Tapentadol Prolonged Release for Long-Term Treatment of Pain in Children

Purpose: Investigation of the efficacy and safety of tapentadol prolonged release (PR) compared with morphine PR for long-term treatment of pain in children. / Patients and Methods: Children aged 6 to < 18 years requiring long-term treatment with opioids were studied in a 12-month, 2-part, multi-center trial: Part 1, 14-day open-label, randomized, active-controlled, parallel group non-inferiority trial comparing twice daily tapentadol PR with morphine PR; Part 2, open-label treatment with tapentadol PR for up to 12 months or no treatment “safety observation period”. Pain intensity was rated with visual analogue scale or Faces Pain Scale-Revised, and non-inferiority was assessed by comparison of “treatment responders” (those completing the 14-day treatment period and showing pre-defined changes in pain rating) in each group. / Results: Twenty-three of 48 centers enrolled 73 patients. In Part 1, 45 and 24 patients received tapentadol or morphine, respectively, of which 40 and 22 completed 14-day treatment. In Part 2, thirty-six and 58 patients entered the tapentadol PR or observation periods, respectively, with 20/36 completing at least 12 weeks of treatment; 10 of the 36 had received morphine in Part 1. Forty-four of the 58 patients in the safety observation period had received tapentadol. Tapentadol PR was non-inferior to morphine PR (lower limit of confidence interval above negative non-inferiority margin of − 0.2) in Part 1. Rates of adverse events were as expected with nausea (22.2%) and constipation (15.6%) in the tapentadol PR group, and with vomiting (33.3%), nausea and constipation (each 16.7%) in the morphine PR group. No new safety issues were identified; the safety profile of tapentadol over the 12 months treatment and observation periods was comparable to that established in subjects > 18 years old. / Conclusion: Tapentadol PR was well tolerated and equivalent to morphine PR for both efficacy and safety in children (6 to < 18 years old) requiring long-term treatment with opioids

Understanding self-reported difficulties in decision-making by people with autism spectrum disorders.

Autobiographical accounts and a limited research literature suggest that adults with autism spectrum disorders can experience difficulties with decision-making. We examined whether some of the difficulties they describe correspond to quantifiable differences in decision-making when compared to adults in the general population. The participants (38 intellectually able adults with autism spectrum disorders and 40 neurotypical adults) were assessed on three tasks of decision-making (Iowa Gambling Task, Cambridge Gamble Task and Information Sampling Task), which quantified, respectively, decision-making performance and relative attention to negative and positive outcomes, speed and flexibility, and information sampling. As a caution, all analyses were repeated with a subset of participants ( nASD = 29 and nneurotypical = 39) who were not taking antidepressant or anxiolytic medication. Compared to the neurotypical participants, participants with autism spectrum disorders demonstrated slower decision-making on the Cambridge Gamble Task, and superior performance on the Iowa Gambling Task. When those taking the medications were excluded, participants with autism spectrum disorders also sampled more information. There were no other differences between the groups. These processing tendencies may contribute to the difficulties self-reported in some contexts; however, the results also highlight strengths in autism spectrum disorders, such as a more logical approach to, and care in, decision-making. The findings lead to recommendations for how adults with autism spectrum disorders may be better supported with decision-making.The research reported here was carried out by the first author (Lydia Vella, née Luke) as part of her PhD in the Department of Psychiatry, University of Cambridge, and was supported by a Pinsent Darwin Studentship in Mental Health; University of Cambridge Domestic Research Studentship; the Charles Slater Fund; and the Marmaduke Sheild Fund. IC was supported during the preparation of this paper by the National Institute of Health Research (NIHR) Collaboration for Applied Health Research and Care (CLAHRC) East of England at Cambridgeshire & Peterborough NHS Foundation Trust. We are grateful to all our funders for their support. The paper describes independent research and the views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health

Higher risk of opioid-induced respiratory depression in children with neurodevelopmental disability: a retrospective cohort study of 12,904 patients

BACKGROUND: Children with neurodevelopmental disabilities may be at risk of opioid-induced respiratory depression. We aimed to quantify the risks and effectiveness of morphine nurse-controlled analgesia (morphine-NCA) for postoperative pain in children with neurodevelopmental disabilities. METHODS: We carried out a retrospective cohort study of 12 904 children who received postoperative i.v. morphine-NCA. Subjects were divided into a neurodevelopmental disability group and a control group. Rates of clinical satisfaction, respiratory depression, and serious adverse events were obtained, and statistical analysis, including multilevel logistic regression using Bayesian inference, was performed. RESULTS: Of 12 904 patients, 2390 (19%) had neurodevelopmental disabilities. There were 88 instances of respiratory depression and 52 serious adverse events; there were no opioid-related deaths. The cumulative incidence of respiratory depression in the neurodevelopmental disability group was 1.09% vs 0.59% in the control group [odds ratio 1.8 (98% chance that the true odds ratio was >1)]. A significant interaction between postoperative morphine dose and neurodevelopmental disabilities was observed, with higher risk of respiratory depression with increasing dose. Satisfaction with morphine-NCA was very high overall, although children with neurodevelopmental disabilities were 1% more likely to have infusions rated as fair or poor (3.3 vs 2.1%, χ2P<0.001). CONCLUSIONS: Children with neurodevelopmental disabilities were 1.8 times more likely to suffer respiratory depression, absolute risk difference 0.5%; opioid-induced respiratory depression in this group may relate to increased sensitivity to dose-relate respiratory effects of morphine. Morphine-NCA as described was an acceptable technique for children with and without neurodevelopmental disabilities

