Effective fall prevention exercise in residential aged care: an intervention component analysis from an updated systematic review.

OBJECTIVE: The effect of fall prevention exercise programmes in residential aged care (RAC) is uncertain. This paper reports on an intervention component analysis (ICA) of randomised controlled trials (RCTs), from an update of a Cochrane review, to develop a theory of features of successful fall prevention exercise in RAC. METHODS: Trial characteristics were extracted from RCTs testing exercise interventions in RAC identified from an update of a Cochrane review to December 2022 (n=32). Eligible trials included RCTs or cluster RCTs in RAC, focusing on participants aged 65 or older, assessing fall outcomes with stand-alone exercise interventions. ICA was conducted on trials with >30 participants per treatment arm compared with control (n=17). Two authors coded trialists' perceptions on intervention features that may have contributed to the observed effect on falls. Inductive thematic analysis was used to identify the key differences between the trials which might account for positive and negative outcomes. RESULTS: 32 RCTs involving 3960 residents including people with cognitive (57%) and mobility (41%) impairments were included. ICA on the 17 eligible RCTs informed the development of a theory that (1) effective fall prevention exercise delivers the right exercise by specifically targeting balance and strength, tailored to the individual and delivered simply at a moderate intensity and (2) successful implementation needs to be sufficiently resourced to deliver structured and supervised exercise at an adequate dose. CONCLUSIONS: This analysis suggests that delivering the right exercise, sufficiently resourced, is important for preventing falls in RAC. This clinical guidance requires confirmation in larger trials.

Communicating cardiovascular risk: Systematic review of qualitative evidence.

INTRODUCTION: Cardiovascular risk prediction models are widely used to help individuals understand risk and make decisions. METHODS: Systematic review of qualitative evidence. We searched MEDLINE, Embase, PsycINFO and CINAHL. We included English-language qualitative studies on the communication of cardiovascular risk. We assessed study quality using Hawker et al.'s tool and synthesised data thematically. RESULTS: Thirty-seven studies were included. Many patients think that risk scores are of limited practical value. Other sources of information feed into informal estimates of risk, which may lead patients to reject the results of clinical risk assessment when the two conflict. Clinicians identify a number of barriers to risk communication, including patients' limited understanding of risk and excessive anxiety. They use a range of strategies for adapting risk communication. Both clinicians and individuals express specific preferences for risk communication formats. DISCUSSION: Ways of communicating risk that provide some comparison or reference point seem more promising. The broader context of communication around risk may be more important than the risk scoring instrument. Risk communication interventions, in practice, may be more about appeals to emotion than a rationalistic model of decision-making.

Critical features of multifactorial interventions for effective falls reduction in residential aged care: a systematic review, intervention component analysis and qualitative comparative analysis.

BACKGROUND: Multifactorial fall prevention trials providing interventions based on individual risk factors have variable success in aged care facilities. To determine configurations of trial features that reduce falls, intervention component analysis (ICA) and qualitative comparative analysis (QCA) were undertaken. METHODS: Randomised controlled trials (RCTs) from a Cochrane Collaboration review (Cameron, 2018) with meta-analysis data, plus trials identified in a systematic search update to December 2021 were included. Meta-analyses were updated. A theory developed through ICA of English publications of trialist's perspectives was assessed through QCA and a subgroup meta-analysis. RESULTS: Pooled effectiveness of multifactorial interventions indicated a falls rate ratio of 0.85 (95% confidence interval, CI, 0.65-1.10; I2 = 85%; 11 trials). All tested interventions targeted both environmental and personal risk factors by including assessment of environmental hazards, a medical or medication review and exercise intervention. ICA emphasised the importance of co-design involving facility staff and managers and tailored intervention delivery to resident's intrinsic factors for successful outcomes. QCA of facility engagement plus tailored delivery was consistent with greater reduction in falls, supported by high consistency (0.91) and coverage (0.85). An associated subgroup meta-analysis demonstrated strong falls reduction without heterogeneity (rate ratio 0.61, 95%CI 0.54-0.69, I2 = 0%; 7 trials). CONCLUSION: Multifactorial falls prevention interventions should engage aged care staff and managers to implement strategies which include tailored intervention delivery according to each resident's intrinsic factors. Such approaches are consistently associated with a successful reduction in falls, as demonstrated by QCA and subgroup meta-analyses. Co-design approaches may also enhance intervention success.

