-in-100 year and 1-in-200 year extreme storms, with the Glasgow to Edinburgh line showing more total misoperations than the Preston to Lancaster section of the West Coast Main Line. A 1-in-100 year or 1-in-200 year extreme storm would result in misoperations over an extended period of time, with most occurring over a duration of 2-3 h either side of the peak of the storm.

Social anxiety, behavioural activation and depression risk in older men: protection through Men's Shed membership.

Reducing rates of depressive symptoms in older adults is a public health priority. Men's Sheds are a community organisation that may protect against depressive symptoms in older men. It is currently unclear how social anxiety and behavioural activation may relate to depressive symptoms for Men's Shed members. We employed a cross-sectional design to explore whether the relationships between social anxiety, behavioural activation and depressive symptoms were contingent upon Shed social network quality in a sample of 164 Men's Shed members. Conditional effects analysis found social anxiety (B = -0.08, p < 0.01) and behavioural activation's (B = 0.02, p < 0.001) relationships with depression to be contingent on Shed social network quality. Additionally, we found evidence for a conditional effect of social anxiety on the relationship between behavioural activation and depression (B = -0.03, p < 0.01) such that this relationship was stronger for those with higher levels of social anxiety. Our findings suggest that a strong social network within a Men's Shed weakens the association between social anxiety and depression, that the relationship between behavioural activation and depression is stronger in those with poorer Shed social networks, and that the relationship between behavioural activation and depression may be stronger for those with higher levels of social anxiety. We suggest that our findings contribute to increasing quantitative support for the mental health benefits of Men's Shed membership, highlight the potential importance of Shed social network quality and explore how social anxiety may affect the mental health outcomes for members.

Artificial Intelligence framework with traditional computer vision and deep learning approaches for optimal automatic segmentation of left ventricle with scar.

Automatic segmentation of the cardiac left ventricle with scars remains a challenging and clinically significant task, as it is essential for patient diagnosis and treatment pathways. This study aimed to develop a novel framework and cost function to achieve optimal automatic segmentation of the left ventricle with scars using LGE-MRI images. To ensure the generalization of the framework, an unbiased validation protocol was established using out-of-distribution (OOD) internal and external validation cohorts, and intra-observation and inter-observer variability ground truths. The framework employs a combination of traditional computer vision techniques and deep learning, to achieve optimal segmentation results. The traditional approach uses multi-atlas techniques, active contours, and k-means methods, while the deep learning approach utilizes various deep learning techniques and networks. The study found that the traditional computer vision technique delivered more accurate results than deep learning, except in cases where there was breath misalignment error. The optimal solution of the framework achieved robust and generalized results with Dice scores of 82.8 ± 6.4% and 72.1 ± 4.6% in the internal and external OOD cohorts, respectively. The developed framework offers a high-performance solution for automatic segmentation of the left ventricle with scars using LGE-MRI. Unlike existing state-of-the-art approaches, it achieves unbiased results across different hospitals and vendors without the need for training or tuning in hospital cohorts. This framework offers a valuable tool for experts to accomplish the task of fully automatic segmentation of the left ventricle with scars based on a single-modality cardiac scan.

Pathways from Men's Shed engagement to wellbeing, health-related quality of life, and lower loneliness.

Extensive qualitative evidence, but limited quantitative evidence, indicates that mutual aid organizations such as Men's Sheds have positive impacts on wellbeing, health-related quality of life, and loneliness. A recently developed theoretical model proposes that Men's Sheds may have these impacts via mediating factors such as broadening social networks, increasing behavioural activation and physical activity, reducing alcohol use, and providing meaning in life. The aim of this study was to quantitatively test a model whereby psychological safety (feeling safe, accepted, and valued) is associated with Men's Shed engagement (frequency of attendance, duration of membership, diversity of activities), which is associated with the hypothesized mediators, which, in turn, are associated with wellbeing, health-related quality of life, and loneliness. Men's Shed members (N = 333, Mage = 70.90 years, SD = 10.34, 98% male) completed a survey assessing the factors in the model. The hypothesized path model provided an excellent fit to the data. Findings indicated that higher psychological safety was associated with higher engagement, which, in turn, was associated with larger social networks and more meaning in life, which were associated with higher wellbeing and lower loneliness. Higher behavioural activation and less alcohol use were also associated with higher wellbeing. Higher Men's Shed engagement was not associated with higher behavioural activation and physical activity, or less alcohol use, but behavioural activation and alcohol use were directly associated with health-related quality of life. Implications for optimizing health outcomes within Men's Sheds are discussed.

