Assessment of post-trauma microstructural alterations in the rabbit knee cartilage and subchondral bone.

Early diagnosis of post-traumatic osteoarthritis (PTOA) is critical for designing better treatments before the degradation becomes irreversible. We utilized multimodal high-resolution imaging to investigate early-stage deterioration in articular cartilage and the subchondral bone plate from a sub-critical impact to the knee joint, which initiates PTOA. The knee joints of 12 adult rabbits were mechanically impacted once on the femoral articular surface to initiate deterioration. At 2- and 14-week post-impact surgery, cartilage-bone blocks were harvested from the impact region in the animals (N = 6 each). These blocks were assessed for deterioration using polarized light microscopy (PLM), microcomputed tomography (µCT), and biochemical analysis. Statistically significant changes were noted in the impact tissues across the calcified zone (CZ) at 14 weeks post-impact: the optical retardation values in the CZ of impact cartilage had a drop of 29.0% at 14 weeks, while the calcium concentration in the CZ of impact cartilage also had a significant drop at 14 weeks. A significant reduction of 6.3% in bone mineral density (BMD) was noted in the subchondral bone plate of the impact samples at 14 weeks. At 2 weeks post-impact, only minor, non-significant changes were measured. Furthermore, the impact knees after 14 weeks had greater structural changes compared with the 2-week impact knees, indicating progressive degradation over time. The findings of this study facilitated a connection between mineralization alterations and the early deterioration of knee cartilage after a mechanical injury. In a broader context, these findings can be beneficial in improving clinical strategies to manage joint injuries.

Impact of seasonal malaria chemoprevention based on the number of medicines doses received on malaria burden among children aged 3-59 months in Nigeria: A propensity score-matched analysis.

BACKGROUND: Seasonal malaria chemoprevention using sulfadoxine-pyrimethamine plus amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine on Day 1 and amodiaquine on both Day 2 and Day 3) is delivered to children aged 3-59 months in areas of highly season malaria transmission. While the overall population-level impact of seasonal malaria chemoprevention on malaria control has been documented in various countries and time periods, there is no clear evidence regarding seasonal malaria chemoprevention impact based on the number of medicine doses children receive in one cycle in routine programmatic conditions. METHODS: Data were extracted from Nigeria's routinely collected seasonal malaria chemoprevention end-of-round coverage surveys (2021, 2022). We matched seasonal malaria chemoprevention-targeted children who received specific numbers of seasonal malaria chemoprevention medicines with those who did not receive any doses of seasonal malaria chemoprevention medicines (non-sulfadoxine-pyrimethamine plus amodiaquine) using multiple sets of propensity score matches. We performed multilevel logistic regression for each matched group to evaluate the association between the number of doses of seasonal malaria chemoprevention medicines and monthly confirmed malaria cases (caregiver-reported malaria infection diagnosed by rapid diagnostic test at a health facility following the penultimate cycle of seasonal malaria chemoprevention). RESULTS: Among 21,621 SMC-targeted children, 9.7% received non-sulfadoxine-pyrimethamine plus amodiaquine, 0.5% received only Day 1 sulfadoxine-pyrimethamine plus amodiaquine, 1.0% received Day 1 sulfadoxine-pyrimethamine plus amodiaquine and either Day 2 amodiaquine or Day 3 amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine), and 88.8% received Day 1 sulfadoxine-pyrimethamine plus amodiaquine and both Day 2 and Day 3 amodiaquine (sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine + amodiaquine). Children receiving only Day 1 sulfadoxine-pyrimethamine plus amodiaquine did not have significant lower odds of rapid diagnostic tests-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.77, 0.42-1.42). However, children receiving sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine had significantly lower odds of rapid diagnostic tests-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.42, 95% CI 0.28-0.63). Similarly, children receiving sulfadoxine-pyrimethamine plus amodiaquine + amodiaquine + amodiaquine also had significantly lower odds of rapid diagnostic test-confirmed malaria than those receiving non-sulfadoxine-pyrimethamine plus amodiaquine (OR 0.54, 95% CI 0.47-0.62). CONCLUSION: Adherence to at least one daily dose of amodiaquine administration following receipt of Day 1 sulfadoxine-pyrimethamine plus amodiaquine by eligible children is crucial to ensure the effectiveness of seasonal malaria chemoprevention. This demonstrates the importance of enhancing caregiver awareness regarding the importance of amodiaquine and identifying barriers toward amodiaquine administration at the community level.

Assessment of articular cartilage degradation in response to an impact injury using µMRI.

