Applying Patient and Public Involvement in preclinical research: A co-created scoping review.

BACKGROUND: Patient and Public Involvement (PPI) in research aims to improve the quality, relevance and appropriateness of research. PPI has an established role in clinical research where there is evidence of benefit, and where policymakers and funders place continued emphasis on its inclusion. However, for preclinical research, PPI has not yet achieved the same level of integration. As more researchers, including our team, aim to include PPI in preclinical research, the development of an evidence-based approach is important. Therefore, this scoping review aimed to identify and map studies where PPI has been used in preclinical research and develop principles that can be applied in other projects. METHODS: A scoping review was conducted to search the literature in Medline (PubMed), EMBASE, CINAHL, PsycInfo and Web of Science Core Collection to identify applied examples of preclinical PPI. Two independent reviewers conducted study selection and data extraction separately. Data were extracted relating to PPI in terms of (i) rationale and aims, (ii) approach used, (iii) benefits and challenges, (iv) impact and evaluation and (v) learning opportunities for preclinical PPI. Findings were reviewed collaboratively by PPI contributors and the research team to identify principles that could be applied to other projects. RESULTS: Nine studies were included in the final review with the majority of included studies reporting PPI to improve the relevance of their research, using approaches such as PPI advisory panels and workshops. Researchers report several benefits and challenges, although evidence of formal evaluation is limited. CONCLUSION: Although currently there are few examples of preclinical research studies reporting empirical PPI activity, their findings may support those aiming to use PPI in preclinical research. Through collaborative analysis of the scoping review findings, several principles were developed that may be useful for other preclinical researchers. PATIENT OR PUBLIC CONTRIBUTION: This study was conducted as part of a broader project aiming to develop an evidence base for preclinical PPI that draws on a 5-year preclinical research programme focused on the development of advanced biomaterials for spinal cord repair as a case study. A PPI Advisory Panel comprising seriously injured rugby players, clinicians, preclinical researchers and PPI facilitators collaborated as co-authors on the conceptualization, execution and writing of this review, including refining the findings into the set of principles reported here.

Medium-term outcomes of a cohort of revision rotator cuff repairs.

BACKGROUND: There are limited medium- and long-term studies investigating clinical outcomes following revision rotator cuff surgery. The aim of the current study was to analyze the medium-term pain and functional outcomes of a cohort of revision rotator cuff repairs. METHODS: This was a multicenter, prospective cohort study of revision rotator cuff repairs undertaken between March 2009 and December 2010. Pain, function (Flex-SF), and postoperative data were collected at baseline; 6, 12, and 24 months; and 5 years. RESULTS: A total of 125 revision rotator cuff repairs were included in this study. Average improvement in Flex-SF and pain from baseline to 5 years was 8.5 (P < .001) and 2.1 points, respectively (P < .001). The improvement was not as pronounced as those who underwent primary repair. Significantly lower pain scores were seen in nonsmokers (P < .001) and in those who underwent tenotomy rather than tenodesis (2 vs. 3.5, P < .05) for a damaged long head of biceps. Significantly higher function scores were seen in those with only 1 tendon involved (P < .05). The patient-reported retear rate was 32.6%, and the reoperation rate was 34.7%. CONCLUSION: Revision rotator cuff repair provides significant improvement in both pain and function at 5 years postoperation, though not as good as primary repair. Superior clinical outcomes are seen in nonsmokers, those with only 1 tendon affected, and those who undergo tenotomy instead of tenodesis for a damaged long head of biceps tendon.

Toluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling.

Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long-term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure. Metabolomics conducted on cortical tissue established that acute exposure to toluene produces alterations in cellular metabolism indicative of a glutamatergic and GABAergic profile. Similarly, in vitro electrophysiology in Xenopus oocytes found that acute toluene exposure reduced NMDA receptor signalling. Finally, in an adolescent rodent model of chronic intermittent exposure to toluene (10 000 ppm), we found that, while toluene exposure did not affect initial learning, it induced a deficit in updating that learning when response-outcome relationships were reversed or degraded in an instrumental conditioning paradigm. There were also group differences when more effort was required to obtain the reward; toluene-exposed animals were less sensitive to progressive ratio schedules and to delayed discounting. These behavioural deficits were accompanied by changes in subunit expression of both NMDA and GABA receptors in adulthood, up to 10 weeks after the final exposure to toluene in the hippocampus, prefrontal cortex and ventromedial striatum; regions with recognized roles in behavioural flexibility and decision-making. Collectively, our data suggest that exposure to toluene is sufficient to induce adaptive changes in glutamatergic and GABAergic systems and in adaptive behaviour that may underlie the deficits observed following adolescent inhalant abuse, including susceptibility to further drug-use.