Enhancing the Initial Acceleration Performance of Elite Rugby Backs. Part II: Insights From Multiple Longitudinal Individual-Specific Case-Study Interventions.

PURPOSE: This study implemented 18-week individual-specific sprint acceleration training interventions in elite male rugby backs based on their predetermined individual technical needs and evaluated the effectiveness of these interventions. METHODS: Individual-specific interventions were prescribed to 5 elite rugby backs over an 18-week period. Interventions were informed by the relationships between individual technique strategies and initial acceleration performance, and their strength-based capabilities. Individual-specific changes in technique and initial acceleration performance were measured at multiple time points across the intervention period and compared with 3 control participants who underwent their normal training. RESULTS: Of the technique variables intentionally targeted during the intervention period, moderate to very large (|d| = 0.93-3.99) meaningful changes were observed in the participants who received an individual-specific intervention but not in control participants. Resultant changes to the intervention participants' whole-body kinematic strategies were broadly consistent with the intended changes. Moderate to very large (|d| = 1.11-2.82) improvements in initial acceleration performance were observed in participants receiving individual-specific technical interventions but not in the control participants or the participant who received an individual-specific strength intervention. CONCLUSIONS: Individual-specific technical interventions were more effective in manipulating aspects of acceleration technique and performance compared with the traditional "one-size-fits-all" approach adopted by the control participants. This study provides a novel, evidence-based approach for applied practitioners working to individualize sprint-based practices to enhance acceleration performance.

Enhancing the Initial Acceleration Performance of Elite Rugby Backs. Part I: Determining Individual Technical Needs.

PURPOSE: This study sought to quantify the within-individual relationships between spatiotemporal variables and initial acceleration sprint performance in elite rugby backs and to establish a normative data set of relevant strength-based measures. METHODS: First, the spatiotemporal variables, ratios of step length to step rate and of contact time to flight time, and initial acceleration performance were obtained from 35 elite male rugby backs (mean [SD] age 25 [3] y) over the first 4 steps of 3 sprints. Angular and linear kinematic aspects of technique and strength-based qualities were collected from 25 of these participants. Second, the same spatiotemporal variables were collected from 19 of the participants on 3 further occasions (12 trials in total) to determine the within-individual associations of these variables and initial acceleration performance. RESULTS: Moderate to very large meaningful within-individual relationships (|r| = .43-.88) were found between spatiotemporal variables and initial acceleration performance in 17 of the 19 participants. From these relationships, a theoretically "desirable" change in whole-body kinematic strategy was individually determined for each participant, and normative strength-based measures to contextualize these were established. CONCLUSIONS: Meaningful within-individual relationships are evident between sprint spatiotemporal variables and initial acceleration performance in elite rugby backs. Individualized approaches are therefore necessary to understand how aspects of technique relate to initial acceleration performance. This study provides an objective, evidence-based approach for applied practitioners to identify the initial acceleration technical needs of individual rugby backs.

Pulmonary Artery Strain Predicts Prognosis in Pulmonary Arterial Hypertension.

