Secondary failure of lentiviral vector gene therapy in a cerebral adrenoleukodystrophy patient with an ABCD1 whole-gene deletion.

A 9-year-old boy with adrenoleukodystrophy due to ABCD1 whole-gene deletion was diagnosed with active cerebral adrenoleukodystrophy characterized by demyelination and gadolinium enhancement on brain MRI. He underwent hematopoietic cell transplant (HCT) with autologous CD34+ cells transduced with an ABCD1-expressing lentiviral vector (eli-cel [elivaldogene autotemcel]) as part of the ALD-104 clinical trial. Fifty days after HCT, the patient's MRI showed gadolinium resolution; the whole-blood vector copy number (VCN) was 0.666 copies/mL. Six months following HCT, an MRI showed re-emergence of gadolinium enhancement; the VCN had decreased to 0.029 copies/mL. Polyclonal antibodies to the ABCD1 gene product were detectable 9 months after transplant, showing reactivity to peroxisomes, suggesting an immune response; however, no antibody binding to human CD34+ cells could be shown. The patient underwent a successful allogeneic HCT 12 months after gene therapy with resultant gadolinium resolution, cerebral disease stabilization, and the disappearance of antibodies. The coincident VCN loss and appearance of antibody to the ABCD1 gene product is of interest, and we postulate that it is related to the patient's whole ABCD1 gene deletion. We suggest close monitoring of loss of gene therapy efficacy due to immune response in patients with full deletions who are considering gene therapy.

The COVID-19 quandemic.

BACKGROUND: The terms syndemic and infodemic have both been applied to the COVID-19 pandemic, and emphasize concurrent socio-cultural dynamics that are distinct from the epidemiological outbreak itself. We argue that the COVID-19 pandemic has exposed yet another important socio-political dynamic that can best be captured by the concept of a quandemic - a portmanteau of "quantification" and "pandemic". MAIN TEXT: The use of quantifiable metrics in policymaking and evaluation has increased throughout the last decades, and is driven by a synergetic relationship between increases in supply and advances in demand for data. In most regards this is a welcome development. However, a quandemic, refers to a situation where a small subset of quantifiable metrics dominate policymaking and the public debate, at the expense of more nuanced and multi-disciplinary discourse. We therefore pose that a quandemic reduces a complex pandemic to a few metrics that present an overly simplified picture. During COVID-19, these metrics were different iterations of case numbers, deaths, hospitalizations, diagnostic tests, bed occupancy rates, the R-number and vaccination coverage. These limited metrics came to constitute the internationally recognized benchmarks for effective pandemic management. Based on experience from the Nordic region, we propose four distinct dynamics that characterize a quandemic: 1) A limited number of metrics tend to dominate both political, expert, and public spheres and exhibit a great deal of rigidity over time. 2) These few metrics crowd-out other forms of evidence relevant to pandemic response. 3) The metrics tend to favour certain outcomes of pandemic management, such as reducing hospitalization rates, while not capturing potential adverse effects such as social isolation and loneliness. 4) Finally, the metrics are easily standardized across countries, and give rise to competitive dynamics based on international comparisons and benchmarking. CONCLUSION: A quandemic is not inevitable. While metrics are an indispensable part of evidence-informed policymaking, being attentive to quandemic dynamics also means identifying relevant evidence that might not be captured by these few but dominant metrics. Pandemic responses need to account for and consider multilayered vulnerabilities and risks, including socioeconomic inequities and comorbidities.

A systematic review of measures of healthcare workers' vaccine confidence.

Healthcare workers (HCW) perceptions toward vaccines influence patient and community vaccine decision making. In an era of rising vaccine hesitancy, understanding HCW vaccine confidence is critical. This systematic review aims to review instruments that have been validated to measure HCW vaccine confidence. We conducted a search in five databases in June 2023. Data was descriptively synthesized. Twelve articles describing 10 different tools were included. Most tools included dimensions or items on vaccine knowledge (n = 9), safety (n = 8), vaccine usefulness (n = 8), recommendation behavior (n = 8), and self-vaccination practice (n = 7). All, except one study, were conducted in high-income countries. There was variability in the quality of the validation process. There is limited existing literature on development and validation of tools for HCW vaccine confidence. Based on the tools currently available, the Pro-VC-Be tool is the most well validated. Further research needs to include low- and middle-income contexts.

Linking communities and health facilities to improve child health in low-resource settings: a systematic review.

