Mathematical Modeling to Assess the Drivers of the Recent Emergence of Typhoid Fever in Blantyre, Malawi

BACKGROUND: Multiyear epidemics of Salmonella enterica serovar Typhi have been reported from countries across eastern and southern Africa in recent years. In Blantyre, Malawi, a dramatic increase in typhoid fever cases has recently occurred, and may be linked to the emergence of the H58 haplotype. Strains belonging to the H58 haplotype often exhibit multidrug resistance and may have a fitness advantage relative to other Salmonella Typhi strains.

METHODS: To explore hypotheses for the increased number of typhoid fever cases in Blantyre, we fit a mathematical model to culture-confirmed cases of Salmonella enterica infections at Queen Elizabeth Central Hospital, Blantyre. We explored 4 hypotheses: (1) an increase in the basic reproductive number (R0) in response to increasing population density; (2) a decrease in the incidence of cross-immunizing infection with Salmonella Enteritidis; (3) an increase in the duration of infectiousness due to failure to respond to first-line antibiotics; and (4) an increase in the transmission rate following the emergence of the H58 haplotype.

RESULTS: Increasing population density or decreasing cross-immunity could not fully explain the observed pattern of typhoid emergence in Blantyre, whereas models allowing for an increase in the duration of infectiousness and/or the transmission rate of typhoid following the emergence of the H58 haplotype provided a good fit to the data.

CONCLUSIONS: Our results suggest that an increase in the transmissibility of typhoid due to the emergence of drug resistance associated with the H58 haplotype may help to explain recent outbreaks of typhoid in Malawi and similar settings in Africa.

Fatigue two months after myocardial infarction may indicate risk for persistent fatigue

Fatigue two months after myocardial infarction may indicate risk for persistent fatigue

Chronic inflammation in CF airways - a persistent issue for A20

Cystic Fibrosis (CF) is characterised by prolonged and exaggerated airways inflammation. Despite recent developments to overcome the underlying functional defect in CFTR (cystic fibrosis transmembrane conductance regulator), there is still an unmet need to reduce the inflammatory response. The NF-kB regulator A20 is a key target to normalise the inflammatory response and is reduced in CF. Here, we describe the plethora of functions of A20 as they apply to innate immune function within the airways. Pharmacological compounds can enhance A20 mRNA and protein expression, but we observed a blunted effect in CF primary epithelial cells. In CF cells pre-treatment with gibberellic acid (GA3) shows anti-inflammatory effects only in some patients. We show that cells with higher basal p38 expression respond with an increase in pro-inflammatory cytokines. Furthermore, all CF PNECs show increased p38 mRNA when stimulated in the presence of GA3. Our results suggest that those patients may benefit from therapeutics targeting p38.