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Abstract An increase in dopamine (DA) synthesis capacity in the dorsal striatum (DS) during the prodromal stage of schizophrenia becomes more pronounced as patients progress to the full disorder. Understanding this progression is critical to intervening in disease course. We developed an animal model—Enhanced Dopamine in Prodromal Schizophrenia (EDiPS)—which uses a genetic construct to increase DA synthesis capacity in the DS of male rats. We assessed pre-pulse inhibition (PPI) and amphetamine (AMPH)-induced locomotion (0.6 mg/kg) in EDiPS animals longitudinally after post-natal day 35 (when the EDiPS construct is administered). We also assessed their response to repeated acute restraint stress. In adult EDiPS animals, we measured baseline and evoked extracellular DA levels, and their stereotyped responses to 5 mg/kg AMPH. AMPH-induced hyperlocomotion was apparent in EDiPS animals 6-weeks after construct administration. There was an overall PPI deficit in EDiPS animals across all timepoints, however the stress response of EDiPS animals was unaltered. Adult EDiPS animals show normal baseline and potassium-evoked DA release in the DS. These findings suggest that key behavioural phenotypes in EDiPS animals show a progressive onset, similar to that demonstrated by patients as they transition to schizophrenia. The EDiPS model could therefore be used to investigate the molecular mechanisms underlying the prodrome of schizophrenia.

Abstract Background Randomised controlled trials (RCTs) are considered the ‘gold standard’ of medical evidence; however, recruitment can be challenging. The MACRO trial is a NIHR-funded RCT for chronic rhinosinusitis (CRS) addressing the challenge of comparing surgery, antibiotics and placebo. The embedded MACRO conversation study (MCS) used qualitative research techniques pioneered by the University of Bristol QuinteT team to explore recruitment issues during the pilot phase, to maximise recruitment in the main trial. Methods Setting: Five outpatient Ear Nose and Throat (ENT) departments recruiting for the pilot phase of the MACRO trial (ISRCTN Number: 36962030, prospectively registered 17 October 2018). We conducted a thematic analysis of telephone interviews with 18 recruiters and 19 patients and 61 audio-recordings of recruitment conversations. We reviewed screening and recruitment data and mapped patient pathways at participating sites. We presented preliminary findings to individual site teams. Group discussions enabled further exploration of issues, evolving strategies and potential solutions. Findings were reported back to the funder and used together with recruitment data to justify progression to the main trial. Results Recruitment in the MACRO pilot trial began slowly but accelerated in time to progress successfully to the main trial. Research nurse involvement was pivotal to successful recruitment. Engaging the wider network of clinical colleagues emerged as an important factor, ensuring the patient pathway through primary and secondary care did not inadvertently affect trial eligibility. The most common reason for patients declining participation was treatment preference. Good patient-clinician relationships engendered trust and supported patient decision-making. Overall, trial involvement appeared clearly presented by recruiters, possibly influenced by pre-trial training. The weakest area of understanding for patients appeared to be trial medications. A clear presentation of medical and surgical treatment options, together with checking patient understanding, had the potential to allay patient concerns. Conclusion The MACRO conversation study contributed to the learning process of optimising recruitment by helping to identify and address recruitment issues. Although some issues were trial-specific, others have applicability to many clinical trial situations. Using qualitative research techniques to identify/explore barriers and facilitators to recruitment may be valuable during the pilot phase of many RCTs including those with complex designs.