Educational interventions targeting pregnant women to optimise the use of caesarean section: What are the essential elements? A qualitative comparative analysis.

BACKGROUND: Caesarean section (CS) rates are increasing globally, posing risks to women and babies. To reduce CS, educational interventions targeting pregnant women have been implemented globally, however, their effectiveness is varied. To optimise benefits of these interventions, it is important to understand which intervention components influence success. In this study, we aimed to identify essential intervention components that lead to successful implementation of interventions focusing on pregnant women to optimise CS use. METHODS: We re-analysed existing systematic reviews that were used to develop and update WHO guidelines on non-clinical interventions to optimise CS. To identify if certain combinations of intervention components (e.g., how the intervention was delivered, and contextual characteristics) are associated with successful implementation, we conducted a Qualitative Comparative Analysis (QCA). We defined successful interventions as interventions that were able to reduce CS rates. We included 36 papers, comprising 17 CS intervention studies and an additional 19 sibling studies (e.g., secondary analyses, process evaluations) reporting on these interventions to identify intervention components. We conducted QCA in six stages: 1) Identifying conditions and calibrating the data; 2) Constructing truth tables, 3) Checking quality of truth tables; 4) Identifying parsimonious configurations through Boolean minimization; 5) Checking quality of the solution; 6) Interpretation of solutions. We used existing published qualitative evidence synthesis to develop potential theories driving intervention success. RESULTS: We found successful interventions were those that leveraged social or peer support through group-based intervention delivery, provided communication materials to women, encouraged emotional support by partner or family participation, and gave women opportunities to interact with health providers. Unsuccessful interventions were characterised by the absence of at least two of these components. CONCLUSION: We identified four key essential intervention components which can lead to successful interventions targeting women to reduce CS. These four components are 1) group-based delivery, 2) provision of IEC materials, 3) partner or family member involvement, and 4) opportunity for women to interact with health providers. Maternal health services and hospitals aiming to better prepare women for vaginal birth and reduce CS can consider including the identified components to optimise health and well-being benefits for the woman and baby.

Carfentanil is a ß-arrestin-biased agonist at the µ opioid receptor.

BACKGROUND AND PURPOSE: The illicit use of fentanyl-like drugs (fentanyls), which are µ opioid receptor agonists, and the many overdose deaths that result, has become a major problem. Fentanyls are very potent in vivo, leading to respiratory depression and death. However, the efficacy and possible signalling bias of different fentanyls is not clearly known. Here, we compared the relative efficacy and bias of a series of fentanyls. EXPERIMENTAL APPROACH: For agonist signalling bias and efficacy measurements, Bioluminescence Resonance Energy Transfer experiments were undertaken in HEK293T cells transiently transfected with µ opioid receptors, to assess Gi protein activation and ß-arrestin 2 recruitment. Agonist-induced cell surface receptor loss was assessed using an enzyme-linked immunosorbent assay, whilst agonist-induced G protein-coupled inwardly rectifying potassium channel current activation was measured electrophysiologically from rat locus coeruleus slices. Ligand poses in the µ opioid receptor were determined in silico using molecular dynamics simulations. KEY RESULTS: Relative to the reference ligand DAMGO, carfentanil was ß-arrestin-biased, whereas fentanyl, sufentanil and alfentanil did not display bias. Carfentanil induced potent and extensive cell surface receptor loss, whilst the marked desensitisation of G protein-coupled inwardly rectifying potassium channel currents in the continued presence of carfentanil in neurones was prevented by a GRK2/3 inhibitor. Molecular dynamics simulations suggested unique interactions of carfentanil with the orthosteric site of the receptor that could underlie the bias. CONCLUSIONS AND IMPLICATIONS: Carfentanil is a ß-arrestin-biased opioid drug at the µ receptor. It is uncertain how such bias influences in vivo effects of carfentanil relative to other fentanyls.

The anomalous pharmacology of fentanyl.

