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Background: The deteriorating mental health of children and young people in the United Kingdom poses a challenge that services and policy makers have found difficult to tackle. Kailo responds to this issue with a community-based participatory and systemically informed strategy, perceiving mental health and well-being as a dynamic state shaped by the interplay of broader health determinants. The initiative works to explore, define and implement locally relevant solutions to challenges shaping the mental health and well-being of young people. Kailo unfolds in three stages within each locale. These stages encompass: "early discovery", "deeper discovery and co-design" and "implementation". This document delves into the participatory group model building and design protocol occurring in the "deeper discovery and co-design" stage of the project., Methods: Participatory methods, such as group model building, are effective in articulating and building consensus on complex issues like the social determinants of adolescent mental health. This paper describes the protocol for application of group model building within the Kailo design process to develop causal loop diagrams and pinpoint leverage points for improving adolescent mental health. It also suggests a method for considering modifications to delivery within a unique project context and in alignment with participants' needs. This paper sets out to define the approach and clarify the objectives these engagements aim to fulfil. The method adapts existing group model building (GMB) protocols for use in a community setting. The engagements will involve groups of local young people and existing community members. To assess the success of the session's implementation post-delivery, the study utilizes existing frameworks for fidelity evaluations, which define a core and flex model., Discussion: The method described enables an integration of diverse local understandings of complex processes which provides a platform for creating co-designed interventions. This protocol can be used to further strengthen research and design through incorporating complexity and participation into the formulation of contextually relevant policies and practices. The strengths and limitations of the approach are discussed., Competing Interests: Declarations. Ethics approval and consent to participate: This study has been ethically approved by the University College London (UCL) Research Ethics Committee (REC), from the 24 March 2023 until 1 September 2024. Project ID/Title: 18773/002: A system approach to improving adolescent mental health—deeper discovery and co-design phase. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Cystic fibrosis (CF) is a life-limiting disorder that is characterised by respiratory tract inflammation that is mediated by a range of microbial pathogens. Small colony variants (SCVs) of common respiratory pathogens are being increasingly recognised in CF. The aim of this systematic review is to investigate the prevalence of SCVs, clinical characteristics and health outcomes for patients with CF, and laboratory diagnostic features of SCVs compared to non-small colony variants (NCVs) for a range of Gram-positive and Gram-negative respiratory pathogens., Methods: A literature search was conducted (PubMed, Web of Science, Embase and Scopus) in April 2020 to identify articles of interest. Data pertaining to demographic characteristics of participants, diagnostic criteria of SCVs, SCV prevalence and impact on lung function were extracted from included studies for analysis., Results: Twenty-five of 673 studies were included in the systematic review. Individuals infected with SCVs of Staphylococcus aureus (S. aureus) were more likely to have had prior use of the broad-spectrum antibiotic trimethoprim sulfamethoxazole (p < 0.001), and the prevalence of SCVs in patients infected with S. aureus was estimated to be 19.3% (95% CI: 13.5% to 25.9%). Additionally, patients infected with SCVs of Gram-negative and Gram-positive pathogens were identified to have a lower forced expiratory volume in one second percentage predicted (-16.8, 95% CI: -23.2 to -10.4) than those infected by NCVs. Gram-positive SCVs were commonly described as small and non-haemolytic, grown on Mannitol salt or blood agar for 24 h at 35°C and confirmed using tube coagulase testing., Conclusion: The findings of this systematic review demonstrate that SCVs of S. aureus have a high prevalence in the CF community, and that the occurrence of SCVs in Gram-positive and Gram-negative pathogens is linked to poorer respiratory function. Further investigation is necessary to determine the effect of infection by SCVs on the CF population., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Patients with cognitive impairment are at greater risk of hospital acquired complications, longer hospital stays, and poor health outcomes compared to patients without cognitive impairment. The Cognitive Impairment Support Program is a multi-disciplinary approach to improve screening rates and awareness of patients with cognitive impairment and guide clinician response and communication during their hospitalisation to improve health outcomes., Objective: This study evaluated the impact of implementing the Cognitive Impairment Support Program on patient hospital acquired complications, patient reported quality of life and staff satisfaction in an outer metropolitan hospital., Design: A pre-test post-test design was used to collect data in two 6-month time periods between March 2020 and November 2021., Participants: Patients aged ≥ 65 years, admitted to a participating ward for > 24 h., Intervention: The Cognitive Impairment Support Program consisted of four components: cognitive impairment screening, initiation of a Cognitive Impairment Care Plan, use of a Cognitive Impairment Identifier and associated staff education., Measures: The primary outcome was hospital acquired complications experienced by patients with cognitive impairment identified using clinical coding data. Secondary outcomes were patient quality of life and a staff confidence and perceived organisational support to care for patients with cognitive impairment., Results: Hospital acquired complication rates did not vary significantly between the two data collection periods for patients experiencing cognitive impairment with a 0.2% (95% confidence interval: -5.7-6.1%) reduction in admissions with at least one hospital acquired complication. Patients in the post intervention period demonstrated statistically significant improvements in many items in two of the Dementia Quality of Life Measure domains: memory and everyday life. The staff survey indicated statistically significant improvement in clinical staff confidence to care for patients with cognitive impairment (p = 0.003), satisfaction with organisational support for patients (p = 0.004) and job satisfaction (p ≤ 0.001)., Conclusion: This study provides evidence that a multicomponent Cognitive Impairment Support Program had a positive impact on staff confidence and satisfaction and patient quality of life. Broader implementation with further evaluation of the multicomponent cognitive impairment intervention across a range of settings using varied patient outcomes is recommended., (© 2023. Crown.)