Abstract Background Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders which are more common in males. The ‘prenatal sex steroid’ hypothesis links excessive sex-steroid exposure during foetal life with the behavioural differences observed in ASD. However, the reason why sex steroid exposure may be excessive remains unclear. Epidemiological studies have identified several environmental risk factors associated with ASD, including developmental vitamin D (DVD) deficiency. We have demonstrated in an animal model that DVD-deficiency is associated with a hyper-inflammatory response in placentas from male but not female foetuses. Vitamin D also regulates the expression of several steroidogenic enzymes in vitro. Therefore using this animal model, we have examined whether DVD-deficiency leads to increased sex-steroid levels in both the maternal and foetal compartments. Methods Female rats are fed a vitamin D deficient diet from 6 weeks before mating until tissue collection at embryonic day 18. We examined the levels of testosterone, androstenedione and corticosterone in maternal plasma, foetal brains and amniotic fluid. We further examined gene expressions of steroidogenic enzymes and DNA methylation of aromatase promoters in foetal brains as a potential molecular mechanism regulating testosterone expression. Results We show that DVD-deficiency increases testosterone levels in maternal blood. We also show elevated levels of testosterone and androstenedione in the amniotic fluid of female but not male DVD-deficient foetuses. Testosterone levels were also elevated in DVD-deficient male brains. Vitamin D, like other steroid-related hormones, regulates gene expression via methylation. Therefore we examined whether the significant elevation in testosterone in male brains was due to such a potential gene-silencing mechanism. We show that the promoter of aromatase was hyper-methylated compared to male controls. Limitations A reduction in aromatase, in addition to causing excessive testosterone, could also lead to a reduction in estradiol which was not examined here. Conclusions This study is the first to show how an epidemiologically established environmental risk factor for ASD may selectively elevate testosterone in male embryonic brains. These findings provide further mechanistic support for the prenatal sex steroid theory of ASD.

Abstract Background Effective clinical handover is fundamental to clinical practice and recognised as a global quality and safety priority. Problems with clinical handover from the emergency department (ED) to inpatient ward across four hospitals in the Illawarra Shoalhaven Local Health District (ISLHD) were identified in a number of reportable clinical incidents. To address this, an ED to inpatient ward electronic clinical handover tool was developed and implemented. However, site uptake of the tool varied from 45 to 90%. Aim To determine the facilitators and barriers of the ED to Ward Handover Tool (EDWHAT) implementation and design strategy to improve local compliance and inform wider implementation. Methods An exploratory convergent mixed-method approach was used. Data were collected via a 13-item electronic survey informed by the Theoretical Domains Framework (TDF) distributed to eligible nurses across the health district. Descriptive statistics for quantitative data and thematic analysis for qualitative data were conducted. The data were then integrated and mapped to the TDF and the Behaviour Change Wheel to identify specific behaviour change techniques to support implementation. Results There were 300 respondents. The majority of nurses knew where to locate the tool (91.26%), but 45.79% felt that it was not adequate to ensure safe handover. The most frequently reported factors that hindered nurses from using the tool were inability to access a phone near a computer (44.32%) (environmental domain), being told to transfer the patient before being able to complete the form (39.93%) (reinforcement) and the other nurse receiving (or giving) the handover not using the form (38.83%) (social influence). An implementation checklist to identify barriers and solutions to future uptake was developed. Conclusion To improve uptake, the functionality, content, and flow of the handover tool must be revised, alongside environmental restructuring. Nurses would benefit from an awareness of each speciality’s needs to develop a shared mental model and monitoring, and enforcement of tool use should become part of a routine audit.

Abstract Background Internationally, there has been renewed focus on primary healthcare (PHC). PHC revitalisation is one of the mechanisms to emphasise health promotion and prevention. However, it is not always clear who should lead health promotion activities. In some countries, health promotion practitioners provide health promotion; in others, community health workers (CHWs) are responsible. South Africa, like other countries, has embarked on reforms to strengthen PHC, including a nationwide CHW programme – resulting in an unclear role for pre-existing health promoters. This paper examined the tension between these two cadres in two South African provinces in an era of primary health reform. Methodology We used a qualitative case study approach. Participants were recruited from the national, provincial, district and facility levels of the health system. Thirty-seven face-to-face in-depth interviews were conducted with 16 health promotion managers, 12 health promoters and 13 facility managers during a 3-month period (November 2017 to February 2018). Interviews were audio-recorded and transcribed verbatim. Both inductive and deductive thematic content analysis approaches were used, supported by MAXQDA software. Results Two South African policy documents, one on PHC reform and the other on health promotion, were introduced and implemented without clear guidelines on how health promoter job descriptions should be altered in the context of CHWs. The introduction of CHWs triggered anxiety and uncertainty among some health promoters. However, despite considerable role overlap and the absence of formal re-orientation processes to re-align their roles, some health promoters have carved out a role for themselves, supporting CHWs (for example, providing up-to-date health information, jointly discussing how to assist with health problems in the community, providing advice and household-visit support). Conclusions This paper adds to recent literature on the current wave of PHC reforms. It describes how health promoters are ‘working it out’ on the ground, when the policy or process do not provide adequate guidance or structure. Lessons learnt on how these two cadres could work together are important, especially given the shortage of human resources for health in low- and middle-income settings. This is a missed opportunity, researchers and policy-makers need to think more about how to feed experience/tacit knowledge up the system.

