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.

Healthcare workers knowledge of cholera multi-stranded interventions and its determining factors in North-East Nigeria: planning and policy implications.

BACKGROUND: Healthcare workers' (HCWs) knowledge of multi-stranded cholera interventions (including case management, water, sanitation, and hygiene (WASH), surveillance/laboratory methods, coordination, and vaccination) is crucial to the implementation of these interventions in healthcare facilities, especially in conflict-affected settings where cholera burden is particularly high. We aimed to assess Nigerian HCWs' knowledge of cholera interventions and identify the associated factors. METHODS: We conducted a cross-sectional study using a structured interviewer-administered questionnaire with HCWs from 120 healthcare facilities in Adamawa and Bauchi States, North-East Nigeria. A knowledge score was created by assigning a point for each correct response. HCWs' knowledge of cholera interventions, calculated as a score, was recoded for ease of interpretation as follows: 0-50 (low); 51-70 (moderate); ≥ 71 (high). Additionally, we defined the inadequacy of HCWs' knowledge of cholera interventions based on a policy-relevant threshold of equal or lesser than 75 scores for an intervention. Multivariable logistic regression was used to identify the factors associated with the adequacy of knowledge score. RESULTS: Overall, 490 HCWs participated in the study (254 in Adamawa and 236 in Bauchi), with a mean age of 35.5 years. HCWs' knowledge score was high for surveillance/laboratory methods, moderate for case management, WASH, and vaccination, and low for coordination. HCWs' knowledge of coordination improved with higher cadre, working in urban- or peri-urban-based healthcare facilities, and secondary education; cholera case management and vaccination knowledge improved with post-secondary education, working in Bauchi State and urban areas, previous training in cholera case management and response to a cholera outbreak-working in peri-urban areas had a negative effect. HCWs' knowledge of surveillance/laboratory methods improved with a higher cadre, 1-year duration in current position, secondary or post-secondary education, previous training in cholera case management and response to a cholera outbreak. However, HCWs' current position had both positive and negative impacts on their WASH knowledge. CONCLUSIONS: HCWs in both study locations recorded a considerable knowledge of multi-stranded cholera interventions. While HCWs' demographic characteristics appeared irrelevant in determining their knowledge of cholera interventions, geographic location and experiences from the current position, training and involvement in cholera outbreak response played a significant role.

A scoping review of facilitators and barriers influencing the implementation of surveillance and oral cholera vaccine interventions for cholera control in lower- and middle-income countries.

BACKGROUND: Cholera still affects millions of people worldwide, especially in lower- and middle-income countries (LMICs). The Global Task Force on Cholera Control (GTFCC) has identified surveillance and oral cholera vaccines as two critical interventions to actualise the global roadmap goals-reduction of cholera-related deaths by 90% and decreasing the number of cholera endemic countries by half by 2030. Therefore, this study aimed to identify facilitators and barriers to implementing these two cholera interventions in LMIC settings. METHODS: A scoping review using the methods presented by Arksey and O'Malley. The search strategy involved using key search terms (cholera, surveillance, epidemiology and vaccines) in three databases (PubMed, CINAHL and Web of Science) and reviewing the first ten pages of Google searches. The eligibility criteria of being conducted in LMICs, a timeline of 2011-2021 and documents only in English were applied. Thematic analysis was performed, and the findings were presented according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension. RESULTS: Thirty-six documents met the predefined inclusion criteria, covering 2011 to 2021. There were two themes identified regarding the implementation of surveillance: timeliness and reporting (1); and resources and laboratory capabilities (2). As for oral cholera vaccines, there were four themes identified: information and awareness (1); community acceptance and trusted community leaders (2); planning and coordination (3); and resources and logistics (4). Additionally, adequate resources, good planning and coordination were identified to be operating at the interface between surveillance and oral cholera vaccines. CONCLUSION: Findings suggest that adequate and sustainable resources are crucial for timely and accurate cholera surveillance and that oral cholera vaccine implementation would benefit from increased community awareness and engagement of community leaders.

Stakeholder perceptions on scaling-up community-led interventions for prevention and control of non-communicable diseases in Bangladesh: a qualitative study.

