Respiratory Virus-Associated Severe Acute Respiratory Illness and Viral Clustering in Malawian Children in a Setting With a High Prevalence of HIV Infection, Malaria, and Malnutrition.

BACKGROUND: We used data from 4 years of pediatric severe acute respiratory illness (SARI) sentinel surveillance in Blantyre, Malawi, to identify factors associated with clinical severity and coviral clustering. METHODS: From January 2011 to December 2014, 2363 children aged 3 months to 14 years presenting to the hospital with SARI were enrolled. Nasopharyngeal aspirates were tested for influenza virus and other respiratory viruses. We assessed risk factors for clinical severity and conducted clustering analysis to identify viral clusters in children with viral codetection. RESULTS: Hospital-attended influenza virus-positive SARI incidence was 2.0 cases per 10 000 children annually; it was highest among children aged <1 year (6.3 cases per 10 000), and human immunodeficiency virus (HIV)-infected children aged 5-9 years (6.0 cases per 10 000). A total of 605 SARI cases (26.8%) had warning signs, which were positively associated with HIV infection (adjusted risk ratio [aRR], 2.4; 95% confidence interval [CI], 1.4-3.9), respiratory syncytial virus infection (aRR, 1.9; 95% CI, 1.3-3.0) and rainy season (aRR, 2.4; 95% CI, 1.6-3.8). We identified 6 coviral clusters; 1 cluster was associated with SARI with warning signs. CONCLUSIONS: Influenza vaccination may benefit young children and HIV-infected children in this setting. Viral clustering may be associated with SARI severity; its assessment should be included in routine SARI surveillance.

Prevalence and spectrum of illness among hospitalized adults with malaria in Blantyre, Malawi.

BACKGROUND: As control interventions are rolled out, the burden of malaria may shift from young children to older children and adults as acquisition of immunity is slowed and persistence of immunity is short-lived. Data for malaria disease in adults are difficult to obtain because of co-morbid conditions and because parasitaemia may be asymptomatic. Regular surveys of adult admissions to a hospital in Malawi were conducted to characterize the clinical spectrum of malaria and to establish a baseline to monitor changes that occur in future. METHODS: In 2011-2012, at Queen Elizabeth Hospital, Blantyre, four separated one-week surveys in the peak malaria transmission period (wet season) and three one-week surveys in the low transmission period (dry season) were conducted using rapid diagnostic tests (RDT) with confirmation of parasitaemia by microscopy. All adults (aged ≥15) being admitted to the adult medical wards regardless of the suspected diagnosis, were enrolled. Participants with a positive malaria test underwent a standardized physical examination and laboratory tests. Malaria syndromes were characterized by reviewing charts and laboratory results on discharge. RESULTS: 765 adult admissions were screened. 63 (8.2%) were RDT-positive with 61 (8.0%) positive by microscopy. Over the course of the seven study weeks, two patients were judged to have incidental parasitaemia, 31 (4.1%) had uncomplicated malaria and 28 (3.7%) had severe malaria. Both uncomplicated and severe malaria cases were more common in the rainy season than the dry season. Prostration (22/28 cases) and hyperparasitaemia (>250,000 parasites/µl) (9/28) were the most common features of severe malaria. Jaundice (4/28), severe anaemia (2/28), hyperlactataemia (2/28), shock (1/28) and haemoglobinuria (1/28) were less commonly seen, and no patient had severe metabolic derangement or organ failure. There were no deaths attributable to malaria. CONCLUSION: In this study of adults admitted to hospital in southern Malawi, an area with year-round transmission of Plasmodium falciparum, classical metabolic and organ complications of malaria were not encountered. Prostration and hyperparasitaemia were more common indicators of severity in patients admitted with malaria, none of whom died. These data will provide a baseline for monitoring trends in the frequency and clinical patterns of severe malaria in adults.

Surveillance Programme of IN-patients and Epidemiology (SPINE): implementation of an electronic data collection tool within a large hospital in Malawi.

Miguel Sanjoaquin and colleagues describe their experience of setting up an electronic patient records system in a large referral hospital in Blantyre, Malawi.

Lack of decline in childhood malaria, Malawi, 2001-2010.

In some areas of Africa, health facility data have indicated declines in malaria that might have resulted from increasingly effective control programs. Most such reports have been from countries where malaria transmission is highly seasonal or of modest intensity. In Malawi, perennial malaria transmission is intense, and malaria control measures have been scaled up during the past decade. We examined health facility data for children seen as outpatients and parasitemia-positive children hospitalized with cerebral malaria in a large national hospital. The proportion of Plasmodium falciparum-positive slides among febrile children at the hospital declined early in the decade, but no further reductions were observed after 2005. The number of admissions for cerebral malaria did not differ significantly by year. Continued surveillance for malaria is needed to evaluate the effects of the increased malaria control efforts.