Abstract Background The Patient Activation Measure (PAM-13) was developed using Rasch analysis to assess knowledge, skills and confidence in the management of one’s health. Previous studies report positive relationships between PAM-13 scores, self-management behaviours and longitudinal health outcomes in adults with chronic disease. There is little extant measurement property evidence for the use of PAM-13 in specific osteoarthritis (OA) populations. This study tested measurement properties of the PAM-13 in people living with hip and knee OA. Methods Item response frequency analysis was conducted. Rasch analysis evaluated the fit of the PAM-13 data to the Rasch model. Model-data fit was evaluated using infit and outfit statistics; person/item reliability and person separation indices were computed. Unidimensionality was evaluated using Principal Components Analysis of Rasch residuals and the data were assessed for item redundancy. Differential Item Functioning (DIF) examined bias in respondent subgroups and correlations tested relationships between PAM-13 and other patient-reported outcomes. Results Two-hundred-and-seventeen PAM-13 surveys were completed; there were no missing responses, floor or ceiling effects. Person and item reliability were acceptable (0.98 and 0.87 respectively) with good separation (person separation index 2.58). Unidimensionality was evaluated, with 49.4% of the variance explained by the first eigenvector. There was evidence of potential local response-dependence. The Rasch fit statistics were acceptable (except for item-2). There were some issues identified with targeting of the PAM-13 items to people with higher ability and the item difficulty order was different to that proposed in original cohorts. Significant DIF was identified for sex and educational level for a small number of items. PAM-13 scores were moderately correlated with depressive symptoms on the Depression Anxiety Stress Scale and Assessment of Quality of Life-6D. There were small correlations between PAM-13 and Knee injury and Osteoarthritis Outcome Score pain and activities of daily living scores. Conclusions This study provides some evidence of adequate person and item reliability, unidimensionality, and construct validity to support the use of PAM-13 to measure patient activation in people living with hip and knee OA. Possible limitations regarding targeting, different item difficulty order, DIF and local response dependence should be investigated in future research.

Vitamin D is a precursor of the steroid hormone 1,25-dihydroxyvitamin D3, and its deficiency is associated with many adverse health outcomes. Here, Revez et al. perform a genome-wide association study for circulating 25-hydroxyvitamin D in 417,580 individuals and test for potential causal relationships with other traits using Mendelian randomization.

The status of metabolomics as a scientific branch has evolved from proof-of-concept to applications in science, particularly in medical research. To comprehensively evaluate disease metabolomics, multiplatform approaches of NMR combining with mass spectrometry (MS) have been investigated and reported. This mixed-methods approach allows for the exploitation of each individual technique’s unique advantages to maximize results. In this article, we present our findings from combined NMR and MS imaging (MSI) analysis of human lung and prostate cancers. We further provide critical discussions of the current status of NMR and MS combined human prostate and lung cancer metabolomics studies to emphasize the enhanced metabolomics ability of the multiplatform approach.