BACKGROUND: Engaging communities is an important component of multisectoral action to address the growing burden of non-communicable diseases (NCDs) in low- and middle-income countries. We conducted research with non-communicable disease stakeholders in Bangladesh to understand how a community-led intervention which was shown to reduce the incidence of type 2 diabetes in rural Bangladesh could be scaled-up. METHODS: We purposively sampled any actor who could have an interest in the intervention, or that could affect or be affected by the intervention. We interviewed central level stakeholders from donor agencies, national health policy levels, public, non-governmental, and research sectors to identify scale-up mechanisms. We interviewed community health workers, policy makers, and non-governmental stakeholders, to explore the feasibility and acceptability of implementing the suggested mechanisms. We discussed scale-up options in focus groups with community members who had attended a community-led intervention. We iteratively developed our data collection tools based on our analysis and re-interviewed some participants. We analysed the data deductively using a stakeholder analysis framework, and inductively from codes identified in the data. RESULTS: Despite interest in addressing NCDs, there was a lack of a clear community engagement strategy at the government level, and most interventions have been implemented by non-governmental organisations. Many felt the Ministry of Health and Family Welfare should lead on community engagement, and NCD screening and referral has been added to the responsibilities of community health workers and health volunteers. Yet there remains a focus on reproductive health and NCD diagnosis and referral instead of prevention at the community level. There is potential to engage health volunteers in community-led interventions, but their present focus on engaging women for reproductive health does not fit with community needs for NCD prevention. CONCLUSIONS: Research highlighted the need for a preventative community engagement strategy to address NCDs, and the potential to utilise existing cadres to scale-up community-led interventions. It will be important to work with key stakeholders to address gender issues and ensure flexibility and responsiveness to community concerns. We indicate areas for further implementation research to develop scaled-up models of community-led interventions to address NCDs.

Under-five mortality in the Democratic Republic of the Congo: secondary analyses of survey and conflict data by province.

Objective: To compare coverage of key child health policy indicators across provinces and to explore their association with under-five mortality and level of conflict in the Democratic Republic of the Congo. Methods: We made a secondary analysis of nationally representative data from 1380 health facilities and 20 792 households in 2017-2018. We analysed provincial-level data on coverage of 23 different indicators for improving common causes of childhood mortality, combined into mean scores for: newborn health, pneumonia, diarrhoea, malaria and safe environment. Using negative binomial regression we compared the scores with provincial-level under-five mortality. With binary logistic regression at the individual level we compared indicators (outcome) with living in a conflict-affected province (exposure). Findings: All grouped coverage scores demonstrated large ranges across the 26 provinces: newborn health: 20% to 61%; pneumonia: 26% to 86%; diarrhoea: 25% to 63%; malaria: 22% to 53%; and safe environment: 4% to 53%. The diarrhoea score demonstrated the strongest association with under-five mortality (adjusted coefficient: -0.026; 95% confidence interval: -0.045 to -0.007). Conflict-affected provinces had both the highest as well as the lowest mortality rates and indicator coverages. The odds of coverage were higher in conflict-affected provinces for 13 out of 23 indicators, whereas in provinces unaffected by conflict only one indicator had higher odds of coverage. Conclusion: Conflict alone is a poor predictor for child health. Ensuring that children in unaffected provinces are not neglected while addressing the needs of the most vulnerable in conflict settings is important. Prevent, protect and treat strategies for diarrhoeal disease could help improve equity in child survival.

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: 90-93%) in 13.1% (108/826) and severe (SpO2: < 90%) in 8.6% (71/826) and hypoglycaemia was moderate (blood glucose: 2.5-4.0 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.

Care-seeking and managing diabetes in rural Bangladesh: a mixed methods study.

BACKGROUND: Type 2 diabetes mellitus poses a major health challenge worldwide and in low-income countries such as Bangladesh, however little is known about the care-seeking of people with diabetes. We sought to understand the factors that affect care-seeking and diabetes management in rural Bangladesh in order to make recommendations as to how care could be better delivered. METHODS: Survey data from a community-based random sample of 12,047 adults aged 30 years and above identified 292 individuals with a self-reported prior diagnosis of diabetes. Data on health seeking practices regarding testing, medical advice, medication and use of non-allopathic medicine were gathered from these 292 individuals. Qualitative semi-structured interviews and focus group discussions with people with diabetes and semi-structured interviews with health workers explored care-seeking behaviour, management of diabetes and perceptions on quality of care. We explore quality of care using the WHO model with the following domains: safe, effective, patient-centred, timely, equitable and efficient. RESULTS: People with diabetes who are aware of their diabetic status do seek care but access, particularly to specialist diabetes services, is hindered by costs, time, crowded conditions and distance. Locally available services, while more accessible, lack infrastructure and expertise. Women are less likely to be diagnosed with diabetes and attend specialist services. Furthermore costs of care and dissatisfaction with health care providers affect medication adherence. CONCLUSION: People with diabetes often make a trade-off between seeking locally available accessible care and specialised care which is more difficult to access. It is vital that health services respond to the needs of patients by building the capacity of local health providers and consider practical ways of supporting diabetes care. TRIAL REGISTRATION: ISRCTN41083256 . Registered on 30/03/2016.