Fentanyl is a key therapeutic, used in anaesthesia and pain management. It is also increasingly used illicitly and is responsible for a large and growing number of opioid overdose deaths, especially in North America. A number of factors have been suggested to contribute to fentanyl's lethality, including rapid onset of action, in vivo potency, ligand bias, induction of muscle rigidity and reduced sensitivity to reversal by naloxone. Some of these factors can be considered to represent 'anomalous' pharmacological properties of fentanyl when compared with prototypical opioid agonists such as morphine. In this review, we examine the nature of fentanyl's 'anomalous' properties, to determine whether there is really a pharmacological basis to support the existence of such properties, and also discuss whether such properties are likely to contribute to overdose deaths involving fentanyls. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc.

Children's understanding and consent to heart surgery: Multidisciplinary teamwork and moral experiences.

Mainstream law and ethics literature on consent to children's surgery contrasts with moral experiences of children and adults observed in two heart surgery centres. Research interviews were conducted with 45 practitioners and related experts, and with 16 families of children aged 6 to 15, admitted for non-urgent surgery, as well as an online survey. Thematic data analysis was informed by critical realism and childhood studies.Impersonal adult-centric mainstream literature assumes young children cannot consent. It is based on dichotomies: adult/child, competent/incompetent, respect or protect children, inform or distract them, use time swiftly or flexibly, verbal/non-verbal communication, respect or control children and reason/emotion.Through their moral experiences, adults and children resolve these seeming dichotomies. Through understanding young children's reasoning and emotions about complex distressing decisions related to heart surgery, adults share knowledge, control, trust and respect with them. They see children's consent or refusal before non-urgent surgery as a shared personal moral experience within the child's life course, beyond mere legal compliance. Adults help children to understand and 'want' the surgery that offers things they value: better health or to 'be more like their friends'. If children are not convinced, sometimes surgery is postponed or occasionally cancelled.

Interventions targeting healthcare providers to optimise use of caesarean section: a qualitative comparative analysis to identify important intervention features.

BACKGROUND: Rapid increases in caesarean section (CS) rates have been observed globally; however, CS rates exceeding 15% at a population-level have limited benefits for women and babies. Many interventions targeting healthcare providers have been developed to optimise use of CS, typically aiming to improve and monitor clinical decision-making. However, interventions are often complex, and effectiveness is varied. Understanding intervention and implementation features that likely lead to optimised CS use is important to optimise benefits. The aim of this study was to identify important components that lead to successful interventions to optimise CS, focusing on interventions targeting healthcare providers.  METHODS: We used Qualitative Comparative Analysis (QCA) to identify if certain combination of important intervention features (e.g. type of intervention, contextual characteristics, and how the intervention was delivered) are associated with a successful intervention as reflected in a reduction of CS. We included 21 intervention studies targeting healthcare providers to reduce CS, comprising of 34 papers reporting on these interventions. To develop potential theories driving intervention success, we used existing published qualitative evidence syntheses on healthcare providers' perspectives and experiences of interventions targeted at them to reduce CS. RESULTS: We identified five important components that trigger successful interventions targeting healthcare providers: 1) training to improve providers' knowledge and skills, 2) active dissemination of CS indications, 3) actionable recommendations, 4) multidisciplinary collaboration, and 5) providers' willingness to change. Importantly, when one or more of these components are absent, dictated nature of intervention, where providers are enforced to adhere to the intervention, is needed to prompt successful interventions. Unsuccessful interventions were characterised by the absence of these components. CONCLUSION: We identified five important intervention components and combinations of intervention components which can lead to successful interventions targeting healthcare providers to optimise CS use. Health facility managers, researchers, and policy-makers aiming to improve providers' clinical decision making and reduce CS may consider including the identified components to optimise benefits.

Interaction With the Lipid Membrane Influences Fentanyl Pharmacology.

Overdose deaths from fentanyl have reached epidemic proportions in the USA and are increasing worldwide. Fentanyl is a potent opioid agonist that is less well reversed by naloxone than morphine. Due to fentanyl's high lipophilicity and elongated structure we hypothesised that its unusual pharmacology may be explained by its interactions with the lipid membrane on route to binding to the µ-opioid receptor (MOPr). Through coarse-grained molecular dynamics simulations, electrophysiological recordings and cell signalling assays, we determined how fentanyl and morphine access the orthosteric pocket of MOPr. Morphine accesses MOPr via the aqueous pathway; first binding to an extracellular vestibule, then diffusing into the orthosteric pocket. In contrast, fentanyl may take a novel route; first partitioning into the membrane, before accessing the orthosteric site by diffusing through a ligand-induced gap between the transmembrane helices. In electrophysiological recordings fentanyl-induced currents returned after washout, suggesting fentanyl deposits in the lipid membrane. However, mutation of residues forming the potential MOPr transmembrane access site did not alter fentanyl's pharmacological profile in vitro. A high local concentration of fentanyl in the lipid membrane, possibly in combination with a novel lipophilic binding route, may explain the high potency and lower susceptibility of fentanyl to reversal by naloxone.