Ethanol, not detectably metabolized in brain, significantly reduces brain metabolism, probably via action at specific GABA(A) receptors and has measureable metabolic effects at very low concentrations.

Ethanol is a known neuromodulatory agent with reported actions at a range of neurotransmitter receptors. Here, we measured the effect of alcohol on metabolism of [3-¹³C]pyruvate in the adult Guinea pig brain cortical tissue slice and compared the outcomes to those from a library of ligands active in the GABAergic system as well as studying the metabolic fate of [1,2-¹³C]ethanol. Analyses of metabolic profile clusters suggest that the significant reductions in metabolism induced by ethanol (10, 30 and 60 mM) are via action at neurotransmitter receptors, particularly α4ß3δ receptors, whereas very low concentrations of ethanol may produce metabolic responses owing to release of GABA via GABA transporter 1 (GAT1) and the subsequent interaction of this GABA with local α5- or α1-containing GABA(A)R. There was no measureable metabolism of [1,2-¹³C]ethanol with no significant incorporation of ¹³C from [1,2-¹³C]ethanol into any measured metabolite above natural abundance, although there were measurable effects on total metabolite sizes similar to those seen with unlabelled ethanol.

A genome-wide metabolic QTL analysis in Europeans implicates two loci shaped by recent positive selection.

We have performed a metabolite quantitative trait locus (mQTL) study of the (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1)H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11)

Latent biochemical relationships in the blood-milk metabolic axis of dairy cows revealed by statistical integration of 1H NMR spectroscopic data.

A detailed understanding of the relationships between the distinct metabolic compartments of blood and milk would be of potential benefit to our understanding of the physiology of lactation, and potentially for development of biomarkers for health and commercially relevant traits in dairy cattle. NMR methods were used to measure metabolic profiles from blood and milk samples from Holstein cows. Data were analyzed using PLS regression to identify quantitative relationships between metabolic profiles and important traits. Statistical Heterospectroscopy (SHY), a powerful approach to recovering latent biological information in NMR spectroscopic data sets from multiple complementary samples, was employed to explore the metabolic relationships between blood and milk from these animals. The study confirms milk is a distinct metabolic compartment with a metabolite composition largely not influenced by plasma composition under normal circumstances. However, several significant relationships were identified, including a high correlation for trimethylamine (TMA) and dimethylsulfone (DMSO(2)) across plasma and milk compartments, and evidence plasma valine levels are linked to differences in amino acid catabolism in the mammary gland. The findings provide insights into the physiological mechanisms underlying lactation and identification of links between key metabolites and milk traits such as the protein and fat content of milk. The approach has the potential to enable measurement of health, metabolic status and other important phenotypes with milk sampling.

Food, fizzy, and football: promoting unhealthy food and beverages through sport - a New Zealand case study.

