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Abstract Background The growing burden of diabetes mellitus (DM) and hypertension (HTN) on the background of endemic Human Immuno-deficiency Virus (HIV) and tuberculosis (TB) is a concern in low- and middle-income countries. We aimed to describe annual trends in admissions, mortality rates and premature mortality (years of potential life lost—YPLLs) due to HIV, tuberculosis (TB), diabetes mellitus (DM) and hypertension (HTN) in Uganda. Methods We conducted a retrospective cohort study, retrieving electronic records of adults admitted to Mulago and Kiruddu national referral hospitals medical wards between 1st January 2011 and 31st December 2019. We used STATA BE 17.0 and GraphPad Prism 8.0.2 to compute total admissions, inpatient crude mortality rates, and YPLLs; and demonstrate trends using Mann–Kendall test. Results Of 108,357 admissions, 55,620 (51.3%) were female, 15,300 (14.1%) were recorded in 2012, and 22,997 (21.2%) were aged 21–30 years. HIV, TB, DM and HTN accounted for 26,021 (24.0%); 9537 (8.8%); 13,708 (12.7) and 13,252 (12.2%) of all admissions, respectively. Overall inpatient mortality was 16.7% (18,099/108,357), 53.5% (9674/18,099) were male, 21.5% (3898) were aged 31–40 years and 2597 (14.4%) were registered in 2013. HIV, TB, DM and HTN accounted for 35.6% (6444), 14.6% (2646), 9.1% (1648) and 11.8% (2142) of all deaths, respectively. Total admissions (Kendall’s tau-B = − 0.833, p

Combination therapy is becoming the cornerstone of pharmacotherapy. The choice of combination therapy is premised on pharmacodynamic drug – drug interactions (PDDIs). There is a disagreement among the existing PDDI reference models which undermines their utility in prediction of combination outcomes. Accounting for properties of the biological system and not just those of the drugs should enable prediction of in vivo efficacy of drug combinations and rational design of effective drug combinations. Attempts to elucidate mechanisms underlying drug PDDIs based on receptor theory are reviewed hereafter and more potential mechanisms are proposed and analysed. The relationship between the input signal (drug –receptor complex) and the final observed response such that signals react with each other biochemically to form a stimulus which then generates the observed response or one signal modulates/facilitates conversion of the other signal into a stimulus that generates the observed response are proposed and analysed using simulations. The signal reaction model demonstrates the capacity to universally describe all drug combinations and is capable of being extended to describe combinations of more than two drugs, with interpretable effects.

Mycobacterium tuberculosis is the leading cause of sepsis among HIV-infected adults, yet effective treatment remains a challenge. Efficacy of antituberculous drugs is optimized by high Area Under Curve to Minimum Inhibitory Concentration (AUC/MIC) ratios, suggesting that both the drug concentration at the disease site and time above MIC are critical to treatment outcomes. We elaborate on sepsis pathophysiology and show how it adversely affects antituberculous drug kinetics. Expanding distribution volumes secondary to an increased vascular permeability prevents the attainment of target Cmax concentrations for nearly all drugs. Furthermore, sepsis-induced metabolic acidosis promotes protonation, which increases renal clearance of basic drugs such as isoniazid and ethambutol, and hence AUCs are substantially reduced. Compared with the treatment of non-sepsis TB disease, these distorted kinetics underlie the poor treatment outcomes observed with bloodstream infections. In addition to aggressive hemodynamic management, an increase in both the dose and frequency of drug administration are warranted, at least in the early phase of treatment.

Background: Malaria rapid diagnostic tests (RDTs) available as dipsticks or strips, are simple to perform, easily interpretable and do not require electricity nor infrastructural investment. Correct interpretation of and compliance with the RDT results is a challenge to drug sellers. Thus, drug seller interpretation of RDT strips was compared with laboratory scientist re-reading, and PCR analysis of Plasmodium DNA extracted from RDT nitrocellulose strips and fast transient analysis (FTA) cards. Malaria RDT cassettes were also assessed as a potential source of Plasmodium DNA. Methods: A total of 212 children aged between 2 and 60 months, 199 of whom had complete records at two study drug shops in south western Uganda participated in the study. Duplicate 5 μL samples of capillary blood were picked from the 212 children, dispensed onto the sample well of the CareStart™ Pf-HRP2 RDT cassette and a FTA, Whatman™ 3MM filter paper in parallel. The RDT strip was interpreted by the drug seller within 15–20 min, visually re-read centrally by laboratory scientist and from it; Plasmodium DNA was recovered and detected by PCR, and compared with FTA recovered P. falciparum DNA PCR detection. Results: Malaria positive samples were 62/199 (31.2%, 95% CI 24.9, 38.3) by drug seller interpretation of RDT strip, 59/212 (27.8%, 95% CI 22.2, 34.3) by laboratory scientist, 55/212 (25.9%, 95% CI 20.0, 32.6) by RDT nitrocellulose strip PCR and 64/212 (30.2%, 95% CI 24.4, 37.7). The overall agreement between the drug seller interpretation and laboratory scientist re-reading of the RDT strip was 93.0% with kappa value of 0.84 (95% CI 0.75, 0.92). The drug seller compliance with the reported RDT results was 92.5%. The performance of the three diagnostic strategies compared with FTA-PCR as the gold standard had sensitivity between 76.6 and 86.9%, specificity above 90%, positive predictive values ranging from 79.0 to 89.8% and negative predictive values above 90%. Conclusion: Drug sellers can use RDTs in field conditions and achieve acceptable accuracy for malaria diagnosis, and they comply with the RDT results. Plasmodium DNA can be recovered from RDT nitrocellulose strips even in the context of drug shops. Future malaria surveillance and diagnostic quality control studies with RDT cassette as a source of Plasmodium DNA are recommended. [ABSTRACT FROM AUTHOR]