Community-facility linkage interventions are gaining popularity as a way to improve community health in low-income settings. Their aim is to create/strengthen a relationship between community members and local healthcare providers. Representatives from both groups can address health issues together, overcome trust problems, potentially leading to participants' empowerment to be responsible for their own health. This can be achieved via different approaches. We conducted a systematic literature review to explore how this type of intervention has been implemented in rural and low or lower-middle-income countries, its various features and how/if it has helped to improve child health in these settings. Publications from three electronic databases (Web of Science, PubMed and Embase) up to 03 February 2022 were screened, with 14 papers meeting the inclusion criteria (rural setting in low/lower-middle-income countries, presence of a community-facility linkage component, outcomes of interest related to under-5 children's health, peer-reviewed articles containing original data written in English). We used Rosato's integrated conceptual framework for community participation to assess the transformative and community-empowering capacities of the interventions, and realist principles to synthesize the outcomes. The results of this analysis highlight which conditions can lead to the success of this type of intervention: active inclusion of hard-to-reach groups, involvement of community members in implementation's decisions, activities tailored to the actual needs of interventions' contexts and usage of mixed methods for a comprehensive evaluation. These lessons informed the design of a community-facility linkage intervention and offer a framework to inform the development of monitoring and evaluation plans for future implementations.

Enablers and barriers to implementing cholera interventions in Nigeria: a community-based system dynamics approach.

Nigeria accounts for a substantial cholera burden globally, particularly in its northeast region, where insurgency is persistent and widespread. We used participatory group model building (GMB) workshops to explore enablers and barriers to implementing known cholera interventions, including water, sanitation, and hygiene (WASH), surveillance and laboratory, case management, community engagement, oral cholera vaccine, and leadership and coordination, as well as explore leverage points for interventions and collaboration. The study engaged key cholera stakeholders in the northeastern states of Adamawa and Bauchi, as well as national stakeholders in Abuja. Adamawa and Bauchi States' GMB participants comprised 49 community members and 43 healthcare providers, while the 23 national participants comprised government ministry, department and agency staff, and development partners. Data were analysed thematically and validated via consultation with selected participants. The study identified four overarching themes regarding the enablers and barriers to implementing cholera interventions: (1) political will, (2) health system resources and structures, (3) community trust and culture, and (4) spill-over effect of COVID-19. Specifically, inadequate political will exerts its effect directly (e.g., limited funding for prepositioning essential cholera supplies) or indirectly (e.g., overlapping policies) on implementing cholera interventions. The healthcare system structure (e.g., centralisation of cholera management in a state capital) and limited surveillance tools weaken the capacity to implement cholera interventions. Community trust emerges as integral to strengthening the healthcare system's resilience in mitigating the impacts of cholera outbreaks. Lastly, the spill-over effects of COVID-19 helped promote interventions similar to cholera (e.g., WASH) and directly enhanced political will. In conclusion, the study offers insights into the complex barriers and enablers to implementing cholera interventions in Nigeria's cholera-endemic settings. Strong political commitment, strengthening the healthcare system, building community trust, and an effective public health system can enhance the implementation of cholera interventions in Nigeria.

Exploring different health care providers´ perceptions on the management of diarrhoea in cholera hotspots in the Democratic Republic of Congo: A qualitative content analysis.

Global cholera guidelines support wider healthcare system strengthening interventions, alongside vertical outbreak responses, to end cholera. Well-trained healthcare providers are essential for a resilient health system and can create synergies with childhood diarrhoea, which has higher mortality. We explored how the main provider groups for diarrhoea in cholera hotspots interact, decide on treatment, and reflect on possible limiting factors and opportunities to improve prevention and treatment. We conducted focus group discussions in September 2022 with different healthcare provider types in two urban and two rural cholera hotspots in the North Kivu and Tanganyika provinces in the Eastern Democratic Republic of Congo. Content analysis was used with the same coding applied to all providers. In total 15 focus group discussions with medical doctors (n = 3), nurses (n = 4), drug shop vendors (n = 4), and traditional health practitioners (n = 4) were performed. Four categories were derived from the analysis. (i) Provider dynamics: scepticism between all cadres was prominent, whilst also acknowledging the important role all provider groups have in current case management. (ii) Choice of treatment: affordability and strong caregiver demands shaped by cultural beliefs strongly affected choice. (iii) Financial consideration on access: empathy was strong, with providers finding innovative ways to create access to treatment. Concurrently, financial incentives were important, and providers asked for this to be considered when subsiding treatment. (iv) How to improve: the current cholera outbreak response approach was appreciated however there was a strong wish for broader long-term interventions targeting root causes, particularly community access to potable water. Drug shops and traditional health practitioners should be considered for inclusion in health policies for cholera and other diarrhoeal diseases. Financial incentives for the provider to improve access to low-cost treatment and investment in access to potable water should furthermore be considered.