PURPOSE: Degradation of articular cartilage (AC) due to injury to the knee joint may initiate post-traumatic osteoarthritis (PTOA). Failure to diagnose the onset of the disease at an early stage makes the cure ineffective for PTOA. This study investigated the consequences of a mechanical injury to the knee in a rabbit model using microscopic magnetic resonance imaging (µMRI) at high resolution. MATERIALS AND METHODS: A mechanical injury was induced to the knee joints of 12 rabbits. Cartilage blocks were extracted from the non-impacted and impacted knee joints after 2 and 14 weeks post-impact. The specimens were studied using µMRI T2 relaxation and inductively coupled plasma analysis to determine the early degradation of the articular cartilage. RESULTS: The data established a connection between T2 relaxation time and the early progression of knee PTOA after an impact injury. T2 values were found to be higher in the impacted cartilage at both 2 and 14 weeks, in particular, T2-55° values in the impacted samples displayed a significant rise of 6.93% after 2 weeks and 20.02% after 14 weeks. Lower glycosaminoglycan measurement and higher water content in the impacted cartilage confirmed the µMRI results. CONCLUSIONS: This µMRI T2 study was able to detect cartilage damage in the impacted knees. In addition, greater degradation in the affected knees at 14 weeks than at 2 weeks indicated the progressive nature of cartilage deterioration over time. The µMRI results were in accord with the biochemical analysis, indicating the detection of early structural damage in the cartilage.

Predictors of accessing seasonal malaria chemoprevention medicines through non-door-to-door distribution in Nigeria.

BACKGROUND: In Nigeria, seasonal malaria chemoprevention (SMC) is typically administered door-to-door to children under five by community medicine distributors during high transmission seasons. While door-to-door distribution (DDD) is exclusively employed in Nigeria as part of standard operating procedures of SMC programmes, some households access SMC through non-DDD channels, such as fixed-point distributions, health facilities, and private purchase. However, analysis of access to SMC medicines through non-DDD has been limited, with little evidence of its outcomes on adherence to the three-day complete course of SMC medicines and caregiver actions in the event of adverse reactions to SMC medicines. METHODS: Data were obtained from SMC end-of-round coverage surveys conducted in Nigeria in 2021 and 2022, including 25,278 households for the analysis. The proportion of households accessing SMC medicine through non-DDD and the distribution of various non-DDD sources of SMC medicines were described. Multivariate random-effects logistic regression models were performed to identify predictors of accessing SMC medicines through non-DDD. The associations between non-DDD, and caregiver-reporting of adherence to complete administration of SMC medicines and caregiver actions in the event of adverse reactions to SMC medicines were also assessed. RESULTS: Less than 2% (314/24003) of households accessed SMC medicines through non-DDD in the states surveyed. Over 60% of non-DDD access was via health facility personnel and community medicine distributors from different locations. Variables associated with non-DDD access included heads of household being born in the local state (OR = 0.68, 95% CI 0.47 to 0.90), households residing in the study state since the first cycle of the SMC round (OR = 0.39, 95% CI 0.17 to 0.88), households with high wealth index (OR = 1.36, 95% CI 1.01 to 1.82), and caregivers hearing about date of SMC delivery in the previous cycle (OR = 0.18, 95%CI 0.14 to 0.24). Furthermore, non-DDD was associated with reduced SMC adherence and higher caregiver non-reporting of adverse reactions to SMC medicines in children compared with DDD. CONCLUSION: This study provides evidence on the characteristics of households accessing SMC medicines through non-DDD and its potential negative outcomes on adherence to SMC medicine and adverse reaction reporting, underscoring potential implementation issues that may arise if non-DDD delivery models are adopted in SMC, particularly in places where DDD had been firstly used.

Receipt of seasonal malaria chemoprevention by age-ineligible children and associated factors in nine implementation states in Nigeria.

BACKGROUND: As part of implementation quality standards, community distributors are expected to ensure that only age-eligible children (aged 3-59 months) receive seasonal malaria chemoprevention (SMC) medicines during monthly campaigns. There is uncertainty about the extent to which SMC medicines are administered to ineligible children. This study aimed to assess the magnitude of this occurrence, while exploring the factors associated with it across nine states where SMC was delivered in Nigeria during the 2022 round. METHODS: This analysis was based on data from representative end-of-round SMC household surveys conducted in nine SMC-implementing states in Nigeria. Data of 3299 age-ineligible children aged > 5 years and their caregivers were extracted from the survey dataset. Prevalence of receipt of SMC medicines by ineligible children was described by child-, caregiver- and SMC-related factors. Mixed-effects multivariable logistic regression models were fitted to explore the factors associated with ineligible receipt of SMC medicines. RESULTS: 30.30% (95% CI 27.80-32.90) of ineligible children sampled received at least one dose of SMC medicines in 2022, the majority (60.60%) of whom were aged 5-6 years while the rest were aged 7-10 years. There were lower odds of an age-ineligible child receiving SMC among caregivers who had knowledge of SMC age eligibility (OR: 0.53, 95% CI 0.37-0.77, p < 0.001), compared with those who were knowledgeable of age eligibility. Higher odds of receipt of SMC were found among age-ineligible children whose caregivers had higher confidence in the protective effect of SMC against malaria (OR: 2.01, 95% CI 1.07-3.72, p = 0.030), compared with those whose caregivers were less confident. Compared with ineligible children of younger caregivers (aged < 20 years), those whose caregivers were older had lower odds of receiving SMC than those whose caregivers were younger; with lower odds among children of caregivers aged 20-39 years (OR: 0.50, 95% CI 0.30-0.82, p = 0.006). CONCLUSIONS: This study contributes important evidence on the magnitude of the receipt of SMC medicines by age-ineligible children, while identifying individual and contextual factors associated with it. The findings provide potentially useful insights that can help inform and guide context-specific SMC implementation quality improvement efforts.