Background: Effectively bridging the knowledge-policy gap to support the development of evidence-based policies that promote health and well-being remains a challenge for both the research and policy communities. Community-based system dynamics (CBSD) is a participatory modelling approach that aims to build stakeholders' capacity to learn and address complex problems collaboratively. However, limited evidence is available about the contributions of CBSD to knowledge-generating and policy processes across sectors and policy spheres. In the context of a multi-country research project focused on creating an evidence base to inform urban health policies across Latin America, a series of CBSD workshops convened stakeholders from research, policy-making, and other backgrounds working in food and transportation systems. Diverse participants were selected aiming to incorporate multiple perspectives relevant to understanding complex urban systems linked to food and transportation. This study focuses on one of these workshops, whose avenue was São Paulo, Brazil, assembling country-based participants representing local, regional, national, and international institutions with multidisciplinary backgrounds linked to food and transportation systems., Objective: The aim of this case study is to explore the perceived influence of one of these workshops on attendees' understandings of food and transportation systems and their relationship to healthy urban environments, with attention to the role of the workshop in supporting knowledge to policy translation for urban health., Methods: We conducted 18 semi-structured qualitative interviews with attendees one year after their participation in a CBSD workshop held in São Paulo, Brazil. A framework method approach was used to code participants' responses and identify emerging themes., Results: Participants reported that the workshop's group model-building activities influenced their understanding of the knowledge-policy process as it relates to food and transport systems. Workshop contributed to participants' (1) abilities to engage with multisectoral stakeholders, (2) construct a shared language and understanding of urban challenges, (3) improve understanding of the interconnectedness across food and transportation systems, (4) facilitate dialogue across sectors, and (5) apply a systems thinking approach within their sector and professional context. Participants continued to draw on the tools developed during the workshop, and to apply systems thinking to their research and policy-making activities., Conclusions: CBSD may offer valuable opportunities to connect the research sector to the policy-making process. This possibility may contribute to knowledge to policy translation in the interconnection between the urban context, food and transportation systems, and health.

Background: Group model building (GMB) is a method to facilitate shared understanding of structures and relationships that determine system behaviors. This project aimed to determine the feasibility of GMB in a resource-limited setting and to use GMB to describe key barriers and facilitators to effective acute care delivery at a tertiary care hospital in Malawi., Methods: Over 1 week, trained facilitators led three GMB sessions with two groups of healthcare providers to facilitate shared understanding of structures and relationships that determine system behaviors. One group aimed to identify factors that impact patient flow in the paediatric special care ward. The other aimed to identify factors impacting delivery of high-quality care in the paediatric accident and emergency room. Synthesized causal maps of factors influencing patient care were generated, revised, and qualitatively analyzed., Results: Causal maps identified patient condition as the central modifier of acute care delivery. Severe illness and high volume of patients were identified as creating system strain in several domains: (1) physical space, (2) resource needs and utilization, (3) staff capabilities and (4) quality improvement. Stress in these domains results in worsening patient condition and perpetuating negative reinforcing feedback loops. Balancing factors inherent to the current system included (1) parental engagement, (2) provider resilience, (3) ease of communication and (4) patient death. Perceived strengths of the GMB process were representation of diverse stakeholder viewpoints and complex system synthesis in a visual causal pathway, the process inclusivity, development of shared understanding, new idea generation and momentum building. Challenges identified included time required for completion and potential for participant selection bias., Conclusions: GMB facilitated creation of a shared mental model, as a first step in optimizing acute care delivery in a paediatric facility in this resource-limited setting.