BACKGROUND: Current cardiac magnetic resonance (CMR) imaging in pulmonary arterial hypertension (PAH) focuses on measures of ventricular function and coupling. OBJECTIVES: The purpose of this study was to evaluate pulmonary artery (PA) global longitudinal strain (GLS) as a prognostic marker in patients with PAH. METHODS: The authors included 169 patients with PAH from the ASPIRE (Assessing the Spectrum of Pulmonary hypertension Identified at a REferral centre) and INITIATE (Integrated computatioNal modelIng of righT heart mechanIcs and blood flow dynAmics in congeniTal hEart disease) registries, and 82 normal controls with similar age and gender distributions. PA GLS was derived from CMR feature tracking. Right ventricular measurements including volumes, ejection fraction, and right ventricular GLS were also derived from CMR. Patients were followed up a median of 34 months with all-cause mortality as the primary endpoint. Other known risk scores were collected, including the REVEAL (Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) 2.0 and COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) 2.0 scores. RESULTS: Of 169 patients (mean age: 57 ± 15 years; 80% female), 45 (26.6%) died (median follow-up: 34 months). Mean PA GLS was 23% ± 6% in normal controls and 10% ± 5% in patients with PAH (P < 0.0001). Patients with PA GLS <9% had a higher risk of mortality than those with PA GLS ≥9% (P < 0.001), and this was an independent predictor of mortality in PAH on multivariable analysis after adjustment for known risk factors (HR: 2.93; P = 0.010). Finally, in patients with PAH, PA GLS provided incremental prognostic value over the REVEAL 2.0 (global chi-square; P = 0.001; C statistic comparison; P = 0.030) and COMPERA 2.0 (global chi-square; P = 0.001; C statistic comparison; P = 0.048). CONCLUSIONS: PA GLS confers incremental prognostic utility over the established risk scores for identifying patients with PAH at higher risk of death, who may be targeted for closer monitoring and/or intensified therapy.

Quantifying Myocardial Blood Flow and Resistance Using 4D-Flow Cardiac Magnetic Resonance Imaging.

Background: Ischaemia with nonobstructive coronary arteries is most commonly caused by coronary microvascular dysfunction but remains difficult to diagnose without invasive testing. Myocardial blood flow (MBF) can be quantified noninvasively on stress perfusion cardiac magnetic resonance (CMR) or positron emission tomography but neither is routinely used in clinical practice due to practical and technical constraints. Quantification of coronary sinus (CS) flow may represent a simpler method for CMR MBF quantification. 4D flow CMR offers comprehensive intracardiac and transvalvular flow quantification. However, it is feasibility to quantify MBF remains unknown. Methods: Patients with acute myocardial infarction (MI) and healthy volunteers underwent CMR. The CS contours were traced from the 2-chamber view. A reformatted phase contrast plane was generated through the CS, and flow was quantified using 4D flow CMR over the cardiac cycle and normalised for myocardial mass. MBF and resistance (MyoR) was determined in ten healthy volunteers, ten patients with myocardial infarction (MI) without microvascular obstruction (MVO), and ten with known MVO. Results: MBF was quantified in all 30 subjects. MBF was highest in healthy controls (123.8 ± 48.4 mL/min), significantly lower in those with MI (85.7 ± 30.5 mL/min), and even lower in those with MI and MVO (67.9 ± 29.2 mL/min/) (P < 0.01 for both differences). Compared with healthy controls, MyoR was higher in those with MI and even higher in those with MI and MVO (0.79 (±0.35) versus 1.10 (±0.50) versus 1.50 (±0.69), P=0.02). Conclusions: MBF and MyoR can be quantified from 4D flow CMR. Resting MBF was reduced in patients with MI and MVO.

Automatic development of 3D anatomical models of border zone and core scar regions in the left ventricle.

Patients with myocardial infarction are at elevated risk of sudden cardiac death, and scar tissue arising from infarction is known to play a role. The accurate identification of scars therefore is crucial for risk assessment, quantification and guiding interventions. Typically, core scars and grey peripheral zones are identified by radiologists and clinicians based on cardiac late gadolinium enhancement magnetic resonance images (LGE-MRI). Scar regions from LGE-MRI vary in size, shape, heterogeneity, artifacts, and image resolution. Thus, manual segmentation is time consuming, and influenced by the observer's experience (bias effect). We propose a fully automatic framework that develops 3D anatomical models of the left ventricle with border zone and core scar regions that are free from bias effect. Our myocardium (SOCRATIS), border scar and core scar (BZ-SOCRATIS) segmentation pipelines were evaluated using internal and external validation datasets. The automatic myocardium segmentation framework performed a Dice score of 81.9% and 70.0% in the internal and external validation dataset. The automatic scar segmentation pipeline achieved a Dice score of 60.9% for the core scar segmentation and 43.7% for the border zone scar segmentation in the internal dataset and in the external dataset a Dice score of 44.2% for the core scar segmentation and 54.8% for the border scar segmentation respectively. To the best of our knowledge, this is the first study outlining a fully automatic framework to develop 3D anatomical models of the left ventricle with border zone and core scar regions. Our method exhibits high performance without the need for training or tuning in an unseen cohort (unsupervised).