Urban-rural differences in seasonal malaria chemoprevention coverage and characteristics of target populations in nine states of Nigeria: a comparative cross-sectional study.

BACKGROUND: Differences between urban and rural contexts in terms of sociodemographic characteristics, geographical features and risk perceptions may lead to disparities in coverage and related outcomes of community-based preventive interventions, such as seasonal malaria chemoprevention (SMC). This study investigated urban-rural differences in SMC coverage and other programme outcomes, as well as child and caregiver characteristics of target populations in nine implementing states in Nigeria during the 2022 SMC round. METHODS: This is a comparative cross-sectional study based on comprehensive end-of-round household surveys conducted in nine states where SMC was delivered in Nigeria in 2022. Data of 11,880 caregiver-child pairs were included in the analysis. Rural-urban differences in SMC outcomes and child and caregiver characteristics were assessed, first by using Pearsons' chi-square test for independence for categorical variables. Univariate multilevel mixed-effect logistic regression models, with random intercepts for cluster units, were used to quantify the strength of association between location and each SMC coverage and related outcomes. RESULTS: Significant urban-rural differences were observed in caregivers' sociodemographic characteristics, such as age, gender, level of education, occupation status and health-seeking behaviour for febrile childhood illnesses. Disparities were also seen in terms of SMC coverage and related outcomes, with lower odds of the receipt of Day 1 dose direct observation of the administration of Day 1 dose by community distributors, receipt of the full three-day course of SMC medicines and receipt of SMC in all cycles of the annual round among children residing in urban areas, compared with those residing in rural areas. Similarly, urban-dwelling caregivers had lower odds of being knowledgeable of SMC and believing in the protective effect of SMC than rural-dwelling caregivers. CONCLUSION: Findings highlight observable urban-rural disparities in SMC programme delivery and related outcomes, as well as target population characteristics, underscoring the need for context-specific strategies to ensure optimal delivery of SMC and improve programme implementation outcomes in urban settings.

A quasi-experimental study to estimate effectiveness of seasonal malaria chemoprevention in Aweil South County in Northern Bahr El Ghazal, South Sudan.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is an effective intervention to prevent malaria in children in locations where the burden of malaria is high and transmission is seasonal. There is growing evidence suggesting that SMC with sulfadoxine-pyrimethamine and amodiaquine can retain its high level of effectiveness in East and Southern Africa despite resistance concerns. This study aims to generate evidence on the effectiveness of SMC when delivered under programmatic conditions in an area with an unknown anti-malarial drug resistance profile in the Northern Bahr el-Ghazal region of South Sudan. METHODS: A non-randomized quasi experimental study was conducted to compare an intervention county with a control county. Five monthly SMC cycles were delivered between July and November 2022, targeting about 19,000 children 3-59 months old. Data were obtained from repeated cross-sectional household surveys of caregivers of children aged 3-59 months using cluster sampling. Wave 1 survey took place in both counties before SMC implementation; Waves 2 and 3 took place after the second and fourth monthly SMC cycles. Difference-in-differences analyses were performed by fitting logistic regression models with interactions between county and wave. RESULTS: A total of 2760 children were sampled in the study across the three survey waves in both study counties. Children in the intervention arm had 70% lower odds of caregiver-reported fever relative to those in the control arm during the one-month period prior to Wave 2 (OR: 0.30, 95% CI 0.12-0.70, p = 0.003), and 37% lower odds in Wave 3 (OR: 0.63, 95% CI 0.22-1.59, p = 0.306) after controlling for baseline difference between counties in Wave 1. Odds of caregiver-reported RDT-confirmed malaria were 82% lower in the previous 1-month period prior to Wave 2 (OR: 0.18, 95% CI 0.07-0.49, p = 0.001) and Wave 3 (OR: 0.18, 95% CI 0.06-0.54, p = 0.003). CONCLUSION: These results show high effectiveness of SMC using SPAQ in terms of reducing malaria disease during the high transmission season in children 3-59 month. Despite the promising results, additional evidence and insights from chemoprevention efficacy cohort studies, and analyses of relevant resistance markers, are required to assess the suitability of SMC for this specific context.

