Child deaths caused by Klebsiella pneumoniae in sub-Saharan Africa and south Asia: a secondary analysis of Child Health and Mortality Prevention Surveillance (CHAMPS) data.

BACKGROUND: Klebsiella pneumoniae is an important cause of nosocomial and community-acquired pneumonia and sepsis in children, and antibiotic-resistant K pneumoniae is a growing public health threat. We aimed to characterise child mortality associated with this pathogen in seven high-mortality settings. METHODS: We analysed Child Health and Mortality Prevention Surveillance (CHAMPS) data on the causes of deaths in children younger than 5 years and stillbirths in sites located in seven countries across sub-Saharan Africa (Ethiopia, Kenya, Mali, Mozambique, Sierra Leone, and South Africa) and south Asia (Bangladesh) from Dec 9, 2016, to Dec 31, 2021. CHAMPS sites conduct active surveillance for deaths in catchment populations and following reporting of an eligible death or stillbirth seek consent for minimally invasive tissue sampling followed by extensive aetiological testing (microbiological, molecular, and pathological); cases are reviewed by expert panels to assign immediate, intermediate, and underlying causes of death. We reported on susceptibility to antibiotics for which at least 30 isolates had been tested, and excluded data on antibiotics for which susceptibility testing is not recommended for Klebsiella spp due to lack of clinical activity (eg, penicillin and ampicillin). FINDINGS: Among 2352 child deaths with cause of death assigned, 497 (21%, 95% CI 20-23) had K pneumoniae in the causal chain of death; 100 (20%, 17-24) had K pneumoniae as the underlying cause. The frequency of K pneumoniae in the causal chain was highest in children aged 1-11 months (30%, 95% CI 26-34; 144 of 485 deaths) and 12-23 months (28%, 22-34; 63 of 225 deaths); frequency by site ranged from 6% (95% CI 3-11; 11 of 184 deaths) in Bangladesh to 52% (44-61; 71 of 136 deaths) in Ethiopia. K pneumoniae was in the causal chain for 450 (22%, 95% CI 20-24) of 2023 deaths that occurred in health facilities and 47 (14%, 11-19) of 329 deaths in the community. The most common clinical syndromes among deaths with K pneumoniae in the causal chain were sepsis (44%, 95% CI 40-49; 221 of 2352 deaths), sepsis in conjunction with pneumonia (19%, 16-23; 94 of 2352 deaths), and pneumonia (16%, 13-20; 80 of 2352 deaths). Among K pneumoniae isolates tested, 121 (84%) of 144 were resistant to ceftriaxone and 80 (75%) of 106 to gentamicin. INTERPRETATION: K pneumoniae substantially contributed to deaths in the first 2 years of life across multiple high-mortality settings, and resistance to antibiotics used for sepsis treatment was common. Improved strategies are needed to rapidly identify and appropriately treat children who might be infected with this pathogen. These data suggest a potential impact of developing and using effective K pneumoniae vaccines in reducing neonatal, infant, and child deaths globally. FUNDING: Bill & Melinda Gates Foundation.

Causes of death identified in neonates enrolled through Child Health and Mortality Prevention Surveillance (CHAMPS), December 2016 -December 2021.

Each year, 2.4 million children die within their first month of life. Child Health and Mortality Prevention Surveillance (CHAMPS) established in 7 countries aims to generate accurate data on why such deaths occur and inform prevention strategies. Neonatal deaths that occurred between December 2016 and December 2021 were investigated with MITS within 24-72 hours of death. Testing included blood, cerebrospinal fluid and lung cultures, multi-pathogen PCR on blood, CSF, nasopharyngeal swabs and lung tissue, and histopathology examination of lung, liver and brain. Data collection included clinical record review and family interview using standardized verbal autopsy. The full set of data was reviewed by local experts using a standardized process (Determination of Cause of Death) to identify all relevant conditions leading to death (causal chain), per WHO recommendations. For analysis we stratified neonatal death into 24-hours of birth, early (1-<7 days) and late (7-<28 days) neonatal deaths. We analyzed 1458 deaths, 41% occurring within 24-hours, 41% early and 18% late neonatal deaths. Leading underlying causes of death were complications of intrapartum events (31%), complications of prematurity (28%), infections (17%), respiratory disorders (11%), and congenital malformations (8%). In addition to the underlying cause, 62% of deaths had additional conditions and 14% had ≥3 other conditions in the causal chain. The most common causes considering the whole causal chain were infection (40%), prematurity (32%) and respiratory distress syndrome (28%). Common maternal conditions linked to neonatal death were maternal hypertension (10%), labour and delivery complications (8%), multiple gestation (7%), placental complications (6%) obstructed labour and chorioamnionitis (5%, each). CHAMPS' findings showing the full causal chain of events that lead to death, in addition to maternal factors, highlights the complexities involved in each death along with the multiple opportunities for prevention. Highlighting improvements to prenatal and obstetric care and infection prevention are urgently needed in high-mortality settings.