BACKGROUND: High participation rates in sport and increasing recognition of how diet benefits athletic performance suggest sports settings may be ideal locations for promoting healthy eating. While research has demonstrated the effect of tobacco and alcohol sponsorship on consumption, particularly among youth, few studies have examined the extent or impact of food and beverage company sponsorship in sport. Studies using brand logos as a measure suggest unhealthy foods and beverages dominate sports sponsorship. However, as marketing goes beyond the use of brand livery, research examining how marketers support sponsorships that create brand associations encouraging consumer purchase is also required. This study aimed to identify the characteristics and extent of sponsorships and associated marketing by food and non-alcoholic beverage brands and companies through a case study of New Zealand sport. METHODS: We conducted a systematic review of 308 websites of national and regional New Zealand sporting organisations to identify food and beverage sponsors, which were then classified as healthy or unhealthy using nutrient criteria for energy, fat, sodium and fibre levels. We interviewed 18 key informants from national and regional sporting organisations about sponsorships. RESULTS: Food and beverage sponsorship of sport is not extensive in New Zealand. However, both healthy and unhealthy brands and companies do sponsor sport. Relatively few support their sponsorships with additional marketing. Interviews revealed that although many sports organisations felt concerned about associating themselves with unhealthy foods or beverages, others considered sponsorship income more important. CONCLUSIONS: While there is limited food and beverage sponsorship of New Zealand sport, unhealthy food and beverage brands and companies do sponsor sport. The few that use additional marketing activities create repeat exposure for their brands, many of which target children. The findings suggest policies that restrict sponsorship of sports by unhealthy food and beverage manufacturers may help limit children's exposure to unhealthy food marketing within New Zealand sports settings. Given the global nature of the food industry, the findings of this New Zealand case study may be relevant elsewhere.

Tenosynovial giant cell tumours: experience at an Australian tertiary referral centre for musculoskeletal tumours with minimum two-year follow-up.

Aims: Tenosynovial giant cell tumour (TGCT) is a rare benign tumour of the musculoskeletal system. Surgical management is fraught with challenges due to high recurrence rates. The aim of this study was to describe surgical treatment and evaluate surgical outcomes of TGCT at an Australian tertiary referral centre for musculoskeletal tumours and to identify factors affecting recurrence rates. Methods: A prospective database of all patients with TGCT surgically managed by two orthopaedic oncology surgeons was reviewed. All cases irrespective of previous treatment were included and patients without follow-up were excluded. Pertinent tumour characteristics and surgical outcomes were collected for analysis. Results: There were 111 total cases included in the study; 71 (64%) were female, the mean age was 36 years (SD 13.6), and the knee (n = 64; 57.7%) was the most commonly affected joint. In all, 60 patients (54.1%) had diffuse-type (D-TGCT) disease, and 94 patients (84.7%) presented therapy-naïve as "primary cases" (PC). The overall recurrence rate was 46.8% for TGCT. There was a statistically significant difference in recurrence rates between D-TGCT and localized disease (75.0% vs 13.7%, relative risk (RR) 3.40, 95% confidence interval (CI) 2.17 to 5.34; p < 0.001), and for those who were referred in the "revision cases" (RC) group compared to the PC group (82.4% vs 48.9%, RR 1.68, 95% CI 1.24 to 2.28; p = 0.011). Age, sex, tumour volume, and mean duration of symptoms were not associated with recurrence (p > 0.05). Conclusion: Recurrence rates remain high even at a tertiary referral hospital. Highest rates are seen in D-TGCT and "revision cases". Due to the risks of recurrence, the complexity of surgery, and the need for adjuvant therapy, this paper further supports the management of TGCT in a tertiary referral multi-disciplinary orthopaedic oncology service.

Evidence for using point-of-care diagnostics in the management of respiratory tract infections in primary care: a scoping review protocol.

Background:  Antimicrobial resistance (AmR) is widely considered a global health threat and is associated with significant morbidity, mortality and costs. Inappropriate antimicrobial use is the most important modifiable risk factor for AmR. Most human antimicrobial medicines use occurs in primary care [prescribed by general practitioners (GPs), dispensed by community pharmacists (CPs)]. However, up to 50% of use is deemed inappropriate. Point-of-care diagnostic tests are used as a basis for antimicrobial stewardship interventions to improve the diagnostic certainty of respiratory tract infections (RTIs), and therefore ensure prudent antimicrobial use. However, there is a lack of guidance on their use, and they are therefore not routinely used in clinical practice. Objective: A scoping review will be conducted to synthesise the available evidence to inform the development of best practice guidance for using point-of-care diagnostics in the management of RTIs in primary care. Methods: A scoping review will be conducted following guidance from the Joanna Briggs Institute (JBI) and reported using the PRISMA-ScR guidelines. Databases including Web of Science, MEDLINE, CINAHL, EMBASE, the International HTA database and the Cochrane Central Register of Controlled Trials, as well as grey literature, will be searched. Screening will be undertaken independently by two reviewers to identify studies and literature reporting the use of point-of-care diagnostics in the management of RTIs in primary care by GPs and/ or CPs. Findings will be described using narrative synthesis. Conclusion:  The findings of this scoping review will be used to produce draft guidance on the use of point-of-care diagnostic tests in primary care, which will undergo further development using a Delphi consensus methodology involving experts in the field of RTIs, antimicrobial stewardship, point-of-care diagnostics and primary care.