Exploring existing malaria services and the feasibility of implementing community engagement approaches amongst conflict-affected communities in Cameroon: a qualitative study.

BACKGROUND: Cameroon is one of the countries with the highest burden of malaria. Since 2018, there has been an ongoing conflict in the country, which has reduced access to healthcare for populations in affected regions, and little is known about the impact on access to malaria services. The objective of this study was to understand the current situation regarding access to malaria services in Cameroon to inform the design of interventions to remove barriers and encourage the use of available services. METHODS: A qualitative research study was carried out to understand the barriers preventing communities accessing care, the uptake of community health worker (CHW) services, and to gather perceptions on community engagement approaches, to assess whether these could be an appropriate mechanism to encourage uptake of community health worker (CHW) services. Twenty-nine focus group discussions and 11 in-depth interviews were carried out between May and July 2021 in two regions of Cameroon, Southwest and Littoral. Focus group discussions were held with CHWs and community members and semi-structured, in-depth interviews were conducted with key stakeholders including regional government staff, council staff, community leaders and community-based organisations. The data were analysed thematically; open, descriptive coding was combined with exploration of pre-determined investigative areas. RESULTS: The study confirmed that access to healthcare has become increasingly challenging in conflict-affected areas. Although the Ministry of Health are providing CHWs to improve access, several barriers remain that limit uptake of these services including awareness, availability, cost, trust in competency, and supply of testing and treatment. This study found that communities were supportive of community engagement approaches, particularly the community dialogue approach. CONCLUSION: Communities in conflict-affected regions of Cameroon continue to have limited access to healthcare services, in part due to poor use of CHW services provided. Community engagement approaches can be an effective way to improve the awareness and use of CHWs. However, these approaches alone will not be sufficient to resolve all the challenges faced by conflict-affected communities when accessing health and malaria services. Additional interventions are needed to increase the availability of CHWs, improve the supply of diagnostic tests and treatments and to reduce the cost of treatment for all.

Transcriptomic and functional analyses reveal a tumour-promoting role for the IL-36 receptor in colon cancer and crosstalk between IL-36 signalling and the IL-17/ IL-23 axis.

BACKGROUND: The interleukin (IL)-36 cytokines are a sub-family of the IL-1 family which are becoming increasingly implicated in the pathogenesis of inflammatory diseases and malignancies. Initial studies of IL-36 signalling in tumorigenesis identified an immune-mediated anti-tumorigenic function for these cytokines. However, more recent studies have shown IL-36 cytokines also contribute to the pathogenesis of lung and colorectal cancer (CRC). METHODS: The aim of this study was to investigate IL-36 expression in CRC using transcriptomic datasets and software such as several R packages, Cytoscape, GEO2R and AnalyzeR. Validation of results was completed by qRT-PCR on both cell lines and a patient cohort. Cellular proliferation was assessed by flow cytometry and resazurin reduction. RESULTS: We demonstrate that IL-36 gene expression increases with CRC development. Decreased tumoral IL-36 receptor expression was shown to be associated with improved patient outcome. Our differential gene expression analysis revealed a novel role for the IL-36/IL-17/IL-23 axis, with these findings validated using patient-derived samples and cell lines. IL-36γ, together with either IL-17a or IL-22, was able to synergistically induce different genes involved in the IL-17/IL-23 axis in CRC cells and additively induce colon cancer cell proliferation. CONCLUSIONS: Collectively, this data support a pro-tumorigenic role for IL-36 signalling in colon cancer, with the IL-17/IL-23 axis influential in IL-36-mediated colon tumorigenesis.

Factor XIII cross-links fibrin(ogen) independent of fibrin polymerization in experimental acute liver injury.