Degradation by the 26 S proteasome is an intricately regulated process fine tuned by the precise nature of ubiquitin modifications attached to a protein substrate. By debranching ubiquitin chains composed of K48 linkages, the proteasome-associated ubiquitin C-terminal hydrolase UCHL5/UCH37 serves as a positive regulator of protein degradation. How UCH37 achieves specificity for K48 chains is unclear. Here, we use a combination of hydrogen-deuterium mass spectrometry, chemical crosslinking, small-angle X-ray scattering, nuclear magnetic resonance (NMR), molecular docking, and targeted mutagenesis to uncover a cryptic K48 ubiquitin (Ub) chain-specific binding site on the opposite face of UCH37 relative to the canonical S1 (cS1) ubiquitin-binding site. Biochemical assays demonstrate the K48 chain-specific binding site is required for chain debranching and proteasome-mediated degradation of proteins modified with branched chains. Using quantitative proteomics, translation shutoff experiments, and linkage-specific affinity tools, we then identify specific proteins whose degradation depends on the debranching activity of UCH37. Our findings suggest that UCH37 and potentially other DUBs could use more than one S1 site to perform different biochemical functions.

Objectives The main objective of the study was to develop more accurate and precise short-term forecasting models for admissions and bed occupancy for an NHS Trust located in Bristol, England. Subforecasts for the medical and surgical specialties, and for different lengths of stay were realisedDesign Autoregressive integrated moving average models were specified on a training dataset of daily count data, then tested on a 6-week forecast horizon. Explanatory variables were included in the models: day of the week, holiday days, lagged temperature and precipitation.Setting A secondary care hospital in an NHS Trust in South West England.Participants Hospital admissions between September 2016 and March 2020, comprising 1291 days.Primary and secondary outcome measures The accuracy of the forecasts was assessed through standard measures, as well as compared with the actual data using accuracy thresholds of 10% and 20% of the mean number of admissions or occupied beds.Results The overall Autoregressive Integrated Moving Average (ARIMA) admissions forecast was compared with the Trust’s forecast, and found to be more accurate, namely, being closer to the actual value 95.6% of the time. Furthermore, it was more precise than the Trust’s. The subforecasts, as well as those for bed occupancy, tended to be less accurate compared with the overall forecasts. All of the explanatory variables improved the forecasts.Conclusions ARIMA models can forecast non-elective admissions in an NHS Trust accurately on a 6-week horizon, which is an improvement on the current predictive modelling in the Trust. These models can be readily applied to other contexts, improving patient flow.

The “Joint Effort Initiative” (JEI) is an international consortium of clinicians, researchers, and consumers under the auspices of the Osteoarthritis Research Society International (OARSI). The JEI was formed with a vision to improve the implementation of coordinated programs of best evidence osteoarthritis care globally. To better understand some of the issues around osteoarthritis care in low- and middle-income countries (LMICs), the JEI invited clinician researcher representatives from South Africa, Brazil, and Nepal to discuss their perspectives on challenges and opportunities to implementing best-evidence osteoarthritis care at the OARSI World Pre-Congress Workshop. We summarize and discuss the main themes of the presentations in this paper. The challenges to implementing evidence-based osteoarthritis care identified in LMICs include health inequities, unaffordability of osteoarthritis management and the failure to recognize osteoarthritis as an important disease. Fragmented healthcare services and a lack of health professional knowledge and skills are also important factors affecting osteoarthritis care in LMICs. We discuss considerations for developing strategies to improve osteoarthritis care in LMICs. Existing opportunities may be leveraged to facilitate the implementation of best-evidence osteoarthritis care. We also discuss strategies to support the implementation, such as the provision of high-quality healthcare professional and consumer education, and systemic healthcare reforms.