Quantitative CT Evaluation of Small Pulmonary Vessels Has Functional and Prognostic Value in Pulmonary Hypertension.

Background The in vivo relationship between peel pulmonary vessels, small pulmonary vessels, and pulmonary hypertension (PH) is not fully understood. Purpose To quantitatively assess peel pulmonary vessel volumes (PPVVs) and small pulmonary vessel volumes (SPVVs) as estimated from CT pulmonary angiography (CTPA) in different subtypes of PH compared with controls, their relationship to pulmonary function and right heart catheter metrics, and their prognostic value. Materials and Methods In this retrospective single-center study performed from January 2008 to February 2018, quantitative CTPA analysis of total SPVV (TSPVV) (0.4- to 2-mm vessel diameter) and PPVV (within 15, 30, and 45 mm from the lung surface) was performed. Results A total of 1823 patients (mean age, 69 years ± 13 [SD]; 1192 women [65%]) were retrospectively analyzed; 1593 patients with PH (mean pulmonary arterial pressure [mPAP], 43 mmHg ± 13 [SD]) were compared with 230 patient controls (mPAP, 19 mm Hg ± 3). The mean vessel volumes in pulmonary peels at 15-, 30-, and 45-mm depths were higher in pulmonary arterial hypertension (PAH) and PH secondary to lung disease compared with chronic thromboembolic PH (45-mm peel, mean difference: 6.4 mL [95% CI: 1, 11] [P < .001] vs 6.8 mL [95% CI: 1, 12] [P = .01]). Mean small vessel volumes at a diameter of less than 2 mm were lower in PAH and PH associated with left heart disease compared with controls (1.6-mm vessels, mean difference: -4.3 mL [95% CI: -8, -0.1] [P = .03] vs -6.8 mL [95% CI: -11, -2] [P < .001]). In patients with PH, the most significant positive correlation was noted with forced vital capacity percentage predicted (r = 0.30-0.40 [all P < .001] for TSPVVs and r = 0.21-0.25 [all P < .001] for PPVVs). Conclusion The volume of pulmonary small vessels is reduced in pulmonary arterial hypertension and pulmonary hypertension (PH) associated with left heart disease, with similar volume of peel vessels compared with controls. For chronic thromboembolic PH, the volume of peel vessels is reduced. In PH, small pulmonary vessel volume is associated with pulmonary function tests. Clinical trial registration no. NCT02565030 Published under a CC BY 4.0 license Online supplemental material is available for this article.

Validation of Artificial Intelligence Cardiac MRI Measurements: Relationship to Heart Catheterization and Mortality Prediction.

Background Cardiac MRI measurements have diagnostic and prognostic value in the evaluation of cardiopulmonary disease. Artificial intelligence approaches to automate cardiac MRI segmentation are emerging but require clinical testing. Purpose To develop and evaluate a deep learning tool for quantitative evaluation of cardiac MRI functional studies and assess its use for prognosis in patients suspected of having pulmonary hypertension. Materials and Methods A retrospective multicenter and multivendor data set was used to develop a deep learning-based cardiac MRI contouring model using a cohort of patients suspected of having cardiopulmonary disease from multiple pathologic causes. Correlation with same-day right heart catheterization (RHC) and scan-rescan repeatability was assessed in prospectively recruited participants. Prognostic impact was assessed using Cox proportional hazard regression analysis of 3487 patients from the ASPIRE (Assessing the Severity of Pulmonary Hypertension In a Pulmonary Hypertension Referral Centre) registry, including a subset of 920 patients with pulmonary arterial hypertension. The generalizability of the automatic assessment was evaluated in 40 multivendor studies from 32 centers. Results The training data set included 539 patients (mean age, 54 years ± 20 [SD]; 315 women). Automatic cardiac MRI measurements were better correlated with RHC parameters than were manual measurements, including left ventricular stroke volume (r = 0.72 vs 0.68; P = .03). Interstudy repeatability of cardiac MRI measurements was high for all automatic measurements (intraclass correlation coefficient range, 0.79-0.99) and similarly repeatable to manual measurements (all paired t test P > .05). Automated right ventricle and left ventricle cardiac MRI measurements were associated with mortality in patients suspected of having pulmonary hypertension. Conclusion An automatic cardiac MRI measurement approach was developed and tested in a large cohort of patients, including a broad spectrum of right ventricular and left ventricular conditions, with internal and external testing. Fully automatic cardiac MRI assessment correlated strongly with invasive hemodynamics, had prognostic value, were highly repeatable, and showed excellent generalizability. Clinical trial registration no. NCT03841344 Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Ambale-Venkatesh and Lima in this issue. An earlier incorrect version appeared online. This article was corrected on June 27, 2022.