Predictive value of pulse oximetry for mortality in infants and children presenting to primary care with clinical pneumonia in rural Malawi: A data linkage study.

BACKGROUND: The mortality impact of pulse oximetry use during infant and childhood pneumonia management at the primary healthcare level in low-income countries is unknown. We sought to determine mortality outcomes of infants and children diagnosed and referred using clinical guidelines with or without pulse oximetry in Malawi. METHODS AND FINDINGS: We conducted a data linkage study of prospective health facility and community case and mortality data. We matched prospectively collected community health worker (CHW) and health centre (HC) outpatient data to prospectively collected hospital and community-based mortality surveillance outcome data, including episodes followed up to and deaths within 30 days of pneumonia diagnosis amongst children 0-59 months old. All data were collected in Lilongwe and Mchinji districts, Malawi, from January 2012 to June 2014. We determined differences in mortality rates using <90% and <93% oxygen saturation (SpO2) thresholds and World Health Organization (WHO) and Malawi clinical guidelines for referral. We used unadjusted and adjusted (for age, sex, respiratory rate, and, in analyses of HC data only, Weight for Age Z-score [WAZ]) regression to account for interaction between SpO2 threshold (pulse oximetry) and clinical guidelines, clustering by child, and CHW or HC catchment area. We matched CHW and HC outpatient data to hospital inpatient records to explore roles of pulse oximetry and clinical guidelines on hospital attendance after referral. From 7,358 CHW and 6,546 HC pneumonia episodes, we linked 417 CHW and 695 HC pneumonia episodes to 30-day mortality outcomes: 16 (3.8%) CHW and 13 (1.9%) HC patients died. SpO2 thresholds of <90% and <93% identified 1 (6%) of the 16 CHW deaths that were unidentified by integrated community case management (iCCM) WHO referral protocol and 3 (23%) and 4 (31%) of the 13 HC deaths, respectively, that were unidentified by the integrated management of childhood illness (IMCI) WHO protocol. Malawi IMCI referral protocol, which differs from WHO protocol at the HC level and includes chest indrawing, identified all but one of these deaths. SpO2 < 90% predicted death independently of WHO danger signs compared with SpO2 ≥ 90%: HC Risk Ratio (RR), 9.37 (95% CI: 2.17-40.4, p = 0.003); CHW RR, 6.85 (1.15-40.9, p = 0.035). SpO2 < 93% was also predictive versus SpO2 ≥ 93% at HC level: RR, 6.68 (1.52-29.4, p = 0.012). Hospital referrals and outpatient episodes with referral decision indications were associated with mortality. A substantial proportion of those referred were not found admitted in the inpatients within 7 days of referral advice. All 12 deaths in 73 hospitalised children occurred within 24 hours of arrival in the hospital, which highlights delay in appropriate care seeking. The main limitation of our study was our ability to only match 6% of CHW episodes and 11% of HC episodes to mortality outcome data. CONCLUSIONS: Pulse oximetry identified fatal pneumonia episodes at HCs in Malawi that would otherwise have been missed by WHO referral guidelines alone. Our findings suggest that pulse oximetry could be beneficial in supplementing clinical signs to identify children with pneumonia at high risk of mortality in the outpatient setting in health centres for referral to a hospital for appropriate management.

Healthcare provider and service user perspectives on STI risk reduction interventions for young people and MSM in the UK.