Background: Malaria transmission from humans to Anopheles mosquitoes requires the presence of gametocytes in human peripheral circulation, and the dynamics of transmission are determined largely by the density and sex ratio of the gametocytes. Molecular methods are thus employed to measure gametocyte densities, particularly when assessing transmission epidemiology and the efficacy of transmission-blocking interventions. However, accurate quantification of male and female gametocytes with molecular methods requires pure male and female gametocytes as reference standards, which are not widely available., Methods: qRT-PCR assays were used to quantify levels of sex-specific mRNA transcripts in Plasmodium falciparum female and male gametocytes (pfs25 and pfMGET, respectively) using synthetic complimentary RNA standards and in vitro cultured gametocytes. Assays were validated and assay performance was investigated in blood samples of clinical trial participants using these standards and compared to absolute quantification by droplet digital PCR (ddPCR)., Results: The number of transcript copies per gametocyte were determined to be 279.3 (95% CI 253.5-307.6) for the female-specific transcript pfs25, and 12.5 (95% CI 10.6-14.9) for the male-specific transcript pfMGET. These numbers can be used to convert from transcript copies/mL to gametocyte/mL. The reportable range was determined to be 5.71 × 10 6 to 5.71 female gametocytes/mL for pfs25, and 1.73 × 10 7 to 1.73 × 10 1 male gametocytes/mL for pfMGET. The limit of detection was 3.9 (95% CI 2.5-8.2) female gametocytes/mL for pfs25, and 26.9 (95% CI 19.3-51.7) male gametocytes/mL for PfMGET. Both assays showed minimal intra-assay and inter-assay variability with coefficient of variation < 3%. No cross-reactivity was observed in both assays in uninfected human blood samples. Comparison of results from ddPCR to qRT-PCR assays on clinical blood samples indicated a high-level agreement (ICC = 0.998 for pfs25 and 0.995 for pfMGET)., Conclusions: This study reports the validation of qRT-PCR assays that are able to accurately quantify female and male P. falciparum gametocytes at sub-microscopic densities. The assays showed excellent reproducibility, sensitivity, precision, specificity, and accuracy. The methodology will enable the estimation of gametocyte density in the absence of pure female and male gametocyte standards, and will facilitate clinical trials and epidemiological studies.

Background: Excessive gestational weight gain is a modifiable risk factor for the development of obstetric and neonatal complications, and can have a lifelong impact on the health of both mother and offspring. The purpose of this study was to assess whether in addition to standardized medical advice regarding weight gain in pregnancy (including adherence to the Institute of Medicine (IOM) guidelines) (IOM (Institute of Medicine) and NRC (National Research Council, Weight Gain During Pregnancy: Re-examining the guidelines, 2009)), the addition of daily weighing would provide a low cost and simple intervention to reduce excessive weight gain in pregnancy by maintaining weight gain within the target range., Methods: Women presenting for antenatal care to a secondary level hospital were randomised to routine care or daily weight monitoring. Both groups received nutrition and exercise advice., Results: Three hundred and ninety-six women were randomised to either the daily weight monitoring group or control group with complete data available for 326 women. The percentage weight gain above target (86.9% (SD 52.3) v 92.7% (SD 50.8) p = 0.31) and change in weight per week during the study period (0.59 kg (SD 0.30) v 0.63 kg (SD 0.31) p = 0.22) were lesser in those undergoing daily weighing compared to routine management, however these did not reach statistical significance., Conclusion: Daily weight monitoring as a stand-alone intervention has potential to reduce excessive gestational weight gain. It may have a role as a part of a larger intervention involving dietary and exercise modifications., Trial Registration: The trial was prospectively registered with the Australian New Zealand Clinical Trials Registry. (ACTRN12613001165774, 23/10/ 2013).