BackgroundOsteoarthritis (OA) is a major problem globally. First-line management comprises education and self-management strategies. Online support groups may be a low-cost method of facilitating self-management. ObjectiveThe aim of this randomized controlled pilot study is to evaluate the feasibility of the study design and implementation of an evidence-informed, expert-moderated, peer-to-peer online support group (My Knee Community) for people with knee OA. The impacts on psychological determinants of self-management, selected self-management behaviors, and health outcomes were secondary investigations. MethodsThis mixed methods study evaluated study feasibility (participant recruitment, retention, and costs), experimental intervention feasibility (acceptability and fidelity to the proposed design, including perceived benefit, satisfaction, and member engagement), psychological determinants (eg, self-efficacy and social support), behavioral measures, health outcomes, and harms. Of a total of 186, 63 (33.9%) participants (41/63, 65% experimental and 22/63, 35% control) with self-reported knee OA were recruited from 186 volunteers. Experimental group participants were provided membership to My Knee Community, which already had existing nonstudy members, and were recommended a web-based education resource (My Joint Pain). The control group received the My Joint Pain website recommendation only. Participants were not blinded to their group allocation or the study interventions. Participant-reported data were collected remotely using web-based questionnaires. A total of 10 experimental group participants also participated in semistructured interviews. The transcribed interview data and all forum posts by the study participants were thematically analyzed. ResultsStudy feasibility was supported by acceptable levels of retention; however, there were low levels of engagement with the support group by participants: 15% (6/41) of participants did not log in at all; the median number of times visited was 4 times per participant; only 29% (12/41) of participants posted, and there were relatively low levels of activity overall on the forum. This affected the results for satisfaction (overall mean 5.9/10, SD 2.7) and perceived benefit (17/31, 55%: yes). There were no differences among groups for quantitative outcomes. The themes discussed in the interviews were connections and support, information and advice, and barriers and facilitators. Qualitative data suggest that there is potential for people to derive benefit from connecting with others with knee OA by receiving support and assisting with unmet informational needs. ConclusionsAlthough a large-scale study is feasible, the intervention implementation was considered unsatisfactory because of low levels of activity and engagement by members. We recommend that expectations about the support group need to be made clear from the outset. Additionally, the platform design needs to be more engaging and rewarding, and membership should only be offered to people willing to share their personal stories and who are interested in learning from the experiences of others. Trial RegistrationAustralian New Zealand Clinical Trials Registry ACTRN12619001230145; http://anzctr.org.au/Trial/Registration/TrialReview.aspx?id=377958

There is widespread concern over the potential impact of the COVID-19 pandemic on suicide and self-harm globally, particularly in low- and middle-income countries (LMIC) where the burden of these behaviours is greatest. We synthesised the evidence from the published literature on the impact of the pandemic on suicide and self-harm in LMIC. This review is nested within a living systematic review (PROSPERO ID CRD42020183326) that continuously identifies published evidence (all languages) through a comprehensive automated search of multiple databases (PubMed; Scopus; medRxiv, PsyArXiv; SocArXiv; bioRxiv; the WHO COVID-19 database; and the COVID-19 Open Research Dataset by Semantic Scholar (up to 11/2020), including data from Microsoft Academic, Elsevier, arXiv and PubMed Central.) All articles identified by the 4th August 2021 were screened. Papers reporting on data from a LMIC and presenting evidence on the impact of the pandemic on suicide or self-harm were included. Methodological quality was assessed using an appropriate tool, and a narrative synthesis presented. A total of 22 studies from LMIC were identified representing data from 12 countries. There was an absence of data from Africa, the Pacific, and the Caribbean. The reviewed studies mostly report on the early months of COVID-19 and were generally methodologically poor. Few studies directly assessed the impact of the pandemic. The most robust evidence, from time-series studies, indicate either a reduction or no change in suicide and self-harm behaviour. As LMIC continue to experience repeated waves of the virus and increased associated mortality, against a backdrop of vaccine inaccessibility and limited welfare support, continued efforts are needed to track the indirect impact of the pandemic on suicide and self-harm in these countries.

Fast foods contribute to excessive intake of sodium in New Zealand (~3373–3544 mg/day). High sodium consumption is associated with hypertension, a leading risk factor of cardiovascular disease. Our objectives were to (1) estimate sodium reduction targets for New Zealand (NZ) fast-food products and to (2) investigate the potential acceptability of sodium reduction targets, including barriers and facilitators to implementation, and potential methods for execution and monitoring. Sodium contents and serving size of fast-food products were sourced from a 2019 fast food database (Nutritrack). A step-by-step process was used to create food categories and develop sodium targets that are currently met by 35–45% of products. Semi-structured interviews were held with 12 expert stakeholders who work within public health, government agencies, and food science via videoconferencing. Sodium reduction targets per 100 g and per serving were estimated for 17 fast-food categories. The targets ranged from 158 mg (salads) to 665 mg per 100 g (mayonnaise and dressings). On a per serving basis, the targets ranged from 118 mg (sauce) to 1270 mg (burgers with cured meat). The experts agreed that sodium reduction targets for NZ fast foods are needed and acceptable. Barriers to implementation include unequal participation by industry and limited data for monitoring. A voluntary approach led by cross-government collaboration, along with mandating if there is limited uptake, and a robust monitoring system were deemed to be important for implementation. The sodium reduction targets estimated for NZ fast foods were supported by the non-industry stakeholders. While further review and consultation with the industry may be necessary, the newly estimated targets provide a platform for one aspect of a much-needed government-led sodium reformulation programme for NZ, which should also include targets for packaged foods and consumer awareness.

