Phenotyping peripheral neuropathic pain in male and female adolescents

Neuropathic pain (NeuP) can be difficult to diagnose and manage in children. Data regarding prevalence and sex-dependent differences are limited, and more detailed phenotyping is needed. This observational cohort study recruited adolescents (10-17 years) with NeuP or complex regional pain syndrome (CRPS). After pain history and NeuP questionnaires, quantitative sensory testing was performed. Individual z-score plots were calculated with body-region control measures and matched to mechanism-related sensory profiles (sensory loss, thermal hyperalgesia, and mechanical hyperalgesia). Conditioned pain modulation was assessed with pressure pain threshold and a contralateral cold conditioning stimulus, and meaningful conditioned pain modulation defined as twice the standard error of measurement. Patients and parents completed validated questionnaires for child quality of life (QoL), pain catastrophizing, and self-reported anxiety/depression. Males (n = 23) and females (n = 43) with NeuP (n = 52) or CRPS (n = 14) reported moderate–severe pain with neuropathic sensory descriptors. Mixed patterns of sensory gain/loss at pain sites were not sex-dependent. Thermal hyperalgesia was common in both NeuP and CRPS, whereas sensory loss occurred only with NeuP and in a smaller proportion than adult cohorts. Conditioned pain modulation was inhibitory in 54%, facilitatory in 14%, and nonresponders had variable cold conditioning sensitivity. Males and females reported marked impairment of QoL, increased emotional distress, and pain catastrophising. Child–parent QoL scores correlated, but catastrophizing scores were discordant when parents or adolescents reported higher anxiety/depression. NeuP in adolescents is associated with significant pain, physical impairment, and psychosocial impairment. Quantifying alterations in somatosensory profiles, descending modulation, child and parent psychological function will inform individualized therapy and stratification for future clinical trials

Evidence that conflict regarding size of haemodynamic response to interventricular delay optimization of cardiac resynchronization therapy may arise from differences in how atrioventricular delay is kept constant.

Aims: Whether adjusting interventricular (VV) delay changes haemodynamic efficacy of cardiac resynchronization therapy (CRT) is controversial, with conflicting results. This study addresses whether the convention for keeping atrioventricular (AV) delay constant during VV optimization might explain these conflicts. / Method and results: Twenty-two patients in sinus rhythm with existing CRT underwent VV optimization using non-invasive systolic blood pressure. Interventricular optimization was performed with four methods for keeping the AV delay constant: (i) atrium and left ventricle delay kept constant, (ii) atrium and right ventricle delay kept constant, (iii) time to the first-activated ventricle kept constant, and (iv) time to the second-activated ventricle kept constant. In 11 patients this was performed with AV delay of 120 ms, and in 11 at AV optimum. At AV 120 ms, time to the first ventricular lead (left or right) was the overwhelming determinant of haemodynamics (13.75 mmHg at ±80 ms, P < 0.001) with no significant effect of time to second lead (0.47 mmHg, P = 0.50), P < 0.001 for difference. At AV optimum, time to first ventricular lead again had a larger effect (5.03 mmHg, P < 0.001) than time to second (2.92 mmHg, P = 0.001), P = 0.02 for difference. / Conclusion: Time to first ventricular activation is the overwhelming determinant of circulatory function, regardless of whether this is the left or right ventricular lead. If this is kept constant, the effect of changing time to the second ventricle is small or nil, and is not beneficial. In practice, it may be advisable to leave VV delay at zero. Specifying how AV delay is kept fixed might make future VV delay research more enlightening

Diabat method for polymorph free energies: Extension to molecular crystals

Lattice-switch Monte Carlo and the related diabat methods have emerged as efficient and accurate ways to compute free energy differences between polymorphs. In this work, we introduce a one-to-one mapping from the reference positions and displacements in one molecular crystal to the positions and displacements in another. Two features of the mapping facilitate lattice-switch Monte Carlo and related diabat methods for computing polymorph free energy differences. First, the mapping is unitary so that its Jacobian does not complicate the free energy calculations. Second, the mapping is easily implemented for molecular crystals of arbitrary complexity. We demonstrate the mapping by computing free energy differences between polymorphs of benzene and carbamazepine. Free energy calculations for thermodynamic cycles, each involving three independently computed polymorph free energy differences, all return to the starting free energy with a high degree of precision. The calculations thus provide a force field independent validation of the method and allow us to estimate the precision of the individual free energy differences