Background: The 2013 update of the Infection Prevention and Control (IP&C) Guideline outlined recommendations to prevent the spread of CF respiratory pathogens. We aimed to investigate the current infection control practices used in Australian and New Zealand (NZ) CF centers., Methods: Two online surveys were distributed to Australian and NZ CF centers regarding the uptake of selected IP&C recommendations. One survey was distributed to all the Medical Directors and Lead CF Nurses and the second survey was distributed to all the Lead CF Physiotherapists., Results: The response rate was 60% (60/100) for medical/nursing and 58% (14/24) for physiotherapy. Over 90% (55/60) of CF centers followed CF-specific infection control guidelines and consistent infection control practices were seen in most CF centers; 76% (41/54) had implemented segregation strategies for ambulatory care and no CF centers housed people with CF in shared inpatient accommodation. However, the application of contact precautions (wearing gloves and apron/gown) by healthcare professionals when reviewing a CF person was variable between CF center respondents but was most often used when seeing CF persons with MRSA infection in both ambulatory care and hospital admission (20/50, 40% and 42/45, 93% of CF centers, respectively). Mask wearing by people with CF was implemented into 61% (36/59) of centers. Hospital rooms were cleaned daily in 79% (37/47) of CF centers and the ambulatory care consult rooms were always cleaned between consults (49/49, 100%) and at the end of the clinic session (51/51, 100%); however the staff member tasked with cleaning changed with 37% (18/49) of CF centers responding that CF multidisciplinary team (MDT) members cleaned between patients whereas at the end of the clinic session, only 12% (6/51) of the CF MDT cleaned the consult room., Conclusions: Overall, Australian and NZ CF centers have adopted many recommendations from the IP&C. Although, the application of contact precautions was inconsistent and had overall a low level of adoption in CF centers. In ~ 25% of centers, mixed waiting areas occurred in the ambulatory care. Given the variability of responses, additional work is required to achieve greater consistency between centers.

Background: Neoadjuvant immunotherapy targeting immune checkpoint programmed death-1 (PD-1) is under investigation in various tumour settings including non-small-cell lung cancer (NSCLC). Preclinical models demonstrate the superior power of the immunotherapy provided in a neoadjuvant (pre-operative) compared with an adjuvant (post-operative) setting to eradicate metastatic disease and induce long-lasting antigen-specific immunity. Novel effective immunotherapy combinations are widely sought in the oncology field, targeting non-redundant mechanisms of immune evasion. A promising combination partner with anti-PD1 in NSCLC is denosumab, a monoclonal antibody blocking receptor activator of NF-κB ligand (RANKL). In preclinical cancer models and in a large retrospective case series in NSCLC, anti-cancer activity has been reported for the combination of immune checkpoint inhibition (ICI) and denosumab. Furthermore, clinical trials of ICI and denosumab are underway in advanced melanoma and clear-cell renal cell carcinoma. However, the mechanism of action of combination anti-PD1 and anti-RANKL is poorly defined., Methods: This open-label multicentre trial will randomise by minimisation 30 patients with resectable stage IA (primary > 2 cm) to IIIA NSCLC to a neoadjuvant treatment regime of either two doses of nivolumab (3 mg/kg every 2 weeks) or two doses of nivolumab (same regimen) plus denosumab (120 mg every 2 weeks, following nivolumab). Each treatment arm is of equal size and will be approximately balanced with respect to histology (squamous vs. non-squamous) and clinical stage (I-II vs. IIIA). All patients will receive surgery for their tumour 2 weeks after the final dose of neoadjuvant therapy. The primary outcome will be translational research to define the tumour-immune correlates of combination therapy compared with monotherapy. Key secondary outcomes will include a comparison of rates of the following between each arm: toxicity, response (pathological and radiological), and microscopically complete resection., Discussion: The POPCORN study provides a unique platform for translational research to determine the mechanism of action of a novel proposed combination immunotherapy for cancer., Trial Registration: Prospectively registered on Australian New Zealand Clinical Trials Registry (ACTRN12618001121257) on 06/07/2018.

