Mechanisms by which the cystic fibrosis transmembrane conductance regulator may influence SARS-CoV-2 infection and COVID-19 disease severity.

Patients with cystic fibrosis (CF) exhibit pronounced respiratory damage and were initially considered among those at highest risk for serious harm from SARS-CoV-2 infection. Numerous clinical studies have subsequently reported that individuals with CF in North America and Europe-while susceptible to severe COVID-19-are often spared from the highest levels of virus-associated mortality. To understand features that might influence COVID-19 among patients with cystic fibrosis, we studied relationships between SARS-CoV-2 and the gene responsible for CF (i.e., the cystic fibrosis transmembrane conductance regulator, CFTR). In contrast to previous reports, we found no association between CFTR carrier status (mutation heterozygosity) and more severe COVID-19 clinical outcomes. We did observe an unexpected trend toward higher mortality among control individuals compared with silent carriers of the common F508del CFTR variant-a finding that will require further study. We next performed experiments to test the influence of homozygous CFTR deficiency on viral propagation and showed that SARS-CoV-2 production in primary airway cells was not altered by the absence of functional CFTR using two independent protocols. On the contrary, experiments performed in vitro strongly indicated that virus proliferation depended on features of the mucosal fluid layer known to be disrupted by absent CFTR in patients with CF, including both low pH and increased viscosity. These results point to the acidic, viscous, and mucus-obstructed airways in patients with cystic fibrosis as unfavorable for the establishment of coronaviral infection. Our findings provide new and important information concerning relationships between the CF clinical phenotype and severity of COVID-19.

Liposomal Bupivacaine Versus Continuous Nerve Block: Liposomal Bupivacaine May be Non-inferior and More Cost Effective.

BACKGROUND: Regional anesthesia with adductor canal block has become the standard of care for pain management after total knee arthroplasty (TKA). We hypothesized that liposomal bupivacaine (LB) may be noninferior to continuous nerve block with a pain pump in terms of average pain scores, 30- and 90-day readmissions, and emergency department (ED) visits while reducing cost. METHODS: A retrospective chart review was performed on primary TKA patients from 2015 to 2020 by 23 orthopaedic surgeons at a single institution. The inclusion criteria was treatment with LB or a pain pump, and exclusion criteria was receipt of both anesthetics and revision surgery. A total of 2,378 patients met the inclusion criteria with 1,640 patients treated with LB and 738 treated with the pain pump. Demographic differences were not statistically significant. Primary outcomes were average pain scores, 30- and 90-day readmissions, and ED visits. Secondary outcomes were average milligram morphine equivalents per admission, hospital lengths of stay , and costs. RESULTS: There was no significant difference in pain scores on postoperative days 0, 1, 2, or 3 (P = .77, .86, 0.08, and 0.40, respectively), 30- or 90- day readmissions (P = .527 and P = .374), ED visits (P = .129 and P = .108), milligram morphine equivalents utilizations (P = .194), or average hospital LOS (P = .348). We estimated a potential cost savings of $95 per patient and $155,800 over the course of the study. CONCLUSION: LB was found to be noninferior to a pain pump, and the transition to this medication was associated with cost savings.

UBC9 Mutant Reveals the Impact of Protein Dynamics on Substrate Selectivity and SUMO Chain Linkages.

SUMO, a conserved ubiquitin-like protein, is conjugated to a multitude of cellular proteins to maintain genomic integrity and resist genotoxic stress. Studies of the SUMO E2 conjugating enzyme mutant, UBC9P123L, suggested that altered substrate specificity enhances cell sensitivity to DNA damaging agents. Using nuclear magnetic resonance chemical shift studies, we confirm that the mutation does not alter the core globular fold of UBC9, while 15N relaxation measurements demonstrate mutant-induced stabilization of distinct chemical states in residues near the active site cysteine and substrate recognition motifs. We further demonstrate that the P123L substitution induces a switch from the preferential addition of SUMO to lysine residues in unstructured sites to acceptor lysines embedded in secondary structures, thereby also inducing alterations in SUMO chain linkages. Our results provide new insights regarding the impact that structural dynamics of UBC9 have on substrate selection and specifically SUMO chain formation. These findings highlight the potential contribution of nonconsensus SUMO targets and/or alternative SUMO chain linkages on DNA damage response and chemotherapeutic sensitivity.

