Eicosanoids represent a diverse family of lipid mediators with fundamental roles in physiology and disease. Within the eicosanoid superfamily are prostanoids, which are specifically derived from arachidonic acid by the enzyme cyclooxygenase (COX). COX has two isoforms; COX‐1 and COX‐2. COX‐2 is the therapeutic target for the nonsteroidal anti‐inflammatory drug (NSAID) class of pain medications. Of the prostanoids, prostacyclin, first discovered by Sir John Vane in 1976, remains amongst the best studied and retains an impressive pedigree as one of the fundamental cardiovascular protective pathways. Since this time, we have learnt much about how eicosanoids, COX enzymes and prostacyclin function in the cardiovascular system, knowledge that has allowed us, for example, to harness the power of prostacyclin as therapy to treat pulmonary arterial hypertension and peripheral vascular disease. However, there remain many unanswered questions in our basic understanding of the pathways, and how they can be used to improve human health. Perhaps, the most important and controversial outstanding question in the field remains; ‘how do NSAIDs produce their much publicized cardiovascular side‐effects?’ This review summarizes the history, biology and cardiovascular function of key eicosanoids with particular focus on prostacyclin and other COX products and discusses how our knowledge of these pathways can applied in future drug discovery and be used to explain the cardiovascular side‐effects of NSAIDs.http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.8/issuetocThis article is part of a themed section on Eicosanoids 35 years from the 1982 Nobel: where are we now? To view the other articles in this section visit  ADMAasymmetric dimethyl arginineBCL‐6B‐cell lymphoma 6 protein2cPLA2cytosolic phospholipase ACREBcAMP response element‐binding proteinEPACexchange protein directly activated by cAMP2iPLA2calcium‐independent phospholipase ANFATnuclear factor of activated T cellsNSAIDnon‐steroidal anti‐inflammatory drugPGXprostaglandin X (prostacyclin)2sPLA2secretory phospholipase ACOX‐1 is constitutively expressed in many cell types whereas COX‐2 is constitutively expressed only in certain regions but is readily induced in inflammation and cancer. Arguably the most studied area of COX biology concerns inflammation and pain and this is not surprising as COX‐2 is the therapeutic target for nonsteroidal anti‐inflammatory drugs (NSAIDs), which are amongst the most commonly taken medications worldwide. Indeed, ibuprofen and aspirin, two members of the NSAID family, along with paracetamol, which is not an NSAID but exerts its analgesic effects by inhibiting COX, are members of the WHO Model List of Essential Medicines. However, the importance of COX to the cardiovascular system, particularly within blood vessels, cannot be overstated. This is illustrated by a PubMed search of the term ‘COX’ that delivers 56 082 returns, of these publications 9006 return with the terms ‘COX’ and ‘vascular’. This compares well with the 11 384 publications returning with the terms ‘COX’ and ‘inflammation’. The importance of prostanoids within the cardiovascular system was realized in the remarkable discovery by Sir John Vane in 1976 of a new member of the family made specifically by blood vessels, named at the time, PGX  cytosolic PLA2 (cPLA2), activated by μM concentrations of calcium, (ii) calcium independent (iPLA2) or (iii) secreted (sPLA2), activated by mM concentrations of calcium  is the major isoform responsible for the release of arachidonic acid to produce prostanoids, in blood vessels.Although there is evidence that sPLA2ɑ in prostanoid production by cells of the cardiovascular system was confirmed in recent work from our group  was purified in 1977 from sheep vesicular glands and found to be a haem protein of 70 kDa , Vioxx® (rofecoxib) and Arcoxia® (etoricoxib) were introduced for the treatment of inflammation and pain, designed to diminish the gastric side‐effects associated with older style drugs such as diclofenac and ibuprofen. However, because neither the selective COX‐2 inhibitors nor the older NSAIDs discriminate between blocking the COX‐2 induced at the site of inflammation and the constitutively expressed COX‐2 that protects the cardiovascular system, they cause cardiovascular side‐effects. Indeed, understanding and solving the problem of cardiovascular side‐effects caused by NSAIDs remains amongst the most important unresolved questions in the vascular biology of eicosanoids. As such, the remainder of this review will focus on mechanisms of cardiovascular protection by COX‐2 and the involvement of specific eicosanoid and other mechanistic pathways in this aspect of COX‐2 biology.Early work from our group  the withdrawal of rofecoxib in 2004, (ii) the introduction of ‘black box’ warnings in 2005 and (iii) the reclassification of the over‐the‐counter medication diclofenac as prescription only in 2015 (UK).et al.,Concern regarding cardiovascular events caused by NSAIDs has also resulted in the cautious prescribing of COX‐2 selective drugs  inhibitory, (ii) highly reproducible across models and (iii) independent of platelet activation pathways, the effects of prostacyclin can be subtle and influenced by the resting state of the target cell or organ. This is because prostacyclin signalling utilizes different types of receptors and transduction pathways Figures  and 3. Fadenylate cyclase, which converts ATP to the intracellular signalling molecule cAMP. cAMP then activates PKA, engaging the ‘PKA pathway’ and/or exchange protein directly activated by cAMP (EPAC), engaging the ‘EPAC pathway’. These pathways, reviewed in detail elsewhere  Shabb, ; includiEPAC pathway. There are two EPAC isoforms, EPAC1 and EPAC2  pathway . We have now repeated, validated and extended these observations to show that the effect of COX‐2 inhibition on ADMA levels is reproduced in mice lacking prostacyclin synthase but not in PGE2 synthase knockout mice , thus suggesting they may have a specific, causative role in NSAID cardiovascular toxicity  and to protect those taking NSAIDs (with L‐arginine supplementation). Hypothesis‐testing approaches should be complemented by the integration of genetic data and other ‘‐omic’ approaches to find biomarkers and generate new hypotheses to extend our understanding of COX, prostacyclin and eicosanoids in the cardiovascular system.http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Harding et al.,et al.,Key protein targets and ligands in this article are hyperlinked to corresponding entries in Within the last 5 years, J.A.M. has acted a consultant and expert witness in cases relating to prostacyclin drugs and non‐steroidal anti‐inflammatory drugs. J.A.M. has received unconditional educational awards from pharmaceutical companies including United Therapeutics and Actelion and is on the scientific advisory board of Antibe Therapeutics. The authors report no other conflicts of interest.


Esophageal duplication cysts are rarely encountered in adult patients. Complete cyst resection is achievable employing video‐assisted thoracoscopic surgical techniques, with low morbidity and excellent cosmesis. Esophageal duplication cysts are rarely encountered in adult patients. Complete cyst resection is achievable employing video‐assisted thoracoscopic surgical techniques, with low morbidity and excellent cosmesis. Hematology and biochemistry laboratory tests were within normal limits, and standard chest radiography did not reveal any lung or mediastinal lesions.Contrast‐enhanced computed tomography of the chest showed a well‐defined 3 × 3.5 × 4 cm homogeneous mass on the right side of the distal esophagus, proximal to the gastro‐esophageal junction Figure . TransesDecision was made to perform elective excision of this mass lesion and, since the distal esophagus is usually more accessible from the left, this was carried out employing a left‐sided video‐assisted thoracoscopic surgical (VATS) approach. Using three 5‐mm ports, the lower esophagus was dissected and the mass was identified Figure . AttemptThere were no postoperative complications. The patient returned gradually to full oral intake and was discharged home on the fourth postoperative day in an excellent general condition. He remains symptom‐free after 4 months of follow‐up. Histology confirmed the lesion to be an EDC, with dual muscular layer and a characteristic columnar ciliated epithelial lining surrounded by severe chronic inflammatory infiltrate.3Open surgical resection via conventional posterolateral thoracotomy has long been the standard approach to the treatment of EDCsPublished experiences to date with the VATS approach to EDCs have predominantly been in managing pediatric patients, whereas reports of VATS resection of EDCs in adults are still limited to a handful of cases only.This report extends contemporary archives on the use of VATS techniques to the removal of intramural EDCs in adult patients. Complete VATS resection of an EDC was both safe and achievable with low morbidity and excellent cosmesis. We propose that this approach may be the new surgical technique of choice.None declared.Bassam Darwish: contributed to conception and acquisition of data, drafted the manuscript and revised it critically, and gave final approval of the version to be published. Mohammad Bashar Izzat: contributed to conception and acquisition of data, drafted the manuscript and revised it critically, and gave final approval of the version to be published.All procedures performed in this study were in accordance with the ethical standards of the Damascus University Research Ethics Committee and with the 1964 Helsinki declaration and its later amendments.Informed consent was obtained from all individual participants included in the study.