1H NMR spectroscopy of serum reveals unique metabolic fingerprints associated with subtypes of surgically induced osteoarthritis in sheep.

Osteoarthritis (OA) is a highly prevalent joint disease. Its slow progressive nature and the correlation between pathological changes and clinical symptoms mean that OA is often well advanced by the time of diagnosis. In the absence of any specific pharmacological treatments, there is a pressing need to develop robust biomarkers for OA. We have adopted a nuclear magnetic resonance (NMR)-based metabolomic strategy to identify molecular responses to surgically induced OA in an animal model. Sheep underwent one of three types of surgical procedure (sham (control), meniscal destabilization, MD or anterior cruciate ligament transaction, ACLT), and for every animal a serum sample was collected both pre- and postoperatively, thus, affording two types of "control" data for comparison. 1D 1H NMR spectra were acquired from each sample at 800 MHz and the digitized spectral data were analyzed using principal components analysis and partial least-squares regression discriminant analysis. Our approach, combined with the study design, allowed us to separate the metabolic responses to surgical intervention from those associated with OA. We were able to identify dimethyl sulfone (DMSO2) as being increased in MD after 4 weeks, while ACLT-induced OA exhibited increased 3-methylhistidine and decreased branched chain amino acids (BCAAs). The findings are discussed in the context of interpretation of metabolomic results in studies of human disease, and the selection of appropriate "control" data sets.

Statistical total correlation spectroscopy scaling for enhancement of metabolic information recovery in biological NMR spectra.

The high level of complexity in nuclear magnetic resonance (NMR) metabolic spectroscopic data sets has fueled the development of experimental and mathematical techniques that enhance latent biomarker recovery and improve model interpretability. We previously showed that statistical total correlation spectroscopy (STOCSY) can be used to edit NMR spectra to remove drug metabolite signatures that obscure metabolic variation of diagnostic interest. Here, we extend this "STOCSY editing" concept to a generalized scaling procedure for NMR data that enhances recovery of latent biochemical information and improves biological classification and interpretation. We call this new procedure STOCSY-scaling (STOCSY(S)). STOCSY(S) exploits the fixed proportionality in a set of NMR spectra between resonances from the same molecule to suppress or enhance features correlated with a resonance of interest. We demonstrate this new approach using two exemplar data sets: (a) a streptozotocin rat model (n = 30) of type 1 diabetes and (b) a human epidemiological study utilizing plasma NMR spectra of patients with metabolic syndrome (n = 67). In both cases significant biomarker discovery improvement was observed by using STOCSY(S): the approach successfully suppressed interfering NMR signals from glucose and lactate that otherwise dominate the variation in the streptozotocin study, which then allowed recovery of biomarkers such as glycine, which were otherwise obscured. In the metabolic syndrome study, we used STOCSY(S) to enhance variation from the high-density lipoprotein cholesterol peak, improving the prediction of individuals with metabolic syndrome from controls in orthogonal projections to latent structures discriminant analysis models and facilitating the biological interpretation of the results. Thus, STOCSY(S) is a versatile technique that is applicable in any situation in which variation, either biological or otherwise, dominates a data set at the expense of more interesting or important features. This approach is generally appropriate for many types of NMR-based complex mixture analyses and hence for wider applications in bioanalytical science.

Human metabolic profiles are stably controlled by genetic and environmental variation.

