Trends, Associations, and Antimicrobial Resistance of Salmonella Typhi and Paratyphi in Pakistan.

Typhoid remains a major cause of morbidity and mortality in endemic countries. This review analyzed typhoid burden changes in Pakistan and its association with contextual factors. A retrospective cohort study on blood culture-positive typhoid and antibiotic resistance was conducted from three tertiary hospitals and contextual factor data obtained from primary household surveys. Salmonella Typhi/Paratyphi positivity rates were estimated and trend analysis was carried out using positive cases out of total number of blood cultures performed. Contextual factors' associations were determined through bivariate correlation analysis, using STATA (SataCorp, College Station, TX). We report a total of 17,387 S. Typhi-positive and 8,286 S. Paratyphi A and B-positive specimens from 798,137 blood cultures performed. The results suggest an overall decline in typhoid incidence as S. Typhi positivity rates declined from 6.42% in 1992 to 1.32% in 2015 and S. Paratyphi (A and B) from 1.29% to 0.39%. Subgroup analysis suggests higher S. Typhi prevalence in adults older than 18 years, whereas S. Paratyphi is greater in children aged 5-18 years. The relative contribution of S. Paratyphi to overall confirmed cases increased from 16.8% in 1992 to 23% in 2015. The analysis suggests high burden of fluoroquinolone resistance and multidrug-resistant S. Typhi strains. Statistically significant associations of water, sanitation indicators, and literacy rates were observed with typhoid positivity. Despite some progress, typhoid remains endemic and a strong political will is required for targeted typhoid control strategies. A multipronged approach of improving water, sanitation and hygiene in combination with large-scale immunization in endemic settings of Pakistan could help reduce burden and prevent epidemics.

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11ß-hydroxylase deficiency.

Congenital adrenal hyperplasia (CAH), resulting from mutations in CYP11B1, a gene encoding 11ß-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11ß-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of CYP11B1 revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11ß-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of CYP11B1 gene mutations in the largest international cohort of 108 patients with steroid 11ß-hydroxylase deficiency CAH.