Validation of aortic valve pressure gradient quantification using semi-automated 4D flow CMR pipeline.

OBJECTIVE: Doppler echocardiographic aortic valve peak velocity and peak pressure gradient assessment across the aortic valve (AV) is the mainstay for diagnosing aortic stenosis. Four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) is emerging as a valuable diagnostic tool for estimating the peak pressure drop across the aortic valve, but assessment remains cumbersome. We aimed to validate a novel semi-automated pipeline 4D flow CMR method of assessing peak aortic value pressure gradient (AVPG) using the commercially available software solution, CAAS MR Solutions, against invasive angiographic methods. RESULTS: We enrolled 11 patients with severe AS on echocardiography from the EurValve programme. All patients had pre-intervention doppler echocardiography, invasive cardiac catheterisation with peak pressure drop assessment across the AV and 4D flow CMR. The peak AVPG was 51.9 ± 35.2 mmHg using the invasive pressure drop method and 52.2 ± 29.2 mmHg for the 4D flow CMR method (semi-automated pipeline), with good correlation between the two methods (r = 0.70, p = 0.017). Assessment of AVPG by 4D flow CMR using the novel semi-automated pipeline method shows excellent agreement to invasive assessment when compared to doppler-based methods and advocate for its use as complementary to echocardiography.

CMR Measures of Left Atrial Volume Index and Right Ventricular Function Have Prognostic Value in Chronic Thromboembolic Pulmonary Hypertension.

Providing prognostic information is important when counseling patients and planning treatment strategies in chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to assess the prognostic value of gold standard imaging of cardiac structure and function using cardiac magnetic resonance imaging (CMR) in CTEPH. Consecutive treatment-naive patients with CTEPH who underwent right heart catheterization and CMR between 2011 and 2017 were identified from the ASPIRE (Assessing-the-Specturm-of-Pulmonary-hypertensIon-at-a-REferral-center) registry. CMR metrics were corrected for age and sex where appropriate. Univariate and multivariate regression models were generated to assess the prognostic ability of CMR metrics in CTEPH. Three hundred and seventy-five patients (mean+/-standard deviation: age 64+/-14 years, 49% female) were identified and 181 (48%) had pulmonary endarterectomy (PEA). For all patients with CTEPH, left-ventricular-stroke-volume-index-%predicted (LVSVI%predicted) (p = 0.040), left-atrial-volume-index (LAVI) (p = 0.030), the presence of comorbidities, incremental shuttle walking test distance (ISWD), mixed venous oxygen saturation and undergoing PEA were independent predictors of mortality at multivariate analysis. In patients undergoing PEA, LAVI (p < 0.010), ISWD and comorbidities and in patients not undergoing surgery, right-ventricular-ejection-fraction-%predicted (RVEF%pred) (p = 0.040), age and ISWD were independent predictors of mortality. CMR metrics reflecting cardiac function and left heart disease have prognostic value in CTEPH. In those undergoing PEA, LAVI predicts outcome whereas in patients not undergoing PEA RVEF%pred predicts outcome. This study highlights the prognostic value of imaging cardiac structure and function in CTEPH and the importance of considering left heart disease in patients considered for PEA.

Establishing Minimal Clinically Important Differences in Quality of Life Measures in Opioid-Induced Constipation.

