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Cryo-EM led analysis of open and closed conformations of Chagas vaccine candidate TcPOP.
Get PDFChagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains a significant global public health concern. Despite its profound health impact in both endemic and non-endemic areas, no vaccine is available, and the existing therapies are outdated, producing severe side effects. The 80 kDa prolyl oligopeptidase of Trypanosoma cruzi (TcPOP) has been identified as a leading candidate for Chagas vaccine development. Here we report the three-dimensional structure of TcPOP in open and closed conformation, at a global resolution of 3.8 and 3.6 Å, respectively, determined using single-particle cryo-electron microscopy. Multiple conformations were observed and further characterized using plasmonic optical tweezers and hydrogen-deuterium exchange mass spectrometry. To assess the immunogenic potential of TcPOP, we immunized female mice and evaluated both polyclonal and monoclonal responses against the TcPOP antigen and its homologues. The anti-TcPOP polyclonal response demonstrates invasion blocking properties via parasite lysis. Polyclonal sera were cross-reactive with closely-related POPs but not with human homologues. Collectively, our findings provide structural and functional insights necessary to understand the immunogenicity of TcPOP for future Chagas vaccine development
Reusable Intermittent Catheters are Acceptable but Product Innovation is Needed: An Interview Study of Catheter Users' Experiences.
Get PDFPURPOSE: The purpose of this study was to explore the experiences of intermittent catheter users after using both reusable and single-use catheters, with a particular focus on factors that affected acceptability.
DESIGN: Qualitative descriptive study following a clinical trial.
PARTICIPANTS AND SETTING: Thirty-six participants who had used both reusable and single-use catheters in a clinical trial were interviewed between June 2022 and March 2024. All were living at home in England or Wales, UK.
METHODS: Participants were invited to interview following one-year's use of a reusable catheter as part of a clinical trial. The reusable catheter was used in combination with their usual single-use catheter. Semi-structured telephone and video interviews were used to enable participants to describe their experiences. Data were analyzed using inductive methods and framework analysis to develop themes and subthemes.
RESULTS: Data analysis identified 4 themes. Successful use of the reusable catheter depended on capacity, confidence and willingness of the individual to adapt. Most people found reuse easier to do at home but there were significant barriers when going out. The design of the catheter used in the trial and the process of reuse did not suit everyone. While there was a desire to continue reuse, this was conditional on the provision of single-use catheters to enable users to mix and match both types in different situations.
CONCLUSIONS: This study presents data from participants who were enthusiastic to try reusable catheters, mainly for environmental reasons, as part of a trial. For most there was a desire to mix and match, combining single use and reusable catheters for different situations. Innovation is needed to create a range of reusable catheter designs and cleaning processes that better meet individual needs
Feasibility and safety of transbronchial lung cryobiopsy and mediastinal lymph node cryobiopsy: Experience from a resource limited African setting.