Lack of Association of C677T Methylenetetrahydrofolate Reductase Polymorphism with Breast Cancer Risk in Mali.

Methylenetetrahydrofolate reductase (MTHFR) plays a major role in the metabolism of folates and homocysteine, which in turn can affect gene expression and ultimately promote the development of breast cancer. Thus, mutations in the MTHFR gene could influence homocysteine, methionine, and S-adenosylmethionine levels and, indirectly, nucleotide levels. Imbalance in methionine and S-adenosylmethionine synthesis affects protein synthesis and methylation. These changes, which affect gene expression, may ultimately promote the development of breast cancer. We therefore hypothesized that such mutations could also play an important role in the occurrence and pathogenesis of breast cancer in a Malian population. In this study, we used the PCR-RFLP technique to identify the different genotypic profiles of the C677T MTHFR polymorphism in 127 breast cancer women and 160 healthy controls. The genotypic distribution of the C677T polymorphism in breast cancer cases was 88.2% for CC, 11.0% for CT, and 0.8% for TT. Healthy controls showed a similar distribution with 90.6% for CC, 8.8% for CT, and 0.6% for TT. We found no statistical association between the C677T polymorphism and breast cancer risk for the codominant models CT and TT (p > 0.05). The same trend was observed when the analysis was extended to other genetic models, including dominant (p = 0.50), recessive (p = 0.87), and additive (p = 0.50) models. The C677T polymorphism of MTHFR gene did not influence the risk of breast cancer in the Malian samples.

Relationships between gut microbiota, red meat consumption and colorectal cancer.

Excessive consumption of red and processed meat has been associated with a higher risk of developing colorectal cancer. There are many attempts to explain the risk of colorectal cancer associated with the consumption of red and processed meat: The temperature cooking of meat such as grilling and smoking contribute to the formation of mutagenic compounds including heterocyclic amines and polycyclic aromatic hydrocarbons.Heme iron in red meat is involved in the formation of N-nitroso compounds and lipid peroxidation products in the digestive tract.Fatty red meat is involved in the production of secondary bile acids by the bacteria of the gut microbiota. Many of the products formed are genotoxic and can cause DNA damage and initiate carcinogenesis of colorectal cancer. Various mechanisms contributing to their genotoxic role have been established in human and animal studies. In addition, there is increasing evidence that compounds formed from red and processed meat interact with the gut microbiota in colorectal cancer pathways. Although several early studies in animals and humans suggest a direct causal role of the gut microbiota in the development of colorectal cancer, the links between diet, gut microbiota, and colonic carcinogenesis are largely associations rather than proven causal relationships. Various biological mechanisms, including inflammation and oxidative stress can lead to DNA damage, gut dysbiosis, and therefore increase the risk of colorectal cancer. Dysbiosis of the gut microbiota may increase the risk of colorectal cancer through dietary component promotion of colonic carcinogenesis. In this paper, we review and update current knowledge about the relationships between red meat consumption, gut microbiota, and colorectal cancer.

Type-specific incidence, persistence and factors associated with human papillomavirus infection among female sex workers in Benin and Mali, West Africa.

OBJECTIVES: This study in female sex workers (FSWs) aimed to: (1) estimate type-specific incidence and persistence of human papillomavirus (HPV) infection in Cotonou (Benin) and Bamako (Mali); and (2) identify the factors associated with type-specific incidence and persistence of high-risk HPV (HR-HPV) infection. METHODS: A 1-year prospective cohort study on cervical cancer screening, and HPV and human immunodeficiency virus (HIV) infections was conducted among FSWs in Cotonou and Bamako from 2017 to 2019. Poisson regression models assessed factors associated with the incidence of HR-HPV infection, while log-binomial regression was performed to identify factors associated with the persistence of HR-HPV infection. Adjusted relative risks (ARR) and 95% confidence intervals (95% CI) were estimated. RESULTS: The incidence of HR-HPV infection was 46.98 per 1000 women-months (predominant types HPV16, HPV35 and HPV59). Factors associated with the incidence of HR-HPV infection were age <20 years (ARR 15.10; 95% CI 3.29-69.19), age at sexual debut <18 years (ARR 6.92; 95% CI 1.97-24.27) and sex work duration ≤1 year (ARR 7.40; 95% CI 1.84-29.69). The persistence of HR-HPV infection at 12 months was 38.7% (most persistent types HPV59, HPV52 and HPV51). Persistence of HR-HPV infection was higher in women with chlamydia (P = 0.031), HIV infection (P < 0.001) and multiple-type HPV infections (P < 0.001). CONCLUSION: FSWs in West Africa are at high risk of incident and persistent HR-HPV infection, suggesting an urgent need for cervical cancer screening in this population.

