The Impact of Retail-Sector Delivery of Artemether–Lumefantrine on Malaria Treatment of Children under Five in Kenya: A Cluster Randomized Controlled Trial

In a cluster randomized trial, Beth Kangwana and colleagues find that provision of subsidized packs of the malaria therapy artemether-lumefantrine to shops more than doubled the proportion of children with fever who received drugs promptly

Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis

Background: Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients. Methods and Findings: We performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC) selected because they had either pCR (n = 18) or extensive residual disease (n = 11) after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144) and METABRIC (n = 278) cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02) and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05). Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D) TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of-care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021), and they had significantly higher mutation burden (p < 0.001) and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009). As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort. Conclusions: The comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in TNBC and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC. © 2016 Jiang et al

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

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Understanding the impact of subsidizing artemisinin-based combination therapies (ACTs) in the retail sector--results from focus group discussions in rural Kenya.

BACKGROUND: There is considerable interest in the potential of private sector subsidies to increase availability and affordability of artemisinin-based combination therapies (ACTs) for malaria treatment. A cluster randomized trial of such subsidies was conducted in 3 districts in Kenya, comprising provision of subsidized packs of paediatric ACT to retail outlets, training of retail staff, and community awareness activities. The results demonstrated a substantial increase in ACT availability and coverage, though patient counselling and adherence were suboptimal. We conducted a qualitative study in order to understand why these successes and limitations occurred. METHODOLOGY/PRINCIPAL FINDINGS: Eighteen focus group discussions were conducted, 9 with retailers and 9 with caregivers, to document experiences with the intervention. Respondents were positive about intervention components, praising the focused retailer training, affordable pricing, strong promotional activities, dispensing job aids, and consumer friendly packaging, which are likely to have contributed to the positive access and coverage outcomes observed. However, many retailers still did not stock ACT, due to insufficient supplies, lack of capital and staff turnover. Advice to caregivers was poor due to insufficient time, and poor recall of instructions. Adherence by caregivers to dosing guidelines was sub-optimal, because of a wish to save tablets for other episodes, doses being required at night, stopping treatment when the child felt better, and the number and bitter taste of the tablets. Caregivers used a number of strategies to obtain paediatric ACT for older age groups. CONCLUSIONS/SIGNIFICANCE: This study has highlighted that important components of a successful ACT subsidy intervention are regular retailer training, affordable pricing, a reliable supply chain and community mobilization emphasizing patient adherence and when to seek further care

The effect of an anti-malarial subsidy programme on the quality of service provision of artemisinin-based combination therapy in Kenya: a cluster-randomized, controlled trial.

BACKGROUND: Many patients with suspected malaria in sub-Saharan Africa seek treatment from private providers, but this sector suffers from sub-standard medicine dispensing practices. To improve the quality of care received for presumptive malaria from the highly accessed private retail sector in western Kenya, subsidized pre-packaged artemether-lumefantrine (AL) was provided to private retailers, together with a one day training for retail staff on malaria diagnosis and treatment, job aids and community engagement activities. METHODS: The intervention was assessed using a cluster-randomized, controlled design. Provider and mystery-shopper cross-sectional surveys were conducted at baseline and eight months post-intervention to assess provider practices. Data were analysed based on cluster-level summaries, comparing control and intervention arms. RESULTS: On average, 564 retail outlets were interviewed per year. At follow-up, 43% of respondents reported that at least one staff member had attended the training in the intervention arm. The intervention significantly increased the percentage of providers knowing the first line treatment for uncomplicated malaria by 24.2% points (confidence interval (CI): 14.8%, 33.6%; adjusted p=0.0001); the percentage of outlets stocking AL by 31.7% points (CI: 22.0%, 41.3%; adjusted p=0.0001); and the percentage of providers prescribing AL for presumptive malaria by 23.6% points (CI: 18.7%, 28.6%; adjusted p=0.0001). Generally outlets that received training and job aids performed better than those receiving one or none of these intervention components. CONCLUSION: Overall, subsidizing ACT and retailer training can significantly increase the percentage of outlets stocking and selling AL for the presumptive treatment of malaria, but further research is needed on strategies to improve the provision of counselling advice to retail customers