Genetic engineering has been increasingly applied to many commercially important plant and animal species, generating phenotypic changes that are not observed in natural populations and creating genetic interactions that have not experienced natural selection. The degree to and way in which such human‐induced genetic variation interacts with the rest of the genome is currently largely unknown. Integrating such information into ecological and risk assessment frameworks is crucial to understand the potential effects of genetically modified organisms in natural environments. Here, we performed QTL mapping to investigate the genetic architecture of growth‐related traits in nontransgenic (NT) and growth hormone transgenic (T) coho salmon with large changes in growth and related physiology, with the aim of identifying how an inserted transgene might influence the opportunity for selection. These fish shared the same parental genetic background, thus allowing us to determine whether the same or different loci influence these traits within the two groups. The use of over 1,700 loci, derived from restriction site‐associated DNA sequencing, revealed that different genomic regions were linked with growth over time between the two groups. Additionally, the effect sizes of detected QTL appear to have been influenced by the transgene. Direct comparison of QTL between the T and NT fish during two size‐matched periods identified little overlap in their location. Taken together, the results showed that the transgene altered the genetic basis of growth‐related traits in this species. The study has important implications for effective conservation and management of wild populations experiencing introduction of transgenes. Evolutionary changes and their ecological consequences may occur at different rates and in different directions in NT versus T individuals in response to selection. Thus, assessments of phenotypic change, and hence ecological risk, should be determined periodically to evaluate whether initial estimates made with founder strains remain valid. Individual fish in the population shared the same parental genetic background and experienced large variation in growth and related physiology  containing the OnMTGH1 gene construct stably integrated at a single insertion site in a wild‐type genetic background   to satiation seven times per day as fry and three times per day subsequently, ensuring that all fish had access to excess feed. Coho salmon are anadromous; fish were reared in aerated freshwater (±10.5°C) in 170‐L through 3,000‐L tanks prior to smolt .A single‐pair backcross family was utilized from a cross performed on January 12, 2011, at the Fisheries and Oceans Canada laboratory in West Vancouver, BC, Canada  and transgenic (T) siblings. Due to the rapid growth rate of the latter, a bimodal distribution of fish size soon emerged within the family. On July 26, 2011, the fish were separated into small (slow‐growing) and large (fast‐growing) modal groups, and each fish was weighed and measured for length. At this time, the fast‐growing salmon group had achieved smolt status, confirmed based on loss of parr marks and acquisition of a silver body color. These fast‐growing fish were PIT tagged, adipose fin clipped, genotyped to confirm the presence of the transgene , some exceptions to rank orders of fish existed between length and weight measures, as expected. For the NT group, the small size tail included fish ranging in increasing size rank order from the smallest  to the 75th next largest fish , and in the large size tail fish ranged in diminishing size rank order from the largest  to the 75th next smallest fish . For the T group, the small size tail included fish ranging in increasing size rank order from the smallest  to the 75th next largest fish , and the large fish size tail included fish ranging in diminishing size rank order from the largest  to the 75th next smallest fish .For genotyping and phenotyping, fish were selected (in rank order) from both upper and lower tails of the length distribution of both the NT and T modal groups to enhance the phenotypic divergence among samples analyzed within the resources available. While overall the rank order of fish length and weight were highly correlated for individuals selected for RAD sequencing (nontransgenic Daily growth coefficients (DGC) at each time interval were calculated for all individuals in each family as follows /days.DGC = 100 ×  following the manufacturer's procedures.SbfI, and a 6‐nucleotide barcode was added to each sample for individual identification following protocols described in Baird et al.  sequencing . To determine whether the phenotypic means for each trait differed significantly between females and males, independent two‐sample t tests were performed with or without equality of variances. Phenotypic correlations between each trait pair in male and female offspring for each group were estimated using Pearson's correlations. All statistical tests were performed in R version 3.0.2 (R Development Core Team 2013).Two‐sample 2.7In order to examine whether any QTL were located on a linkage group containing the transgene (details below), markers were grouped via linkage mapping to identify which chromosome harbored the transgene. Specifically, polymorphic loci in the hemizygous father were utilized to perform grouping of the markers. The transgenic locus was coded as heterozygous in the T offspring, and homozygous in the NT offspring, and included in the analyses. Linkage analyses were performed using software for genetic mapping, ONEMAP 2.0–3  analyses for all traits were performed using single‐, two‐, and multiple‐dimensional QTL models in the R‐based software package, R/qtl  was obtained using the bayesint function. Percentage of phenotypic variance explained (PVE) by each QTL was estimated using the fitqtl function, and QTL of major or minor effect  were identified.We used the multiple imputation approach to perform quantitative trait loci analyses for all traits , which in turn has been annotated using data from Kim, Leong, Koop, and Devlin  were then cross‐referenced to determine whether differentially expressed genes from the earlier studies fell within the annotated regions.Potential candidate genes for the QTL were identified using mRNA sequences from two studies that have reported differential gene expression between transgenic and nontransgenic coho salmon . A total of 17 differentially expressed genes from the studies of Devlin et al. (LOC109874801) was linked to Co59610_Co30 at an approximate distance of 500 kb. The product of this gene has been inferred as “complement C3‐like.” This gene was expressed in the pituitary in the comparative analysis of Kim et al.  was linked to the QTL of large effect size expressed in the NT group (Co17102_Co04a). The locus was expressed in the liver in Devlin et al. (Two separate Dam QTL of large effect size on Co04 were detected in the NT (Co17102_Co04a) and T groups (Co09937_Co04b), respectively. The latter was linked to two temporally expressed loci within a 3 MB region . All three loci were located within genes. However, only one of the 21 differentially expressed genes aligned with this chromosome was located within the annotated regions, and this locus . The latter two QTL markers were temporally expressed and the last marker was of large effect size. A total of 31 differentially expressed genes aligned with this chromosome. The gene LOC109899444 “cytochrome P450 2F3‐like” was located within 55 kb of the temporally expressed locus Co58715_Co11b and may be involved in oxidative degradation of compounds such as environmental toxins. This gene was expressed in the liver in the analysis of Devlin et al.  and nontransgenic (NT) offspring, but no QTL in common between T and NT were found except for one QTL on Co30 . QTL based on the segregation information from the dam were detected primarily in the T group but rarely in the NT group. QTL of large effect sizes were observed in both NT and T offspring, but were more frequent in the latter. Five out of eight large effect QTL in the T fish shared the closest linked marker on Co30 and were detected using the sire. Generally, the same markers were linked with QTL for traits measured across the course of development in each group; none of these markers were shared between the groups. Comparison between size‐matched traits at two time points showed that almost none of the QTL were shared between NT and T offspring. Finally, comparison between size‐matched traits at two time points showed that almost none of the QTL were shared between NT and T offspring. We conclude that the insertion of the transgene affects both the expression and the effect sizes of QTL involved in growth‐related traits, thus influencing the phenotypic variance and opportunity for differential selection between T and NT individuals.The study has several underlying assumptions. First, transgenic fish have a rapid growth rate and mature earlier; therefore, temporally matched measures would likely detect different traits between T and NT to a greater degree than would size‐matched traits explained simply by body‐size effects. We note that length and weight in the T fish in the first comparison overlapped with two separate periods in the NT fish, implying that shape varies between the two groups. This result may reflect influences arising from age as well as the transgene. It is therefore possible that we may have measured different traits. However, differences in physiology (and its genetic control) are precisely what the present study is seeking to assess. For example, T coho salmon undergo smoltification within their first few months of life (postfirst feeding) in freshwater, compared to approximately 12–14 months for wild‐type coho salmon, and have enhanced osmoregulatory capability for a given size compared to wild type . Alternatively, if the QTL are shared (and were not detected in one group due to the power of the study), the transgene likely influences the effect sizes of these loci through interactions we were unable to study. These findings support previous observations of large differences in expression levels for genes involved in physiological and endocrine pathways between NT and T fish of the same strain, based on microarrays and RNA‐seq . Current evidence based on genome mapping suggests that Co30 is the sex chromosome in this species  strongly altered the genetic basis of growth‐related traits in this species. Different genomic regions were involved in determining growth over time, and hence, evolutionary changes and ecological consequences may occur in different directions in NT vs. T fish in response to selection within the complexities of environmental conditions in nature. This study provided important insights into genetic complexities associated with understanding phenotype of T fish and has provided the foundation for future efforts in localizing candidate genes shaping growth regulation in T fish. The data also have important implications for assessments of the stability of phenotypes of T strains which is critical for determinations of potential ecological risks should such animals ever escape into natural environments.The authors declare that they have no competing interests in relation to this manuscript.https://doi.org/10.5061/dryad.fs4b1b3.Data available from the Dryad Digital Repository:  Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file. Click here for additional data file.