Transcatheter aortic valve implantation for severe aortic stenosis in the Australian regional population.

OBJECTIVE: To compare clinical and functional outcomes of regional and urban patients after transcatheter aortic valve implantation for severe aortic stenosis. METHODS: Data were collected at patient follow-up post-transcatheter aortic valve implantation at 30 days and 12 months. Patients were stratified by residential postcodes into remoteness areas using the Australian Statistical Geography Standard. DESIGN: Retrospective cohort study. SETTING: Single-centre tertiary referral hospital. PARTICIPANTS: Patients undergoing transcatheter aortic valve implantation (n = 142) from 2009 to 2018 were analysed, with 77 patients (54.2%) residing in regional Victoria and New South Wales. MAIN OUTCOME MEASURES: Procedural success, adverse event rates, readmission rates, mortality rates, loss to follow-up and functional improvement. RESULTS: Patients residing in regional areas had a lower mean age (81.8 vs 83.7 years) and proportion of Stage 4 or 5 chronic kidney disease (1.3% vs 9.2%), compared with urban patients. Procedural characteristics and immediate post-procedural outcomes were similar between both groups. There was no statistically significant difference in mortality, readmission rates or loss to follow-up between the two cohorts. Regional patients demonstrated poorer rates of functional improvement at 30 days (50.7% vs 67.7%); however, this difference was not sustained at 12 months (79.2% vs 71.0%). Frailty was demonstrated to be an independent predictor of poor 30-day functional improvement. CONCLUSION: Regional patients treated with transcatheter aortic valve implantation for severe aortic stenosis have non-inferior 30-day and 12-month outcomes, when compared with urban patients. Frailty is a predictor of poor functional improvement post-transcatheter aortic valve implantation.

Patients' use and views of real-time feedback technology in general practice.

BACKGROUND: There is growing interest in real-time feedback (RTF), which involves collecting and summarizing information about patient experience at the point of care with the aim of informing service improvement. OBJECTIVE: To investigate the feasibility and acceptability of RTF in UK general practice. DESIGN: Exploratory randomized trial. SETTING/PARTICIPANTS: Ten general practices in south-west England and Cambridgeshire. All patients attending surgeries were eligible to provide RTF. INTERVENTION: Touch screens were installed in waiting areas for 12 weeks with practice staff responsible for encouraging patients to provide RTF. All practices received fortnightly feedback summaries. Four teams attended a facilitated reflection session. OUTCOMES: RTF 'response rates' among consulting patients were estimated, and the representativeness of touch screen users were assessed. The frequency of staff-patient interactions about RTF (direct observation) and patient views of RTF (exit survey) were summarized. Associated costs were collated. RESULTS: About 2.5% consulting patients provided RTF (range 0.7-8.0% across practices), representing a mean of 194 responses per practice. Patients aged above 65 were under-represented among touch screen users. Receptionists rarely encouraged RTF but, when this did occur, 60% patients participated. Patients were largely positive about RTF but identified some barriers. Costs per practice for the twelve-week period ranged from £1125 (unfacilitated team-level feedback) to £1887 (facilitated team ± practitioner-level feedback). The main cost was the provision of touch screens. CONCLUSIONS: Response rates for RTF were lower than those of other survey modes, although the numbers of patients providing feedback to each practice were comparable to those achieved in the English national GP patient survey. More patients might engage with RTF if the opportunity were consistently highlighted to them.

DNA topoisomerase I domain interactions impact enzyme activity and sensitivity to camptothecin.

