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Patient and Public Involvement (PPI) and Responsible Research and Innovation (RRI) approaches in mental health projects involving young people: a scoping review protocol
Background: Rather than being perceived as merely ‘part of the problem’, the perspectives and experiences of young people play a pivotal role in devising effective solutions for mental health challenges. Two distinct methodologies that aid in this endeavour are ‘patient and public involvement’ (PPI) and ‘responsible research and innovation’ (RRI). However, there is a tendency to conflate PPI and RRI practices, leading to ambiguity in their application. Moreover, the extent and nature of young people’s involvement in mental health-related projects (namely: research, intervention, product development) employing these methodologies, and the subsequent implications thereof, remain unclear. Consequently, the proposed scoping review aims to identify and analyse literature pertaining to PPI and RRI approaches in mental health projects that engage young people in collaboration. Methods: The selected databases will be MEDLINE, PsycINFO, PsycArticles, Scopus, Web of Science, IBBS, CINAHL (EBSCO) and ASSIA. Comprehensive searches will span from the inception of each database. A pilot test will be conducted to assess the screening criteria and data extraction form, with two authors independently reviewing titles and abstracts. Full-text articles meeting the inclusion criteria will undergo narrative syntheses, with results presented in tabular format. Feedback on the findings from a youth perspective will be sought from young people within our broader research network, namely Sprouting Minds. The review will adhere to the guidelines outlined by the Joanna Briggs Institute (JBI) and follow the PRISMA-ScR procedures. Inclusion criteria will comprise English-language, primary research peer-reviewed articles focused on Patient and Public Involvement (PPI) or Responsible Research and Innovation (RRI), examining mental health-related research processes, interventions, and products developed in collaboration with young people. Studies employing quantitative, qualitative, and mixed-methods approaches will be considered, while non-journal publications will be excluded. Discussion: The intended scoping review aims to map the literature concerning mental health-related projects that engage with young people through PPI or RRI approaches. The outcomes hold promise for enriching the participatory research domain, particularly in studies centred on young people and their mental well-being. Furthermore, by delineating potential overlaps and distinctions between PPI and RRI, the findings stand to aid mental health researchers and practitioners in making informed decisions about the most suitable approach for their projects when partnering with young individuals. Systematic review registration: Open Science Framework (registration: DOI https://doi.org/10.17605/OSF.IO/N4EDB).
Clinical value of cell-based assays in the characterisation of seronegative myasthenia gravis.
OBJECTIVE: Patients with myasthenia gravis without acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) antibodies detected by radioimmunoprecipitation assays (RIAs) are classified as seronegative myasthenia gravis (SNMG). Live cell-based assays (l-CBAs) can detect additional antibodies to clustered AChR, MuSK and low-density lipoprotein receptor-related protein 4 (LRP4), but positivity rates are variable and both clinical relevance and utility of CBA platforms remain unclear. METHODS: Sera from 82 patients with SNMG were tested by l-CBAs. Human embryonic kidney cells were transfected to individually express clustered AChR, MuSK or LRP4; or transfected to jointly express both clustered adult AChR and MuSK. Sera from 30 and 20 patients positive by RIA for AChR or MuSK antibodies were used as comparators. RESULTS: 53 of 82 (72%) patients with SNMG had generalised and 29 (28%) had ocular disease. The clustered AChR CBA detected antibodies in 16 of 82 patients (19.5%; including 4 patients with solely fetal AChR antibodies), while 7 of 82 (8.5%) patients had MuSK antibodies. A novel exploratory combined adult AChR-MuSK l-CBA efficiently detected all these antibodies in a subset of the SNMG cohort. No LRP4 antibodies were identified. Overall, patients with SNMG with clustered AChR antibodies, CBA-positive MuSK-MG or triple seronegative were younger, had less severe disease than patients with RIA-positive MG and had a better clinical outcome when immunotherapy was started soon after disease onset, although the time interval from onset to immunotherapy was not different when compared with patients with RIA-positive MG. CONCLUSION: Around one-third of patients with SNMG had AChR or MuSK antibodies by l-CBAs, which were efficiently detected with a combined l-CBA. The results in this large and unselected cohort of patients with MG demonstrate the diagnostic usefulness of performing CBAs and the importance of making these tests more widely available.