"The Score Matters": Wide Variations in Predictive Performance of 18 Paediatric Track and Trigger Systems

Objective: To compare the predictive performance of 18 Paediatric Early Warning Systems (PEWS) in predicting critical deterioration. / Design: Retrospective case-controlled study. PEWS values were calculated from existing clinical data and the area under the receiver operator characteristic curve (AUROC) compared. / Setting: UK tertiary referral children’s hospital. / Patients: Patients without a ‘do not attempt resuscitation’ order admitted between 1st January 2011 and 31st December 2012. All patients on paediatric wards who suffered a critical deterioration event were designated ‘cases’ and matched with a control closest in age who was present on the same ward at the same time. / Main outcome measures: Respiratory and/or cardiac arrest, unplanned transfer to paediatric intensive care and/or unexpected death. / Results: Twelve ‘scoring’ and 6 ‘trigger’ systems were suitable for comparative analysis. 297 case events in 224 patients were available for analysis. 244 control patients were identified for the 311 events. Three PEWS demonstrated better overall predictive performance with an AUROC of 0.87 or greater. Comparing each system to the highest performing PEWS with Bonferroni’s correction for multiple comparisons resulted in statistically significant differences for 13 systems. Trigger systems performed worse than scoring systems, occupying the 6 lowest places in the AUROC rankings. / Conclusion: There is considerable variation in the performance of published PEWS and as such the choice of PEWS has the potential to be clinically important. Trigger based systems performed poorly overall but it remains unclear what factors determine optimum performance. More complex systems did not necessarily demonstrate improved performance

Allocating the Burdens of Climate Action: Consumption-Based Carbon Accounting and the Polluter-Pays Principle

Action must be taken to combat climate change. Yet, how the costs of climate action should be allocated among states remains a question. One popular answer—the polluter-pays principle (PPP)—stipulates that those responsible for causing the problem should pay to address it. While intuitively plausible, the PPP has been subjected to withering criticism in recent years. It is timely, following the Paris Agreement, to develop a new version: one that does not focus on historical production-based emissions but rather allocates climate burdens in proportion to each state’s annual consumption-based emissions. This change in carbon accounting results in a fairer and more environmentally effective principle for distributing climate duties

Systematic review of paediatric track and trigger systems for hospitalised children

CONTEXT: Early and accurate recognition of the deteriorating hospitalised child is complex. Paediatric track and trigger systems (PTTS) support clinical decision-making by 'tracking' the child’s condition through monitoring of clinical signs and 'triggering' a request for an appropriate review when pre-determined criteria are breeched. OBJECTIVE: To describe the number and nature of published PTTS and appraise the evidence on their validity, calibration, and effect on important patient outcomes (death, cardiac and/or respiratory arrest, unplanned transfer to intensive/high dependency care, immediate/urgent request for review, rapid response system activation). METHOD: GRADE methodology. Papers identified through electronic database and citation searching. RESULTS: Thirty-three PTTS were identified from 55 studies. There was considerable variety in the number and type of parameters, although all contained one or more vital signs. The evidence to support PTTS implementation was very low and the majority of outcomes did not achieve statistical significance. When PTTS was implemented as part of a rapid response system, the evidence was moderate to low but there was some evidence of a statistically significant improvement in outcome. CONCLUSION: There is now some limited evidence for the validity and clinical utility of PTTS scores. The high (and increasing) number of systems is a significant confounder. Further research is needed particularly around the thresholds for the vital signs and the reliability, accuracy and calibration of PTTS in different settings

Missed opportunities: incomplete and inaccurate recording of paediatric early warning scores