Sertoli cells (SeC) are responsible for the immunoprivileged status of the testis thanks to which allogeneic or xenogeneic engraftments can survive without pharmacological immune suppression if co‐injected with SeC. This peculiar ability of SeC is dependent on secretion of a plethora of factors including maturation factors, hormones, growth factors, cytokines and immunomodulatory factors. The anti‐inflammatory and trophic properties of SeC have been largely exploited in several experimental models of diseases, diabetes being the most studied. Duchenne muscular dystrophy (DMD) is a lethal X‐linked recessive pathology in which lack of functional dystrophin leads to progressive muscle degeneration culminating in loss of locomotion and premature death. Despite a huge effort to find a cure, DMD patients are currently treated with anti‐inflammatory steroids. Recently, encapsulated porcine SeC (MC‐SeC) have been injected ip in the absence of immunosuppression in an animal model of DMD resulting in reduction of muscle inflammation and amelioration of muscle morphology and functionality, thus opening an additional avenue in the treatment of DMD. The novel protocol is endowed with the advantage of being potentially applicable to all the cohort of DMD patients regardless of the mutation. This mini‐review addresses several issues linked to the possible use of MC‐SeC injected ip in dystrophic people. In 1767, during his studies on transplantation, John Hunter observed that rooster testes transplanted into the abdominal cavity of a hen maintained normal structure over time.Intriguing results about SeC derive from their use as encapsulated cells in several pre‐clinical studies. Alginate‐based microcapsules containing SeC (MC‐SeC) have been successfully employed as a single intraperitoneal (ip) injection in experimental models of type 1 and type 2 diabetes, acute hepatic failure, skin graft and Huntington’s disease.The trophic and immunomodulatory properties of SeC are dependent on the complex SeC secretory activity resulting in a cocktail of factors whose formulation is difficult to dissect, being affected by the biological status of the cells and likely by environmental cues. While the composition of SeC’ secretory product still awaits to be identified, it includes maturation factors, hormones, growth factors, cytokines and immunomodulatory factors Table .However, the immunomodulatory effect of SeC is obtained by a multimodal mechanism. SeC secrete (still unidentified) factors thatblock T lymphocyte proliferation and interleukin (IL)‐2 production,3DMD), the biggest gene of the human genome for which about 4700 different mutations have been reported.DMD gene mutations translating into absence of dystrophin or expression of functionally inefficient protein lead to the Duchenne phenotype, in which loss of the integrity of DAPC causes myofibre degeneration and progressive loss of muscle efficiency, wheelchair dependency before teenage years, and premature death by cardiac and respiratory failure.Duchenne muscular dystrophy (DMD) is an X‐linked recessive disease due to mutations in the dystrophin gene mdx mice  and GRMD (golden retriever muscular dystrophy) dogs,Therapeutic approaches to DMD have been experiencing multiple obstacles against their success Table . FirstlyDMD gene pointing to recovery of the reading frame and production of truncated but functional forms of dystrophin, and translating into a switch from the DMD pathology to the milder phenotype known as Becker muscular dystrophy (BMD).O‐methyl‐p phosphorothioate oligonucleotides (PS) and phosphorodiamidate morpholino oligomers (PMO) have shown high stability and efficacy, and low toxicity. One major limit of AON is that they are only useful for DMD patients with specific mutations and not applicable to the remaining cohort of patients. The PS, Drisapersen and the more promising PMO, Eteplirsen, both of which are in clinical trials, are specific for skipping of exon 51, which applies to 14% of patients, that is, the largest cohort of DMD subjects who may benefit from single exon skipping.Exon skipping is an approach to overcome specific regions with deletions, duplications or small mutations in the Cell therapy represents a second front of therapeutic approaches to DMD. It tries to use different cell types  from healthy donors or genetically engineered cells from the patients themselves to obtain the re‐expression of dystrophin in muscle tissue and recovery of muscle performance.Healthy human satellite cells and myoblasts  induce dystrophin expression in DMD patients to a certain extent when injected intramuscularlymdx limb muscles begins only when the high neonatal levels of utrophin become reduced to adult levels.The existence of the dystrophin paralogue, utrophin, has fostered another approach to rescue homeostasis in the muscles of DMD patients. Utrophin shares a very high degree of sequence identity with dystrophin and even associates with members of the DAPC, thus mimicking the role of dystrophin in dystrophin‐negative myofibres.Several alternative approaches to treat DMD are currently under investigation Table . They in4DMD gene.More recently, researchers are trying to useCRISPR/Cas9 genome editing system to remove mutated exons from the Such an extremely varying scenario in the therapeutic approaches to DMD is the result of the difficulty and, at the same time, the intense effort to find a cure for this pathology. Thus, the current gold standard therapy for DMD patients remains the use of anti‐inflammatory steroids , which improve the quality of life reducing loss of muscle strength and functionality and loss of ambulation, and delaying respiratory failure.5mdx mice with a single ip injection of porcine MC‐SeC  in the absence of any pharmacologic immunosuppression, and found a rapid amelioration of muscle morphology and functionality.Tibialis anterior muscle. At the same time, MC‐SeC–treated mdx mice showed increased muscle performance and resistance to exercise‐induced muscle damage. Indeed, treated mice ran similar distances in a similar time to untreated WT mice, recovering ~80% of dystrophic‐dependent deficit, and showed a ~70% reduction of damaged (Evans blue dye–positive) myofibres after treadmill exercise tests. The anti‐inflammatory effect of MC‐SeC was observed already 1 week after injection, when ~70% reduction of macrophages infiltrating muscle tissue could been observed. At the same time, these macrophages showed a tissue‐repairing (M2) phenotype, as suggested by their reduced expression of inflammatory cytokines  and up‐regulation of the anti‐inflammatory IL‐10 and the M2 markers, arginase 1, CD163 and CD206.mdx animal model. No signs of immune response against injected MC‐SeC could be detected at this time.Having the peculiar secretory properties of SeC in mind, we treated acute and chronic dystrophic, ets‐related GABPα/β transcription factor complex to the utrophin‐A promoter.mdx mice,Another important aspect of SeC treatment is that SeC release heregulin β1, which is a major inducer of the expression of utrophin in muscle cells.mdx mice.Microcapsules containing SeC–based protocol resulted efficacious also in pre‐symptomatic (2‐week‐old) and in chronic (12‐month‐old) mdx muscles. However, anti‐heregulin β1 antibody had no significant effects on the reduction of the inflammatory infiltrate, suggesting that this latter effect is under the control of anti‐inflammatory factors. On the converse, only a partial loss of anti‐necrotic effects could be observed on myofibres of mdx mice treated with MC‐SeC in the presence of anti‐heregulin β1 antibody, due to a balance between increased damage extent of (dystrophin‐negative/utrophin‐negative) myofibres and the effects of anti‐inflammatory factors.The above reported results about the use of MC‐SeC have opened an additional avenue in the scenario of DMD treatment. Intraperitoneally injected MC‐SeC act as a micro‐biofactory that from the peritoneal cavity of dystrophic animals release factors into the bloodstream thus being able to reach every muscle where they exert a double effect: (a) an anti‐inflammatory effect (as expected) due to immunomodulatory factors; and (b) the induction of utrophin expression due to the SeC‐secreted heregulin β1.Several considerations give particular relevance to the porcine MC‐SeC–based therapeutic approach Table . On the The use of pig cells, tissues and organs meets the general need to satisfy the increasing request for transplantation by humans who do not find sufficient availability among members of their species. Pigs represent suitable animals for human xenotransplantation because they share a similar organ physiology and size, for the relatively low costs of breeding and for the possibility to be genetically modified. One concern in xenotransplantation using pigs as a donor species is represented by porcine endogenous retroviruses (PERVs). This is because PERVs are present in almost all strains of pigs and cannot be removed even if pigs are being raised in sterile conditions. PERVs are inactive and harmless in pigs; however, transplantation into humans could activate the viruses and lead to human diseases with the risk of spreading to the entire community.via somatic cell nuclear transfer using a cell line in which PERVs were inactivated by CRISPR/Cas9 technology.However, porcine pancreatic islets were demonstrated to produce PERV and infect NOD/SCID  mice after transplantation, suggesting that PERV infection is a risk to take into account when pig xenotransplantation involves immunocompromised subjects.Among the factors secreted by SeC are mitogenic factors that could potentially sustain cell growth and induce the formation of tumour masses in the recipient. However, this event has not been reported in any study involving the use of SeC, including the above‐mentioned clinical study.via the recruitment of Toll‐like receptors expressed on SeC surface and subsequent release of proinflammatory cytokines and chemokines.Another issue about the use of SeC is related to their immunosuppressive effect, representing a potential problem in case of lifelong clinical applications. However, results from several pre‐clinical and clinical studies suggest that SeC have an immunomodulatory rather than immunosuppressive effect.Although data obtained in macaques 6Duchenne muscular dystrophy is a lethal muscular dystrophy affecting 1 in 3600‐5000 male live births worldwide.Intraperitoneal injection of MC‐SeC translates into the release into the bloodstream of a cocktail of factors of which at least two components  are independently active on dystrophic muscles,Encapsulation represents an additional point of force of the proposed approach as encapsulation encloses the cells in a defined space, avoiding cell migration throughout the host body, and potentially allowing the recovery of injected cells if the injection is performed in a confined region of the body, such as the peritoneal cavity.It is noteworthy that treatment with MC‐SeC has the advantage to be a universal approach to treat DMD since it is potentially applicable to the entire cohort of DMD patients regardless of the kind of mutation. Moreover, it is potentially applicable in general to myopathies characterized by chronic inflammation or immune dysregulation, such as autoimmune myositis.Elucidation of several aspects in the near future, including the biological status of SeC inside the microcapsules over time, the dose‐response of MC‐SeC, potential direct effects of SeC on muscle precursor cells, the analysis of the mechanism(s) underpinning the anti‐inflammatory effect of SeC, and the demonstration of the safety of MC‐SeC in long‐term treatments will accelerate the application of this novel therapeutic approach to DMD patients.The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; and in the decision to publish the results.