¹H Nuclear Magnetic Resonance spectroscopy (¹H NMR) is increasingly used to measure metabolite concentrations in sets of biological samples for top-down systems biology and molecular epidemiology. For such purposes, knowledge of the sources of human variation in metabolite concentrations is valuable, but currently sparse. We conducted and analysed a study to create such a resource. In our unique design, identical and non-identical twin pairs donated plasma and urine samples longitudinally. We acquired ¹H NMR spectra on the samples, and statistically decomposed variation in metabolite concentration into familial (genetic and common-environmental), individual-environmental, and longitudinally unstable components. We estimate that stable variation, comprising familial and individual-environmental factors, accounts on average for 60% (plasma) and 47% (urine) of biological variation in ¹H NMR-detectable metabolite concentrations. Clinically predictive metabolic variation is likely nested within this stable component, so our results have implications for the effective design of biomarker-discovery studies. We provide a power-calculation method which reveals that sample sizes of a few thousand should offer sufficient statistical precision to detect ¹H NMR-based biomarkers quantifying predisposition to disease.

Male autistic youth experiences of belonging in integrated physical education.

LAY ABSTRACT: Recent years have seen calls to amplify the voices of autistic people in research about their subjective experiences. Despite this, we know little about how autistic youth experience integrated physical education, particularly in the United States. The term integrated is used to describe a setting in which all students, regardless of educational needs, are educated in the same physical space. In this study, we sought to explore the perspectives of autistic youth toward their experiences in integrated physical education, and the roles of social interactions and relationships with peers in those experiences. Findings noted that several factors influenced the ways and extent to which our participants interacted with their peers during physical education. Unfortunately, most of our participants recalled experiencing bullying, and that physical education offered an environment where bullying was most frequent and comparatively unique compared to other contexts throughout the school day. The locker room, a space linked to physical education, was of particular concern because of a lack of teacher presence. Despite the negative views of and experiences in physical education, there was evidence of participants actively pursuing to connect with peers in this context. However, most instances where participants recalled pursuing friendship were not welcomed from others, which stunted their sense of belonging in this space. Given the role that belonging plays in what it means "to be included," our research supports emerging ideas that even though autistic students were educated in the same physical spaces as their non-autistic peers, feelings of inclusion were largely absent.

Do Age, Demographics, and Tear Characteristics Affect Outcomes After Rotator Cuff Repair? Results of Over 2000 Rotator Cuff Repairs at 5-Year Follow-up.

Background: The New Zealand Rotator Cuff Registry represents the largest prospective cohort of rotator cuff repairs. Despite this, there are limited medium- to long-term data of rotator cuff repair outcomes. Purpose: To (1) analyze the pain and functional outcomes of a large cohort of primary rotator cuff repairs and (2) evaluate the effect of patient factors and tear characteristics on medium-term outcomes. Study Design: Cohort study; Level of evidence, 2. Methods: This was a multicenter, multisurgeon prospective cohort study of rotator cuff repairs from March 2009 until December 2010. Surgical data were collected by the operating surgeon. Primary outcome measures were the Flexilevel Scale of Shoulder Function (FLEX-SF) and a pain score, collected at baseline, 6, 12, and 24 months, and 5 years. Univariate and multivariate analyses were carried out. Results: Overall, 2533 primary rotator cuff repairs were analyzed with 81% follow-up at 5 years. The mean age of the cohort was 56 years. In the 2052 patients with final follow-up data, improvement on the FLEX-SF continued until 24 months postoperatively and remained high at 5 years. Mean improvement in FLEX-SF from baseline to 5 years was 15 points. Patients aged >70 years had lower FLEX-SF scores but no significant difference in improvement compared with patients ≤70 years. The mean anteroposterior tear size was 2.2 cm, and on multivariate analysis, tears >4 cm had worse 5-year FLEX-SF scores. If the affected tendon was easily reducible, there was no difference in FLEX-SF score for retracted or larger tears compared with smaller tears. The reoperation rate was 6.2%. Conclusion: Results indicated that rotator cuff repairs provide a sustained clinical improvement out past 5 years. Most functional improvement and pain relief occurred within the first 6 months, but improvement continued out to 24 months. Most population groups did well after rotator cuff repairs, including those >70 years. Tear size >4 cm and tendon reducibility correlated with outcome. Even patients with large tear sizes had clinically significant improvement in FLEX-SF scores after repair.

