A Web-Based Tool to Assess Social Inclusion and Support Care Planning in Mental Health Supported Accommodation: Development and Preliminary Test Study.

BACKGROUND: Individuals with severe mental illness living in supported accommodation are often socially excluded. Social inclusion is an important aspect of recovery-based practice and quality of life. The Social Inclusion Questionnaire User Experience (SInQUE) is a measure of social inclusion that has been validated for use with people with mental health problems. Previous research has suggested that the SInQUE could also help support care planning focused on enabling social inclusion in routine mental health practice. OBJECTIVE: This study aims to develop a web-based version of the SInQUE for use in mental health supported accommodation services, examine its acceptability and perceived usefulness as a tool to support care planning with service users, determine the extent of uptake of the tool in supported accommodation settings, and develop a program theory and logic model for the online SInQUE. METHODS: This study involved a laboratory-testing stage to assess the acceptability of the SInQUE tool through "think-aloud" testing with 6 supported accommodation staff members and a field-testing stage to assess the acceptability, utility, and use of the SInQUE tool over a 5-month period. An implementation strategy was used in 1 London borough to encourage the use of the SInQUE. Qualitative interviews with 12 service users and 12 staff members who used the tool were conducted and analyzed using thematic analysis. The use of the SInQUE was compared with that in 2 other local authority areas, 1 urban and 1 rural, where the tool was made available for use but no implementation strategy was used. RESULTS: Overall, 17 staff members used the SInQUE with 28 different service users during the implementation period (approximately 10% of all service users living in supported accommodation in the study area). The staff and service users interviewed felt that the SInQUE was collaborative, comprehensive, user-friendly, and relevant. Although some staff were concerned that particular questions might be too personal, service users did not echo this view. Participants generally felt that the SInQUE could help identify individuals' priorities regarding different aspects of social inclusion by prompting in-depth conversations and tailoring specific support to address service users' inclusion goals. Some interviewees also suggested that the tool could highlight areas of unmet or unmeetable needs across the borough that could feed into service planning. The SInQUE was not used in the comparison areas that had no implementation strategy. CONCLUSIONS: The online SInQUE is an acceptable and potentially useful tool that can be recommended to assess and support care planning to enable social inclusion of people living in mental health supported accommodation services. Despite this, uptake rates were modest during the study period. A concerted implementation strategy is key to embedding its use in usual care, including proactive endorsement by senior leaders and service managers.

The Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA): investigating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin pharmacokinetics from birth to adolescence.

BACKGROUND: Pharmacokinetic (PK) data underlying paediatric penicillin dosing remain limited, especially in critical care. OBJECTIVES: The primary objective of the Neonatal and Paediatric Pharmacokinetics of Antimicrobials study (NAPPA) was to characterize PK profiles of commonly used penicillins using data obtained during routine care, to further understanding of PK variability and inform future evidence-based dosing. METHODS: NAPPA was a multicentre study of amoxicillin, co-amoxiclav, benzylpenicillin, flucloxacillin and piperacillin/tazobactam. Patients were recruited with informed consent. Antibiotic dosing followed standard of care. PK samples were obtained opportunistically or at optimal times, frozen and analysed using UPLC with tandem MS. Pharmacometric analysis was undertaken using NONMEM software (v7.3). Model-based simulations (n = 10 000) tested PTA with British National Formulary for Children (BNFC) and WHO dosing. The study had ethical approval. RESULTS: For the combined IV PK model, 963 PK samples from 370 participants were analysed simultaneously incorporating amoxicillin, benzylpenicillin, flucloxacillin and piperacillin data. BNFC high-dose regimen simulations gave these PTA results (median fT>MIC at breakpoints of specified pathogens): amoxicillin 100% (Streptococcus pneumoniae); benzylpenicillin 100% (Group B Streptococcus); flucloxacillin 48% (MSSA); and piperacillin 100% (Pseudomonas aeruginosa). Oral population PK models for flucloxacillin and amoxicillin enabled estimation of first-order absorption rate constants (1.16 h-1 and 1.3 h-1) and bioavailability terms (62.7% and 58.7%, respectively). CONCLUSIONS: NAPPA represents, to our knowledge, the largest prospective combined paediatric penicillin PK study undertaken to date, and the first paediatric flucloxacillin oral PK model. The PTA results provide evidence supportive of BNFC high-dose IV regimens for amoxicillin, benzylpenicillin and piperacillin.

Hydroxychloroquine and azithromycin alter the contractility of living porcine heart slices.