The Pandemic EVIDENCE Collaboration Pillar 1: diagnostics and transmission
The COVID-19 pandemic starkly revealed a lack of high-quality evidence for non-pharmacological interventions (NPIs). The evidence produced to support the optimal deployment of NPIs to reduce transmission of SARS-CoV-2 was often of poor quality, and decisions were made without considering the wealth of previous research on respiratory virus transmission from human challenge studies. Respiratory virus infections cause illnesses varying from the “common cold” to invasive pneumonitis with multisystem involvement with severity dependent on the host-virus-immune response interaction. Despite the learnings from the recent pandemic, significant gaps remain in our understanding of the diagnosis of acute respiratory viral infections and their sequelae, the modes of transmission, and how to effectively synthesise the existing evidence from the past 70 years of research on respiratory viruses. It is crucial to examine further the evidence on how common respiratory viral agents are transmitted. The transmission dynamics to allow for a replication-competent virus to move from a reservoir to a susceptible host and establish an invasive infection is complex and it is likely multiple modes of transmission exist from direct reservoir-to-host (contact, droplet deposition, transplacental) and indirect reservoir-to-intermediary-to- host (vehicle-borne, foodborne, waterborne, and airborne) routes. To enhance our understanding of both diagnostics and transmission, we need to characterise viral entry and attachment, viral load dynamics, duration of virus infectivity both inside and outside the host, duration of viral nucleic acid shedding using molecular testing, the role of whole genome sequencing, and factors that may affect the duration of infectivity and transmission. There are still uncertainties surrounding current testing strategies and their connection to NPIs, as well as fundamental issues such as the accuracy of symptom reporting during acute respiratory infections. The importance of animal-to-animal, human-to-animal and human-to-human challenge studies in expanding our knowledge of the transmission of respiratory viruses cannot be overstated.
Cancer inequalities in the United Kingdom and the data used to measure them: a scoping review.
Significant cancer inequalities may exist across the United Kingdom (UK). Data are required to delineate and quantify these inequalities. This scoping review was undertaken to map the research evidence on UK cancer inequalities and determine the current data available, and the data gaps, that, if filled, could inform a strategy to reduce them. 444 studies were included. Their distribution across inequality domains, care pathways and cancer sites was uneven. The majority of studies were based on administrative datasets, notably cancer registry data, with a wide-range of methods used to define inequality groups. No UK-wide population-based evidence was identified. The landscape of data available in the UK to study cancer inequalities is uneven. Although there is a large volume of evidence available, there remain major gaps in both the data available and the knowledge base they are deployed to generate. This deficit needs to be addressed as a matter of urgency.
Selective advantage of mutant stem cells in human clonal hematopoiesis is associated with attenuated response to inflammation and aging.
Clonal hematopoiesis (CH) arises when hematopoietic stem cells (HSCs) acquire mutations, most frequently in the DNMT3A and TET2 genes, conferring a competitive advantage through mechanisms that remain unclear. To gain insight into how CH mutations enable gradual clonal expansion, we used single-cell multi-omics with high-fidelity genotyping on human CH bone marrow (BM) samples. Most of the selective advantage of mutant cells occurs within HSCs. DNMT3A- and TET2-mutant clones expand further in early progenitors, while TET2 mutations accelerate myeloid maturation in a dose-dependent manner. Unexpectedly, both mutant and non-mutant HSCs from CH samples are enriched for inflammatory and aging transcriptomic signatures, compared with HSCs from non-CH samples, revealing a non-cell-autonomous effect. However, DNMT3A- and TET2-mutant HSCs have an attenuated inflammatory response relative to wild-type HSCs within the same sample. Our data support a model whereby CH clones are gradually selected because they are resistant to the deleterious impact of inflammation and aging.
Years of life lost to COVID-19 in 81 countries.