Educating pharmacy students through a pandemic: Reflecting on our COVID-19 experience.

The impact of the COVID-19 pandemic on pharmacy education worldwide has been immense, affecting students, educators and regulatory agencies. Pharmacy programmes have had to rapidly adapt in their delivery of education, maintaining standards while also ensuring the safety of all stakeholders. In this commentary, we describe the challenges, compromises and solutions adopted by our institution throughout the pandemic, the lessons learnt, adaptive measures taken, and strategies to develop and future-proof our curricula.

Statistical integration of 1H NMR and MRS data from different biofluids and tissues enhances recovery of biological information from individuals with HIV-1 infection.

Nuclear magnetic resonance (NMR) spectroscopy is widely used in metabonomics studies, but optimal recovery of latent biological information requires increasingly sophisticated statistical methods to identify quantitative relationships within these often highly complex data sets. Statistical heterospectroscopy (SHY) extracts latent relationships between NMR and mass spectrometry (MS) data from the same samples. Here we extend this concept to identify novel metabolic correlations between different biofluids and tissues from the same individuals. We acquired NMR data from blood plasma and cerebrospinal fluid (CSF) (N = 19) from HIV-1-infected individuals, who are known to be susceptible to neuropsychological dysfunction. We compared two computational approaches to SHY, namely the Pearson's product moment correlation and the Spearman's rank correlation. High correlations were observed for glutamine, valine, and polyethylene glycol, a drug delivery vehicle. Orthogonal projections to latent structures (OPLS) identified metabolites in blood plasma spectra that predicted the amounts of key CSF metabolites such as lactate, glutamine, and myo-inositol. Finally, brain metabolic data from magnetic resonance spectroscopy (MRS) measurements in vivo were integrated with CSF data to identify an association between 3-hydroxyvalerate and frontal white matter N-acetyl aspartate levels. The results underscore the utility of tools such as SHY and OPLS for coanalysis of high dimensional data sets to recover biological information unobtainable when such data are analyzed in isolation.

Multi-Stakeholder Retrospective Acceptability of a Peer Support Intervention for Exercise Referral.

Perceived social support opportunities are central to successful exercise referral scheme (ERS) client experiences. However, there remains a lack of guidance on how ERSs can embed social support opportunities within their provision. This study presents retrospective acceptability findings from a 12-week social-identity-informed peer support intervention to enhance perceived social support among clients of an English ERS. Five peer volunteers were recruited, trained, and deployed in supervised ERS sessions across two sites. Peers assisted exercise referral officers (EROs) by providing supplementary practical, informational, motivational, and emotional support to ERS clients. Individual semi-structured interviews were conducted with peers (n = 4), EROs (n = 2), and clients (n = 5) and analysed thematically. The analysis identified three primary themes. The first theme detailed how EROs utilised peer volunteers to supplement the ERS client experience. This theme delineated peer roles within the ERS context and identified salient individual peer characteristics that contributed to their success. The second theme described peer acceptability among the various stakeholders. Peers were valued for their ability to reduce burden on EROs and to enhance perceptions of comfort among ERS clients. The final theme presented participant feedback regarding how the intervention may be further refined and enhanced. Peers represented a cost-effective and acceptable means of providing auxiliary social support to ERS clients. Moving forward, the structured integration of peers can improve the accessibility of social support among ERS participants, thus facilitating better rates of ERS completion.

Impact of smoking on pain and function in rotator cuff repair: a prospective 5-year cohort follow-up of 1383 patients.