The cardiotoxicity risk of hydroxychloroquine (HCQ) and azithromycin (AZM) has been the subject of intensive research triggered by safety concerns in COVID-19 patients. HCQ and AZM have been associated with QT interval prolongation and drug-induced arrhythmias, however other cardiotoxicity mechanisms remain largely unexplored. Our group has pioneered the living heart slice preparation, an ex-vivo platform that maintains native cardiac tissue architecture and physiological electrical and contractile properties. Here, we evaluated the cardiotoxic effect of HCQ and AZM applied alone or in combination on cardiac contractility by measuring contractile force and contraction kinetics in heart slices prepared from porcine hearts. Our results show that clinically relevant concentrations of HCQ monotherapy (1-10 µM) reduced contractile force and contraction kinetics in porcine slices in a dose-dependent manner. However, AZM monotherapy decreased contractile force and contraction kinetics only at higher concentrations (30 µM). Combination of HCQ and AZM induced a dose-dependent effect similar to HCQ alone. Furthermore, pre-treating porcine heart slices with the L-type calcium channel agonist Bay K8644 prevented the effect of both drugs, while administration of Bay K8644 after drugs interventions largely reversed the effects, suggesting a mechanism involving inhibition of L-type calcium channels. These findings indicate that HCQ and AZM alter cardiac function beyond QT prolongation with significant contractile dysfunction in intact cardiac tissue. Our porcine heart slices provide a powerful platform to investigate mechanisms of drug cardiotoxicity.

Spelling Errors in Brief Computer-Mediated Texts Implicitly Lead to Linearly Additive Penalties in Trustworthiness.

Background: Spelling errors in documents lead to reduced trustworthiness, but the mechanism for weighing the psychological assessment (i.e., integrative versus dichotomous) has not been elucidated. We instructed participants to rate content of texts, revealing that their implicit trustworthiness judgments show marginal differences specifically caused by spelling errors. Methods: An online experiment with 100 English-speaking participants were asked to rate 27 short text excerpts (∼100 words) about multiple sclerosis in the format of unmoderated health forum posts. In a counterbalanced design, some excerpts had no typographic errors, some had two errors, and some had five errors. Each participant rated nine paragraphs with a counterbalanced mixture of zero, two or five errors. A linear mixed effects model (LME) was assessed with error number as a fixed effect and participants as a random effect. Results: Using an unnumbered scale with anchors of "completely untrustworthy" (left) and "completely trustworthy" (right) recorded as 0 to 100, two spelling errors resulted in a penalty to trustworthiness of 5.91 ± 1.70 (robust standard error) compared to the reference excerpts with zero errors, while the penalty for five errors was 13.5 ± 2.47; all three conditions were significantly different from each other (P < 0.001). Conclusion: Participants who rated information about multiple sclerosis in a context mimicking an online health forum implicitly assigned typographic errors nearly linearly additive trustworthiness penalties. This contravenes any dichotomous heuristic or local ceiling effect on trustworthiness penalties for these numbers of typographic errors. It supports an integrative model for psychological judgments of trustworthiness.

It was not easy to identify the study design from the title and abstract of articles indexed as diagnostic (test) accuracy studies in EMBASE in 2012 and 2019.

OBJECTIVE: To quantify use of shorthand description of research design in the titles and abstracts of diagnostic test accuracy studies, comparing 2012 and 2019. STUDY DESIGN AND SETTING: Joint examination, using pre-specified criteria, by two investigators of 320 randomly sampled articles indexed as "diagnostic (test) accuracy studies" in EMBASE in 2012 and 2019. RESULTS: The percentage of abstracts with shorthand descriptions of study design was 11% in 2012 and 15% in 2019, a difference of 4% (95% CI -3, 12). Although use of the term accuracy in the abstract did increase (58% in 2012 to 74% in 2019, difference 16% (95% CI 5, 26)), accuracy was only used to convey purpose or design in 49% (95% CI 43, 56) of abstracts where accuracy appeared (2012+2019). CONCLUSION: It is difficult to identify the study design of test evaluations from information in the title and abstract. This is important because bias is associated with different study designs. Developing a limited number of standardised, widely understood study design descriptions could greatly improve clarity of the only freely available information on many pieces of medical research. It may be helpful that the fact that a study addresses test accuracy be part of shorthand descriptions.

Symptom scores in the diagnosis of pediatric cow's milk protein allergy: A systematic review.

BACKGROUND: Cow's milk protein allergy (CMPA) is an immune-mediated allergic response to proteins in milk that is common in infants. Broad CMPA symptoms make diagnosis a challenge, particularly in primary care. Symptom scores may improve a clinician's awareness of symptoms, indicating a need for further testing. This systematic review examined the development and evaluation of such symptom scores for use in infants. METHODS: CENTRAL, MEDLINE, EMBASE and CINAHL databases were searched from inception to 3 December 2019 (Updated 14 November 2020) for diagnostic accuracy studies, randomised controlled trials, observational studies, economic evaluations, qualitative studies and studies reporting development of the tools. Data were not suitable for meta-analysis due to clinical and methodological heterogeneity, so were narratively synthesised. RESULTS: We found two symptom scores evaluated in one and fourteen studies, respectively. Estimated sensitivity and specificity ranged from 37% to 98% and 38% to 93%. The evaluations of each tool were at high risk of bias or failed to address issues such as clinical and cost-effectiveness. CONCLUSIONS: Estimates of accuracy of symptom scores for CMPA offered so far should be interpreted cautiously. Rigorous, conflict-free research based on well-defined roles for the tools is urgently required.