Intravascular fibrin clot formation follows a well-ordered series of reactions catalyzed by thrombin cleavage of fibrinogen leading to fibrin polymerization and cross-linking by factor XIIIa (FXIIIa). Extravascular fibrin(ogen) deposits are observed in injured tissues; however, the mechanisms regulating fibrin(ogen) polymerization and cross-linking in this setting are unclear. The objective of this study was to determine the mechanisms of fibrin polymerization and cross-linking in acute liver injury induced by acetaminophen (APAP) overdose. Hepatic fibrin(ogen) deposition and cross-linking were measured following APAP overdose in wild-type mice, mice lacking the catalytic subunit of FXIII (FXIII-/-), and in FibAEK mice, which express mutant fibrinogen insensitive to thrombin-mediated fibrin polymer formation. Hepatic fibrin(ogen) deposition was similar in APAP-challenged wild-type and FXIII-/- mice, yet cross-linking of hepatic fibrin(ogen) was dramatically reduced (>90%) by FXIII deficiency. Surprisingly, hepatic fibrin(ogen) deposition and cross-linking were only modestly reduced in APAP-challenged FibAEK mice, suggesting that in the APAP-injured liver fibrin polymerization is not strictly required for the extravascular deposition of cross-linked fibrin(ogen). We hypothesized that the oxidative environment in the injured liver, containing high levels of reactive mediators (eg, peroxynitrite), modifies fibrin(ogen) such that fibrin polymerization is impaired without impacting FXIII-mediated cross-linking. Notably, fibrin(ogen) modified with 3-nitrotyrosine adducts was identified in the APAP-injured liver. In biochemical assays, peroxynitrite inhibited thrombin-mediated fibrin polymerization in a concentration-dependent manner without affecting fibrin(ogen) cross-linking over time. These studies depict a unique pathology wherein thrombin-catalyzed fibrin polymerization is circumvented to allow tissue deposition and FXIII-dependent fibrin(ogen) cross-linking.

IL-36 expression is increased in NSCLC with IL-36 stimulation of lung cancer cells promoting a pro-tumorigenic phenotype.

The IL-36 cytokines are a recently described subset of the IL-1 family of cytokines, and have been shown to play a role in the pathogenesis of respiratory diseases such as asthma and COPD. Given the common aetiological links between COPD and lung cancer development, as well as the involvement of other IL-1 family members in lung tumorigenesis, the aim of this work was to investigate the role of IL-36 cytokines in the pathogenesis of lung cancer. In this study we demonstrate that expression of IL-36 cytokines and receptor mRNA and protein are significantly increased in lung cancer tissue compared to adjacent non-tumour tissue. In vitro assays showed that stimulation of two lung cancer cell lines, SKMES-1 human squamous cell and LLC murine lung cancer, with IL-36R agonists resulted in increased cellular migration and proliferation. All IL-36 cytokines induced the expression of pro-inflammatory chemokines in both lung cancer cell lines with synergistic effects identified upon co-stimulation of cells with IL-17, IL-22 and TNFα. Furthermore, we report that IL-36 cytokines induce protein expression of the immune checkpoint inhibitor protein PD-L1 on lung cancer cells. Taken together, this data indicates that targeting IL-36R signalling may be a useful targeted therapy for lung cancer patients with IL-36R+ cancer cells.

Early patellofemoral cartilage and bone pathology in a rat model of noninvasive anterior cruciate ligament rupture.

OBJECTIVE: Anterior cruciate ligament rupture (ACLR) is a risk factor for the development of post-traumatic osteoarthritis (PTOA). While PTOA in the tibiofemoral joint compartment is well-characterized, very little is known about pathology in the patellofemoral compartment after ACL injury. Here, we evaluated the extent to which ACLR induces early patellofemoral joint damage in a rat model. METHODS: Adult female Lewis rats were randomized to noninvasive ACLR or Sham. Two weeks post-injury, contrast-enhanced micro-computed tomography (µCT) of femoral and patellar cartilage was performed using 20% v/v ioxaglate. Morphometric parameters of femoral trochlear and patellar cartilage, subchondral bone, and trabecular bone were derived from µCT. Sagittal Safranin-O/Fast-Green-stained histologic sections were graded using the OARSI score in a blinded fashion. RESULTS: Cartilage and bone remodelling consistent with an early PTOA phenotype were observed in both femoral trochleas and patellae. ACLR caused osteophyte formation of the patella and pathology in the superficial zone of articular cartilage, including surface fibrillation, fissures, increased cellularity, and abnormal chondrocyte clustering. There were significant increases in thickness of patellar and trochlear cartilage. Loss of subchondral bone thickness, bone volume fraction, and tissue mineral density, as well as changes to patellar and trochlear trabecular microarchitecture, were indicative of catabolic bone remodelling. Several injury-induced changes, including increased cartilage thickness and trabecular spacing and decreased trabecular number were more severe in the patella compared to the trochlea. CONCLUSION: The patellofemoral joint develops mild but evident pathology in the early period following ACL rupture, extending the utility of this model to the study of patellofemoral PTOA.