A population-based combination strategy to improve the cervical cancer screening coverage rate in Bamako, Mali.

INTRODUCTION: Cervical cancer screening coverage rate is <5% in Sub-Saharan Africa and <2% in French- speaking African countries. In 2016, we implemented strategies to improve cervical cancer screening in Bamako, the "Weekend70 program". The present study objectives are to determine the effect of this program on women's participation in cervical cancer screening in Bamako, and to estimate the cervical cancer screening coverage rate in Bamako. MATERIAL AND METHODS: From 1 January 2016 to 31 July 2020, we conducted an operational research by developing several strategies to improve the cervical cancer screening coverage rate among adolescents and women ≥15 years old in Bamako, Mali. The strategies consisted of awareness-raising activities, strengthening of screening practices in healthcare facilities and cost-free cervical cancer screening during the weekend. Descriptive statistics were presented. The cervical cancer coverage rate was calculated by dividing the number of women screened by the total number of women ≥20 years old, based on Mali demographic data. RESULTS: The total number of women screened was 289 924. Residents from Bamako represented 91.9% (266 436/289 924) vs 8.1% (23 488/289 924) who lived outside Bamako. The mean age was 33.2 (± 11.5) years old. Around 46.1% of participants attending the cervical cancer screening were between 30 and 49 years old (World Health Organization prioritized target age for cervical cancer screening). Women ≥60 years old represented <5%. Cervical cancer screening participation increased significantly, from <800 women screened per week before the implementation of the program to a peak of 4100 women screened per week during the "Weekend70 program". Overall, the cervical cancer screening coverage rates at the end of the study among women ≥20 years old was 47.3%, and 56.9% in the WHO target population. CONCLUSION: In an impoverished context, a multi-component strategy significantly increases cervical cancer screening participation.

Cervical Cancer in Sub-Saharan Africa: A Multinational Population-Based Cohort Study of Care and Guideline Adherence.

BACKGROUND: Cervical cancer (CC) is the most common female cancer in many countries of sub-Saharan Africa (SSA). We assessed treatment guideline adherence and its association with overall survival (OS). METHODS: Our observational study covered nine population-based cancer registries in eight countries: Benin, Ethiopia, Ivory Coast, Kenya, Mali, Mozambique, Uganda, and Zimbabwe. Random samples of 44-125 patients diagnosed from 2010 to 2016 were selected in each. Cancer-directed therapy (CDT) was evaluated for degree of adherence to National Comprehensive Cancer Network (U.S.) Guidelines. RESULTS: Of 632 patients, 15.8% received CDT with curative potential: 5.2% guideline-adherent, 2.4% with minor deviations, and 8.2% with major deviations. CDT was not documented or was without curative potential in 22%; 15.7% were diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage IV disease. Adherence was not assessed in 46.9% (no stage or follow-up documented, 11.9%, or records not traced, 35.1%). The largest share of guideline-adherent CDT was observed in Nairobi (49%) and the smallest in Maputo (4%). In patients with FIGO stage I-III disease (n = 190), minor and major guideline deviations were associated with impaired OS (hazard rate ratio [HRR], 1.73; 95% confidence interval [CI], 0.36-8.37; HRR, 1.97; CI, 0.59-6.56, respectively). CDT without curative potential (HRR, 3.88; CI, 1.19-12.71) and no CDT (HRR, 9.43; CI, 3.03-29.33) showed substantially worse survival. CONCLUSION: We found that only one in six patients with cervical cancer in SSA received CDT with curative potential. At least one-fifth and possibly up to two-thirds of women never accessed CDT, despite curable disease, resulting in impaired OS. Investments into more radiotherapy, chemotherapy, and surgical training could change the fatal outcomes of many patients. IMPLICATIONS FOR PRACTICE: Despite evidence-based interventions including guideline-adherent treatment for cervical cancer (CC), there is huge disparity in survival across the globe. This comprehensive multinational population-based registry study aimed to assess the status quo of presentation, treatment guideline adherence, and survival in eight countries. Patients across sub-Saharan Africa present in late stages, and treatment guideline adherence is remarkably low. Both factors were associated with unfavorable survival. This report warns about the inability of most women with cervical cancer in sub-Saharan Africa to access timely and high-quality diagnostic and treatment services, serving as guidance to institutions and policy makers. With regard to clinical practice, there might be cancer-directed treatment options that, although not fully guideline adherent, have relevant survival benefit. Others should perhaps not be chosen even under resource-constrained circumstances.

p.Arg72Pro polymorphism of P53 and breast cancer risk: a meta-analysis of case-control studies.