OBJECTIVE: Behavioural interventions have been shown to reduce sexual behaviours associated with increased risk of sexually transmitted infections in young people (<25 years) and men who have sex with men (MSM) internationally, but evidence from England is limited. We aimed to explore service provider and user experiences and perspectives on behavioural interventions to reduce sexual behaviour risks, and the use of automated methods to triage individuals to these services. METHODS: We conducted a sequential mixed methods study with sexual health service providers and users in 2015/2016. Qualitative interviews with providers and service users (heterosexual young people and MSM) in London and Brighton allowed us to explore a range of experiences and expectations. A subsequent national web-survey of service providers measured the feasibility of delivery within existing resources and preferences for intervention attributes. RESULTS: We conducted 35 service user (15 heterosexual young people; 20 MSM) and 26 provider interviews and had 100 web-survey responses. We found considerable heterogeneity in prevention services offered. Service users and providers were broadly supportive of tailoring interventions offered, but service users raised concerns about automated, data-driven triage, particularly around equity and fairness of service delivery. Digital technologies, including social media or apps, were appealing to providers, being less resource intensive. However, one-to-one talking interventions remained popular with both service users and providers, being familiar, trustworthy and personal. Key tensions between desirability of interventions and availability of resources to deliver them were acknowledged/recognised by providers and users. CONCLUSION: Overall, behavioural interventions to reduce sexual behaviour risks were viewed favourably by service providers and users, with key considerations including: privacy, personalisation and convenience. However, introducing desirable targeted interventions within heterogeneous sexual health settings will require resources to adapt interventions and research to fully understand the barriers and facilitators to use within routine services.

Participatory learning and action to address type 2 diabetes in rural Bangladesh: a qualitative process evaluation.

BACKGROUND: Diabetes is 7th largest cause of death worldwide, and prevalence is increasing rapidly in low-and middle-income countries. There is an urgent need to develop and test interventions to prevent and control diabetes and develop the theory about how such interventions can be effective. We conducted a participatory learning and action (PLA) intervention with community groups in rural Bangladesh which was evaluated through a cluster randomised controlled trial. There was a large reduction in the combined prevalence of type 2 diabetes and intermediate hyperglycaemia in the PLA group compared with the control group. We present findings from qualitative process evaluation research to explore how this intervention was effective. METHODS: We conducted group interviews and focus group discussions using photovoice with purposively sampled group attenders and non-attenders, and intervention implementers. Data were collected before the trial analysis. We used inductive content analysis to generate theory from the data. RESULTS: The intervention increased the health literacy of individuals and communities - developing their knowledge, capacity and self-confidence to enact healthy behaviours. Community, household and individual capacity increased through social support and social networks, which then created an enabling community context, further strengthening agency and enabling community action. This increased opportunities for healthy behaviour. Community actions addressed lack of awareness about diabetes, gendered barriers to physical activity and lack of access to blood glucose testing. The interaction between the individual, household, and community contexts amplified change, and yet there was limited engagement with macro level, or 'state', barriers to healthy behaviour. CONCLUSIONS: The participatory approach enabled groups to analyse how context affected their ability to have healthy behaviours and participants engaged with issues as a community in the ways that they felt comfortable. We suggest measuring health literacy and social networks in future interventions and recommend specific capacity strengthening to develop public accountability mechanisms and health systems strengthening to complement community-based interventions. TRIAL REGISTRATION: Registered at ISRCTN on 30th March 2016 (Retrospectively Registered) Registration number: ISRCTN41083256 .

Associations between the use of herbal medicines and adverse pregnancy outcomes in rural Malawi: a secondary analysis of randomised controlled trial data.

BACKGROUND: The use of herbal medicines during pregnancy is very high globally and previous studies have pointed out possible associations with adverse pregnancy outcomes. Nevertheless, the safety of herbal medicines in pregnancy is under-explored in low-income countries experiencing high maternal and neonatal complications. We investigated the associations between self-reported use of Mwanamphepo (a group of herbal medicines commonly used to induce or hasten labour) and adverse maternal and neonatal outcomes in rural Malawi. METHODS: We conducted a cross-sectional analysis of secondary household data relating to 8219 births that occurred between 2005 and 2010 in Mchinji district, Malawi. The data were collected as part of a cluster-randomised controlled trial (RCT) that evaluated community interventions designed to reduce maternal and neonatal mortality. Data were gathered on maternity history, demographic characteristics, pregnancy outcomes and exposure to Mwanamphepo. Associations between self-reported use of Mwanamphepo and maternal morbidity as well as neonatal death or morbidity were examined using mixed-effects models, adjusted for relevant covariates. All analyses were also adjusted for the clustered nature of the survey. RESULTS: Of the 8219 births, Mwanamphepo was used in 2113 pregnancies, representing an estimated prevalence of 25.7%. The self-reported use of Mwanamphepo was significantly associated with increased occurrence of maternal morbidity and neonatal death or morbidity. Specifically, the odds of maternal morbidity were 28% higher among self-reported users than non-users of Mwanamphepo (AOR = 1.28; 95% CI = 1.09-1.50) and the probabilities of neonatal death or morbidity were 22% higher (AOR =1.22; 95% CI = 1.06-1.40) among neonates whose mother reportedly used Mwanamphepo than those who did not. CONCLUSION: The use of Mwanamphepo was associated with adverse pregnancy outcomes in rural Malawi. Thus, herbal medicines may not be safe in pregnancy. Where possible, pregnant women should be discouraged from using herbal medicines of unconfirmed safety and those who report to have used should be closely monitored by health professionals. The study was limited by the self-report of exposure and unavailability of data relating to some possible confounders.