Fundamental limitations for quantum and nano thermodynamics

The relationship between thermodynamics and statistical physics is valid in the thermodynamic limit - when the number of particles becomes very large. Here, we study thermodynamics in the opposite regime - at both the nano scale, and when quantum effects become important. Applying results from quantum information theory we construct a theory of thermodynamics in these limits. We derive general criteria for thermodynamical state transformations, and as special cases, find two free energies: one that quantifies the deterministically extractable work from a small system in contact with a heat bath, and the other that quantifies the reverse process. We find that there are fundamental limitations on work extraction from nonequilibrium states, owing to finite size effects and quantum coherences. This implies that thermodynamical transitions are generically irreversible at this scale. As one application of these methods, we analyse the efficiency of small heat engines and find that they are irreversible during the adiabatic stages of the cycle.Comment: Final, published versio

Identification of Rhoptry Trafficking Determinants and Evidence for a Novel Sorting Mechanism in the Malaria Parasite Plasmodium falciparum

The rhoptry of the malaria parasite Plasmodium falciparum is an unusual secretory organelle that is thought to be related to secretory lysosomes in higher eukaryotes. Rhoptries contain an extensive collection of proteins that participate in host cell invasion and in the formation of the parasitophorous vacuole, but little is known about sorting signals required for rhoptry protein targeting. Using green fluorescent protein chimeras and in vitro pull-down assays, we performed an analysis of the signals required for trafficking of the rhoptry protein RAP1. We provide evidence that RAP1 is escorted to the rhoptry via an interaction with the glycosylphosphatidyl inositol-anchored rhoptry protein RAMA. Once within the rhoptry, RAP1 contains distinct signals for localisation within a sub-compartment of the organelle and subsequent transfer to the parasitophorous vacuole after invasion. This is the first detailed description of rhoptry trafficking signals in Plasmodium

Are Ethnic and Gender Specific Equations Needed to Derive Fat Free Mass from Bioelectrical Impedance in Children of South Asian, Black African-Caribbean and White European Origin? Results of the Assessment of Body Composition in Children Study

Background Bioelectrical impedance analysis (BIA) is a potentially valuable method for assessing lean mass and body fat levels in children from different ethnic groups. We examined the need for ethnic- and gender-specific equations for estimating fat free mass (FFM) from BIA in children from different ethnic groups and examined their effects on the assessment of ethnic differences in body fat. Methods Cross-sectional study of children aged 8–10 years in London Primary schools including 325 South Asians, 250 black African-Caribbeans and 289 white Europeans with measurements of height, weight and arm-leg impedance (Z; Bodystat 1500). Total body water was estimated from deuterium dilution and converted to FFM. Multilevel models were used to derive three types of equation {A: FFM = linear combination(height+weight+Z); B: FFM = linear combination(height2/Z); C: FFM = linear combination(height2/Z+weight)}. Results Ethnicity and gender were important predictors of FFM and improved model fit in all equations. The models of best fit were ethnicity and gender specific versions of equation A, followed by equation C; these provided accurate assessments of ethnic differences in FFM and FM. In contrast, the use of generic equations led to underestimation of both the negative South Asian-white European FFM difference and the positive black African-Caribbean-white European FFM difference (by 0.53 kg and by 0.73 kg respectively for equation A). The use of generic equations underestimated the positive South Asian-white European difference in fat mass (FM) and overestimated the positive black African-Caribbean-white European difference in FM (by 4.7% and 10.1% respectively for equation A). Consistent results were observed when the equations were applied to a large external data set. Conclusions Ethnic- and gender-specific equations for predicting FFM from BIA provide better estimates of ethnic differences in FFM and FM in children, while generic equations can misrepresent these ethnic differences

Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway

In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10−5 M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding – differential affinity, rapid ligand exchange and conformational flexibility

Consensus for methods and outcomes in trials of oral morphine versus transmucosal diamorphine for breakthrough pain in children in the UK: the DIPPER study

Objectives: No randomised controlled trials have been conducted for breakthrough pain in paediatric palliative care and there are currently no standardised outcome measures. The DIPPER study aims to establish the feasibility of conducting a prospective randomised controlled trial comparing oral and transmucosal administration of opioids for breakthrough pain. The aim of the current study was to achieve consensus on design aspects for a small-scale prospective study to inform a future randomised controlled trial of oral morphine, the current first-line treatment, versus transmucosal diamorphine. / Methods: The nominal group technique was used to achieve consensus on best practice for mode of administration, dose regimen and a range of suitable pain intensity outcome measures for transmucosal diamorphine in children and young people with breakthrough pain. An expert panel of ten clinicians in paediatric palliative care and three parent representatives participated. Consensus was achieved when agreement was reached and no further comments from participants were forthcoming. / Results: The panel favoured the buccal route of administration, with dosing according to the recommendations in the Association for Paediatric Palliative Medicine formulary (fifth Edition, 2020). The verbal Numerical Rating Scale was selected to measure pain in children 8 years old and older, the Faces Pain Scale-Revised for children between 4 and 8 years old, and Face, Legs, Activity, Cry and Consolability (FLACC)/FLACC-Revised as the observational tools. / Conclusions: The nominal group technique allowed consensus to be reached for a small-scale, prospective, cohort study and provided information to inform the design of a randomised controlled trial