Correction: Spelling Errors and Shouting Capitalization Lead to Additive Penalties to Trustworthiness of Online Health Information: Randomized Experiment With Laypersons.

[This corrects the article DOI: 10.2196/15171.].

Spelling Errors and Shouting Capitalization Lead to Additive Penalties to Trustworthiness of Online Health Information: Randomized Experiment With Laypersons.

BACKGROUND: The written format and literacy competence of screen-based texts can interfere with the perceived trustworthiness of health information in online forums, independent of the semantic content. Unlike in professional content, the format in unmoderated forums can regularly hint at incivility, perceived as deliberate rudeness or casual disregard toward the reader, for example, through spelling errors and unnecessary emphatic capitalization of whole words (online shouting). OBJECTIVE: This study aimed to quantify the comparative effects of spelling errors and inappropriate capitalization on ratings of trustworthiness independently of lay insight and to determine whether these changes act synergistically or additively on the ratings. METHODS: In web-based experiments, 301 UK-recruited participants rated 36 randomized short stimulus excerpts (in the format of information from an unmoderated health forum about multiple sclerosis) for trustworthiness using a semantic differential slider. A total of 9 control excerpts were compared with matching error-containing excerpts. Each matching error-containing excerpt included 5 instances of misspelling, or 5 instances of inappropriate capitalization (shouting), or a combination of 5 misspelling plus 5 inappropriate capitalization errors. Data were analyzed in a linear mixed effects model. RESULTS: The mean trustworthiness ratings of the control excerpts ranged from 32.59 to 62.31 (rating scale 0-100). Compared with the control excerpts, excerpts containing only misspellings were rated as being 8.86 points less trustworthy, those containing inappropriate capitalization were rated as 6.41 points less trustworthy, and those containing the combination of misspelling and capitalization were rated as 14.33 points less trustworthy (P<.001 for all). Misspelling and inappropriate capitalization show an additive effect. CONCLUSIONS: Distinct indicators of incivility independently and additively penalize the perceived trustworthiness of online text independently of lay insight, eliciting a medium effect size.

Global shortage of neonatal and paediatric antibiotic trials: rapid review.

OBJECTIVES: There have been few clinical trials (CTs) on antibiotics that inform neonatal and paediatric drug labelling. The rate of unlicensed and off-label prescribing in paediatrics remains high. It is unclear whether the current neonatal and paediatric antibiotic research pipeline is adequate to inform optimal drug dosing. Using the ClinicalTrials.gov registry, this review aims to establish the current global status of antibiotic CTs in children up to 18 years of age. METHODS: Studies were identified using key word searches of the ClinicalTrials.gov registry and were manually filtered using prespecified inclusion/exclusion criteria. RESULTS: 76 registered open CTs of antibiotics in children were identified globally; 23 (30%) were recruiting newborns (only 8 (11%) included preterm neonates), 52 (68%) infants and toddlers, 58 (76%) children and 54 (71%) adolescents. The majority of registered trials were late phase (10 (15%) phase 3 and 23 (35%) phase 4/pharmacovigilance). Two-thirds were sponsored by non-profit organisations, compared with pharmaceutical companies (50 (66%) vs 26 (34%), respectively). A greater proportion of non-profit funded trials were efficacy-based strategic trials (n=34, 68%), in comparison with industry-led trials, which were most often focused on safety or pharmacokinetic data (n=17, 65%). Only 2 of the 37 antibiotics listed on the May 2016 Pew Charitable Trusts antibiotic development pipeline, currently being studied in adults, appear to be currently recruiting in open paediatric CTs. CONCLUSIONS: This review highlights that very few paediatric antibiotic CTs are being conducted globally, especially in neonates. There is a striking disparity noted between antibiotic drug development programmes in adults and children.

Systematic analysis of factors influencing observations of biased agonism at the mu-opioid receptor.