Pulse oximetry for children with pneumonia treated as outpatients in rural Malawi.

OBJECTIVE: To investigate implementation of outpatient pulse oximetry among children with pneumonia, in Malawi. METHODS: In 2011, 72 health-care providers at 18 rural health centres and 38 community health workers received training in the use of pulse oximetry to measure haemoglobin oxygen saturations. Data collected, between 1 January 2012 and 30 June 2014 by the trained individuals, on children aged 2-59 months with clinically diagnosed pneumonia were analysed. FINDINGS: Of the 14 092 children included in the analysis, 13 266 (94.1%) were successfully checked by oximetry. Among the children with chest indrawing and/or danger signs, those with a measured oxygen saturation below 90% were more than twice as likely to have been referred as those with higher saturations (84.3% [385/457] vs 41.5% [871/2099]; P < 0.001). The availability of oximetry appeared to have increased the referral rate for severely hypoxaemic children without chest indrawing or danger signs from 0% to 27.2% (P < 0.001). In the absence of oximetry, if the relevant World Health Organization (WHO) guidelines published in 2014 had been applied, 390/568 (68.7%) severely hypoxaemic children at study health centres and 52/84 (61.9%) severely hypoxaemic children seen by community health workers would have been considered ineligible for referral. CONCLUSION: Implementation of pulse oximetry by our trainees substantially increased the referrals of Malawian children with severe hypoxaemic pneumonia. When data from oximetry were excluded, retrospective application of the guidelines published by WHO in 2014 failed to identify a considerable proportion of severely hypoxaemic children eligible only via oximetry.

Predictors of treatment failure for non-severe childhood pneumonia in developing countries--systematic literature review and expert survey--the first step towards a community focused mHealth risk-assessment tool?

BACKGROUND: Improved referral algorithms for children with non-severe pneumonia at the community level are desirable. We sought to identify predictors of oral antibiotic failure in children who fulfill the case definition of World Health Organization (WHO) non-severe pneumonia. Predictors of greatest interest were those not currently utilized in referral algorithms and feasible to obtain at the community level. METHODS: We systematically reviewed prospective studies reporting independent predictors of oral antibiotic failure for children 2-59 months of age in resource-limited settings with WHO non-severe pneumonia (either fast breathing for age and/or lower chest wall indrawing without danger signs), with an emphasis on predictors not currently utilized for referral and reasonable for community health workers. We searched PubMed, Cochrane, and Embase and qualitatively analyzed publications from 1997-2014. To supplement the limited published evidence in this subject area we also surveyed respiratory experts. RESULTS: Nine studies met criteria, seven of which were performed in south Asia. One eligible study occurred exclusively at the community level. Overall, oral antibiotic failure rates ranged between 7.8-22.9%. Six studies found excess age-adjusted respiratory rate (either WHO-defined very fast breathing for age or 10-15 breaths/min faster than normal WHO age-adjusted thresholds) and four reported young age as predictive for oral antibiotic failure. Of the seven predictors identified by the expert panel, abnormal oxygen saturation and malnutrition were most highly favored per the panel's rankings and comments. CONCLUSIONS: This review identified several candidate predictors of oral antibiotic failure not currently utilized in childhood pneumonia referral algorithms; excess age-specific respiratory rate, young age, abnormal oxygen saturation, and moderate malnutrition. However, the data was limited and there are clear evidence gaps; research in rural, low-resource settings with community health workers is needed.

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.

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.