Living bioethics, clinical ethics committees and children's consent to heart surgery.

This discussion paper considers how seldom recognised theories influence clinical ethics committees. A companion paper examined four major theories in social science: positivism, interpretivism, critical theory and functionalism, which can encourage legalistic ethics theories or practical living bioethics, which aims for theory-practice congruence. This paper develops the legalistic or living bioethics themes by relating the four theories to clinical ethics committee members' reported aims and practices and approaches towards efficiency, power, intimidation, justice, equality and children's interests and rights. Different approaches to framing ethical questions are also considered. Being aware of the four theories' influence can help when seeking to understand and possibly change clinical ethics committee routines. The paper is not a research report but is informed by a recent study in two London paediatric cardiac units. Forty-five practitioners and related experts were interviewed, including eight members of ethics committees, about the work of informing, preparing and supporting families during the extended process of consent to children's elective heart surgery. The mosaic of multidisciplinary teamwork is reported in a series of papers about each profession, including this one on bioethics and law and clinical ethics committees' influence on clinical practice. The qualitative social research was funded by the British Heart Foundation, in order that more may be known about the perioperative views and needs of all concerned. Questions included how disputes can be avoided, how high ethical standards and respectful cooperation between staff and families can be encouraged, and how minors' consent or refusal may be respected, with the support of clinical ethics committees.

CFTR Modulators: From Mechanism to Targeted Therapeutics.

People with cystic fibrosis (CF) suffer from a multi-organ disorder caused by loss-of-function variants in the gene encoding the epithelial anion channel cystic fibrosis transmembrane conductance regulator (CFTR). Tremendous progress has been made in both basic and clinical sciences over the past three decades since the identification of the CFTR gene. Over 90% of people with CF now have access to therapies targeting dysfunctional CFTR. This success was made possible by numerous studies in the field that incrementally paved the way for the development of small molecules known as CFTR modulators. The advent of CFTR modulators transformed this life-threatening illness into a treatable disease by directly binding to the CFTR protein and correcting defects induced by pathogenic variants. In this chapter, we trace the trajectory of structural and functional studies that brought CF therapies from bench to bedside, with an emphasis on mechanistic understanding of CFTR modulators.

Comparison of national surveillance systems for Lyme disease in humans in Europe and North America: a policy review.

BACKGROUND: Lyme disease incidence is increasing in Europe, the USA, and Canada. In 2010, a comparison of surveillance systems for Lyme disease (LD) in humans in 28 European countries showed that systems highly varied, making epidemiological comparisons difficult. Details by country were not published. In 2018, one of LD clinical manifestations, neuroborreliosis, was added under European Union (EU) surveillance to standardise definitions. In this study, we identified and compared, 10 years after the European inventory, the characteristics of national surveillance systems and policies for LD in humans, with additional countries. METHODS: Thirty-four European and North American countries were included. Information on national "traditional" systems (which compile data reported by clinicians and laboratories) and "public participatory" websites and mobile applications (which collect information directly from the public) were searched in MEDLINE, a systematic evidence map, and Google. An existing framework on LD surveillance was adapted to capture information on the administration level, indicators, reporting entities, coverage, and obligation to report. RESULTS: A surveillance system was found for 29 (85%) countries. Twenty-four had a traditional system alone, one had a public participatory system alone, and the remaining had both. Among countries with traditional systems, 23 (82%) administered them at the national level. Nineteen (68%) required mandatory reporting. Sixteen (57%) used both clinicians and laboratories as reporting entities. Eighteen (64%) employed case definitions, most of which considered both neuroborreliosis and erythema migrans (n = 14). Others monitored the number of positive laboratory tests and/or patient consultations. Public participatory systems were only implemented in countries employing either also sentinels or voluntary surveys, or no traditional system, suggesting their use as a complementary tool. Only 56% of EU countries had neuroborreliosis as an indicator. CONCLUSION: The situation remains similar to 2010 with persisting heterogeneity between systems, suggesting that countries prioritise different surveillance objectives for LD. Without a common indicator in Europe, it is difficult to get a clear epidemiological picture. We discuss four factors that potentially influence LD surveillance strategies: perceptions of severity, burden on resources, two-way communication, and the medical conflicts about LD. Addressing these with countries might help moving towards the adoption of common practices.