Biased agonism describes the ability of distinct G protein-coupled receptor (GPCR) ligands to stabilise distinct receptor conformations leading to the activation of different cell signalling pathways that can deliver different physiologic outcomes. This phenomenon is having a major impact on modern drug discovery as it offers the potential to design ligands that selectively activate or inhibit the signalling pathways linked to therapeutic effects with minimal activation or blockade of signalling pathways that are linked to the development of adverse on-target effects. However, the explosion in studies of biased agonism at multiple GPCR families in recombinant cell lines has revealed a high degree of variability on descriptions of biased ligands at the same GPCR and raised the question of whether biased agonism is a fixed attribute of a ligand in all cell types. The current study addresses this question at the mu-opioid receptor (MOP). Here, we have systematically assessed the impact of differential cellular protein complement (and cellular background), signalling kinetics and receptor species on our previous descriptions of biased agonism at MOP by several opioid peptides and synthetic opioids. Our results show that all these factors need to be carefully determined and reported when considering biased agonism. Nevertheless, our studies also show that, despite changes in overall signalling profiles, ligands that previously showed distinct bias profiles at MOP retained their uniqueness across different cell backgrounds.

Plasma membrane localization of the µ-opioid receptor controls spatiotemporal signaling.

Differential regulation of the µ-opioid receptor (MOR), a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, contributes to the clinically limiting effects of opioid analgesics, such as morphine. We used biophysical approaches to quantify spatiotemporal MOR signaling in response to different ligands. In human embryonic kidney (HEK) 293 cells overexpressing MOR, morphine caused a Gßγ-dependent increase in plasma membrane-localized protein kinase C (PKC) activity, which resulted in a restricted distribution of MOR within the plasma membrane and induced sustained cytosolic extracellular signal-regulated kinase (ERK) signaling. In contrast, the synthetic opioid peptide DAMGO ([d-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin) enabled receptor redistribution within the plasma membrane, resulting in transient increases in cytosolic and nuclear ERK activity, and, subsequently, receptor internalization. When Gßγ subunits or PKCα activity was inhibited or when the carboxyl-terminal phosphorylation sites of MOR were mutated, morphine-activated MOR was released from its restricted plasma membrane localization and stimulated a transient increase in cytosolic and nuclear ERK activity in the absence of receptor internalization. Thus, these data suggest that the ligand-induced redistribution of MOR within the plasma membrane, and not its internalization, controls its spatiotemporal signaling.

Biased Agonism of Endogenous Opioid Peptides at the µ-Opioid Receptor.

Biased agonism is having a major impact on modern drug discovery, and describes the ability of distinct G protein-coupled receptor (GPCR) ligands to activate different cell signaling pathways, and to result in different physiologic outcomes. To date, most studies of biased agonism have focused on synthetic molecules targeting various GPCRs; however, many of these receptors have multiple endogenous ligands, suggesting that "natural" bias may be an unappreciated feature of these GPCRs. The µ-opioid receptor (MOP) is activated by numerous endogenous opioid peptides, remains an attractive therapeutic target for the treatment of pain, and exhibits biased agonism in response to synthetic opiates. The aim of this study was to rigorously assess the potential for biased agonism in the actions of endogenous opioids at the MOP in a common cellular background, and compare these to the effects of the agonist d-Ala2-N-MePhe4-Gly-ol enkephalin (DAMGO). We investigated activation of G proteins, inhibition of cAMP production, extracellular signal-regulated kinase 1 and 2 phosphorylation, ß-arrestin 1/2 recruitment, and MOP trafficking, and applied a novel analytical method to quantify biased agonism. Although many endogenous opioids displayed signaling profiles similar to that of DAMGO, α-neoendorphin, Met-enkephalin-Arg-Phe, and the putatively endogenous peptide endomorphin-1 displayed particularly distinct bias profiles. These may represent examples of natural bias if it can be shown that they have different signaling properties and physiologic effects in vivo compared with other endogenous opioids. Understanding how endogenous opioids control physiologic processes through biased agonism can reveal vital information required to enable the design of biased opioids with improved pharmacological profiles and treat diseases involving dysfunction of the endogenous opioid system.

Biological redundancy of endogenous GPCR ligands in the gut and the potential for endogenous functional selectivity.

This review focuses on the existence and function of multiple endogenous agonists of the somatostatin and opioid receptors with an emphasis on their expression in the gastrointestinal tract. These agonists generally arise from the proteolytic cleavage of prepropeptides during peptide maturation or from degradation of peptides by extracellular or intracellular endopeptidases. In other examples, endogenous peptide agonists for the same G protein-coupled receptors can be products of distinct genes but contain high sequence homology. This apparent biological redundancy has recently been challenged by the realization that different ligands may engender distinct receptor conformations linked to different intracellular signaling profiles and, as such the existence of distinct ligands may underlie mechanisms to finely tune physiological responses. We propose that further characterization of signaling pathways activated by these endogenous ligands will provide invaluable insight into the mechanisms governing biased agonism. Moreover, these ligands may prove useful in the design of novel therapeutic tools to target distinct signaling pathways, thereby favoring desirable effects and limiting detrimental on-target effects. Finally we will discuss the limitations of this area of research and we will highlight the difficulties that need to be addressed when examining endogenous bias in tissues and in animals.