Understanding the mortality impact of COVID-19 requires not only counting the dead, but analyzing how premature the deaths are. We calculate years of life lost (YLL) across 81 countries due to COVID-19 attributable deaths, and also conduct an analysis based on estimated excess deaths. We find that over 20.5 million years of life have been lost to COVID-19 globally. As of January 6, 2021, YLL in heavily affected countries are 2-9 times the average seasonal influenza; three quarters of the YLL result from deaths in ages below 75 and almost a third from deaths below 55; and men have lost 45% more life years than women. The results confirm the large mortality impact of COVID-19 among the elderly. They also call for heightened awareness in devising policies that protect vulnerable demographics losing the largest number of life-years.
Cardiac output-guided haemodynamic therapy for patients undergoing major gastrointestinal surgery: OPTIMISE II randomised clinical trial.
OBJECTIVES: To evaluate the clinical effectiveness and safety of a perioperative algorithm for cardiac output-guided haemodynamic therapy in patients undergoing major gastrointestinal surgery. DESIGN: Multicentre randomised controlled trial. SETTING: Surgical services of 55 hospitals worldwide. PARTICIPANTS: 2498 adults aged ≥65 years with an American Society of Anesthesiologists physical status classification of II or greater and undergoing major elective gastrointestinal surgery, recruited between January 2017 and September 2022. INTERVENTIONS: Participants were assigned to minimally invasive cardiac output-guided intravenous fluid therapy with low dose inotrope infusion during and four hours after surgery, or to usual care without cardiac output monitoring. MAIN OUTCOME MEASURES: The primary outcome was postoperative infection within 30 days of randomisation. Safety outcomes were acute cardiac events within 24 hours and 30 days. Secondary outcomes were acute kidney injury within 30 days and mortality within 180 days. RESULTS: In 2498 patients (mean age 74 (standard deviation 6) years, 57% women), the primary outcome occurred in 289/1247 (23.2%) intervention patients and 283/1247 (22.7%) usual care patients (adjusted odds ratio 1.03 (95% confidence interval 0.84 to 1.25); P=0.81). Acute cardiac events within 24 hours occurred in 38/1250 (3.0%) intervention patients and 21/1247 (1.7%) usual care patients (adjusted odds ratio 1.82 (1.06 to 3.13); P=0.03). This difference was primarily due to an increased incidence of arrhythmias among intervention patients. Acute cardiac events within 30 days occurred in 85/1249 (6.8%) intervention patients and 79/1247 (6.3%) usual care patients (adjusted odds ratio 1.06 (0.77 to 1.47); P=0.71). Other secondary outcomes did not differ. CONCLUSIONS: This clinical effectiveness trial in patients undergoing major elective gastrointestinal surgery did not provide evidence that cardiac output-guided intravenous fluid therapy with low dose inotrope infusion could reduce the incidence of postoperative infections. The intervention was associated with an increased incidence of acute cardiac events within 24 hours, in particular tachyarrhythmias. Based on these findings, the routine use of this treatment approach in unselected patients is not recommended. TRIAL REGISTRATION: ISRCTN Registry ISRCTN39653756.
Acceptability of improved cook stoves-a scoping review of the literature.
Improved cooking stoves (ICS) are intended to reduce indoor air pollution and the inefficient use of fuel yet there is often reticence to shift permanently to ICS. Drawing on a scoping review, this article aims to provide a comprehensive overview of factors affecting the acceptability of ICS. A scoping review was carried out using a systematic search strategy of literature. All articles identified in three major databases that included Pubmed/Medline, Scopus and Web of Science underwent screening followed by content analysis to generate major and minor themes using a structured social level analysis. The analysis identified factors at micro, meso, and macro-social levels that potentially contribute to an adoption of an improved cooking stove (ICS). The findings from the review were discussed and refined among a group of experts identified based on their prior academic or commercial contributions related to ICS. Adoption of ICS was dependent on functional outputs (e.g. cleanliness, and cooking efficiency) while meeting local social and cultural demands (e.g. cooking large meals, traditional meals, and taste). Health and cost benefits played an important role in the adoption and sustained use of ICS. The adoption of ICS was enabled by use among neighbors and other community members. Sustained use of ICS depended on fuel supply, fuel security and policies promoting its use. Policies offering subsidies in support of supply-chain garnered institutional trust among community members and resulted in the sustained use of ICS. In addition to design attributes of ICS that could meet both scientific and social demands, policies supporting promotion of clean energy, subsidies and supplies can substantially enhance the adoption of ICS.