Optimizing the role of 'lead mothers' in seasonal malaria chemoprevention (SMC) campaigns: formative research in Kano State, northern Nigeria.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a safe and effective intervention for preventing malaria in children under 5 years of age. Lead mothers are community health volunteers that help caregivers comply with monthly administration of anti-malarial drugs during SMC campaigns. The lead mother approach is used in several SMC implementing states across Nigeria, but there is lack of evidence about their roles and how effective they are. This study sought to better understand the current role of lead mothers, identify areas for improvement and ways to optimize the role of lead mothers during SMC campaigns. METHODS: This paper reports the formative phase of a three-phased intervention development study. The formative phase involved semi-structured interviews with stakeholders from national, state, local government and community levels (n = 20). Thematic analysis was used to identify key themes, forming the basis of a subsequent co-design workshop with stakeholders routinely involved in SMC campaigns. RESULTS: The findings of the formative phase converged around four overarching themes: skills and attributes required of lead mothers; factors that affect lead mother's roles; how lead mothers interact with Community Health Influencers Promoters Services (CHIPS) agents and re-imagining the role of lead mothers during SMC campaigns. CONCLUSION: This formative work in Kano state indicates that through their strong connection to communities and unique relationship with caregivers, lead mothers can and do influence caregivers to adopt healthy behaviours during SMC campaigns. However, there is room for improvement in how they are recruited, trained and supervised. There is need to improve lead mothers' knowledge and skills through adequate training and supporting materials, so they can deliver targeted health messages to caregivers. Sustainability of the lead mother approach is at risk if policymakers do not find a way of transitioning their role into the existing community health worker infrastructure, for example by using CHIPs agents, and ensuring less reliance on external donor support.

A non-randomized controlled trial to assess the protective effect of SMC in the context of high parasite resistance in Uganda.

BACKGROUND: Until recently, due to widespread prevalence of molecular markers associated with sulfadoxine-pyrimethamine (SP) and amodiaquine (AQ) resistance in east and southern Africa, seasonal malaria chemoprevention (SMC) has not been used at scale in this region. This study assessed the protective effectiveness of monthly administration of SP + AQ (SPAQ) to children aged 3-59 months in Karamoja sub-region, Uganda, where parasite resistance is assumed to be high and malaria transmission is seasonal. METHODS: A two-arm quasi-experimental, open-label prospective non-randomized control trial (nRCT) was conducted in three districts. In two intervention districts, 85,000 children aged 3-59 months were targeted to receive monthly courses of SMC using SPAQ during the peak transmission season (May to September) 2021. A third district served as a control, where SMC was not implemented. Communities with comparable malaria attack rates were selected from the three districts, and households with at least one SMC-eligible child were purposively selected. A total cohort of 600 children (200 children per district) were selected and followed using passive surveillance for breakthrough confirmed malaria episodes during the five-month peak transmission season. Malaria incidence rate per person-months and number of malaria episodes among children in the two arms were compared. Kaplan-Meier failure estimates were used to compare the probability of a positive malaria test. Other factors that may influence malaria transmission and infection among children in the two arms were also assessed using multivariable cox proportional hazards regression model. RESULTS: The malaria incidence rate was 3.0 and 38.8 per 100 person-months in the intervention and control groups, respectively. In the intervention areas 90.0% (361/400) of children did not experience any malaria episodes during the study period, compared to 15% (29/200) in the control area. The incidence rate ratio was 0.078 (95% CI 0.063-0.096), which corresponds to a protective effectiveness of 92% (95% CI 90.0-94.0) among children in the intervention area. CONCLUSION: SMC using SPAQ provided high protective effect against malaria during the peak transmission season in children aged 3-59 months in the Karamoja sub-region of Uganda.

Barriers and facilitators of the return-to-school process affecting adolescent recipients of allogeneic hematopoietic cell transplantation: A qualitative interview study of caregivers.

BACKGROUND: Adolescent hematopoietic cell transplant (HCT) recipients remain out of school for a prolonged period of time; navigating their return to school after completion of therapy can be challenging for caregivers. METHODS: Between August 2020 and June 2021, we conducted individual semi-structured interviews of 19 caregivers of adolescent HCT recipients (10-18 years of age at HCT; 1-7 years post HCT) to understand the challenges faced at the time of their child's return to in-person school post HCT. Conventional content analysis was used to analyze interview transcripts, and thematic analysis was used to identify and organize emerging themes. RESULTS: Three themes emerged from the caregivers' experiences. First, caregivers reported facing several challenges related to lack of communication between their child's healthcare and school teams, which was burdensome for them. Second, some caregivers reported receiving support from school and healthcare professionals, as well as their child's peers, which helped reduce the burden of return to school. Caregivers also reported providing motivational, emotional, and spiritual support to patients. Lastly, caregivers made several recommendations regarding the need for better communication between family, healthcare professionals, and school professionals and availability of supportive care such as mental health counseling and neuropsychological testing. Notably, the need for a return-to-school navigator emerged as a key finding from our analysis. CONCLUSIONS: Caregivers of adolescent HCT recipients face several challenges supporting their children's return to school post HCT, which are related to lack of communication between patients' healthcare and school teams. While some reported receiving support from school and healthcare professionals and their child's peers, the need to coordinate the return-to-school process was burdensome for several caregivers. Additional work is needed to optimize support for HCT recipients and their caregivers during their return-to-school process to minimize burden. Our study findings have the potential to serve as a framework for developing and testing supportive care interventions to improve the return-to-school experience of HCT survivors and ultimately their quality of life.