The prevalence of chronic benzodiazepine use in primary care settings remains high despite clear evidence of adverse health outcomes resulting from long‐term use and the availability of effective alternative behavioural therapies. Eliciting factors influencing past or current usage experience of benzodiazepine users and their future behavioural intention regarding discontinuation or alternative behavioural therapy adoption could be useful in developing informed strategies facilitating successful benzodiazepine withdrawal in long‐term users. The aim of this study was to identify patient factors influencing their current long‐term benzodiazepine use, past withdrawal attempt, and future intention to trial safer alternative behavioural therapies. Additionally, the study also aimed to explore patients' preference for information sources on behavioural therapies.Point of purchase surveys were conducted with patients obtaining benzodiazepines from selected pharmacies across New South Wales (NSW), Australia. Survey items included the Beliefs about Medicines Questionnaire (BMQ‐specific), questions about patient's sociodemographic characteristics, as well as their views about long‐term benzodiazepine use and behavioural therapies.Seventy‐five patients were recruited from 12 pharmacies across New South Wales (NSW). The surveys were conducted from November 2016 to July 2017. The mean (±SD) age of the participants was 54.3 (±16.7) with a range of 23 to 86 years, and 67% of the participants had been using the benzodiazepine for at least 1 year. Lower‐education levels, stronger beliefs about the necessity of use, and lower concerns about ongoing benzodiazepine use were significantly associated with prolonged use. Sixty‐four percent of the participants were not interested in behavioural therapies, and there was a significant relationship between the participants' future preference for behavioural therapies and their concerns about the potential adverse effects of benzodiazepines. A majority of the participants rated general practitioners (GPs) as their first choice and pharmacists as the second choice for discussing behavioural therapies.Specific individual sociodemographic characteristics of benzodiazepine users and their medication‐related beliefs influence their current benzodiazepine usage and future intention to trial behavioural therapies as an alternative to their benzodiazepines. Based on the reported preferences of benzodiazepine users in this study, developing and evaluating GP‐pharmacist collaborative services to improve the uptake of behavioural therapies as an alternative to benzodiazepines can be recommended. The Royal Australian College of General Practitioners (RACGP) recommends that benzodiazepines should not be prescribed for longer than 4 weeks.The benefits of de‐prescribing benzodiazepines have been highlighted in several studies. For example, in elderly nursing home residents, benzodiazepine withdrawal significantly improved memory and cognitive functioning compared with those who continued to take benzodiazepines; withdrawal did not give rise to anxiety, agitation, or sleeplessness.Despite the prescribing guidelines, the listed adverse effects of prolonged benzodiazepine use and robust evidence supporting behavioural therapies over benzodiazepines, the long‐term use of benzodiazepines remains high. While the pattern of benzodiazepine prescribing varies globally, prolonged use of benzodiazepines is a common phenomenon in the United Kingdom, Europe, and North America.Both patient‐ and prescriber‐related factors appear to be linked with prolonged benzodiazepine use. Prescribers' perceptions and attitudes have been reported to be a key factor leading to prolonged benzodiazepine use.necessity and (2) concerns. While the necessity theme assesses individuals' beliefs about the necessity of using their medication, the concerns theme evaluates their concerns about the medication . Thus, in the case of benzodiazepine use, it may be hypothesised that the balance between the concerns about the risk related to continued use of benzodiazepines versus the beliefs about the necessity of the medication may dictate a patients' past, current, and future decisions related to their medications, eg, attempting withdrawal, seeking safer alternatives, or continuing use. Gauging the patients' position on these opposing belief sets (necessity vs concerns) can allow health professionals to employ targeted information provision or counselling to enhance effective withdrawal. Where medication discontinuation is desirable, based on the reasoning behind the BMQ‐specific, beliefs that foster medication discontinuation (higher‐risk perception about the medication and a lesser perceived necessity for use) could serve as a triggering point at which patients can be empowered and pragmatic strategies offered to facilitate withdrawal. In support of this notion, a qualitative study in patients with anxiety indicated that strong beliefs around the necessity of using benzodiazepines and a lower level of concern about long‐term use were associated with resistance to benzodiazepine discontinuation.Other patient‐related factors that can influence ongoing use of benzodiazepines include beliefs and attitudes of the users towards their medication.Although there has been considerable research to characterize such individual sociodemographic and belief factors, there are, to date, few real‐life studies available on patients' perceptions around benzodiazepine use and withdrawal. Minimal attention has been paid to the complexity of factors affecting the decision making involved in withdrawing benzodiazepines. Successful and sustained withdrawal behaviours require a prior intention, and past behaviour may contribute to this future intention.past , current , as well as future behaviours . Additionally, the study aimed to explore the patients' source preference for information about alternative behavioural therapies. The findings of this study will potentially inform effective, patient‐centred, and evidence‐based interventions for reducing long‐term benzodiazepine use and disseminating behavioural therapies with greater scope and sustainability.Therefore, the present study primarily aimed to investigate the association of participants' sociodemographic variables and beliefs about the benzodiazepine, with their benzodiazepine use behaviours, including 22.1Given that this study aimed to explore real‐life behaviour, a point of purchase survey of benzodiazepine consumers was used. This method allows researchers to study consumer behaviour for informing interventions and policy development.2.2Pharmacies throughout the Australian state of New South Wales (NSW) were invited to participate utilizing a convenience sampling approach . The surveys were conducted from November 2016 to July 2017. Consent for a researcher (FTNS) to be present in a pharmacy was obtained from pharmacy owners. Potential participants included adult (18 years old and above) patients who were supplied benzodiazepines upon prescription on the day of the survey. The Anatomical Therapeutic Chemical (ATC) Classification System2.3Completed survey questionnaires were assigned a code before initiating the analysis. Data were entered into the IBM SPSS Statistics package for Windows, Version 22.0 , and entered data were checked for normality using the Kolmogorov‐Smirnov (K‐S) test3past , current (long‐term use of benzodiazepine), and future behaviours. Finally, participants' preferred sources of information for behavioural therapies are descriptively reported.The results are outlined with reference to our study's stated aims; these included exploring the association of participant's benzodiazepine usage behaviours with their sociodemographic characteristics and medication‐related beliefs. A secondary aim of the study was to confirm participants' preferences for information sources on alternative behavioural techniques. Accordingly, in the results section, firstly participants' demographics and then their scores on the BMQ‐specific questionnaire2 floor space) and two were large‐sized (350‐500 m2 floor space) pharmacies; eight were independently owned; 10 were from metropolitan, and two were from regional areas. All the participants completed the survey questionnaire at the pharmacy, even though the option to complete at home and mail back was available. The mean (±SD) age of the participants was 54.3 (±16.7), with a range of 23 to 86 years. Seventy‐one percent of the participants had at least high school level education. Sixty‐seven percent of the participants had been taking benzodiazepines for at least 1 year. The reported reasons for benzodiazepine use were sleep disorders (59%), psychiatric disorders (31%), pain management (7%), and other problems (4%). For the BMQ scale, the mean score (±SD) calculated for the necessity theme was 17.7 (±5.6), and the concerns theme was 13.6 (±4.7). While 65% of the sample had strong beliefs in the necessity of their benzodiazepine use as indicated by a BMQ‐specific score of greater than 15, only 40% reported strong concerns about the potential adverse effects of the medication (BMQ‐specific scores greater than 15). Descriptive statistics for the participants are shown in Table A total of 75 participants  out of 107 approached (70% response rate) were recruited for this study from 12 different pharmacies across NSW. Of these 12 pharmacies, 10 were medium‐sized (150‐350 m3.1n = 35) of the participants had attempted to withdraw the benzodiazepine, and in these cases, sudden cessation of the benzodiazepine was the most commonly reported strategy applied to withdraw the medication. The reported reasons for attempting benzodiazepine withdrawal included concerns about health (49%), fear of developing dependence (40%), doctors' suggestion (37%), and other reasons (17%). Details about the reasons and strategies for withdrawing the benzodiazepine are presented in Table In the sample, 47%  were significantly associated with a benzodiazepine withdrawal attempt. There was no significant correlation between the BMQ themes and past withdrawal attempts.3.2rs [75] = −0.390, p = 0.001) between current chronic benzodiazepine use and participants' level of education. The correlation between current long‐term use of benzodiazepines in the sample with either of the BMQ‐specific themes was only moderately strong. There was a positive  correlation of the scores from the BMQ‐specific theme around necessity and a negative  correlation of the scores from the concerns theme with current long‐term use of benzodiazepines. Details about the correlations between current long‐term benzodiazepine use, level of education, BMQ themes as well as past and future behaviours are presented in Table There was a moderately strong negative correlation  of the participants were not willing to consider behavioural therapies as a substitution for their benzodiazepines . In these cases, participants' lack of confidence about the efficacy of behavioural therapies and their lack of time to try behavioural therapies were the main two reasons for not considering behavioural therapies. The reported reasons for not considering behavioural therapies are highlighted in Table In the sample, about two thirds n = 8 of the We observed no statistically significant association between past benzodiazepine use behaviours  and the future intentions of trialling behavioural therapies Table .rs [75] = 0.297, p = 0.010) relationship between the BMQ concerns theme and future preference for behavioural therapies . Following doctors, most of the participants preferred pharmacists as the second , internet as the third , and psychologists as the fourth choice  to consult about behavioural therapies.Doctors were rated as the most preferred source of information for learning more about behavioural therapies . A few participants had tried different strategies to withdraw from benzodiazepines. Many of these strategies  were inappropriate. Participants' lower level of education and their beliefs (low concerns and high necessity) appeared to contribute to the current high rate of long‐term benzodiazepine use in this Australian sample. Participants' beliefs appeared not to be associated with their past withdrawal attempts; however, the item used in our questionnaire simply probed whether participants had made any attempt to withdraw their benzodiazepine, not the actual number of attempts made, which may have been a variable associated with the patients concerns about use. We observed, however, an association between concerns about use and future intention to try behavioural alternatives. Using