Menopausal hormone therapy and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition.

Menopausal hormone therapy (HT) may influence colorectal cancer risk. A total of 136,275 postmenopausal women from the European Prospective Investigation into Cancer and Nutrition were followed for an average of 9 years, during which time 1,186 colorectal cancers were diagnosed. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models stratified by center and age, and adjusted for body mass index, smoking, diabetes, physical activity and alcohol consumption. Compared to never use of HT at study enrollment, current use of estrogen-only (HR, 1.02; 95% CI, 0.79-1.31) or estrogen plus progestin (HR, 0.94; 95% CI, 0.77-1.14) was not significantly associated with the risk of colorectal cancer, and these associations did not vary by recency, duration, route of administration, regimen or specific constituent of HT. Our results show no significant association of estrogen-only or estrogen plus progestin therapy with colorectal cancer risk.

Seasonal and geographic differences in treatment-seeking and household cost of febrile illness among children in Malawi.

BACKGROUND: Households in malaria endemic countries experience considerable costs in accessing formal health facilities because of childhood malaria. The Ministry of Health in Malawi has defined certain villages as hard-to-reach on the basis of either their distance from health facilities or inaccessibility. Some of these villages have been assigned a community health worker, responsible for referring febrile children to a health facility. Health facility utilization and household costs of attending a health facility were compared between individuals living near the district hospital and those in hard-to-reach villages. METHODS: Two cross-sectional household surveys were conducted in the Chikhwawa district of Malawi; one during each of the wet and dry seasons. Half the participating villages were located near the hospital, the others were in areas defined as hard-to-reach. Data were collected on attendance to formal health facilities and economic costs incurred due to recent childhood febrile illness. RESULTS: Those living in hard-to-reach villages were less likely to attend a formal health facility compared to those living near the hospital (Dry season: OR 0.35, 95%CI0.18-0.67; Wet season: OR 0.46, 95%CI0.27-0.80). Analyses including community health workers (CHW) as a source of formal health-care decreased the strength of this relationship, and suggested that consulting a CHW may reduce attendance at health facilities, even if indicated. Although those in hard-to-reach villages were still less likely to attend in both the dry (OR 0.53, 95%CI 0.25-1.11) and wet (OR 0.60, 95%CI 0.37-0.98) seasons. Household costs for those who attended a health facility were greater for those in HTR villages (Dry: USD5.24; Wet: USD5.60) than for those living near the district hospital (Dry: USD3.45; Wet: USD4.46). CONCLUSION: Those living in hard-to-reach areas were less likely to attend a health facility for a childhood febrile event and experienced greater associated household costs. Consulting CHWs was infrequent, but appeared to reduce attendance at a health facility, even when indicated. Health service planners must consider geographic and financial barriers to accessing public health facilities in designing appropriate interventions.

Assessing genuine parents-offspring trios for genetic association studies.

OBJECTIVES: Family-based association tests such as the transmission disequilibrium test (TDT) are dependent on the successful ascertainment of true nuclear family trios. Relationship misspecification inevitably occurs in a proportion of trios collected for genotyping which undetected can lead to a loss of power and increased Type I error due to biases in over-transmission of common alleles. Here, we introduce a method for evaluating the authenticity of nuclear family trios. METHODS: Operating in a Bayesian framework, our approach assesses the extent of pedigree inconsistent genotype configurations in the presence of genotyping errors. Unlike other approaches, our method: (i) utilizes information from three individuals collectively (the whole trio) rather than consider two independent pairwise relationships; (ii) down-weighs SNPs with poor performance; (iii) does not require the user to pre-define a rate of genotyping error, which is often unknown to the user and seldom fixed across the different SNPs considered which available methods unrealistically assumed. RESULTS: Simulation studies and comparisons with a real set of data showed that our approach is more likely to correctly identify the presence of true and misspecified trios compared to available software, accurately infers the extent of relationship misspecification in a trio and accurately estimates the genotyping error rates. CONCLUSIONS: Assessing relationship misspecification depends on the fidelity of the genotype data used. Available algorithms are not optimised for genotyping technology with varying rates of errors across the markers. Through our comparison studies, our approach is shown to outperform available methods for assessing relationship misspecifications.

Malaria and vitamin A deficiency in African children: a vicious circle?