BACKGROUND & AIMS: Opioids have a role in chronic pain management. However, opioid-induced constipation may cause patients to skip or reduce opioid doses, leading to inadequate pain relief and negatively impacting quality of life. We sought to establish a minimal clinically important difference to understand whether changes in quality of life scores are of value to patients. METHODS: Integrated data from the double-blind, controlled, phase 3 COMPOSE-1 and COMPOSE-2 trials of naldemedine in chronic noncancer pain and opioid-induced constipation were used to determine minimal clinically important differences using Patient Assessment of Constipation Symptoms (PAC-SYM) and Patient Assessment of Constipation Quality of Life (PAC-QOL) questionnaires. Patients completed the questionnaires (5-point Likert scale; predose, Weeks 2, 4, and 12), kept a daily log of Bowel Movement and Constipation Assessment, and rated satisfaction at end of study. Minimal clinically important differences were computed using an anchor-based method with 6 anchors: 5 from the Bowel Movement and Constipation Assessment and 1 from patient satisfaction. Threshold values for each anchor were set to define responders versus nonresponders based on score definitions. Clinically meaningful cutoff values for changes in PAC-SYM and PAC-QOL scores were determined using receiver operating characteristic curves. RESULTS: Data from 1095 patients (549, naldemedine; 546, placebo) were analyzed. The area under the curve for the receiver operating characteristic curves (ranges, 0.719 to 0.798 for PAC-SYM and 0.734 to 0.833 for PAC-QOL) indicated that both instruments can discriminate responders and nonresponders for each anchor. PAC-SYM cutoff values ranged from -1.04 to -0.83; PAC-QOL cutoff values ranged from -0.93 to -0.82. CONCLUSIONS: Based on data derived from the anchor method, reductions in PAC-SYM and PAC-QOL scores of >1.0 in patients with chronic noncancer pain and opioid-induced constipation are clinically meaningful. CLINICALTRIALS: gov Registration: NCT01965158; NCT01993940.

Mars' plasma system. Scientific potential of coordinated multipoint missions: "The next generation".

The objective of this White Paper, submitted to ESA's Voyage 2050 call, is to get a more holistic knowledge of the dynamics of the Martian plasma system, from its surface up to the undisturbed solar wind outside of the induced magnetosphere. This can only be achieved with coordinated multi-point observations with high temporal resolution as they have the scientific potential to track the whole dynamics of the system (from small to large scales), and they constitute the next generation of the exploration of Mars analogous to what happened at Earth a few decades ago. This White Paper discusses the key science questions that are still open at Mars and how they could be addressed with coordinated multipoint missions. The main science questions are: (i) How does solar wind driving impact the dynamics of the magnetosphere and ionosphere? (ii) What is the structure and nature of the tail of Mars' magnetosphere at all scales? (iii) How does the lower atmosphere couple to the upper atmosphere? (iv) Why should we have a permanent in-situ Space Weather monitor at Mars? Each science question is devoted to a specific plasma region, and includes several specific scientific objectives to study in the coming decades. In addition, two mission concepts are also proposed based on coordinated multi-point science from a constellation of orbiting and ground-based platforms, which focus on understanding and solving the current science gaps.

Characterising initial sprint acceleration strategies using a whole-body kinematics approach.

Sprint acceleration is an important motor skill in team sports, thus consideration of techniques adopted during the initial steps of acceleration is of interest. Different technique strategies can be adopted due to multiple interacting components, but the reasons for, and performance implications of, these differences are unclear. 29 professional rugby union backs completed three maximal 30 m sprints, from which spatiotemporal variables and linear and angular kinematics during the first four steps were obtained. Leg strength qualities were also obtained from a series of strength tests for 25 participants, and 13 participants completed the sprint protocol on four separate occasions to assess the reliability of the observed technique strategies. Using hierarchical agglomerative cluster analysis, four clear participant groups were identified according to their normalised spatiotemporal variables. Whilst significant differences in several lower limb sprint kinematic and strength qualities existed between groups, there were no significant between-group differences in acceleration performance, suggesting inter-athlete technique degeneracy in the context of performance. As the intra-individual whole-body kinematic strategies were stable (mean CV = 1.9% to 6.7%), the novel approach developed and applied in this study provides an effective solution for monitoring changes in acceleration technique strategies in response to technical or physical interventions.