the benzodiazepine for sleep‐related problems was a predictor for willingness to consider alternative behavioural therapies. Only a third of participants expressed an interest in considering behavioural therapies as an alternative to the use of benzodiazepines. Doctors and pharmacists were the two main health professionals of choice with whom benzodiazepine users wanted to discuss potential behavioural therapies. Therefore, it is clear that a collaborative effort in primary care between doctors and pharmacists may help to ensure quality use of benzodiazepines. Based on the study findings, strategies for shifting from ongoing benzodiazepine use to considering behavioural therapies should include counselling patients about the balance between the necessity of using benzodiazepines and the risks associated with ongoing use in the primary care settings.The observed negative association between the participants' level of education and the current chronic use of benzodiazepines suggests that individuals with a lower level of education perhaps require particular review and targeted information provision. While past withdrawal attempts do indicate previous positive inclination to cease benzodiazepine use, failure at these attempts perhaps reinforces the necessity of continuing the medication as well as reduces the user's perception of their ability to be able to cease use. Therefore, based on theories such as those around planned behaviourcurrent behaviour) highlights that the decision to continue benzodiazepines reflected the balance between these two opposing belief sets. However, we observed that future intentions around continued benzodiazepine use  were only related with the concerns theme, highlighting that if targeted information provision can help build realistic concerns about ongoing use, benzodiazepine users may be swayed to discontinue and switch to behavioural alternatives in the future. The results of this study, therefore, suggest that the BMQ could be a useful instrument to elicit medication beliefs and increase health care professionals' understanding of patients' attitudes towards the medication, which can, in turn, potentially facilitate the de‐prescribing process. Martin et al describe the use of the BMQ‐specific questionnaire to compare patients' beliefs about their benzodiazepines before and after an educational program designed to facilitate decisions about discontinuing benzodiazepines; they report a significantly lower‐necessity score and higher‐concerns score after the intervention.The observed positive relationship of the necessity theme and the negative relationship of the concerns theme with actual long‐term benzodiazepine use , a sample of 75 may be sufficient to demonstrate significance at a 0.05 significance level with 75% power.5Specific characteristics of benzodiazepine users and their beliefs about taking the benzodiazepine can inform the provision of individualised interventions by GPs to help switch patients currently on long‐term benzodiazepines to alternative behavioural therapies. This study highlights the significance of informing patients about the balance between the necessity of use versus the concerns that long‐term use of benzodiazepines raises. Given that GPs are very time pressured, introducing practice pharmacists within general practices could be time efficient and enhance GPs' capacity for providing behavioural therapies, and this area of collaborative care in de‐prescribing unwarranted use of high‐risk medications warrants future research.This research did not receive any specific grant from funding agencies in the public commercial or not‐for‐profit sectors. However, the authors acknowledge the PhD scholarship support received by the first author from NeuroSleep, a Centre of Research Excellence supported by a grant from the Australian National Health and Medical Research Council. The funding sources were not involved in study design; collection, analysis, or interpretation of data; writing of the report; or the decision to submit the report for publication.None.Conceptualization: Fatema‐Tun‐Naher Sake, Keith Wong, Bandana SainiFormal Analysis: Fatema‐Tun‐Naher Sake, Keith Wong, Bandana SainiWriting : Fatema‐Tun‐Naher SakeWriting (review and editing): Fatema‐Tun‐Naher Sake, Keith Wong, Delwyn Bartlett, Bandana SainiAll authors have read and approved the final version of the manuscript.Fatema‐Tun‐Naher Sake had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.


Despite advances in our understanding of what mental health systems and services can do to enhance recovery and wellbeing outcomes for people seeking support, there is limited evidence demonstrating that this body of work has translated successfully into mental health service practice. The Collaborative Recovery Model (CRM) is a practice framework that has been designed to support application of recovery and wellbeing oriented principles and practices within mental health service delivery. The aims of this study were to assess consumer and staff perceptions of implementation frequency during service engagement and the value of this approach for assisting recovery within a setting where the CRM approach had been adopted.n = 116) and staff practitioner (n = 62) perspectives. A series of paired sample t-tests assessed for differences between consumer and staff perceptions of the: (i) importance of key practice elements for assisting recovery, and the (ii) frequency that key practice elements are utilised during engagement sessions. Spearman’s r correlational analysis explored associations between importance, frequency and helpfulness of sessions.The setting was a large Australian community managed mental health organisation. The study involved a cross-sectional analysis of consumer  contains supplementary material, which is available to authorized users. The activism, advocacy, and narrative based literature generated by people with a lived experience of mental illness and recovery has driven a transformational shift in how mental health and recovery is understood –4. What shift in attention. That is, mental health services need to broaden their scope of attention beyond illness and symptom alleviation, towards that of enhancing health and wellbeing [shift in engagement style beyond traditional approaches and positional roles where a person accessing mental health services is seen as a passive recipient of clinical expertise [Threaded throughout recovery and wellbeing oriented international research and policy literature are two compelling themes fundamental to mental health service practice transformation. Firstly, there is persuasive evidence and argument for a ellbeing , 12–17. ellbeing , and delellbeing . Secondlxpertise , 20, 21.xpertise –26. Coacxpertise –29.The strength of this knowledge is evident in the health policy missions and standards for mental health care provision in a growing number of countries . HoweverThe development of conceptual frameworks and practice models for services and practitioner staff to draw on represent a potentially valuable step in diminishing this knowledge to practice gap . TraininAside from well-designed learning and practice development opportunities, of critical importance to practitioner uptake is whether or not an approach is seen as responsive to consumer needs, strengths, personal characteristics and sociocultural context . PositivThe Collaborative Recovery Model (CRM) is a person centred and strengths based coaching model . The modDespite extensive attention to identifying the key elements for practice and the development of models, frameworks and guidelines aimed at improving mental health service practice, there is as yet limited literature demonstrating that services and practitioner staff are enacting these in everyday practice , 26, 31.This paper presents findings from a large study aimed at exploring implementation fidelity to the Collaborative Recovery Model within an Australian community managed mental health organisation, Neami National. Implementation fidelity refers to the extent to which a practice model is being delivered as intended by its designers . Fidelitimportance of the model’s key practice elements for assisting recovery and the frequency by which these are applied, (2) a file audit of consumer support plans to examine whether self-reports of practice application were consistent with documentary evidence, and, (3) the perceptions of staff across management and non-direct service delivery roles regarding policy and process transformations that have arisen as a result of an organisation wide systems approach to implementation of the model.The full study integrated multiple units of analysis—(1) the perceptions of consumers and practitioner staff regarding the Are the key practice elements within the CRM considered important in assisting recovery?To what extent are the key practice elements of the CRM applied during support engagement activities?Is there any relationship between how the key practice elements of the CRM are valued and the frequency by which they are applied?Is there any relationship between the frequency in which the key practice elements are implemented and consumer perceptions of helpfulness of support engagement sessions?This paper focuses attention on the first unit of analysis and seeks to answer four questions:The method was designed to assess the frequency by which the Collaborative Recovery Model was implemented, and its value for assisting recovery, from the viewpoints of consumers and staff receiving and delivering support framed by this approach. A cross-sectional survey was conducted that assessed the parallel between consumer and practitioner staff perceptions. The study was reviewed and approved by University Human Research Ethics. The procedure outlines the protocols implemented with respect to ethical considerations relevant to this study.The study was undertaken within an Australian community managed mental health organisation. The organisation is one of the many community managed organisations  in Australia that provide support services to people living with and/or experiencing mental illness and distress. The Australian mental health service sector includes those delivered by government i.e. Public Health System; those delivered privately e.g. private psychiatrist; and those that are delivered by community managed organisations. Community-managed organisations are typically not for profit and deliver supports from a psychosocial framework of care. In Australia the majority of mental health service consumers access mental health support through the public and private sectors with approximately 3.1% of psychosocial mental health services expenditure spent in the NGO sector .At the time of the study, the organisation provided support to 3512 consumers and employed 607 staff from 36 service site locations ranging from inner-city and suburbs to regional and remote areas across five states of Australia. Seven sites were excluded from the study due to service parameters that required non-standard use of the CRM. This included short stay residential services and homelessness outreach services. A proportional random selection process was undertaken to select 12 sites from the remaining 29. Service site participation distribution across states included; Western Australia  and VictConsumer researchers were employed and renumerated in line with industry based rates commensurate to researcher responsibilities. The consumer researchers had no prior experience in receiving services or being employed by the organisation involved in this study. This procedure was adopted to create an arms-length between service delivery practices and research activities to minimise the potential for bias, maximise confidentiality and safety for participants and minimise potential coercion and/or perceptions of coercion. Furthermore, consumer participants have been found to respond more truthfully when research activities are undertaken with a consumer researcher , 58.Names of ‘active’ consumers from the 12 sites were extracted from the organisational database, Carelink+, and a randomisation procedure was applied to sort consumer names in ascending order for invitation to participate. Active consumers are those who are currently receiving support as opposed to those who have completed their service engagement or on a wait list to receive support. The extraction of consumer names and the randomisation procedure was undertaken by an employee from the study setting holding custodial responsibility for the collection, management, storage and transmission of all administrative data that is collected