During processes such as DNA replication and transcription, DNA topoisomerase I (Top1) catalyzes the relaxation of DNA supercoils. The nuclear enzyme is also the cellular target of camptothecin (CPT) chemotherapeutics. Top1 contains four domains: the highly conserved core and C-terminal domains involved in catalysis, a coiled-coil linker domain of variable length, and a poorly conserved N-terminal domain. Yeast and human Top1 share a common reaction mechanism and domain structure. However, the human Top1 is ∼100-fold more sensitive to CPT. Moreover, substitutions of a conserved Gly(717) residue, which alter intrinsic enzyme sensitivity to CPT, induce distinct phenotypes in yeast. To address the structural basis for these differences, reciprocal swaps of yeast and human Top1 domains were engineered in chimeric enzymes. Here we report that intrinsic Top1 sensitivity to CPT is dictated by the composition of the conserved core and C-terminal domains. However, independent of CPT, biochemically similar chimeric enzymes produced strikingly distinct phenotypes in yeast. Expression of a human Top1 chimera containing the yeast linker domain proved toxic, even in the context of a catalytically inactive Y723F enzyme. Lethality was suppressed either by splicing the yeast N-terminal domain into the chimera, deleting the human N-terminal residues, or in enzymes reconstituted by polypeptide complementation. These data demonstrate a functional interaction between the N-terminal and linker domains, which, when mispaired between yeast and human enzymes, induces cell lethality. Because toxicity was independent of enzyme catalysis, the inappropriate coordination of N-terminal and linker domains may induce aberrant Top1-protein interactions to impair cell growth.

Quality of care and its determinants in longer term mental health facilities across Europe; a cross-sectional analysis.

BACKGROUND: The Quality Indicator for Rehabilitative Care (QuIRC) is an international, standardised quality tool for the evaluation of mental health facilities that provide longer term care. Completed by the service manager, it comprises 145 items that assess seven domains of care: living environment; treatments and interventions; therapeutic environment; self-management and autonomy; social interface; human rights; and recovery based practice. We used the QuIRC to investigate associations between characteristics of longer term mental health facilities across Europe and the quality of care they delivered to service patients. METHODS: QuIRC assessments were completed for 213 longer term mental health units in ten countries that were at various stages of deinstitutionalisation of their mental health services. Associations between QuIRC domain scores and unit descriptive variables were explored using simple and multiple linear regression that took into account clustering at the unit and country level. RESULTS: We found wide variation in QuIRC domain scores between individual units, but across countries, fewer than a quarter scored below 50 % on any domains. The quality of care was higher in units that were smaller, of mixed sex, that had a defined expected maximum length of stay and in which not all patients were severely disabled. CONCLUSIONS: This is the first time longer term mental health units across a number of European countries have been compared using a standardised measure. Further use of the QuIRC will allow greater understanding of the quality of care in these units across Europe and provide an opportunity to monitor pan-European quality standards of care for this vulnerable patient group.

Membrane interactions and biological activity of antimicrobial peptides from Australian scorpion.

UyCT peptides are antimicrobial peptides isolated from the venom of the Australian scorpion. The activity of the UyCT peptides against Gram positive and Gram negative bacteria and red blood cells was determined. The membrane interactions of these peptides were evaluated by dye release (DR) of the fluorophore calcein from liposomes and isothermal titration calorimetry (ITC); and their secondary structure was determined by circular dichroism (CD). Three different lipid systems were used to mimic red blood cells, Escherichia coli and Staphylococcus aureus membranes. UyCT peptides exhibited broad spectrum antimicrobial activity with low MIC for S. aureus and multi-drug resistant Gram negative strains. Peptide combinations showed some synergy enhancing their potency but not hemolytic activity. The UyCT peptides adopted a helical structure in lipid environments and DR results confirmed that the mechanism of action is by disrupting the membrane. ITC data indicated that UyCT peptides preferred prokaryotic rather than eukaryotic membranes. The overall results suggest that UyCT peptides could be pharmaceutical leads for the treatment of Gram negative multiresistant bacterial infections, especially against Acinetobacter baumanni, and candidates for peptidomimetics to enhance their potency and minimize hemolysis. This article is part of a Special Issue entitled: Interfacially Active Peptides and Proteins. Guest Editors: William C. Wimley and Kalina Hristova.