Delivery of seasonal malaria chemoprevention with enhanced infection prevention and control measures during the COVID-19 pandemic in Nigeria, Burkina Faso and Chad: a cross-sectional study.

BACKGROUND: Seasonal malaria chemoprevention (SMC) is a WHO-recommended intervention for children aged 3-59 months living in areas of high malaria transmission to provide protection against malaria during the rainy season. Operational guidelines were developed, based on WHO guidance, to support countries to mitigate the risk of coronavirus disease 2019 (COVID-19) transmission within communities and among community distributors when delivering SMC. METHODS: A cross-sectional study to determine adherence to infection prevention and control (IPC) measures during two distribution cycles of SMC in Nigeria, Chad and Burkina Faso. Community distributors were observed receiving equipment and delivering SMC. Adherence across six domains was calculated as the proportion of indications in which the community distributor performed the correct action. Focus group discussions were conducted with community distributors to understand their perceptions of the IPC measures and barriers and facilitators to adherence. RESULTS: Data collectors observed community distributors in Nigeria (n = 259), Burkina Faso (n = 252) and Chad (n = 266) receiving IPC equipment and delivering SMC. Adherence to IPC indications varied. In all three countries, adherence to mask use was the highest (ranging from 73.3% in Nigeria to 86.9% in Burkina Faso). Adherence to hand hygiene for at least 30 s was low (ranging from 3.6% in Nigeria to 10.3% in Burkina Faso) but increased substantially when excluding the length of time spent hand washing (ranging from 36.7% in Nigeria to 61.4% in Burkina Faso). Adherence to safe distancing in the compound ranged from 5.4% in Chad to 16.4% in Nigeria. In Burkina Faso and Chad, where disinfection wipes widely available compliance with disinfection of blister packs for SMC was low (17.4% in Burkina Faso and 16.9% in Chad). Community distributors generally found the IPC measures acceptable, however there were barriers to optimal hand hygiene practices, cultural norms made social distancing difficult to adhere to and caregivers needed assistance to administer the first dose of SMC. CONCLUSION: Adherence to IPC measures for SMC delivery during the COVID-19 pandemic varied across domains of IPC, but was largely insufficient, particularly for hand hygiene and safe distancing. Improvements in provision of protective equipment, early community engagement and adaptations to make IPC measures more feasible to implement could increase adherence.

Preoperative anemia and complications after surgery for pelvic organ prolapse: an analysis of the national surgical quality improvement program database.

INTRODUCTION AND HYPOTHESIS: Preoperative anemia is a well-established risk factor for adverse perioperative outcomes in major surgery, but studies exploring complications after pelvic reconstructive surgery are limited. The objective of this study is to examine the impact of preoperative anemia on 30-day adverse outcomes in patients undergoing pelvic organ prolapse surgery. METHODS: A retrospective cohort of women undergoing pelvic organ prolapse surgery was captured from the National Surgery Quality Improvement Program database (2014-2019). The primary outcome was a composite of postoperative medical complications such as pulmonary embolism, acute renal failure, stroke, myocardial infarction, cardiac arrest, deep vein thrombosis, and sepsis. Secondary outcomes included surgical site infection, bleeding requiring blood transfusion, readmission within 7 days of surgery, and return to the operating room within 30 days. Multivariate logistic regression was used to adjust for important pre-specified potential confounders. RESULTS: A total of 50,848 women were included in the analysis and 9.9% (4,579) met the criteria for anemia (hematocrit <36%). Potentially serious medical complications were rare, occurring in only 348 women (0.7%), and were more common among anemic patients (1.1% vs 0.6%, p < 0.001). On multivariate analysis, preoperative anemia was associated with higher odds of both potentially serious medical complications (OR 1.38, 95% CI 1.01-1.88) and returning to the operating room (OR 1.55, 95% CI 1.23-1.94). Anemic patients had a four-fold increase in the odds of requiring a blood transfusion (OR 4.47, 95% CI 3.60-5.56). CONCLUSIONS: Preoperative anemia is associated with an increased risk of adverse postoperative outcomes in women having surgery for pelvic organ prolapse.

Pelvic floor muscle training as an adjunct to a midurethral sling: a single-blind randomised controlled trial.