Get PDFBACKGROUND: Transbronchial lung cryobiopsy (TBLC) is a relatively new technique recommended for sampling of lung parenchyma in patients with suspected interstitial lung disease (ILD) and as an alternative to surgical lung biopsy. A more recently introduced technique is endobronchial ultrasound-guided transbronchial mediastinal lymph node lymph node cryobiopsy (EBUS-TMC) to enable tissue biopsy of mediastinal lymph nodes. However, there are no data on the feasibility of implementing these techniques in a resource-limited African setting, where there is a chronic bed shortage and same-day discharges are preferable. OBJECTIVES: To determine the feasibility and diagnostic yield of TBLC and EBUS-TMC in a resource-limited African setting. METHODS: We performed an audit of lung and lymph node cryobiopsy procedures performed at the E16 Respiratory Clinic at Groote Schuur Hospital, Cape Town, South Africa. Indications, diagnostic performance outcomes and lessons learned were documented and analysed. RESULTS: Sixteen patients underwent 19 cryobiopsy procedures that were performed under general anaesthesia (n=11 TBLC, n=8 EBUS TMC, including 3 patients in whom both TBLC and EBUS-TMC were concurrently performed). The main indications were evaluation of ILD and suspected lymph node malignancy. The diagnostic yield was 63.6% for TBLC (n=7/11; 2 nonspecific interstitial pneumonia, 2 sarcoidosis, 1 espiratory bronchiolitis-ILD, 1 organising pneumonia, 1 nonspecific chronic inflammation) and 50.0% for EBUS-TMC (n=4/8; 1 plasmacytoma, 1 lymphoma, 1 cryptococcus infection, 1 patient with both cryptococcus infection and tuberculosis). Of the patients, 2 had moderate bleeding and 3 had mild bleeding, and 14 were discharged on the day of the procedure. CONCLUSION: TBLC and EBUS-TMC, with avoidance of surgical lung biopsy in most patients and same-day discharge in most patients, are feasible in an African setting. These data inform clinical practice and programme implementation in resource-limited settings. STUDY SYNOPSIS: What the study adds. Although transbronchial lung cryobiopsy (TBLC) is widely accessible in resource-rich settings such as Europe and the USA, there are no data from resource-limited African settings. Endobronchial ultrasound-guided transbronchial mediastinal lymph node cryobiopsy (EBUS-TMC) is a newer technique for which there are limited data. We provide feasibility and implementation data from an African setting.Implications of the findings. We provide useful programmatic implementational data for resource-limited African settings and show that implementation of these techniques with same-day discharge is feasible in a setting where there is limited access to overnight beds and anaesthetic support. Important implementational lessons learned that will facilitate initiation of a new TLBC/EBUS-TMC service are outlined
Rationale and design of SCOPE trial: a prospective, multicentre, open-label, randomised controlled trial to evaluate the overall efficacy and safety of a short-term anticoagulation strategy versus conventional single antiplatelet therapy in patients with severe aortic stenosis without indications for anticoagulation or dual antiplatelet therapy post-transcatheter aortic valve replacement.
Get PDFINTRODUCTION: While transcatheter aortic valve replacement (TAVR) has become a well-established standard of care for patients with symptomatic severe aortic stenosis, the optimal antithrombotic strategy post-TAVR remains a subject of debate, particularly in patients without clear indications for anticoagulation or dual antiplatelet therapy. This study aims to investigate the safety and efficacy of rivaroxaban compared with antiplatelet monotherapy in this specific patient population. METHODS AND ANALYSIS: This study is designed as a prospective, multicentre, open-label, randomised controlled trial. A total of 454 patients, who have successfully undergone TAVR and do not have indications for long-term anticoagulation or dual antiplatelet therapy, will be consecutively enrolled from seven centres across China. Participants will be randomly assigned to receive either anticoagulation with rivaroxaban (20/15 mg) or conventional antiplatelet therapy (aspirin or clopidogrel) for 1 month. Follow-up evaluations are scheduled at 1, 3, 6 and 12 months post-procedure. After the initial 1-month antithrombotic therapy, the regimen may be adjusted by the investigator based on the patient's clinical and imaging follow-up results. The primary endpoint is a hierarchical composite of cardiovascular death, first occurrence of myocardial infarction or stroke, first occurrence of life-threatening, disabling or major bleeding, and grade 3 or higher hypo-attenuated leaflet thickening and reduced leaflet motion at 12 months post-TAVR. The win ratio method will be employed to analyse the primary endpoint. ETHICS AND DISSEMINATION: This trial was approved by the Ethics Committee of the Beijing AnZhen Hospital. All relevant results will be disseminated through publications in peer-reviewed journals and presentations at conferences. TRIAL REGISTRATION NUMBER: ChiCTR2400087453
Development of a mental health-related structural stigma measurement framework in the healthcare system setting: A modified Delphi study.