High-resolution twin-ion metabolite extraction (HiTIME) mass spectrometry: nontargeted detection of unknown drug metabolites by isotope labeling, liquid chromatography mass spectrometry, and automated high-performance computing.

The metabolic fate of a compound can often determine the success of a new drug lead. Thus, significant effort is directed toward identifying the metabolites formed from a given molecule. Here, an automated and nontargeted procedure is introduced for detecting drug metabolites without authentic metabolite standards via the use of stable isotope labeling, liquid chromatography mass spectrometry (LC/MS), and high-performance computing. LC/MS of blood plasma extracts from rats that were administered a 1:1 mixture of acetaminophen (APAP) and (13)C6-APAP resulted in mass spectra that contained "twin" ions for drug metabolites that were not detected in control spectra (i.e., no APAP administered). Because of the development of a program (high-resolution twin-ion metabolite extraction; HiTIME) that can identify twin-ions in high-resolution mass spectra without centroiding (i.e., reduction of mass spectral peaks to single data points), 9 doublets corresponding to APAP metabolites were identified. This is nearly twice that obtained by use of existing programs that make use of centroiding to reduce computational cost under these conditions with a quadrupole time-of-flight mass spectrometer. By a manual search for all reported APAP metabolite ions, no additional twin-ion signals were assigned. These data indicate that all the major metabolites of APAP and multiple low-abundance metabolites (e.g., acetaminophen hydroxy- and methoxysulfate) that are rarely reported were detected. This methodology can be used to detect drug metabolites without prior knowledge of their identity. HiTIME is freely available from https://github.com/bjpop/HiTIME .

Structure, molecular modeling, and function of the novel potassium channel blocker urotoxin isolated from the venom of the Australian scorpion Urodacus yaschenkoi.

This communication reports the structural and functional characterization of urotoxin, the first K(+) channel toxin isolated from the venom of the Australian scorpion Urodacus yaschenkoi. It is a basic peptide consisting of 37 amino acids with an amidated C-terminal residue. Urotoxin contains eight cysteines forming four disulfide bridges with sequence similarities resembling the α-potassium channel toxin 6 (α-KTx-6) subfamily of peptides; it was assigned the systematic number of α-KTx-6.21. Urotoxin is a potent blocker of human voltage-gated potassium channel (Kv)1.2 channels, with an IC50 of 160 pM, whereas its affinity for other channels tested was in the nanomolar range (hKv1.1, IC50 = 253 nM; hKv1.3, IC50 = 91 nM; and hKCa3.1, IC50 = 70 nM). The toxin had no effect on hKv1.4, hKv1.5, human ether-à-go-go-related gene type 1 (hERG1), or human ether-à-go-go-like (hELK2) channels. Multiple sequence alignments from the venom gland transcriptome showed the existence of four other new peptides similar to urotoxin. Computer modeling of urotoxin's three-dimensional structure suggests the presence of the α/ß-scaffold characteristic of other scorpion toxins, although very likely forming an uncommon disulfide pairing pattern. Using molecular dynamics, a model for the binding of this peptide to human Kv1.2 and hKv1.1 channels is presented, along with the binding of an in silico mutant urotoxin (Lys25Ala) to both channels. Urotoxin enriches our knowledge of K(+) channel toxins and, due to its high affinity for hKv1.2 channels, it may be a good candidate for the development of pharmacologic tools to study the physiologic functions of K(+) channels or related channelopathies and for restoring axonal conduction in demyelinated axons.