The involvement and autonomy of young children undergoing elective paediatric cardiac surgery: a qualitative study.

BACKGROUND: Standards generally reported in the literature about informing children and respecting their consent or refusal before elective heart surgery may differ from actual practice. This research aims to summarize the main themes in the literature about paediatric anaesthesia and compare these with research findings on how health professionals counsel young children before elective heart surgery, respect their consent or refusal, and maintain patient-centred care. METHODS: This qualitative research involved: literature reviews about children's consent to surgery and major interventions; observations of wards, clinics and medical meetings in two paediatric cardiology departments, October 2019 to February 2020; audio-recorded semi-structured interviews with 45 hospital staff, including 5 anaesthetists, and related experts, November 2019 to April 2021; interviews with 16 families, with children aged 6- to 15-years and their parents shortly after elective heart surgery, and some months later (reported in other papers); thematic data analysis; and research reports on how different professions contribute to children's informed decisions for heart surgery. RESULTS: The medical, ethics and English legal literature tend to assume legal minors cannot refuse major recommended treatment, and cannot consent until they are 12 years or older. Little is said about informing pre-competent children. If children resist, some anaesthetists rely on sedation and distraction, and avoid much informed discussion, aiming to reduce peri-operative anxiety. However, interviewees reported informing young children, and respecting their consent or refusal before elective surgery. They may delay elective surgery and provide further information and support, aiming to reduce fear and promote trust. Six years of age was commonly cited as the threshold for respecting consent to heart transplantation. CONCLUSION: Differing views about younger children's competence, anxiety and best interests support different reactions to children's consent and refusal before elective heart surgery. This paper reports the zero-restraint policy followed for over a decade in at least one leading surgery centre. The related law and literature need to be updated, to take more account of evidence of actual practice.

'Leading from the front' implementation increases the success of influenza vaccination drives among healthcare workers: a reanalysis of systematic review evidence using Intervention Component Analysis (ICA) and Qualitative Comparative Analysis (QCA).

BACKGROUND: Seasonal influenza vaccination of healthcare workers (HCW) is widely recommended to protect staff and patients. A previous systematic review examined interventions to encourage uptake finding that hard mandates, such as loss of employment for non-vaccination, were more effective than soft mandates, such as signing a declination form, or other interventions such as incentives. Despite these overarching patterns the authors of the review concluded that 'substantial heterogeneity' remained requiring further analysis. This paper reanalyses the evidence using Intervention Component Analysis (ICA) and Qualitative Comparative Analysis (QCA) to examine whether the strategies used to implement interventions explain the residual heterogeneity. METHODS: We used ICA to extract implementation features and trialists' reflections on what underpinned the success of the intervention they evaluated. The ICA findings then informed and structured two QCA analyses to systematically examine associations between implementation features and intervention outcomes. Analysis 1 examined hard mandate studies. Analysis 2 examined soft mandates and other interventions. RESULTS: In Analysis 1 ICA revealed the significance of 'leading from the front' rather than 'top-down' implementation of hard mandates. Four key features underpinned this: providing education prior to implementation; two-way engagement so HCW can voice concerns prior to implementation; previous use of other strategies so that institutions 'don't-go-in-cold' with hard-mandates; and support from institutional leadership. QCA revealed that either of two configurations were associated with greater success of hard mandates. The first involves two-way engagement, leadership support and a 'don't-go-in-cold' approach. The second involves leadership support, education and a 'don't-go-in-cold' approach. Reapplying the 'leading from the front' theory in Analysis 2 revealed similar patterns. CONCLUSIONS: Regardless of intervention type a 'leading from the front' approach to implementation will likely enhance intervention success. While the results pertain to flu vaccination among HCWs, the components identified here may be relevant to public health campaigns regarding COVID-19 vaccination.

Consumption and effects of caffeinated energy drinks in young people: an overview of systematic reviews and secondary analysis of UK data to inform policy.