BACKGROUND: The effect of the p.Arg72Pro variant of the P53 gene on the risk of development ofbreast cancer remains variable in populations. However, the use ofstrategies such aspoolingage-matched controls with disease may provide a consistent meta-analysis. Our goal was to perform a meta-analysis in order to assess the association of p.Arg72Pro variant of P53 gene with the risk of breast cancer. METHODS: Databases such as PubMed, Genetics Medical Literature, Harvard University Library, Web of Science and Genesis Library were used to search articles. Case-control studies with age-matched on breast cancer havingevaluated the genotype frequencies of the TP53 p.Arg72Pro polymorphism were selected. The fixed and random effects (Mantel-Haenszel) were calculated using pooled odds ratio of 95% CI to determine the risk of disease. Inconsistency was calculated to determine heterogeneity among the studies. The publication bias was estimated using the funnel plot. RESULTS: Twenty-one publications with 7841 cases and 8876 controls were evaluated in this meta-analysis. Overall, our results suggested that TP53 p.Arg72Pro was associated with the risk of breast cancer for the dominant model (OR = 1.09, 95% CI = 1.02-1.16, P = 0.01) and the additive model (OR = 1.09, 95% CI = 1.01-1.17, P = 0.03), but not for the recessive model (OR = 1.07, 95% CI = 0.97-1.18, P = 0.19). According to the ethnic group analysis, Pro allele was associated with the risk of breast cancer in Caucasians for the dominant model and additive model (P = 0.02), and Africans for the recessive model and additive model (P = 0.03). CONCLUSIONS: This meta-analysis found a significant association between TP53 p.Arg72Pro polymorphism and the risk of breast cancer. Individuals carrying at least one Pro allele were more likely to have breast cancer than individuals harboring the Arg allele.

Differences in patterns of high-risk human papillomavirus infection between urban and rural low-resource settings: cross-sectional findings from Mali.

BACKGROUND: The burden of cervical cancer is disproportionately high in low-resource settings. With limited implementation of human papillomavirus (HPV) vaccines on the horizon in the developing world, reliable data on the epidemiology of high-risk HPV (HR-HPV) infection in distinct geographic populations is essential to planners of vaccination programs. The purpose of this study was to determine whether urban patterns of HR-HPV occurrence can be generalized to rural areas of the same developing country, using data from Mali, West Africa, as an example. METHODS: Urban and rural women in Mali participated in a structured interview and clinician exam, with collection of cervical samples for HPV DNA testing, to determine HR-HPV prevalence and correlates of infection. Correlates were assessed using bivariate analysis and logistic regression. RESULTS: A total of 414 women (n=202 urban women; n=212 rural women) were recruited across both settings. The prevalence of HR-HPV infection in rural women was nearly twice that observed in urban women (23% v. 12%). Earlier age of sexual debut and fewer pregnancies were associated with HR-HPV infection among urban women, but not rural women. Twenty-six percent of urban women who had sexual intercourse by age 14 had an HR-HPV infection, compared to only 9% of those who had later sexual debut (p<0.01). Overall, age, income, and polygamy did not appear to have a relationship with HR-HPV infection. CONCLUSIONS: Compared to urban women, rural women were significantly more likely to be infected with high-risk HPV. The patterns and risk factors of HR-HPV infection may be different between geographic areas, even within the same developing country. The high prevalence in both groups suggests that nearly all rural women and most urban women in Mali will be infected with HR-HPV during their lifetime, so the effects of risk factors may not be statistically apparent. To control HPV and cervical cancer in West Africa and the rest of the developing world, planners should prioritize vaccination in high-burden areas.

Risk factors for high-risk human papillomavirus infection in unscreened Malian women.

OBJECTIVE: To investigate the epidemiology of human papillomavirus (HPV) infection in Malian women, for whom cervical cancer is the most common cancer and the second most common cause of cancer-related mortality. METHODS: Pilot study of 202 women aged 15-65 to determine the prevalence rate of high-risk HPV infection among unscreened Malian women. Information on risk factors was collected through a standardized, structured interview and clinical examination. High-risk (HR) HPV DNA was detected using signal amplification methods (hybrid capture II). RESULTS: High-risk HPV DNA was detected in 12% of unscreened women, while visual inspection after application of acetic acid and Lugol's iodine (VIA/VILI) identified suspicious abnormalities in 2.5% of unscreened women. Histopathological evaluation of VIA/VILI-positive biopsies revealed no evidence of cervical intraepithelial neoplasia or cervical cancer. The majority of infections occurred among women in the 15-24 year old range. Compared to women who were married or widowed, single women were 3.5 times more likely to be infected with HR HPV. CONCLUSIONS: The prevalence of infection with cancer causing types of HPV in this study was 12%. These prevalence estimates are consistent with what has been reported previously for other West African countries.