'Let him die in peace': understanding caregiver's refusal of medical oxygen treatment for children in Nigeria.

INTRODUCTION: Efforts to improve oxygen access have focused mainly on the supply side, but it is important to understand demand barriers, such as oxygen refusal among caregivers. We therefore aimed to understand caregiver, community and healthcare provider (HCP) perspectives and experiences of medical oxygen treatments and how these shape oxygen acceptance among caregivers of sick children in Lagos and Jigawa states, which are two contrasting settings in Nigeria. METHODS: Between April 2022 and January 2023, we conducted an exploratory qualitative study using reflexive thematic analysis, involving semistructured interviews with caregivers (Jigawa=18 and Lagos=7), HCPs (Jigawa=7 and Lagos=6) and community group discussions (Jigawa=4 and Lagos=5). We used an inductive-deductive approach to identify codes and themes through an iterative process using the theoretical framework of acceptability and the normalisation process theory as the analytic lens. RESULTS: Medical oxygen prescription was associated with tension, characterised by fear of death, hopelessness about a child's survival and financial distress. These were driven by community narratives around oxygen, past negative experiences and contextual differences between both settings. Caregiver acceptance of medical oxygen was a sense-making process from apprehension and scepticism about their child's survival chances to positioning prescribed oxygen as an 'appropriate' or 'needed' intervention. Achieving this transition occurred through various means, such as trust in HCPs, a perceived sense of urgency for care, previous positive experience of oxygen use and a symbolic perception of oxygen as a technology. Misconceptions and pervasive negative narratives were acknowledged in Jigawa, while in Lagos, the cost was a major reason for oxygen refusal. CONCLUSION: Non-acceptance of medical oxygen treatment for sick children is modifiable in the Nigerian context, with the root causes of refusal being contextually specific. Therefore, a one-size-fits-all policy is unlikely to work. Financial constraints and community attitudes should be addressed in addition to improving client-provider interactions.

Hypoxaemia and risk of death among children: rethinking oxygen saturation, risk-stratification, and the role of pulse oximetry in primary care.

Pulse oximeters are essential for assessing blood oxygen levels in emergency departments, operating theatres, and hospital wards. However, although the role of pulse oximeters in detecting hypoxaemia and guiding oxygen therapy is widely recognised, their role in primary care settings is less clear. In this Viewpoint, we argue that pulse oximeters have a crucial role in risk-stratification in both hospital and primary care or outpatient settings. Our reanalysis of hospital and primary care data from diverse low-income and middle-income settings shows elevated risk of death for children with moderate hypoxaemia (ie, peripheral oxygen saturations [SpO2] 90-93%) and severe hypoxaemia (ie, SpO2 <90%). We suggest that moderate hypoxaemia in the primary care setting should prompt careful clinical re-assessment, consideration of referral, and close follow-up. We provide practical guidance to better support front-line health-care workers to use pulse oximetry, including rethinking traditional binary SpO2 thresholds and promoting a more nuanced approach to identification and emergency treatment of the severely ill child.

Targeting VEGF-mediated blood-brain barrier disruption in advanced cerebral leukodystrophy.

The earliest clinical manifestation of cerebral adrenoleukodystrophy (CALD) is adrenal insufficiency (AI) characterized by elevations in ACTH and loss of cortisol. We showed high (though physiologically achievable) levels of ACTH increases endothelial permeability, increases anisotropy, and increases VEGF secretion. An ACBD1 knockout endothelial cell line had increased sensitivity to ACTH and VEGF. Inhibition of VEGF via application of anti-VEGF (bevacizumab) improved permeability. Six boys with advanced CALD were treated with bevacizumab combined with dexamethasone and ruxolitinib as immune suppressants. Most boys had decreases in gadolinium enhancement on MRI indicating improvement in endothelial function, though all boys continued to progress symptomatically.

Designing a Smartphone-Based Pulse Oximeter for Children in South Africa (Phefumla Project): Qualitative Analysis of Human-Centered Design Workshops With Health Care Workers.