In children, diets high in sodium and low in potassium lead to increased blood pressure and risk of cardiovascular disease later in life. This study aimed to describe the major packaged food sources of sodium for New Zealand children aged 5 to 14 years and explored changes in the sodium content of these foods. Descriptive secondary analysis of 24 h dietary recall data from the 2002 National Children Nutrition Survey was undertaken to identify the major sources of sodium for children, and linear regression using Nutritrack data was used to assess changes in the sodium content of these foods from 2013 to 2019. For all NZ children, the major packaged food sources of sodium were white bread (contributing 23.1% to sodium intake),sausages (4.2%), ham (4.0%), canned spaghetti (3.5%) and wholemeal bread (3.2%). The results were comparable when analysed by gender, although boys attained more sodium from wholemeal bread and canned baked beans than girls (3.8% vs. 2.3% and 3.9% vs 1.8%, respectively). By age, white bread was the top contributor to sodium intake (25.6% for children aged 5–6 years and 22.6% for children aged 7–10 years and 11–14 years). Differences by ethnicity show that white bread made sodium contributions of 27.2% for Māori, 32.5% for Pacific and 20.6% for New Zealand European and others (NZEO). Sodium obtained from noodles was also higher among Māori and Pacific children (3.3% and 4.7%, respectively) than NZEO children (2.3%) as was sodium attained from extruded snacks and other crisps (Māori 2.0%, 2.5% Pacific and 0.9% NZEO). From 2013 to 2019, a significant decrease of 0.2 mg/100 g (95% CI: −70.2, −13.5) was found in the sodium content of white bread and whole hams and similar products (−0.4 mg/100 g, 95% CI: −636.2, −151.0) but an increase in the sodium content of noodles (0.2 mg/100 g, CI: 197.7, 703.2) over the same period of time. Understanding the major contributing packaged food sources of sodium and potassium for diverse New Zealand children is essential in protecting against future risk of cardiovascular disease and impetus for future public health initiatives aimed at reducing sodium intake.

For potato crops, host resistance is currently the most effective and sustainable tool to manage diseases caused by the plasmodiophorid Spongospora subterranea. Arguably, zoospore root attachment is the most critical phase of infection; however, the underlying mechanisms remain unknown. This study investigated the potential role of root-surface cell-wall polysaccharides and proteins in cultivars resistant/susceptible to zoospore attachment. We first compared the effects of enzymatic removal of root cell-wall proteins, N-linked glycans and polysaccharides on S. subterranea attachment. Subsequent analysis of peptides released by trypsin shaving (TS) of root segments identified 262 proteins that were differentially abundant between cultivars. These were enriched in root-surface-derived peptides but also included intracellular proteins, e.g., proteins associated with glutathione metabolism and lignin biosynthesis, which were more abundant in the resistant cultivar. Comparison with whole-root proteomic analysis of the same cultivars identified 226 proteins specific to the TS dataset, of which 188 were significantly different. Among these, the pathogen-defence-related cell-wall protein stem 28 kDa glycoprotein and two major latex proteins were significantly less abundant in the resistant cultivar. A further major latex protein was reduced in the resistant cultivar in both the TS and whole-root datasets. In contrast, three glutathione S-transferase proteins were more abundant in the resistant cultivar (TS-specific), while the protein glucan endo-1,3-beta-glucosidase was increased in both datasets. These results imply a particular role for major latex proteins and glucan endo-1,3-beta-glucosidase in regulating zoospore binding to potato roots and susceptibility to S. subterranea.