Vitamin A deficiency and malaria are both highly prevalent health problems in Africa. Vitamin A deficiency affects over 30 million children, most of whom are in the age-group (under five years) most affected by malaria. Vitamin A deficiency increases all-cause mortality in this part of the population, and malaria is an important cause of death in children at this age. A low serum retinol concentration (a marker of vitamin A deficiency) is commonly found in children suffering from malaria, but it is not certain whether this represents pre-existing vitamin A deficiency, a contribution of malaria to vitamin A deficiency, or merely an acute effect of malaria on retinol metabolism or binding. In this paper, available evidence in support of a causal relationship in each direction between vitamin A deficiency and malaria is reviewed. If such a relationship exists, and especially if this is bidirectional, interventions against either disease may convey an amplified benefit for health.

Epidemiology of Severe Acute Respiratory Illness and Risk Factors for Influenza Infection and Clinical Severity among Adults in Malawi, 2011-2013.

Data on the epidemiology of severe acute respiratory illness (SARI) in adults from low-income, high human immunodeficiency virus (HIV) prevalence African settings are scarce. We conducted adult SARI surveillance in Blantyre, Malawi. From January 2011 to December 2013, individuals aged ≥ 15 years with SARI (both inpatients and outpatients) were enrolled at a large teaching hospital in Blantyre, Malawi. Nasopharyngeal aspirates were tested for influenza and other respiratory viruses by polymerase chain reaction. We estimated hospital-attended influenza-positive SARI incidence rates and assessed factors associated with influenza positivity and clinical severity (Modified Early Warning Score > 4). We enrolled 1,126 SARI cases; 163 (14.5%) were positive for influenza. Human immunodeficiency virus prevalence was 50.3%. Annual incidence of hospital-attended influenza-associated SARI was 9.7-16.8 cases per 100,000 population. Human immunodeficiency virus was associated with a 5-fold greater incidence (incidence rate ratio 4.91, 95% confidence interval [CI]: 3.83-6.32). On multivariable analysis, female gender, as well as recruitment in hot, rainy season (December to March; adjusted odds ratios (aOR): 2.82, 95% CI: 1.57-5.06) and cool, dry season (April to August; aOR: 2.47, 95% CI: 1.35-4.15), was associated with influenza positivity, whereas influenza-positive patients were less likely to be HIV-infected (aOR: 0.59, 95% CI: 0.43-0.80) or have viral coinfection (aOR: 0.51, 95% CI: 0.36-0.73). Human immunodeficiency virus infection (aOR: 1.86; 95% CI: 1.35-2.56) and recruitment in hot, rainy season (aOR: 4.98, 95% CI: 3.17-7.81) were independently associated with clinical severity. In this high HIV prevalence population, influenza was associated with nearly 15% of hospital-attended SARI. Human immunodeficiency virus infection is an important risk factor for clinical severity in all-cause and influenza-associated SARI. Expanded access to HIV testing and antiretroviral treatment, as well as targeted influenza vaccination, may reduce the burden of SARI in Malawi and other high HIV prevalence settings.

Colorectal cancer incidence, mortality and survival in South-east England between 1972 and 2001.

We report incidence, mortality and survival from colorectal cancer in South-east England using data from 162,022 incident cases and 97,697 deaths collected between 1972 and 2001 at the Thames Cancer Registry, which currently covers 14 million people. Overall, there was an increase in the incidence of colorectal cancer among men aged 50 years and over, and a decrease among the youngest age groups. In women, there was a clear decrease in incidence among those aged less than 60 years but a slight increase among those aged 60-79 years. Furthermore, there has been a steady decrease in mortality for all ages, larger in women than in men, and an increase in the 10-year relative survival for both sexes from just over 30% among those followed-up during 1981-1986 to just over 45% among those followed-up during 1997-2001.

Understanding Interpretations of and Responses to Childhood Fever in the Chikhwawa District of Malawi.