BACKGROUND: This overview and analysis of UK datasets was commissioned by the UK government to address concerns about children's consumption of caffeinated energy drinks and their effects on health and behaviour. METHODS: We searched nine databases for systematic reviews, published between 2013 and July 2021, in English, assessing caffeinated energy drink consumption by people under 18 years old (children). Two reviewers rated or checked risk of bias using AMSTAR2, and extracted and synthesised findings. We searched the UK Data Service for country-representative datasets, reporting children's energy-drink consumption, and conducted bivariate or latent class analyses. RESULTS: For the overview, we included 15 systematic reviews; six reported drinking prevalence and 14 reported associations between drinking and health or behaviour. AMSTAR2 ratings were low or critically low. Worldwide, across reviews, from 13% to 67% of children had consumed energy drinks in the past year. Only two of the 74 studies in the reviews were UK-based. For the dataset analysis, we identified and included five UK cross-sectional datasets, and found that 3% to 32% of children, across UK countries, consumed energy drinks weekly, with no difference by ethnicity. Frequent drinking (5 or more days per week) was associated with low psychological, physical, educational and overall well-being. Evidence from reviews and datasets suggested that boys drank more than girls, and drinking was associated with more headaches, sleep problems, alcohol use, smoking, irritability, and school exclusion. GRADE (Grading of Recommendations, Assessment, Development and Evaluation) assessment suggests that the evidence is weak. CONCLUSIONS: Weak evidence suggests that up to a third of children in the UK consume caffeinated energy drinks weekly; and drinking 5 or more days per week is associated with some health and behaviour problems. Most of the evidence is from surveys, making it impossible to distinguish cause from effect. Randomised controlled trials are unlikely to be ethical; longitudinal studies could provide stronger evidence. PROSPERO REGISTRATIONS: CRD42018096292 - no deviations. CRD42018110498 - one deviation - a latent class analysis was conducted.

Children's informed signified and voluntary consent to heart surgery: Professionals' practical perspectives.

BACKGROUND: The law and literature about children's consent generally assume that patients aged under-18 cannot consent until around 12 years, and cannot refuse recommended surgery. Children deemed pre-competent do not have automatic rights to information or to protection from unwanted interventions. However, the observed practitioners tend to inform young children s, respect their consent or refusal, and help them to "want" to have the surgery. Refusal of heart transplantation by 6-year-olds is accepted. RESEARCH QUESTION: What are possible reasons to explain the differences between theories and practices about the ages when children begin to be informed about elective heart surgery, and when their consent or refusal begins to be respected? RESEARCH DESIGN, PARTICIPANTS AND CONTEXT: Research methods included reviews of related healthcare, law and ethics literature; observations and conversations with staff and families in two London hospitals; audio-recorded semi-structured interviews with a purposive sample of 45 healthcare professionals and related experts; interviews and a survey with parents and children aged 6- to 15-years having elective surgery (not reported in this paper); meetings with an interdisciplinary advisory group; thematic analysis of qualitative data and co-authorship of papers with participants. ETHICAL CONSIDERATIONS: Approval was granted by four research ethics committees/authorities. All interviewees gave their informed written consent. FINDINGS: Interviewees explained their views and experiences about children's ages of competence to understand and consent or refuse, analysed by their differing emphases on informed, signified or voluntary consent. DISCUSSION: Differing views about children's competence to understand and consent are associated with emphases on consent as an intellectual, practical and/or emotional process. Conclusion: Greater respect for children's practical signified, emotional voluntary and intellectual informed consent can increase respectful understanding of children's consent. Nurses play a vital part in children's practitioner-patient relationships and physical care and therefore in all three elements of consent.

A small molecule CFTR potentiator restores ATP-dependent channel gating to the cystic fibrosis mutant G551D-CFTR.