for service operations across the organisation. In this role the employee has responsibility to implement appropriate physical, technical and ethical safeguards to protect the confidentiality and integrity of organisational data. The funder and the researchers involved this project had no influence over the list creations and randomisation procedure other than providing the parameters related to length of time in service (minimum 3 months) and requirement for participants to be ‘active consumers’ as opposed to no longer receiving services or on a waiting list. Sorted lists were provided in Excel spreadsheets directly to consumer researchers and included consumer names, contact details, ID codes for later use and names of staff practitioners who were the key workers for each consumer. Consumer researchers requested site managers advise them about any consumers currently in hospital. Those names were also omitted from the lists.Consumer researchers started at the top of the list to contact consumers by phone and invite participation. They introduced themselves to participants as having a lived experience of mental illness and recovery and being employed as a researcher by the service development department of the organisation. After introducing themselves, they provided verbal information about the study and what participation would involve.For consumers who indicated interest in knowing more, a meeting time and place was set for the consumer researcher and consumer to discuss the project more fully. Consumers were provided with full information (including written) about the study and what participation would involve, invited to discuss and ask questions, and offered time to consider and talk to significant others (e.g. family) about whether or not they would want to participate. Consumer participants were asked to relate back to the researchers their understanding of the nature of the study and what participation involved prior to providing formal and signed consent. Researchers stopped recruitment once participation numbers reached 10 per site. In total 263 consumers were contacted about the study and 116 (44%) agreed to participate and provided signed consent. One participant withdrew from the study due to a change in their circumstances.Once a consumer had completed participation in the study, consumer researchers contacted staff members who were identified in the Excel spreadsheet as being the key worker for the participating consumer. After introducing themselves and advising the staff member that a consumer they worked with was involved in the study they provided verbal information about the nature of the study and what participation would involve. If a staff member indicated interest they met with a consumer researcher and were provided with full study and participation information (including written) and offered time to consider their decision. All staff participants were taken through a formal information and consent process involving signed consent to participate.Staff participants were the key workers holding primary responsibility for the coordination and delivery of support to the consumer participants in this study. Key workers at this organisation may be responsible for a portfolio of between five and fifteen consumers. There was 65 staff identified on the Excel lists as being key workers to the 116 consumers who participated in the study. Two staff had left the organisation at the time of recruitment and one did not consent to participate. In total, 62 out of 63 staff members invited to participate did so. Staff participants completed separate measures for each consumer participant they were key worker for. As such, staff participants often completed measures in reference to more than one consumer participant.In all communications between researchers and participants the voluntary nature of participation was clearly communicated along with options for withdrawing consent. All participants were reminded that a decision to not participate would have no impact on their relationship with the organisation of this study setting, on the service they receive (consumer participants) or their employment (staff participants). Participants were informed of protocols to protect participant confidentiality including the (1) designation of private rooms or option for alternative location of choice , (2) use of participant ID no. on all paper based and data-based data with only researcher access to the ID key, (3) all paper-based data stored in locked filing cabinets with only researcher access (4) signed consent forms stored separately to paper-based data responses.Following information and consent processes, consumer researchers met separately with consumer and staff participants to undertake the completion of measures used in this study. All recruitment, information and consent processes, and data collection activities were undertaken in settings ensuring privacy and comfort for participants. No service delivery staff member had access or knowledge of consumer participant responses. Likewise no consumer participant had access or knowledge of staff member responses. Information about who did not consent to participate was only known to the consumer researchers involved in this study.The Consumer Evaluation of CRM (CEO-CRM) and the Staff Evaluation of CRM (SEO-CRM) are matched self-report questionnaires, developed by university and consumer researchers  to assesimportant they perceive nine key CRM practice elements as assisting their recovery according to a 4-point Likert scale; 0 = not important, 1 = moderately important, 2 = important, 3 = very important. The measure then asks consumer participants to rate the frequency in which the same nine key practice elements are applied during engagement sessions according to a 5-point Likert scale; 0 = never, 1 = occasionally, 2 = sometimes, 3 = usually, 4 = always. An engagement session is a time designated for a consumer and staff member to meet face to face for the consumer to receive mental health and wellbeing support. Table importance and frequency ratings consumer participants are asked to rate how helpful the sessions with their key worker had been towards assisting their personal recovery process over the past 3 months according to a 4-point Likert scale; 0 = not at all helpful, 1 = moderately helpful, 2 = helpful, 3 = very helpful.In preparation for this study, we consulted with three consumers, three staff and five consumer researchers to review the measures. Some small adjustments were made to the wording and sequence of the statements including a change in the Likert rating scale for ‘importance’ ratings. The option for ‘somewhat important’ was removed because it was considered too similar to ‘moderately important’. After additional consultation with the university researchers and developers of the CRM, two additional practice elements were also added. These related to values clarification and strengths identification that were not in the original version but considered key practice elements to the CRM. Supplementary files present the CEO-CRM and SEO-CRM measures  and staff practitioners (n = 62) of an Australian community managed mental health service. ‘Active consumers’ refers to consumers who were receiving support at the time of the study as opposed to those who had completed their service engagement or were on a wait list to receive support. Participant demographics are presented in Tables Participants of the current study were active consumers n = 16 and sters n = 6 of an AuThe 62 staff participants were the practitioner staff providing mental health service supports to the consumer participants in this study. Out of the 62 staff participants, 61 had attended 3 day induction training in CRM, 54 had attended at least one CRM 6 month booster, and 48 had attended at least one CRM annual booster. The CRM training programme is intended to enhance and reinforce practitioner staff knowledge, skills and confidence to utilise the CRM therapeutic approach. Staff also engage in fortnightly coaching sessions which allow them to discuss consumer progress, and their own personal development within a CRM framework .Table Results indicated that the vast majority of consumer participants rated all key practice elements of the CRM as important in terms of assisting their recovery. The percentage of consumer ratings in the important and very important range was 87% with a range of (76–91%) across elements. On average, they were rated by consumers as not important 4% of the time (range across elements 0–7%). Staff participant ratings of importance were similar with the percentage of ratings in the important and very important range also being 87% with a range of (70–96%) across elements.t-test’s using Bonferroni adjusted alpha levels of .003 were conducted to compare consumer and staff perceptions of importance at the level of individual items. Results indicated no significant differences between mean ratings of importance for eight out of the nine items. However ‘respect shown for right not to have to take key worker advice’ was regarded more highly by staff participants than consumer participants t (107) = − 4.46, p < .001, with a medium effect size, Cohen’s d = .59.Paired-sample Consumer and staff participant mean frequency ratings for each of the key practice elements are presented in Table t-test’s using Bonferroni adjusted alpha levels of .003 were conducted to compare consumer and staff participant ratings of application frequency at the individual item level. Results indicated no significant differences between consumer and staff mean ratings of application frequency for six out of the nine items. However, there was a statistically significant difference for the ratings of application for three elements.Paired-sample t (105) = − 4.94, p < .00; with a substantial effect size, Cohen’s d = .69. The element ‘involvement in considering choices and decisions about my recovery’ was rated as being applied less often by consumers than staff rated themselves as applying it, t (106) = − 4.57, p < .00, with a medium effect size, Cohen’s d = .58; and ‘respect shown for right not to have to take practitioner advice’ was also rated as being applied less often by consumers, than staff rated themselves as applying it, t (107) = − 4.31, p < .00, with a medium effect size, Cohen’s d = .55.The key practice element ‘help with motivation’ was on average rated as being applied more often by consumers than staff rated themselves as applying it r correlations between consumer and staff ratings of overall importance and frequency. Significant moderate positive correlations were found between consumer importance and consumer application frequency ratings (r = .50) and between staff importance and staff frequency ratings (r = .49). Small but significant positive correlations were found between staff frequency ratings and consumer importance and frequency ratings (ranges = .20– .25).Table n = 103/111) of consumer participants perceived sessions with their key worker as being helpful or very helpful  towards assisting their personal recovery, 5% as moderately helpful (n = 6/111) and only 2% as not at all helpful (n = 2/111). Staff ratings were lower  with 76% (n = 84/110) perceiving sessions as being helpful or very helpful and 24% (n = 26/110) as being moderately helpful.Ninety-three percent  associations with higher perceptions of helpfulness of sessions. The strongest association with helpfulness was for ‘encouragement to set tasks to complete between support visits’. For staff, significant albeit small associations were found between higher implementation of six of the nine key practice elements with higher perceptions of helpfulness. There was a greater proportion of items showing associations between application frequency and helpfulness, than that of importance and helpfulness. Table The Collaborative Recovery Model (CRM) promotes consumer and staff engagement with an individualised and holistic approach to recovery and wellbeing . ResultsAt the individual item level, results indicated no significant differences between consumer and staff perceptions of importance for eight out of the nine key practice elements. However, for one item; ‘involvement in considering choices and decisions about recovery’, it was found that although consumer ratings of importance for this were high (M = 2.49 out of 3) staff ratings were higher (M = 2.66 out of 3). Central to the concept of empowerment is a person having the opportunity to voice their ideas, opinions and concerns . This fiFor the second question, the majority of consumers (79%) and staff (80%) rated the key practice elements as being applied during service interactions, as either usually or always. There was no significant difference between the total item means between consumers and staff. This represents a substantial agreement between consumer and staff perceptions of application and suggests implementation of the model is detectable and able to be rated as occurring. The model’s use of applied positive psychology constructs, such as cultivating a growth mindset and a focus on values and strengths, provides a framework for translation at the organisational, staff and consumer levels .A component of the model that may have contributed to these results is the expanded use of the ‘parallel process’ . Furthert-test’s comparing consumer and staff application frequency ratings at the individual item level revealed no significant difference between consumer and staff perceptions of application frequency for six out of the nine elements. However, there was a disparity between consumer and staff reports for the application of three elements. Firstly, ‘help with motivation’ was on average perceived by consumers as being applied more frequently during engagement interactions than staff rated themselves as applying it. For practitioners implementing the CRM approach, the ability to engage in discussions and activities that enhance and maintain motivation, are supported through ongoing training. The content of training includes theoretical concepts emerging from the recovery literature and align with knowledge from the positive psychology and wellbeing sciences pertaining to hope, change and growth [Paired-sample d growth . Practitd growth . The disd growth , 25, 60.M = 3.35 and M = 3.32 out of 4), staff ratings were significantly higher (M = 3.76 and M = 3.80 out of 4). This disparity may indicate a bias on the part of practitioner staff ratings, which is common to practitioner self-reports of adherence to a practice approach [The key practice elements ‘involvement in considering choices and decisions about my recovery’ and ‘respect shown for right not to have to take staff advice’ were rated on average by consumers as being applied less often than staff rated themselves as applying it. Although consumer application rating means for these items were high  of consumers rated the sessions with staff practitioners as being helpful or very helpful towards assisting recovery. Staff perceptions about helpfulness of sessions were somewhat lower with 76% rating sessions at the helpful or very helpful level and 24% at the moderately helpful level.r = .40) with consumer perceptions of helpfulness of sessions to assist recovery. This finding stands in contrast to other findings from this study where task setting was perceived as least important and the least frequently implemented element.Correlations revealed that perceptions of helpfulness of sessions were related to the frequency that the key practice elements were applied, both at the individual item level and the total scale level. Higher ratings of CRM application were associated with higher levels of perceived helpfulness of sessions to assist recovery. The implementation of ‘encouragement to set tasks to complete between support visits to achieve own goals’ demonstrated the strongest association . The value of ‘non-technical’ aspects of practice, such as the therapeutic relationship, meaning making and the mobilisation of hope are often underestimated by mental health practitioners [The pattern of relations shows that consumer perceptions of helpfulness of sessions were more strongly associated with application of the key CRM practice elements than staff perceptions of helpfulness with application. The disparity raises questions about whether staff may underestimate the value and impact of the work they are doing. The greatest disparity was for ‘help with motivation’  for consumer participation in this study was relatively low and may impact on the reliability of the results. There is a chance that consumers who chose to participate were those more satisfied with the service. However steps were taken in the recruitment procedure to limit such bias, which may also have impacted the response rates. Firstly, recruitment for this study was undertaken by consumer researchers without any previous relationship with the consumers contacted for potential participation. Recruitment rates may have been higher if consumers had been recruited by staff practitioners with whom they had existing relationships. However, in order to minimise perceptions of coercion and limit bias the study involved consumer researchers to invite participants. Secondly, recruitment to participate in mental health research is often influenced by clinician decision making as to whether a person is deemed suitable . In this study we sought to limit clinician decision making and optimise consumer choice for opting in or out of participation . Given tThe findings presented in this paper suggest that recovery and wellbeing oriented knowledge and evidence, are translatable to real world mental health service settings. Since the model’s inception, the researchers/developers worked closely with real world mental health service settings and consumers to develop and refine the model for use in everyday practice , 23, 63.Translating recovery-oriented knowledge into mental health service systems and practice has proven to be a persistent challenge . AssessiFindings revealed that the key practice elements were perceived as being applied during service interactions at a high level and perceived by consumers and staff as being valuable for assisting recovery. There was a substantial level of agreement between consumer and staff perceptions of value and application frequency indicating visibility and positive engagement with the CRM approach in the study context. Congruent with existing research, higher perceptions of value were found to be associated with higher levels of implementation, strengthening the proposition that positive attitudes about the value of an approach can increase the likelihood of consumer engagement and staff uptake –46. VariBy combining recovery knowledge and policy with practices known to enhance mental health and wellbeing, along with a coaching orientation and organisational change principles, the CRM framework may offer a practical solution for mental health services to translate recovery policy into practice . FurtherAdditional file 1. CEO-CRM Consumer Evaluation of CRM.Additional file 2. SEO-CRM Staff Evaluation of CRM.


The rate at which biological diversity is altered on both land and in the sea, makes temporal community development a critical and fundamental part of understanding global change. With advancements in trait‐based approaches, the focus on the impact of temporal change has shifted towards its potential effects on the functioning of the ecosystems. Our mechanistic understanding of and ability to predict community change is still impeded by the lack of knowledge in long‐term functional dynamics that span several trophic levels. To address this, we assessed species richness and multiple dimensions of functional diversity and dynamics of two interacting key organism groups in the marine food web: fish and zoobenthos. We utilized unique time series‐data spanning four decades, from three environmentally distinct coastal areas in the Baltic Sea, and assembled trait information on six traits per organism group covering aspects of feeding, living habit, reproduction and life history. We identified gradual long‐term trends, rather than abrupt changes in functional diversity  trait turnover, and overall multi‐trait community composition. The linkage between fish and zoobenthic functional community change, in terms of correlation in long‐term trends, was weak, with timing of changes being area and trophic group specific. Developments of fish and zoobenthos traits, particularly size  and feeding habits , suggest changes in trophic pathways. We summarize our findings by highlighting three key aspects for understanding functional change across trophic groups: (a) decoupling of species from trait richness, (b) decoupling of richness from density and (c) determining of turnover and multi‐trait dynamics. We therefore argue for quantifying change in multiple functional measures to help assessments of biodiversity change move beyond taxonomy and single trophic groups. In this study, we identified gradual long‐term trends in functional diversity, trait turnover, and overall multi‐trait community composition spanning a period of 40 years and two key trophic groups: fish and zoobenthos, in three coastal marine areas. The study highlights the need for multiple measures and cross‐trophic level assessments to understand empirical functional (trait) change and serves as a baseline for functional change in the Baltic Sea region and other coastal and estuarine ecosystems worldwide. The findings contribute to the general understanding of biodiversity change and can be useful for developing predictions and models of community change. Zoobenthic data covered the time period 1972–2013 for Kattegat, 1980–2013 for the Baltic Proper, and 1976–2013 for the Bothnian Sea, with in total only five sampling‐years missing , supplemented with peer‐reviewed sources  richness (SRic) and three complementary multi‐trait functional indices: trait richness (TRic), functional evenness (FEve) and functional dispersion  turnover (Fturn) and multi‐trait dynamics. These analyses were performed per group and area on community‐weighted mean (CWM) traits . We fitted linear regressions on each measure, for each group and area separately, with year as a single predictor using either linear  and the detailed variability, that is maximum number of points identified. Missing values were replaced by the average of the neighbouring two years. Assessing development in this way also allowed for comparison between groups and a reference to previously identified significant time periods of change in taxonomically‐based measures  shifts in the trophic groups and assessed timing of statistically relevant changes in each measure using change‐point analysis (Killick and Eckley 2014). We determine change‐points in time, related to shifted mean and variance in the time series using the binary segmentation method with a Bayesian information criterion (BIC) as penalty criteria (Killick and Eckley 2014). We identified both the gross change‐point of a time series  and Bothnian Sea (p = 0.05), while no linear change was found in Kattegat  in the Baltic Proper fish community, which became more uneven over time  was found in all areas, hence, indicating a change over time of the abundant zoobenthic taxa in trait space , while an increase in turnover was found in both the Kattegat (p < 0.001) and Bothnian Sea (p < 0.01) zoobenthic communities  and the Baltic Proper (p < 0.05)  and decreased in the Bothnian Sea (p < 0.01)  occurred in all areas but were group specific  Figure . Trait c) Figure . The lin) Figure .Change‐point analysis of turnover corresponded with the results for the diversity indices in that shifts were found during the same time period within each group, particularly for the zoobenthic communities .Species richness of fish and zoobenthos showed positively correlated temporal dynamics in two out of the three areas  have, in our case, had the potential to interact directly, through predatory–prey and/or other non‐trophic interactions through time, although this remains to be specifically assessed. A large portion of the fish community in the assembled data is benthivorous, or feeds on both zoobenthos and other fish species, especially in the Kattegat and Baltic Proper , trait turnover, and overall multi‐trait community composition spanning a period of 40 years and two key trophic groups in three coastal marine areas. Although the linkage between fish and zoobenthic functional community change was weak, with timing of changes being area and trophic group specific, developments in specific fish and zoobenthos community traits, particularly size and feeding habits, suggest changes in trophic pathways. Apart from serving a baseline for functional change in the region and other coastal and estuarine ecosystems worldwide, the results highlight the need for multiple measures and cross‐trophic level assessments to understand empirical functional (trait) change. Thereby, our findings contribute to the general understanding of biodiversity change and can be useful for developing predictions and models of community change. Click here for additional data file. Click here for additional data file.