Positive-strand RNA virus replication organelles at a glance.
Membrane-bound replication organelles (ROs) are a unifying feature among diverse positive-strand RNA viruses. These compartments, formed as alterations of various host organelles, provide a protective niche for viral genome replication. Some ROs are characterised by a membrane-spanning pore formed by viral proteins. The RO membrane separates the interior from immune sensors in the cytoplasm. Recent advances in imaging techniques have revealed striking diversity in RO morphology and origin across virus families. Nevertheless, ROs share core features such as interactions with host proteins for their biogenesis and for lipid and energy transfer. The restructuring of host membranes for RO biogenesis and maintenance requires coordinated action of viral and host factors, including membrane-bending proteins, lipid-modifying enzymes and tethers for interorganellar contacts. In this Cell Science at a Glance article and the accompanying poster, we highlight ROs as a universal feature of positive-strand RNA viruses reliant on virus-host interplay, and we discuss ROs in the context of extensive research focusing on their potential as promising targets for antiviral therapies and their role as models for understanding fundamental principles of cell biology.
ARF4-mediated intracellular transport as a broad-spectrum antiviral target.
Host factors that are involved in modulating cellular vesicular trafficking of virus progeny could be potential antiviral drug targets. ADP-ribosylation factors (ARFs) are GTPases that regulate intracellular vesicular transport upon GTP binding. Here we demonstrate that genetic depletion of ARF4 suppresses viral infection by multiple pathogenic RNA viruses including Zika virus (ZIKV), influenza A virus (IAV) and SARS-CoV-2. Viral infection leads to ARF4 activation and virus production is rescued upon complementation with active ARF4, but not with inactive mutants. Mechanistically, ARF4 deletion disrupts translocation of virus progeny into the Golgi complex and redirects them for lysosomal degradation, thereby blocking virus release. More importantly, peptides targeting ARF4 show therapeutic efficacy against ZIKV and IAV challenge in mice by inhibiting ARF4 activation. Our findings highlight the role of ARF4 during viral infection and its potential as a broad-spectrum antiviral target for further development.
Ancient genomic linkage of α-globin and Nprl3 couples metabolism with erythropoiesis.
Red blood cell development from erythroid progenitors requires profound reshaping of metabolism and gene expression. How these transcriptional and metabolic alterations are coupled is unclear. Nprl3 (an inhibitor of mTORC1) has remained in synteny with the α-globin genes for >500 million years, and harbours most of the a-globin enhancers. However, whether Nprl3 serves an erythroid role is unknown. We found that while haematopoietic progenitors require basal Nprl3 expression, erythroid Nprl3 expression is further boosted by the α-globin enhancers. This lineage-specific upregulation is required for sufficient erythropoiesis. Loss of Nprl3 affects erythroblast metabolism via elevating mTORC1 signalling, suppressing autophagy and disrupting glycolysis. Broadly consistent with these murine findings, human NPRL3-knockout erythroid progenitors produce fewer enucleated cells and demonstrate dysregulated mTORC1 signalling in response to nutrient availability and erythropoietin. Therefore, we propose that the anciently conserved linkage of NprI3, α-globin and their associated enhancers has coupled metabolic and developmental control of erythropoiesis.
The Double-Edged Sword of Anthropomorphism in LLMs †.
Humans may have evolved to be "hyperactive agency detectors". Upon hearing a rustle in a pile of leaves, it would be safer to assume that an agent, like a lion, hides beneath (even if there may ultimately be nothing there). Can this evolutionary cognitive mechanism-and related mechanisms of anthropomorphism-explain some of people's contemporary experience with using chatbots (e.g., ChatGPT, Gemini)? In this paper, we sketch how such mechanisms may engender the seemingly irresistible anthropomorphism of large language-based chatbots. We then explore the implications of this within the educational context. Specifically, we argue that people's tendency to perceive a "mind in the machine" is a double-edged sword for educational progress: Though anthropomorphism can facilitate motivation and learning, it may also lead students to trust-and potentially over-trust-content generated by chatbots. To be sure, students do seem to recognize that LLM-generated content may, at times, be inaccurate. We argue, however, that the rise of anthropomorphism towards chatbots will only serve to further camouflage these inaccuracies. We close by considering how research can turn towards aiding students in becoming digitally literate-avoiding the pitfalls caused by perceiving agency and humanlike mental states in chatbots.