BACKGROUND AND PURPOSE: Cystic fibrosis transmembrane conductance regulator (CFTR) potentiators are small molecules developed to treat the genetic disease cystic fibrosis (CF). They interact directly with CFTR Cl- channels at the plasma membrane to enhance channel gating. Here, we investigate the action of a new CFTR potentiator, CP-628006 with a distinct chemical structure. EXPERIMENTAL APPROACH: Using electrophysiological assays with CFTR-expressing heterologous cells and CF patient-derived human bronchial epithelial (hBE) cells, we compared the effects of CP-628006 with the marketed CFTR potentiator ivacaftor. KEY RESULTS: CP-628006 efficaciously potentiated CFTR function in epithelia from cultured hBE cells. Its effects on the predominant CFTR variant F508del-CFTR were larger than those with the gating variant G551D-CFTR. In excised inside-out membrane patches, CP-628006 potentiated wild-type, F508del-CFTR, and G551D-CFTR by increasing the frequency and duration of channel openings. CP-628006 increased the affinity and efficacy of F508del-CFTR gating by ATP. In these respects, CP-628006 behaved like ivacaftor. CP-628006 also demonstrated notable differences with ivacaftor. Its potency and efficacy were lower than those of ivacaftor. CP-628006 conferred ATP-dependent gating on G551D-CFTR, whereas the action of ivacaftor was ATP-independent. For G551D-CFTR, but not F508del-CFTR, the action of CP-628006 plus ivacaftor was greater than ivacaftor alone. CP-628006 delayed, but did not prevent, the deactivation of F508del-CFTR at the plasma membrane, whereas ivacaftor accentuated F508del-CFTR deactivation. CONCLUSIONS AND IMPLICATIONS: CP-628006 has distinct effects compared to ivacaftor, suggesting a different mechanism of CFTR potentiation. The emergence of CFTR potentiators with diverse modes of action makes therapy with combinations of potentiators a possibility.

Sufficient conditions for effective psychological treatment of chronic pain: a qualitative comparative analysis.

ABSTRACT: Chronic pain (CP) is the leading cause of years lived with disability globally. Treatment within Western medicine is often multicomponent; the psychological element of treatment varies, yet the optimal conditions for effective reduction of pain-related outcomes remain unclear. This study used qualitative comparative analysis, a relatively new form of evidence synthesis in the field based on set theory to ascertain configurations of intervention components and processes of psychological treatment of chronic pain in adults that lead to more effective interventions. Data were extracted from 38 studies identified in a concurrent Cochrane review and were then subjected to qualitative comparative analysis. Two analyses were conducted: one to examine what is most effective for reducing disability and one to examine what is most effective for reducing distress. Analysis and comparison of the 10 treatments with best outcomes with the 10 treatments with poorest outcomes showed that interventions using graded exposure, graded exercise or behavioural rehearsal (exposure/activity), and interventions aiming to modify reinforcement contingencies (social/operant) reduced disability levels when either approach was applied but not both. Exposure/activity can improve distress levels when combined with cognitive restructuring, as long as social/operant methods are not included in treatment. Clinical implications of this study suggest that treatment components should not be assumed to be synergistic and provided in a single package.

Cost-effectiveness of Microsoft Academic Graph with machine learning for automated study identification in a living map of coronavirus disease 2019 (COVID-19) research.

Background: Identifying new, eligible studies for integration into living systematic reviews and maps usually relies on conventional Boolean updating searches of multiple databases and manual processing of the updated results. Automated searches of one, comprehensive, continuously updated source, with adjunctive machine learning, could enable more efficient searching, selection and prioritisation workflows for updating (living) reviews and maps, though research is needed to establish this. Microsoft Academic Graph (MAG) is a potentially comprehensive single source which also contains metadata that can be used in machine learning to help efficiently identify eligible studies. This study sought to establish whether: (a) MAG was a sufficiently sensitive single source to maintain our living map of COVID-19 research; and (b) eligible records could be identified with an acceptably high level of specificity. Methods: We conducted an eight-arm cost-effectiveness analysis to assess the costs, recall and precision of semi-automated workflows, incorporating MAG with adjunctive machine learning, for continually updating our living map. Resource use data (time use) were collected from information specialists and other researchers involved in map production. Our systematic review software, EPPI-Reviewer, was adapted to incorporate MAG and associated machine learning workflows, and also used to collect data on recall, precision, and manual screening workload. Results: The semi-automated MAG-enabled workflow dominated conventional workflows in both the base case and sensitivity analyses. At one month our MAG-enabled workflow with machine learning, active learning and fixed screening targets identified 469 additional, eligible articles for inclusion in our living map, and cost £3,179 GBP per week less, compared with conventional methods relying on Boolean searches of Medline and Embase. Conclusions: We were able to increase recall and coverage of a large living map, whilst reducing its production costs. This finding is likely to be transferrable to OpenAlex, MAG's successor database platform.