Get PDFINTRODUCTION: There is a worldwide dearth in literature on the nature, causes, and consequences of structural stigma in mental healthcare. This study aimed to address this gap by exploring key components for measuring structural stigma in healthcare system settings.
METHODS: We used a modified Delphi method consisting of 3 rounds with global experts (stigma researchers, persons with lived experiences of mental health conditions (PWLEs), and policymakers). In the first round, indicators identified through a literature review (n = 39 studies) were appraised through expert consultation workshops with 22 panellists, including 54.5% women, 41% PWLEs, and 68.2% from low-and-middle income countries (LMICs). Round 2 (n = 53 panellists; 51% women, 8.3% PWLEs, and 56.6% from LMICs) involved ranking indicators through an online survey, and Round 3 (n = 58 panellists; 46% women, 21.7% PWLEs, and 60.4% from LMICs) involved re-ranking the results from Round 2. Smith's salience index was calculated to measure consensus and Kendall's coefficient of concordance to determine the degree of agreement. Narrative opinions and feedback from panellists during all three Delphi rounds were also sought.
RESULTS: A list of indicators within five core measurement domains was identified in Round 1. Round 2 results were heterogeneous as indicated by the low to moderate salience of most indicators. Round 3 resulted in 4-5 indicators in each domain, that were ranked as highly salient by the expert panellists. Experts also provided narrative feedback on the definition of structural stigma, barriers to its measurement, domain-specific comments, and indicators-specific comments.
CONCLUSION: The framework aids in defining mental health-related structural stigma in healthcare and framing it in terms of inequities within healthcare system structures. These structures result in negative experiences of PWLEs and limit their access to quality healthcare. This conceptualization, informed by PWLE and stakeholders in LMICs, makes it easier to measure structural stigma and monitor changes in diverse healthcare settings around the world
Analytical approaches to evaluate risk factors of multimorbidity: a systematic scoping review protocol.
Get PDFINTRODUCTION: Understanding causal risk factors that contribute to the development of multimorbidity is essential for designing and targeting effective preventive strategies. Despite a large body of research in this field, there has been little critical discussion about the appropriateness of the various analytical approaches used. This proposed scoping review aims to summarise and appraise the analytical approaches used in the published literature that evaluated risk factors of multimorbidity and to provide guidance for researchers conducting analyses in this field.
METHODS AND ANALYSIS: We will systematically search three electronic databases-Embase, Global Health and MEDLINE, as well as the reference lists of identified relevant review articles, from inception to September 2024. We will screen titles and abstracts using the artificial intelligence-aided software ASReview, followed by screening for eligible articles in full text and extracting data. We will then categorise the analytical approaches used across studies, provide a comprehensive overview of the methodology and discuss the potential strengths and limitations of each analytical approach.
ETHICS AND DISSEMINATION: We will undertake a secondary analysis of published literature; therefore, ethical approval is not required. The results will be disseminated through an open-access, peer-reviewed publication. This systematic scoping review will serve as a guide for researchers in selecting analytical approaches for aetiological multimorbidity research, thereby improving the quality and comparability of research in this field
Changes in self-reported physical and mental health, behaviour and economic status among adults by known seropositivity and sociodemographic factors before and after the COVID-19 pandemic outbreak in Ischgl, Austria.
Get PDFINTRODUCTION: In early March 2020, a SARS-CoV-2 outbreak occurred in the ski resort of Ischgl, in Austria. After an initial seroprevalence study in April 2020, a follow-up study in November 2020 showed persistence of high levels of seropositivity. The impacts of SARS-CoV-2 infections and non-pharmaceutical interventions required to reduce transmission were wide-ranging, including worsened mental and physical health and economic damage.
METHODS: We analysed data from the Ischgl follow-up study. Of the 1,259 adults that participated in the Ischgl-1 study (Ischgl-1), 801 were followed-up. Seropositivity was defined using presence of binding and neutralizing antibodies at Ischgl-1. At follow-up, 7 months later (Ischgl-2), participants reported changes to self-rated mental and physical health, physical activity, alcohol consumption, smoking and economic status. Changes were compared by serological status, using multivariable logistic and multinomial regression models, where appropriate, and adjusting for factors including age, sex, and morbidity.