A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape in >170,000 individuals of the GIANT Consortium
Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analyzed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
Leveraging cross-species transcription factor binding site patterns: from diabetes risk loci to disease mechanisms.
Genome-wide association studies have revealed numerous risk loci associated with diverse diseases. However, identification of disease-causing variants within association loci remains a major challenge. Divergence in gene expression due to cis-regulatory variants in noncoding regions is central to disease susceptibility. We show that integrative computational analysis of phylogenetic conservation with a complexity assessment of co-occurring transcription factor binding sites (TFBS) can identify cis-regulatory variants and elucidate their mechanistic role in disease. Analysis of established type 2 diabetes risk loci revealed a striking clustering of distinct homeobox TFBS. We identified the PRRX1 homeobox factor as a repressor of PPARG2 expression in adipose cells and demonstrate its adverse effect on lipid metabolism and systemic insulin sensitivity, dependent on the rs4684847 risk allele that triggers PRRX1 binding. Thus, cross-species conservation analysis at the level of co-occurring TFBS provides a valuable contribution to the translation of genetic association signals to disease-related molecular mechanisms.
Perceptions of a Buruli ulcer controlled human infection model: How, who, and why?
BACKGROUND: Infection with Mycobacterium ulcerans causes slowly progressive skin lesions known as Buruli ulcer (BU). An M. ulcerans controlled human infection model (MuCHIM) is likely to accelerate our understanding of this otherwise neglected disease, and may be an efficient platform for testing vaccines and other interventions. The aim of this study was to understand perceptions of this model across a range of key stakeholders in an endemic Australian community setting. METHODS: We recruited young adults who live near an Australian BU endemic area but without a personal history of BU, clinicians involved in the management of BU, young adults with a personal history of a small, treated BU, and participants of any age with a demonstrated interest in public advocacy related to their personal BU lived experience. Participants reviewed an abridged version of the provisional protocol. A series of three focus groups were then conducted by video, and the transcribed text was analysed using reflexive thematic analysis to generate themes for exploration. RESULTS: Participants universally valued the outcomes that MuCHIM might deliver. The predominant theme was that informed consent required fully transparent communication with potential participants regarding what their participation would involve, how it would impact their lives, and both the expected outcome and 'worst-case scenario'. They also offered actionable recommendations on how best to communicate the tension between the expected outcome and the 'worst-case scenario' of disease associated with delayed diagnosis and comorbidity, as typically portrayed by the media. Participants recommended including images and testimonials from people who have had BU to support the conditions for informed consent. Focus groups also gave a clear sense of who they believed would volunteer for this type of research. CONCLUSIONS: This study offers valuable guidance regarding the content and presentation of information to inform potential participants, with focus group participants suggesting a multimodal approach of communication, including lived experience testimonials and clinical images of the expected outcome. This information will inform development of materials for enrolment to adequately communicate risks and expectations to potential study participants.
Rationale and Ethical Assessment of an Oropharyngeal Gonorrhoea Controlled Human Infection Model.
Infection with Neisseria gonorrhoeae, the causative agent of gonorrhoea, causes significant morbidity worldwide and can have long-term impacts on reproductive health. The greatest global burden of gonorrhoea occurs in low- and middle-income settings. Global public health significance is increasing due to rising antimicrobial resistance (AMR), which threatens future gonorrhoea management. The oropharynx is an important asymptomatic reservoir for gonorrhoea transmission and a high-risk site for development of AMR and treatment failure. Controlled human infection model (CHIM) studies using N. gonorrhoeae may provide a means to accelerate the development of urgently needed therapeutics, vaccines and other biomedical prevention strategies. A gonorrhoea urethritis CHIM has been used since the 1980s with no reported serious adverse events. Here, we describe the rationale for an oropharyngeal gonorrhoea CHIM, including analysis of potential ethical issues that should inform the development of this novel study design.