INTRODUCTION AND HYPOTHESIS: This single-blind, randomised controlled trial was aimed at determining whether peri-operative physiotherapist-supervised pelvic floor muscle (PFM) training was superior to standard care (handout) in terms of improvements in stress urinary incontinence (SUI) symptoms, cure rate, and/or post-operative filling or voiding symptoms among women undergoing surgical mid-urethral sling (MUS) insertion for SUI. METHODS: Women with SUI were recruited from surgical wait lists at four participating urogynecology clinics. Participants were assessed at baseline (V1) then randomised (1:1 allocation) to receive supervised PFM training or a handout. Immediately following the 12-week intervention period (V2) and at 12 weeks following surgery (V3) the groups were compared based on the Female Lower Urinary Tract Symptoms (FLUTS) questionnaire total score and urinary incontinence, filling, and voiding subscale scores as well as on a standardised 30-min pad test administered by a blinded assessor. Intention-to-treat analyses were performed. RESULTS: A total of 52 participants were randomised to physiotherapy and 51 to the control group between December 2012 and August 2016. The groups were not different on any outcomes at V1 and all were improved at V3 compared with V1 (p < 0.001). At V3 the physiotherapy group reported significantly fewer UI symptoms (FLUTS UI subscale score) than the control group; yet, there were no group differences in FLUTS overall score or the pad test (p > 0.05). Based on a FLUTS UI subscale score <4, the cure rate at V3 was higher in the intervention group (73%) than in the control group (47%); (2.36 < OR < 3.47, p = 0.012). There were no group differences in cure rate at V3 based on a pad test (p = 0.27). No group differences were found in the filling or voiding symptoms at V3 (p > 0.05). No adverse events were reported. CONCLUSION: Physiotherapist-supervised PFM training improves SUI cure rates associated with surgical MUS insertion when considering symptoms of SUI, but does not improve post-operative continence function as measured by a pad test, nor does it lead to fewer post-operative voiding or filling symptoms.

IL-36 cytokines in inflammatory and malignant diseases: not the new kid on the block anymore.

The IL-36 family of cytokines were first identified in 2000 based on their sequence homology to IL-1 cytokines. Over subsequent years, the ability of these cytokines to either agonise or antagonise an IL-1R homologue, now known as the IL-36 Receptor (IL-36R), was identified and these cytokines went through several cycles of renaming with the current nomenclature being proposed in 2010. Despite being identified over 20 years ago, it is only during the last decade that the function of these cytokines in health and disease has really begun to be appreciated, with both homeostatic functions in wound healing and response to infection, as well as pathological functions now ascribed. In the disease context, over activation of IL-36 has now been associated with many inflammatory diseases including Psoriasis and inflammatory bowel diseases, with roles in cancer also now being investigated. This review summarises the current knowledge of IL-36 biology, its role in inflammatory diseases and focuses on an emerging role for IL-36 in cancer.

Extending seasonal malaria chemoprevention to five cycles: a pilot study of feasibility and acceptability in Mangodara district, Burkina Faso.

BACKGROUND: Seasonal malaria chemoprevention (SMC) involves administering antimalarial drugs at monthly intervals during the high malaria transmission period to children aged 3 to 59 months as recommended by the World Health Organization. Typically, a full SMC course is administered over four monthly cycles from July to October, coinciding with the rainy season. However, an analysis of rainfall patterns suggest that the malaria transmission season is longer and starting as early as June in the south of Burkina Faso, leading to a rise in cases prior to the first cycle. This study assessed the acceptability and feasibility of extending SMC from four to five cycles to coincide with the earlier rainy season in Mangodara health district. METHODS: The mixed-methods study was conducted between July and November 2019. Quantitative data were collected through end-of-cycle and end-of-round household surveys to determine the effect of the additional cycle on the coverage of SMC in Mangodara. The data were then compared with 22 other districts where SMC was implemented by Malaria Consortium. Eight focus group discussions were conducted with caregivers and community distributors and 11 key informant interviews with community, programme and national-level stakeholders. These aimed to determine perceptions of the acceptability and feasibility of extending SMC to five cycles. RESULTS: The extension was perceived as acceptable by caregivers, community distributors and stakeholders due to the positive impact on the health of children under five. However, many community distributors expressed concern over the feasibility, mainly due to the clash with farming activities in June. Stakeholders highlighted the need for more evidence on the impact of the additional cycle on parasite resistance prior to scale-up. End-of-cycle survey data showed no difference in coverage between five SMC cycles in Mangodara and four cycles in the 22 comparison districts. CONCLUSIONS: The additional cycle should begin early in the day in order to not coincide with the agricultural activities of community distributors. Continuous sensitisation at community level is critical for the sustainability of SMC and acceptance of an additional cycle, which should actively engage male caregivers. Providing additional support in proportion to the increased workload from a fifth cycle, including timely remuneration, is critical to avoid the demotivation of community distributors. Further studies are required to understand the effectiveness, including cost-effectiveness, of tailoring SMC according to the rainy season. Understanding the impact of an additional cycle on parasite resistance to SPAQ is critical to address key informants' concerns around the deviation from the current four-cycle policy recommendation.