RESULTS: 1 in 2 participants reported experiencing a moderate or severe impact of the pandemic. One fifth of participants reported a worsening in their mental health from November 2019 to November 2020; women and participants aged ≥35 to <70 years were disproportionately affected. Seropositivity was associated with a decline in physical health but no decline in mental health or behaviour changes. Very few participants reported any changes in behaviours. The overriding impact the population of Ischgl was economic-50% of participants reported a worsening of their professional and/or financial situation. Declines in self-reported mental health were associated with the overall experience of the pandemic and economic factors.
CONCLUSION: The population of Ischgl demonstrated a high level of resilience to the pandemic as measured by health. However, certain segments of the population were disproportionately affected, particularly with regard to mental health and economic wellbeing. Future pandemic preparedness must consider how pandemic mitigation strategies can be responsive to context and the wider impacts on mental health and social and economic wellbeing while minimising mortality and safeguarding health systems
Advancing the evidence for water, sanitation, and hygiene (WASH) systems strengthening: A Delphi study to define research priorities
Get PDFDespite significant progress in the provision of water, sanitation, and hygiene (WASH) services, 2.3 billion people still lack access to essential services, and many existing services fail to remain functional, reliable, and safe over time. Strengthening WASH systems is critical to ensure long-term service reliability, equity, and resilience. However, empirical evidence on WASH systems strengthening remains limited. This study employed a Delphi process to identify high-priority research questions to guide systems strengthening efforts, future investments, and policymaking. To collate questions on WASH system strengthening, the research team conducted a rapid scoping review of peer-reviewed and grey literature and extracted questions from international conferences. These questions were categorised, reviewed, and refined by the research leads, covering topics such as understanding the functioning of WASH systems, identifying pathways of change, and addressing systemic challenges of resilience, inclusion, sustainability, and governance. A diverse panel of WASH experts participated in a multi-round Delphi process, reaching consensus on key research priorities. The highest research priorities reflected all WASH system building blocks, with each question linked to at least three of the four domains. Five overarching themes emerged: 1) integrating climate resilience into systems strengthening, 2) enhancing gender, equity, and social inclusion in system approaches, 3) strengthening governance, financing, and accountability mechanisms, 4) improving monitoring, evaluation, and measurement of system change, and 5) understanding the political economy of WASH service delivery. This study highlights the growing recognition that WASH systems strengthening requires a broad approach, addressing dynamic linkages between building blocks, context, and actors. It also underscores the importance of improved knowledge sharing to bridge gaps between researchers, implementers, and policymakers and provides a guide to generate evidence that informs sectoral investments and interventions. By addressing key research priorities, it supports evidence-based decision-making to enhance the reliability, inclusion, and sustainability of WASH services
Longer-term survival, quality of life, and cost-effectiveness of conservative versus liberal oxygenation targets in critically ill children: a pre-specified analysis from Oxy-PICU, a multicentre, open, parallel-group, randomised controlled trial.