Background: Pulse oximeters noninvasively measure blood oxygen levels, but these devices have rarely been designed for low-resource settings and are inconsistently available at outpatient clinics. Objective: The Phefumla project aims to develop and validate a pediatric smartphone-based pulse oximeter designed specifically for this context. We present the process of human-centered oximeter design with health care workers in South Africa. Methods: We purposively sampled 19 health care workers from 5 clinics in Khayelitsha, Cape Town. Using a human-centered design approach, we conducted participatory workshops with four activities with health care workers: (1) they received 3D-printed prototypes of potential oximeter designs to provide feedback; (2) we demonstrated on dolls how they would use the novel oximeter; (3) they used pile sorting to rank design features and suggest additional features they desired; and (4) they designed their preferred user interface using a whiteboard, marker, and magnetized features that could be repositioned. We audio recorded the workshops, photographed outputs, and took detailed field notes. Analysis involved iterative review of these data to describe preferences, identify key design updates, and provide modifications. Results: Participants expressed a positive sentiment toward the idea of a smartphone pulse oximeter and suggested that a pediatric device would address an important gap in outpatient care. Specifically, participants expressed a preference for the prototype that they felt enabled more diversity in the way it could be used. There was a strong tendency to prioritize pragmatic design features, such as robustness, which was largely dictated by health care worker context. They also added features that would allow the oximeter device to serve other clinical functions in addition to oxygen saturation measurement, such as temperature and respiratory rate measurements. Conclusions: Our end user-centered rapid participatory approach led to tangible design changes and prompted design discussions that the team had not previously considered. Overall, health care workers prioritized pragmatism for pediatric pulse oximeter device design.

COVID-19 knowledge and practices in Jigawa State, Nigeria: A cross-sectional survey conducted during the second wave.

Population knowledge of COVID-19 and adherence to prevention measures may not be equitably distributed, limiting the success of public health measures. We aimed to understand whether COVID-19 knowledge differed by socio-economic status in a rural low-income setting of Jigawa State, Nigeria. We conducted a secondary analysis of the baseline cross-sectional survey of the INSPIRING cluster randomised controlled trial in Kiyawa Local Government Area, Jigawa State, from January-June 2021. Compounds were selected using simple random sampling proportional to trial cluster size. Within each compound, a representative head of compound and all women aged 16-49 years were eligible to complete a survey, which asked about socioeconomics, knowledge of COVID-19 symptoms, prevention strategies and risks for poor outcomes. We converted these into binary outcomes of "good knowledge" for symptoms, prevention and risks. Associations between woman and head of compound characteristics and good knowledge were assessed using adjusted logistic regression. We surveyed 3800 compound heads and 9564 women. Overall, <1% of respondents had been tested for COVID-19, but access to facemasks (HoC 60.0%; women 86.3%) and willingness to be vaccinated (HoC 73.9%; women 73.4%) were high. COVID-19 knowledge was low, with 33.2% of heads of compounds and 26.0% of women having good symptom knowledge, 39.5% and 30.4% having good prevention knowledge, and 17.7% and 15.4% having good risk knowledge, respectively. Those with more education, from higher wealth quintiles and access to a radio had better knowledge. Access to a mobile phone was associated with good symptom knowledge, but worse prevention and risk knowledge. We found significant differences in COVID-19 knowledge associated with socio-economic factors in rural Jigawa state, and access to communication devices was not consistently associated with better knowledge. Public health messaging in Nigeria needs to be adapted and delivered in way that ensures accessibility to all.

Facility capacity and provider knowledge for cholera surveillance and diarrhoea case management in cholera hotspots in the Democratic Republic of Congo - a mixed-methods study.

BACKGROUND: Wider healthcare-strengthening interventions are recommended in cholera hotspots and could benefit other types of diarrhoeal diseases which contribute to greater mortality than cholera. OBJECTIVE: Describe facility capacity and provider knowledge for case management of diarrhoea and cholera surveillance in cholera hotspots in the Democratic Republic of Congo (DRC) among health facilities, drug shops, and traditional health practitioners. METHODS: We conducted a sequential exploratory mixed-method study, using focus group discussions, facility audits, and provider knowledge questionnaires during September and October 2022 in North Kivu and Tanganyika provinces, Eastern DRC. Content analysis was used for qualitative data. Quantitative data were summarised by facility level and healthcare provider type. Audit and knowledge scores (range 0-100) were generated. Multivariable linear regression estimated association between scores and explanatory factors. Qualitative and quantitative data were triangulated during interpretation. RESULTS: Overall, 244 facilities and 308 providers were included. The mean audit score for health facilities was 51/100 (SD: 17). Private facilities had an -11.6 (95% CI, -16.7 to -6.6) lower adjusted mean score compared to public. Mean knowledge score was 59/100 (95% CI, 57 to 60) for health facility personnel, 46/100 (95% CI, 43 to 48) for drug shop vendors and 37/100 (95% CI, 34 to 39) for traditional health practitioners. Providers had particularly low knowledge concerning when to check for low blood sugar, use of nasogastric tubes, and dosing schedules. Knowledge about case definitions for cholera was similar between groups (range 41-58%) except for traditional health practitioners for the definition during an outbreak 15/73 (21%). CONCLUSIONS: Increasing awareness of cholera case definitions in this context could help improve cholera surveillance and control. Increased support and supervision, especially for private providers, could help ensure facilities are equipped to provide safe care. More nuanced aspects of case management should be emphasised in provider training.