BACKGROUND: This multicentre cohort study investigates the effect of smoking on the outcome of rotator cuff repair (RCR), with attention to age at presentation for surgery, pre-operative and post-operative pain and function and intra-operative findings. METHODS: Patient information was collected pre-operatively, including Flex Shoulder Function (Flex SF) and visual analogue scale pain, then at 6 months, 1, 2 and 5 years post-operatively. Intra-operative technical data were collected by the operating surgeon. Current smokers were classified by daily cigarette consumption. RESULTS: A total of 1383 RCRs in as many patients were included with an 84% 5-year follow-up. Smokers were on average 6.7 years younger than non-smokers (51.8 vs. 58.5, P < 0.001). There was no difference in intra-operatively assessed tear size both in anteroposterior dimension (P = 0.5) and retraction (P = 0.9). Pre-operative Flex SF score in smokers was below that of non-smokers (23.0 vs. 24.5, P = 0.002) and at 6 months (P = 0.02) but no different at 5 years (P = 0.7). Pain scores were higher in smokers than non-smokers both pre-operatively (5.34 vs. 4.67, P < 0.001) and up to 2 years (P < 0.001) but not at 5 years (P = 0.073). CONCLUSION: Smokers undergoing RCR were younger than non-smokers, and had worse pre-operative pain scores and shoulder function. Poorer post-operative function persisted to 6 months, and with higher reported pain to 2 years in smokers. However, at 5-year follow-up, patient-reported outcomes were not affected by smoking status.

Patient and Public Involvement (PPI) in preclinical research: A scoping review protocol.

Introduction: Patient and public involvement (PPI) aims to improve the quality, relevance, and appropriateness of research and ensure that it meets the needs and expectations of those affected by particular conditions to the greatest possible degree. The evidence base for the positive impact of PPI on clinical research continues to grow, but the role of PPI in preclinical research (an umbrella term encompassing 'basic', 'fundamental', 'translational' or 'lab-based' research) remains limited. As funding bodies and policymakers continue to increase emphasis on the relevance of PPI to preclinical research, it is timely to map the PPI literature to support preclinical researchers involving the public, patients, or other service users in their research. Therefore, the aim of this scoping review is to explore the literature on patient and public involvement in preclinical research from any discipline. Methods: This scoping review will search the literature in Medline (PubMed), Embase, CINAHL, PsycINFO, Web of Science Core Collection, Scopus, and OpenGrey.net to explore the application of PPI in preclinical research. This review will follow the Joanna Briggs Institute (JBI) guidelines for scoping reviews. It will be reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). Two reviewers will independently review articles for inclusion in the final review. Data extraction will be guided by the research questions. The PPI advisory panel will then collaboratively identify themes in the extracted data. Discussion: This scoping review will provide a map of current evidence surrounding preclinical PPI, and identify the body of literature on this topic, which has not been comprehensively reviewed to date. Findings will inform ongoing work of the research team, support the work of other preclinical researchers aiming to include PPI in their own research, and identify knowledge and practice gaps. Areas for future research will be identified.

γ-Hydroxybutyrate and the GABAergic footprint: a metabolomic approach to unpicking the actions of GHB.

Gamma-hydroxybutyrate is found both naturally in the brain and self-administered as a drug of abuse. It has been reported to act at endogenous γ-hydroxybutyrate (GHB) receptors and GABA(B) receptors [GABA(B)R], and may also be metabolized to GABA. Here, the metabolic fingerprints of a range of concentrations of GHB were measured in brain cortical tissue slices and compared with those of ligands active at GHB and GABA-R using principal components analysis (PCA) to identify sites of GHB activity. Low concentrations of GHB (1.0 µM) produced fingerprints similar to those of ligands active at GHB receptors and α4-containing GABA(A)R. A total of 10 µM GHB clustered proximate to mainstream GABAergic synapse ligands, such as 1.0 µM baclofen, a GABA(B)R agonist. Higher concentrations of GHB (30 µM) clustered with GABA(C)R agonists and the metabolic responses induced by blockade of the GABA transporter-1 (GAT1). The metabolic responses induced by 60 and 100 µM GHB were mimicked by simultaneous blockade of GAT1 and GAT3, addition of low concentrations of GABA(C)R antagonists, or increasing cytoplasmic GABA concentrations by incubation with the GABA transaminase inhibitor vigabatrin. These data suggest that at concentrations > 30 µM, GHB may be active via metabolism to GABA, which is then acting upon an unidentified GABAergic master switch receptor (possibly a high-affinity extrasynaptic receptor), or GHB may itself be acting directly on an extrasynaptic GABA-R, capable of turning off large numbers of cells. These results offer an explanation for the steep dose-response curve of GHB seen in vivo, and suggest potential target receptors for further investigation.