Get PDFBACKGROUND: Peripheral oxygen saturation (SpO2) above 94% is typical in children in paediatric intensive critical care units (PICUs) who are receiving invasive ventilation and supplemental oxygen. In a previous report from the Oxy-PICU trial, we showed that lower (conservative) oxygenation targets (SpO2 88-92%) are beneficial, showing small but statistically significant differences in duration of organ support and large but non-significant cost reductions at 30 days. In this pre-specified analysis of the Oxy-PICU trial, we compare longer-term outcomes and cost-effectiveness of conservative versus liberal (SpO2 >94%) oxygenation targets in children with emergency PICU admission. METHODS: Oxy-PICU was a pragmatic, multicentre, open-label, randomised controlled trial in England and Scotland. Eligible children were older than 38 weeks and younger than 16 years and had been admitted for emergency care in one of 15 participating PICUs, where they received invasive respiratory support for abnormal gas exchange. Participants were randomly assigned (1:1) to either a conservative oxygenation target (SpO2 88-92%) or liberal oxygenation target (SpO2 >94%). Survival status was assessed at 90 days and 1 year, and health-related quality of life (HRQoL), quality-adjusted life-years (QALYs), health-care costs, and incremental net monetary benefit were assessed at 1 year after the index hospital admission and randomisation. HRQoL was measured with age-appropriate Paediatric Quality of Life Generic Core Scales and mapped onto the Child Health Utility 9D index score. HRQoL and survival data were combined to construct QALYs. Costs at 1 year were derived from use of hospital, outpatient, and community health services. The trial was registered in the ISRCTN registry (ISRCTN92103439). FINDINGS: 2040 children were enrolled between Sept 1, 2020 and May 15, 2022. 1868 (91·6%) children were included in the 90-day survival analysis; of these 930 (49·8%) had been assigned liberal oxygen and 938 (50·2%) conservative oxygen. 1867 (91·5%) children were included in the 1-year survival analysis; 930 (49·8%) had been assigned liberal oxygenation and 937 (50·2%) conservative oxygen. At 90 days, 35 (3·7%) patients in the conservative oxygenation group and 45 (4·8%) patients in the liberal oxygenation group had died (adjusted hazard ratio [aHR] 0·75 [95% CI 0·48 to 1·17]). By 1 year, 52 (5·5%) patients in the conservative oxygenation group and 66 (7·1%) patients in the liberal oxygenation group had died (aHR 0·77 [95%CI 0·53 to 1·10]). Overall, mean HRQoL, life-years, and QALYs at 1 year were similar in the two groups. The adjusted incremental effect on cost of conservative oxygenation versus liberal oxygenation was -£879 (95% CI -9036 to 7278), whereas the incremental difference in QALYs was estimated at 0·001 (-0·010 to 0·011), leading to an incremental net monetary benefit of £894 (-7290 to 9078) associated with conservative oxygenation relative to liberal oxygenation. These results did not vary by age (94%) for invasively ventilated children who are admitted as an emergency to a PICU, conservative oxygenation (SpO2 88-92%) was not associated with differences in longer-term survival, costs, or cost-effectiveness. Taken together with previous findings of Oxy-PICU that conservative oxygenation compared with liberal oxygenation leads to better patient-centred and parent-centred outcomes at 30 days, these findings support the use of conservative oxygenation targets for this population. FUNDING: UK National Institute for Health and Social Care Research Health Technology Assessment Programme
Barriers and enablers of access to diabetes eye care in Auckland, New Zealand: a qualitative study.
Get PDFOBJECTIVE: To explore the barriers and enablers to accessing diabetes eye care services among adults in Auckland.
DESIGN: This was a qualitative study that used semistructured interviews. We performed a thematic analysis and described the main barriers and enablers to accessing services using the Theoretical Domains Framework.
SETTING: The study took place in two of the three public funding and planning agencies that provide primary and secondary health services in Auckland, the largest city in Aotearoa New Zealand.
PARTICIPANTS: Thirty people with diabetes in Auckland who had experienced interrupted diabetes eye care, having missed at least one appointment or being discharged back to their general practitioner after missing several appointments.
RESULTS: We identified barriers and enablers experienced by our predominantly Pacific and Māori participants that aligned with 7 (of the 14) domains in the Theoretical Domains Framework. The most reported barriers were transport issues, lack of awareness regarding the importance of retinal screening, time constraints, limited and/or inflexible appointment times and competing family commitments. Enablers included positive interactions with healthcare providers and timely appointment notifications and reminders.
CONCLUSIONS: Diabetes eye services could be made more responsive by addressing systemic barriers such as service location and transport links, appointment availability and meaningful information to aid understanding