BACKGROUND: Paediatric early warning scores (PEWS) are widely used as an adjunct to support staff in recognising deterioration in hospitalised children. Relatively little is known about how staff use these systems. // OBJECTIVE: To examine the completeness and accuracy of PEWS recording in hospitalised children in a tertiary specialist children's hospital. // DESIGN: This is a secondary analysis of retrospective, case-controlled study data. Case patients suffering from a critical deterioration event were matched with controls present on the same ward at the same time and matched for age. Data were extracted from the PEWS chart for the 48 hours before the critical deterioration event for case patients and the corresponding 48 hours period for the control. Observation sets were assessed for completeness and accuracy of PEWS scoring. // RESULTS: In total 297 case events in 224 patients were available for analysis. Overall 13 816 observations sets were performed, 8543 on cases and 5273 on controls. Only 4958 (35.9%) of observation sets contained a complete set of vital sign parameters and a concurrent PEWS. Errors were more prevalent in the observation sets of case patients versus controls (19.5% vs 14.1%). More errors resulted in the PEWS value being underscored rather than overscored for all observation sets (p<0.0001). 9.1% of inaccuracies for case patients were clinically significant, as the accurately calculated PEWS would have prompted a different escalation from the documented value. // CONCLUSION: Failure to record complete and accurate PEWS may jeopardise recognition of children who are deteriorating. Technology may offer an effective solution

The Dutch SCORE-based risk charts seriously underestimate the risk of cardiovascular disease.

INTRODUCTION: Dutch cardiovascular disease (CVD) prevention guidelines recommend the use of modified SCORE risk charts to estimate 10-year risk of fatal and nonfatal CVD (myocardial infarction, cerebrovascular disease and congestive heart failure). This combined risk is derived from the SCORE mortality risk using multipliers. These multipliers have been shown to underestimate overall CVD risk. We aimed to compare the current Dutch risk charts with charts that estimate a broader range of clinically relevant CVD using updated multipliers. METHODS: We constructed new risk charts for 10-year CVD using updated, recently published multipliers from the EPIC-Norfolk study, based on ratios of fatal CVD to clinically relevant CVD (fatal plus nonfatal CVD requiring hospitalisation for ischaemic heart disease, cardiac failure, cerebrovascular disease, peripheral artery disease, and aortic aneurysm). Our primary outcome was the proportion of the three risk categories, i. e. 'high risk' (>20% 10-year risk), 'intermediate risk' (10-19%) and 'low risk' (<10%) in the new risk charts as compared with the current risk charts. RESULTS: Applying the updated fatal CVD/clinical CVD multipliers led to a marked increase in the high-risk categories (109 (27%) vs. 244 (61%), (p < 0.001)), an absolute increase of 229%. Similarly, the number of low-risk categories decreased (190 (48%) vs. 81 (20%) (p < 0.001)). CONCLUSION: The current Dutch risk charts seriously underestimate the risk of clinical CVD, even in the first 10 years. Even when analyses are restricted to CVD events that required hospitalisation, true 10-year risks are more than double the currently estimated risks. Future guidelines may be revised to reflect these findings.This work was not supported by any institution or individuals. EPIC-Norfolk is supported by program grants from the Medical Research Council UK (MRC G0401527, MRC G0701863, MRC G1000143) and Cancer Research UK (CRUK 8257)

Heterogeneous response and progression patterns reveal phenotypic heterogeneity of tyrosine kinase inhibitor response in metastatic renal cell carcinoma

SC was funded by fellowships from NIHR and Cancer Research UK. IK was funded by the UCLH Experimental Cancer Centre and UCLH NIHR Biomedical Research Centre. TP was funded by grants from Cancer Research UK (the Experimental Cancer Medicine Centre). MG was funded by grants from Cancer Research UK, Prostate Cancer UK, the Prostate Cancer Foundation, the Schottlander Research Charitable Trust, the Royal Marsden NIHR Biomedical Research Centre for Cancer and the Wellcome Trust (grant number: 105104/Z/14/Z