Large‐scale epidemiological studies have demonstrated a protective effect of clozapine on mortality in people with schizophrenia. Clozapine is reserved for use in patients with treatment‐resistant schizophrenia (TRS), but evidence of clozapine's effect on mortality exclusively within TRS samples is inconclusive. Hence, we aimed to investigate the effect of clozapine use on all‐cause mortality in TRS patients.n = 1025). Cox proportional hazard models were used, adjusting for sociodemographics, clinical monitoring, mental and physical illness severity and functional status.A historical patient cohort sample of 2837 patients, who met criteria for TRS between 1 Jan 2008 and 1 Jan 2016, were selected from the South London and Maudsley NHS Foundation Trust (SLAM) electronic health records (EHR). The national Zaponex Treatment Access System (ZTAS) mandatory monitoring system linked to the SLAM EHR was used to distinguish which patients were initiated on clozapine (P = 0.04).After controlling for potential confounders, the protective effect of clozapine on all‐cause mortality was significant (adjusted hazard ratio 0.61; 95% confidence interval 0.38–0.97; Clozapine reduces the risk of mortality in patients who meet criteria for TRS. We provide further evidence that improving access to clozapine in TRS is likely to reduce the mortality gap in schizophrenia. Among patients with treatment‐resistant schizophrenia (TRS), clozapine users had a reduced mortality risk compared to patients who have not used clozapine, after taking account for differential baseline risks including psychopathology and functional status, and addressing potential impact of survival biases.An automated approach was used to identify patients who meet TRS criteria and who have not been previously trialled on clozapine. This might lead to misclassification, possibly including non‐TRS patients in the analysis. This misclassification is more likely to be non‐differential.There is potential residual confounding by unmeasured confounders such as comorbid cardiovascular disease and smoking.Patients with schizophrenia and other psychoses have approximately three times higher rates of all‐cause mortality and over ten times higher rates of suicide compared to general population A number of epidemiological studies have recently examined how pharmacological treatments may be associated with differences in survival in populations with psychoses. The effects of clozapine, an atypical antipsychotic, on mortality in patients with psychoses has received particular attention Many patients who meet criteria for treatment resistance either never receive clozapine treatment or at least experience considerable delay in receiving it The present historical cohort study investigates the effect of clozapine use on all‐cause mortality in treatment‐resistant schizophrenia patients in the United Kingdom. Using electronic mental health records from community and in‐patient care settings linked to clozapine national registry data, we aimed to address several of the methodological weaknesses identified by a recent systematic review of prior work examining clozapine use and mortality in schizophrenia The Clinical Record Interactive Search (CRIS) has provided an anonymized search system for the electronic health records (EHR) of the South London and Maudsley NHS Foundation Trust (SLAM) from 2007 onwards (25–27). SLAM provides mental health specialist services in four London boroughs , covering roughly 1.36 million of population. Using the Using the CRIS system, researchers can query structured and free‐text data of over 300 000 patients. These patient records are updated by contemporaneous national mortality information (irrespective of current treatment status in SLAM), and enhanced by linkages to external clinical database such as the national Zaponex Treatment Access System (ZTAS) clozapine register.http://www.ztas.co.uk), which is one of the UK mandatory monitoring systems. In order for clinicians to prescribe clozapine, they must register clozapine users on the ZTAS system, with patients’ pretreatment blood test results . The reference blood test results are categorized as green , amber  and red . Patients with ‘green’ blood test results can be prescribed clozapine, within 10 days of this result. In this study, a linkage was performed with all patients whose last recorded pharmacy within the SLAM boroughs, and who had been registered on the ZTAS monitoring service between 1 Jan 2007 and 1 Jan 2016. These data were used to confirm the initiation date of clozapine users first identified from the CRIS database.To prevent clozapine users from agranulocytosis‐related deaths, several countries including the United Kingdom, the United States, Australia and Canada operate a national registry and monitoring system for clozapine users with blood test results. Clozapine patients treated within SLAM are enrolled on ZTAS , and governance is provided for all projects and dissemination through a patient‐led oversight committee.Please see Fig. Treatment‐resistant psychosis patients were defined as those who had ever been selected for clozapine treatment or those who had received a trial of at least three different antipsychotics, where the third novel antipsychotic was initiated during hospitalization between 1 Jan 2008 and 1 Jan 2016, according to SLAM EHR and ZTAS records. Among the initial cohort, 1042 subjects (the clozapine exposed group) had greater than one ‘green’ blood profiles on the ZTAS records. The earliest date was used as an indicative date for clozapine initiation. For the non‐clozapine group, 2089 patients met the definition of treatment resistance, with no evidence of clozapine use. After excluding 2 subjects with invalid dates, 2087 treatment‐resistant patients with non‐clozapine antipsychotic use were identified. Among the identified clozapine and non‐clozapine groups, we then restricted the sample to include only those who had received at least one ICD‐10 schizophrenia (F20) diagnoses  or with the patient's death, whichever occurred first. The follow‐up period was restricted to maximum five years (1826.25 days).Age calculation was based on age at initiation of clozapine or the third novel antipsychotic. Multiple deprivation index was used as a proxy of socioeconomic status As a measure of clinical monitoring, clinical contact days were calculated by summation of all in‐patient and out‐patient visits during the follow‐up, in which one in‐patient visit was counted as one contact day regardless of the duration of admission rd antipsychotic drug initiation date. HoNOS variables used in this study were divided into three categories: mental health symptom severity , additional mental and physical health problems  and functional status . Every variable was categorized as no, minor, mild, moderate and severe problem. In addition, any ICD‐10 diagnoses F11 opiate and F10 alcohol use related disorders, recorded before or during the observation period, were also extracted from structured fields and free‐text records.The clozapine and non‐clozapine groups were meant to be clinically equivalent, but there is still a possibility of selection bias because overall health status can affect clozapine prescription. To address this issue, the present study used the Health of the Nation Outcome Scale (HoNOS) tool stata version 12 All analyses were conducted using n = 1025 clozapine group and n = 1812 non‐clozapine group (Table The mean [standard deviation (SD)] follow‐up time was 1413.8 (559.2) days. A total of 2837 TRS patients consisted of P < 0.001), but less severe baseline psychopathology profiles (P < 0.001) than the non‐clozapine group. The clozapine group had lower rates of substance use disorders, less severe symptoms of agitation, drinking and drug problems, better indices of living conditions and social relationships. The same tendency was observed when we restricted the analysis to the subset of participants with a HoNOS completed prior to clozapine initiation date . The protective effect of clozapine use on 5‐year mortality was not significant in the crude Cox regression model  (Table P = 0.02) showed clozapine was significantly associated with a reduced mortality. Further adjustment for history of substance use disorders, clinical monitoring frequency, mental health symptom severity and additional mental and physical health problems  demonstrated a similar, but non‐significant effect – broadening confidence intervals suggest reduced power due to missing values reducing the available sample, rather than significant attenuation of effect. The final multivariable model, including all measured covariates, showed a statistically significant protective effect of clozapine on all‐cause mortality . Fig. Likelihood‐ratio tests showed the proportional hazards assumptions held P = 0.9. The prWe found a protective effect of clozapine use on all‐cause mortality in TRS patients over a 5‐year follow‐up period. This is the first investigation to use electronic clinical notes (enhanced by linked data provided by a clozapine regulatory body) to describe the association of clozapine with all‐cause mortality in TRS. These data from a comprehensive specialist mental health care service within a geographic catchment, provided a greater depth of information to characterize patients with TRS than prior registry‐based studies P ≤ 0.001) comparing clozapine users to non‐users and/or other antipsychotic users n = 3123) for one year  and used United States Medicaid data, which has restricted coverage related to patients’ income and level of disability. Meanwhile, the Danish study (n = 2370) The direction of effect we found was consistent with a recent meta‐analysis, which reported significant pooled rate ratio of 0.34 in favour of patients using clozapine , with timely linkage to accurate mortality data based on national registers. Specific to this study, the SLAM EHR including mortality data was linked to national ZTAS clozapine registry, which enabled us to improve identification of patients with clozapine initiation.This study had a number of methodological limitations. Cause of death data was not available for analysis within our existing governance arrangements. Registrar reports on death dates are received by NHS organizations routinely from local registrars; however, cause of data death is administered separately by the Office National Statistics, and is only available through specific permissions, which has not been provided for this linked data study. We used an automated approach, similar to the previous study by Wimberley et al. There are several potential pathways for the protective effect of clozapine on mortality. It may be, from a whole clinical population perspective, that the benefits of clozapine's effectiveness in TRS at reducing psychopathology over other antipsychotics, outweighs its associated risk for later cardiometabolic disease In summary, our findings suggest that in TRS, clozapine users have a reduced mortality risk compared to patients who have not received clozapine treatment. We add to the burgeoning evidence that suggests clozapine may help reduce health inequalities experienced by individuals with TRS, and ultimately improve their life‐expectancy RH has received research funding from Roche, Pfizer, Janssen and Lundbeck.This work was supported by the Clinical Records Interactive Search (CRIS) system funded and developed by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London and a joint infrastructure grant from Guy's and St Thomas’ Charity and the Maudsley Charity (grant number BRC‐2011‐10035). JD was supported by a Medical Research Council (MRC) Clinical Research Training Fellowship (MR/L017105/1) and Psychiatry Research Trust Peggy Pollak Research Fellowship in Developmental Psychiatry. RDH was funded by a Medical Research Council (MRC) Population Health Scientist Fellowship (grant number MR/J01219X/1). GK, HS and RH have received salary support from the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The above funding had no role in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.Table S1. Mental and physical health problems and functional status* of the clozapine and non‐clozapine groups in patients with treatment‐resistant schizophreniaClick here for additional data file.