Background: Perinatal depression and/or anxiety disorders are undertreated pregnancy complications. This is partly due to low rates of engagement by women. This study aimed to identify barriers and facilitators to women accessing perinatal mental health services in an outer metropolitan hospital in Queensland, Australia., Methods: Data was collected from pregnant women through a cross-sectional survey. Women rated the extent certain factors influenced their engagement. Respondents were separated into three groups: women who were not offered a referral to perinatal mental health services, women who were offered a referral but did not engage, and women who engaged., Results: A total of 218 women participated. A response rate of 71% was achieved. 38.1% of participants did not believe themselves knowledgeable about mental illness in the perinatal period, and 14.7% did not recall being asked about their mental health during their pregnancy. Of those participants who recalled being asked about their mental health, 37.1% were offered a referral. Of these, just over a third (36.2%) accepted, and out of this group, 40% attended an appointment. Regardless of referral and engagement status, the factors identified as influencing participant engagement were time restraints, lack of childcare support, and encouragement by family and health care professionals. Stigma was not identified as a barrier., Conclusions: Perinatal mental health service engagement could be improved by health services: ensuring universal screening and actively engaging women in the process: assisting with childcare; improving appointment immediacy and accessibility; and educating health care professionals about their influence on women's engagement.

Background: Afghanistan lacks suitable specialized mental healthcare services despite high prevalence of severe mental health disorders which are aggravated by the conflict and numerous daily stressors. Recent studies have shown that Afghans with mental illness are not only deprived of care but are vulnerable in many other ways. Innovative participatory approaches to the design of mental healthcare policies and programs are needed in such challenging context., Methods: We employed community based system dynamics to examine interactions between multiple factors and actors to examine the problem of persistently low service utilization for people with mental illness. Group model building sessions, designed based on a series of scripts and led by three facilitators, took place with NGO staff members in Mazar-I-Sharif in July 2014 and in Kabul in February 2015., Results: We identified major feedback loops that constitute a hypothesis of how system components interact to generate a persistently low rate of service utilization by people with mental illness. In particular, we found that the interaction of the combined burdens of poverty and cost of treatment interact with cultural and social stigmatizing beliefs, in the context of limited clinical or other treatment support, to perpetuate low access to care for people with mental disorders. These findings indicate that the introduction of mental healthcare services alone will not be sufficient to meaningfully improve the condition of individuals with mental illness if community stigma and poverty are not addressed concurrently., Conclusions: Our model highlights important factors that prevent persons with mental illness from accessing services. Our study demonstrates that group model building methods using community based system dynamics can provide an effective tool to elicit a common vision on a complex problem and identify shared potential strategies for intervention in a development and global health context. Its strength and originality is the leadership role played by the actors embedded within the system in describing the complex problem and suggesting interventions.

Background: To learn about the molecular etiology of strabismus, we are studying the genetic basis of 'congenital fibrosis of the extraocular muscles' (CFEOM). These syndromes are characterized by congenital restrictive ophthalmoplegia affecting muscles in the oculomotor and trochlear nerve distribution. Individuals with the classic form of CFEOM are born with bilateral ptosis and infraducted globes. When all affected members of a family have classic CFEOM, we classify the family as a CFEOM1 pedigree. We have previously determined that a CFEOM1 gene maps to the FEOM1 locus on chromosome 12cen. We now identify additional pedigrees with CFEOM1 to determine if the disorder is genetically heterogeneous and, if so, if any affected members of CFEOM1 pedigrees or sporadic cases of classic CFEOM harbor mutations in ARIX, the CFEOM2 disease gene., Results: Eleven new CFEOM1 pedigrees were identified. All demonstrated autosomal dominant inheritance, and nine were consistent with linkage to FEOM1. Two small CFEOM1 families were not linked to FEOM1, and both were consistent with linkage to FEOM3. We screened two CFEOM1 families consistent with linkage to FEOM2 and 5 sporadic individuals with classic CFEOM and did not detect ARIX mutations., Conclusions: The phenotype of two small CFEOM1 families does not map to FEOM1, establishing genetic heterogeneity for this disorder. These two families may harbor mutations in the FEOM3 gene, as their phenotype is consistent with linkage to this locus. Thus far, we have not identified ARIX mutations in any affected members of CFEOM1 pedigrees or in any sporadic cases of classic CFEOM.