BACKGROUND: Universal access to, and community uptake of malaria prevention and treatment strategies are critical to achieving current targets for malaria reduction. Each step in the treatment-seeking pathway must be considered in order to establish where opportunities for successful engagement and treatment occur. We describe local classifications of childhood febrile illnesses, present an overview of treatment-seeking, beginning with recognition of illness, and suggest how interventions could be used to target the barriers experienced. METHODS: Qualitative data were collected between September 2010 and February 2011. A total of 12 Focus Group Discussions and 22 Critical Incident Interviews were conducted with primary caregivers who had reported a recent febrile episode for one of their children. FINDINGS AND CONCLUSION: The phrase 'kutentha thupi', or 'hot body' was used to describe fever, the most frequently mentioned causes of which were malungo (translated as 'malaria'), mauka, nyankhwa and (m)tsempho. Differentiating the cause was challenging because these illnesses were described as having many similar non-specific symptoms, despite considerable differences in the perceived mechanisms of illness. Malungo was widely understood to be caused by mosquitoes. Commonly described symptoms included: fever, weakness, vomiting, diarrhoea and coughing. These symptoms matched well with the biomedical definition of malaria, although they also overlapped with symptoms of other illnesses in both the biomedical model and local illness classifications. In addition, malungo was used interchangeably to describe malaria and fever in general. Caregivers engaged in a three-phased approach to treatment seeking. Phase 1-Assessment; Phase 2-Seeking care outside the home; Phase 3-Evaluation of treatment response. Within this paper, the three-phased approach is explored to identify potential interventions to target barriers to appropriate treatment. Community engagement and health promotion, the provision of antimalarials at community level and better training health workers in the causes and treatment of non-malarial febrile illnesses may improve access to appropriate treatment and outcomes.

Genome-wide and fine-resolution association analysis of malaria in West Africa.

We report a genome-wide association (GWA) study of severe malaria in The Gambia. The initial GWA scan included 2,500 children genotyped on the Affymetrix 500K GeneChip, and a replication study included 3,400 children. We used this to examine the performance of GWA methods in Africa. We found considerable population stratification, and also that signals of association at known malaria resistance loci were greatly attenuated owing to weak linkage disequilibrium (LD). To investigate possible solutions to the problem of low LD, we focused on the HbS locus, sequencing this region of the genome in 62 Gambian individuals and then using these data to conduct multipoint imputation in the GWA samples. This increased the signal of association, from P = 4 × 10(-7) to P = 4 × 10(-14), with the peak of the signal located precisely at the HbS causal variant. Our findings provide proof of principle that fine-resolution multipoint imputation, based on population-specific sequencing data, can substantially boost authentic GWA signals and enable fine mapping of causal variants in African populations.

Folate intake and colorectal cancer risk: a meta-analytical approach.

Adequate consumption of folate may reduce the risk of colorectal cancer. We performed a meta-analysis of 7 cohort and 9 case-control studies that examined the association between folate consumption and colorectal cancer risk. In cohort studies, the association between folate consumption and colorectal cancer risk was stronger for dietary folate (folate from foods alone; relative risk for high vs. low intake = 0.75; 95% CI = 0.64-0.89) than for total folate (folate from foods and supplements; relative risk for high vs. low intake = 0.95; 95% CI = 0.81-1.11) and there was no significant heterogeneity between studies. There was significant heterogeneity between case-control studies. These results offer some support for the hypothesis that folate has a small protective effect against colorectal cancer but confounding by other dietary factors cannot be ruled out.

Nutrition and lifestyle in relation to bowel movement frequency: a cross-sectional study of 20630 men and women in EPIC-Oxford.

OBJECTIVE: To investigate the relationships between nutritional and lifestyle factors and bowel movement frequency. DESIGN: Cross-sectional analysis using data from a prospective study. Mean numbers of bowel movements were calculated in relation to a range of factors. In addition, individuals were categorised according to frequency of bowel movements: fewer than 7 per week ('less than daily') versus 7 or more per week ('daily'), and odds ratios were calculated from logistic regression models. Results for each factor were adjusted for the other factors under consideration. SETTING: The European Prospective Investigation into Cancer and Nutrition, Oxford cohort (EPIC-Oxford), UK. PARTICIPANTS: In total, 20630 men and women aged 22-97 years at recruitment. Thirty per cent of the subjects were vegetarians or vegans. RESULTS: Women had fewer bowel movements on average than men, and were less likely to have daily bowel movements. Mean bowel movement frequency was higher in vegetarians (10.5 in men, 9.1 in women) and especially in vegans (11.6 in men, 10.5 in women) compared with participants who ate meat (9.5 in men, 8.2 in women). There were also significant positive associations between bowel movement frequency and body mass index (BMI), intakes of dietary fibre and non-alcoholic fluids, for both men and women. Vigorous exercise was positively associated with bowel movement frequency in women although results for men were less clear. Alcohol intake was positively associated with bowel movement frequency in men but not in women. CONCLUSION: Being vegetarian and especially vegan is strongly associated with a higher frequency of bowel movements. Moreover, having a high intake of dietary fibre and fluids and a high BMI are associated with an increase in frequency of bowel movements.