Vasoconstrictor responses to vasopressor agents in human pulmonary and radial arteries: an in vitro study.

BACKGROUND: Vasopressor drugs, commonly used to treat systemic hypotension and maintain organ perfusion, may also induce regional vasoconstriction in specialized vascular beds such as the lung. An increase in pulmonary vascular tone may adversely affect patients with pulmonary hypertension or right heart failure. While sympathomimetics constrict pulmonary vessels, and vasopressin does not, a direct comparison between these drugs has not been made. This study investigated the effects of clinically used vasopressor agents on human isolated pulmonary and radial arteries. METHODS: Isolated pulmonary and radial artery ring segments, mounted in organ baths, were used to study the contractile responses of each vasopressor agent. Concentration-response curves to norepinephrine, phenylephrine, metaraminol, and vasopressin were constructed. RESULTS: The sympathomimetics norepinephrine, phenylephrine, and metaraminol caused concentration-dependent vasoconstriction in the radial (pEC50: 6.99 ± 0.06, 6.14 ± 0.09, and 5.56 ± 0.07, respectively, n = 4 to 5) and pulmonary arteries (pEC50: 6.86 ± 0.11, 5.94 ± 0.05 and 5.56 ± 0.09, respectively, n = 3 to 4). Vasopressin was a potent vasoconstrictor of the radial artery (pEC50 9.13 ± 0.20, n = 3), whereas in the pulmonary artery, it had no significant effect. CONCLUSIONS: Sympathomimetic-based vasopressor agents constrict both human radial and pulmonary arteries with similar potency in each. In contrast, vasopressin, although a potent vasoconstrictor of radial vessels, had no effect on pulmonary vascular tone. These findings provide some support for the use of vasopressin in patients with pulmonary hypertension.

The 8-hydroxyquinoline derivative, clioquinol, is an alpha-1 adrenoceptor antagonist.

Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is an antimicrobial agent whose actions as a zinc or copper ionophore and an iron chelator revived the interest in similar compounds for the treatment of fungal and bacterial infections, neurodegeneration and cancer. Recently, we reported zinc ionophores, including clioquinol, cause vasorelaxation in isolated arteries through mechanisms that involve sensory nerves, endothelium and vascular smooth muscle. Here, we report that clioquinol also uniquely acts as a competitive alpha-1 (α1) adrenoceptor antagonist. We employed ex vivo functional vascular contraction and pharmacological techniques in rat isolated mesenteric arteries, receptor binding assays using stabilized solubilized α1 receptor variants, or wild-type human α1-adrenoceptors transfected in COS-7 cells (African green monkey kidney fibroblast-like cells), and molecular dynamics homology modelling based on the recently published α1A adrenoceptor cryo-EM and α1B crystal structures. At higher concentrations, all ionophores including clioquinol cause a non-competitive antagonism of agonist-mediated contraction due to intracellular zinc delivery, as reported previously. However, at lower concentration ranges, clioquinol has an additional mechanism of competitively inhibiting α1-adrenoceptors that contributes to decreasing vascular contractility. Molecular dynamic simulation showed that clioquinol binds stably to the orthosteric binding site (Asp106) of the receptor, confirming the structural basis for competitive α1-adrenoceptor antagonism by clioquinol.

Introducing peer worker roles into UK mental health service teams: a qualitative analysis of the organisational benefits and challenges.