Level of knowledge, and risk perception of Mpox disease among Primary healthcare workers in Nigeria: a cross-sectional study of Jigawa, Oyo and Lagos States

Introduction: in Nigeria, studies on mpox among primary healthcare workers are scarce despite increasing incidence of mpox disease between 2017-2022. This study aimed to assess primary healthcare workers knowledge and perception of mpox in Nigeria. Methods: we conducted a cross-sectional survey among primary healthcare workers in Nigeria (Oyo, Lagos, and Jigawa) to represent different health system capacities and socio-economic contexts. Knowledge of mpox was evaluated in four domains: general knowledge, transmission, signs and symptoms, and prevention and treatment. Each correct response received a score of 1. We categorize the level of knowledge based on the score using the mean score as the cut-off by re-classifying the composite score of respondents for each state into a binary outcome of "good knowledge" if the mean composite score was greater or equals to the mean of overall knowledge score for the three states (16.1), and "poor knowledge" if the mean score equals to sixteen or less than sixteen (≤16). Factors associated with mpox knowledge were explored using multivariable logistic regression at a 5% significance level. Perception of mpox was assessed using five constructs from the health belief model, measured on 3-point Likert scales. Factors associated with each construct were analyzed using Kruskal-Wallis and Mann-Whitney-U tests. Results: in our study on healthcare workers, 78.3% (n=239) were aware of mpox disease. Their overall knowledge was moderate, particularly regarding transmission. Meanwhile, less than 50% knew mpox can be transmitted through sharing utensils, and 65.3% (n=156) understood contact with infected animals could lead to transmission. Lagos had lower overall knowledge scores (15.3±2.3) compared to Jigawa (16.9±2.3) and Oyo (16.3±2.5) (p<0.001). Perceived susceptibility was similar across states (p=0.127), and 97.5% (n=233) believed mpox can affect anyone, while 47.3% (113) felt they couldn't contract it. Jigawa exhibited higher perceived severity (p<0.001) and barriers to prevention (p<0.001). Conclusion: primary healthcare workers in all settings had limited knowledge of mpox transmission, with the perception of mpox varying by state and participants' socio-economic characteristics. The responsibility of HCW encompasses a range of activities that include diagnosis, patient care and education, and public health interventions amongst others. Hence it is important to educate HCWs on mpox disease to successfully curtail the spread of mpox.

Prospective cohort study of referred Malawian children and their survival by hypoxaemia and hypoglycaemia status

Objective To investigate survival in children referred from primary care in Malawi, with a focus on hypoglycaemia and hypoxaemia progression. Methods The study involved a prospective cohort of children aged 12 years or under referred from primary health-care facilities in Mchinji district, Malawi in 2019 and 2020. Peripheral blood oxygen saturation (SpO2) and blood glucose were measured at recruitment and on arrival at a subsequent health-care facility (i.e. four hospitals and 14 primary health-care facilities). Children were followed up 2 weeks after discharge or their last clinical visit. The primary study outcome was the case fatality ratio at 2 weeks. Associations between SpO2 and blood glucose levels and death were evaluated using Cox proportional hazards models and the treatment effect of hospitalization was assessed using propensity score matching. Findings Of 826 children recruited, 784 (94.9%) completed follow-up. At presentation, hypoxaemia was moderate (SpO2: 90­93%) in 13.1% (108/826) and severe (SpO2: < 90%) in 8.6% (71/826) and hypoglycaemia was moderate (blood glucose: 2.5­4.0 mmol/L) in 9.0% (74/826) and severe (blood glucose: < 2.5 mmol/L) in 2.3% (19/826). The case fatality ratio was 3.7% (29/784) overall but 26.3% (5/19) in severely hypoglycaemic children and 12.7% (9/71) in severely hypoxaemic children. Neither moderate hypoglycaemia nor moderate hypoxaemia was associated with mortality. Conclusion Presumptive pre-referral glucose treatment and better management of hypoglycaemia could reduce the high case fatality ratio observed in children with severe hypoglycaemia. The morbidity and mortality burden of severe hypoxaemia was high; ways of improving hypoxaemia identification and management are needed.