BACKGROUND: The provision of peer support as a component of mental health care, including the employment of Peer Workers (consumer-providers) by mental health service organisations, is increasingly common internationally. Peer support is strongly advocated as a strategy in a number of UK health and social care policies. Approaches to employing Peer Workers are proliferating. There is evidence to suggest that Peer Worker-based interventions reduce psychiatric inpatient admission and increase service user (consumer) empowerment. In this paper we seek to address a gap in the empirical literature in understanding the organisational challenges and benefits of introducing Peer Worker roles into mental health service teams. METHODS: We report the secondary analysis of qualitative interview data from service users, Peer Workers, non-peer staff and managers of three innovative interventions in a study about mental health self-care. Relevant data was extracted from interviews with 41 participants and subjected to analysis using Grounded Theory techniques. Organisational research literature on role adoption framed the analysis. RESULTS: Peer Workers were highly valued by mental health teams and service users. Non-peer team members and managers worked hard to introduce Peer Workers into teams. Our cases were projects in development and there was learning from the evolutionary process: in the absence of formal recruitment processes for Peer Workers, differences in expectations of the Peer Worker role can emerge at the selection stage; flexible working arrangements for Peer Workers can have the unintended effect of perpetuating hierarchies within teams; the maintenance of protective practice boundaries through supervision and training can militate against the emergence of a distinctive body of peer practice; lack of consensus around what constitutes peer practice can result in feelings for Peer Workers of inequality, disempowerment, uncertainty about identity and of being under-supported. CONCLUSIONS: This research is indicative of potential benefits for mental health service teams of introducing Peer Worker roles. Analysis also suggests that if the emergence of a distinctive body of peer practice is not adequately considered and supported, as integral to the development of new Peer Worker roles, there is a risk that the potential impact of any emerging role will be constrained and diluted.

The interaction between hepatitis B virus X protein and AIB1 oncogene is required for the activation of NFκB signal transduction.

We identified the interaction between HBV X (HBx) protein and the oncogene AIB1 (amplified in breast cancer 1). A serine/proline motif (SSPSPS) in HBx was found to be required for the interaction. Two LXD motifs [LLXX(X)L, X means any amino acids], LLRNSL and LLDQLHTLL in AIB1 were also found to be involved in the HBx-AIB1 interaction. The HBx-AIB1 interaction was important for the activation of NFκB signal transduction, the HBx mutant that did not interact with AIB1showed dramatically lower NFκB activation activity than the WT HBx. These findings contribute to the new understanding on signal transduction activation mechanisms of HBx.

Cardiac rehabilitation to improve physical functioning in refractory angina: a pilot study.

OBJECTIVES: Refractory angina patients suffer debilitating chest pain despite optimal medical therapy and previous cardiovascular intervention. Cardiac rehabilitation is often not prescribed due to a lack of evidence regarding potential efficacy and patient suitability. A randomised controlled study was undertaken to explore the impact of cardiac rehabilitation on cardiovascular risk factors, physical ability, quality of life and psychological morbidity among refractory angina sufferers. METHODS: Forty-two refractory angina patients (65.1 ± 7.3 years) were randomly assigned to an 8-week Phase III cardiac rehabilitation program or symptom diary control. Physical assessment, Progressive Shuttle Walk test, Hospital Anxiety and Depression Scale, Health Anxiety Questionnaire, the York Angina Beliefs scale, ENRICHD Social Support Instrument and SF-36 were completed before and after intervention and at 8-week follow-up. RESULTS: Following cardiac rehabilitation, patients demonstrated improved physical ability compared with controls in Progressive Shuttle Walk level attainment (p = 0.005) and total distance covered (p = 0.015). Angina frequency and severity remained unchanged in both groups, with the control demonstrating worsening SF-36 pain scale (63.43 ± 22.28 vs. 55.46 ± 23.98, p = 0.025). Cardiac rehabilitation participants showed improved Health Anxiety Questionnaire reassurance (1.71 ± 1.72 vs. 1.14 ± 1.23, p = 0.026) and York Beliefs anginal threat perception (12.42 ± 4.58 vs. 14.35 ± 4.73, p = 0.05) after cardiac rehabilitation. Physical measures were broadly unaffected. CONCLUSIONS: Cardiac rehabilitation can be prescribed to improve physical ability without affecting angina frequency or severity among patients with refractory angina.

PI 3-kinase p110beta: a new target for antithrombotic therapy.

Platelet activation at sites of vascular injury is essential for the arrest of bleeding; however, excessive platelet accumulation at regions of atherosclerotic plaque rupture can result in the development of arterial thrombi, precipitating diseases such as acute myocardial infarction and ischemic stroke. Rheological disturbances (high shear stress) have an important role in promoting arterial thrombosis by enhancing the adhesive and signaling function of platelet integrin alpha(IIb)beta(3) (GPIIb-IIIa). In this study we have defined a key role for the Type Ia phosphoinositide 3-kinase (PI3K) p110beta isoform in regulating the formation and stability of integrin alpha(IIb)beta(3) adhesion bonds, necessary for shear activation of platelets. Isoform-selective PI3K p110beta inhibitors have been developed which prevent formation of stable integrin alpha(IIb)beta(3) adhesion contacts, leading to defective platelet thrombus formation. In vivo, these inhibitors eliminate occlusive thrombus formation but do not prolong bleeding time. These studies define PI3K p110beta as an important new target for antithrombotic therapy.

Bone marrow necrosis and fat embolism syndrome in sickle cell disease during COVID-19 infection treated successfully with sequential red cell and plasma exchange.

Fat embolism syndrome (FES) is a rare life-threatening condition that is particularly seen in milder forms of sickle cell disease (SCD). Widespread systemic fat emboli are generated in the context of extensive bone marrow necrosis. Multi-organ failure with a high morbidity and mortality may quickly develop. Infection with Parvovirus B19 is a common precipitant. Here, the authors report the case of a 35-year-old Afro-Caribbean man with HbSC disease who presented with FES having tested positive for SARS-COV-2. He rapidly became critically ill and required admission to the intensive care unit for organ support. He was treated with red cell exchange and plasma exchange and made a good recovery to leave hospital at week 7.

The development of the Quality Indicator for Rehabilitative Care (QuIRC): a measure of best practice for facilities for people with longer term mental health problems.

BACKGROUND: Despite the progress over recent decades in developing community mental health services internationally, many people still receive treatment and care in institutional settings. Those most likely to reside longest in these facilities have the most complex mental health problems and are at most risk of potential abuses of care and exploitation. This study aimed to develop an international, standardised toolkit to assess the quality of care in longer term hospital and community based mental health units, including the degree to which human rights, social inclusion and autonomy are promoted. METHOD: The domains of care included in the toolkit were identified from a systematic literature review, international expert Delphi exercise, and review of care standards in ten European countries. The draft toolkit comprised 154 questions for unit managers. Inter-rater reliability was tested in 202 units across ten countries at different stages of deinstitutionalisation and development of community mental health services. Exploratory factor analysis was used to corroborate the allocation of items to domains. Feedback from those using the toolkit was collected about its usefulness and ease of completion. RESULTS: The toolkit had excellent inter-rater reliability and few items with narrow spread of response. Unit managers found the content highly relevant and were able to complete it in around 90 minutes. Minimal refinement was required and the final version comprised 145 questions assessing seven domains of care. CONCLUSIONS: Triangulation of qualitative and quantitative evidence directed the development of a robust and comprehensive international quality assessment toolkit for units in highly variable socioeconomic and political contexts.

One size fits all: or horses for courses? Recovery-based care in specialist mental health services.

INTRODUCTION: The 'recovery approach' to the management of severe mental health problems has become a guiding vision of service provision amongst many practitioners, researchers, and policy makers as well as service users. METHOD: This qualitative pilot study explored the meaning of 'recovery' with users of three specialist mental health services (eating disorders, dual diagnosis, and forensic) in 18 semi-structured interviews. RESULTS: The relevance of themes identified in mainstream recovery literature was confirmed; however, the interpretation and relative weight of these themes appeared to be affected by factors that were specific to the diagnosis and treatment context. 'Clinical' recovery themes were also seen as important, as were aspects of care that reflect core human values, such as kindness.