Activity and Interactions of Liposomal Antibiotics in Presence of Polyanions and Sputum of Patients with Cystic Fibrosis

BACKGROUND:To compare the effectiveness of liposomal tobramycin or polymyxin B against Pseudomonas aeruginosa in the Cystic Fibrosis (CF) sputum and its inhibition by common polyanionic components such as DNA, F-actin, lipopolysaccharides (LPS), and lipoteichoic acid (LTA). METHODOLOGY:Liposomal formulations were prepared from a mixture of 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine (DMPC) or 1,2-Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC) and Cholesterol (Chol), respectively. Stability of the formulations in different biological milieus and antibacterial activities compared to conventional forms in the presence of the aforementioned inhibitory factors or CF sputum were evaluated. RESULTS:The formulations were stable in all conditions tested with no significant differences compared to the controls. Inhibition of antibiotic formulations by DNA/F-actin and LPS/LTA was concentration dependent. DNA/F-actin (125 to 1000 mg/L) and LPS/LTA (1 to 1000 mg/L) inhibited conventional tobramycin bioactivity, whereas, liposome-entrapped tobramycin was inhibited at higher concentrations--DNA/F-actin (500 to 1000 mg/L) and LPS/LTA (100 to 1000 mg/L). Neither polymyxin B formulation was inactivated by DNA/F-actin, but LPS/LTA (1 to 1000 mg/L) inhibited the drug in conventional form completely and higher concentrations of the inhibitors (100 to 1000 mg/L) was required to inhibit the liposome-entrapped polymyxin B. Co-incubation with inhibitory factors (1000 mg/L) increased conventional (16-fold) and liposomal (4-fold) tobramycin minimum bactericidal concentrations (MBCs), while both polymyxin B formulations were inhibited 64-fold. CONCLUSIONS:Liposome-entrapment reduced antibiotic inhibition up to 100-fold and the CFU of endogenous P. aeruginosa in sputum by 4-fold compared to the conventional antibiotic, suggesting their potential applications in CF lung infections

Changing Directions: Steering science, technology and innovation towards the Sustainable Development Goals

Science, technology and innovation are failing to address the world’s most urgent sustainability challenges, according to a major new report from the STRINGS project. ‘Changing Directions: Steering science, technology and innovation towards the Sustainable Development Goals’ is the final report of an in-depth study involving collaborators from across the globe. It highlights a glaring mismatch between the priorities of the world’s scientific communities and the United Nations’ Sustainable Development Goals, which were set up to drive change across all areas of social justice and environmental issues

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Blood pressure profiles among Makerere University undergraduate students

The purpose of this study was to set reference values for spot blood pressure and its derivatives among Makerere university undergraduate students. Study Design: This was a cross- sectional study. Materials and methods: A total of 183 undergraduates including 63 females and 120 males participated in the study. Blood pressure was measured, with the respondent seated, using a sphygmomanometer. Mean arterial pressure was determined as the average of the systolic and diastolic values. Pulse pressure was the difference between systolic and diastolic values. Dividing systolic by diastolic values gave the required ratio. Histograms and cumulative percentages of these results were plotted and used to set the central 95th percentile range as the reference values. Results: Empirical ranges were: systolic BP 100-179 mmHg; diastolic BP 60-139 mmHg; systolic: diastolic pressure ratio 1.20-2.30 mmHg, mean arterial pressure 80-159 mmHg and pulse pressure 20-85 mmHg. The reference ranges covering the central 95 percentile were: systolic BP 100-150 mmHg, diastolic BP 64-100, systolic: diastolic BP ratio 1.29-2.03, the mean arterial pressure 85121 mmHg, and pulse pressure 25-70 mmHg. According to the systolic pressure, 35% were normal, 54% pre-hypertensive and 11% hypertensive. According to diastolic values, 48% were normotensive, 43% pre-hypertensive and 18% hypertensive. The mean arterial pressure was distributed like the parent pressures. The pulse pressure and the systolic:diastolic ratio were trimodally distributed with the three peaks corresponding to normotension, pre-hypertension and hypertension. Conclusion and recommendation: Reference values for the university student population have been derived and they are recommended for application in clinical evaluation

Initial attempt to establish population reference values for blood glucose and lipids in Makerere University undergraduate students

The purpose of this study was to establish blood glucose and lipid profile of Makerere University undergraduate students. STUDY DESIGN: This was a cross-sectional study. MATERIALS AND METHODS: A total of 183 students participated in the study. Capillary blood glucose was read instantly on a finger prick sample off Sensore™ glucose analyzer. Venous blood from the antecubital vein was used for lipid assays. Total cholesterol was assayed by the oxidase-peroxidase enzyme system. Plasma triacylglycerols were analyzed using the glycerokinase-oxidase reagents. HDL and LDL cholesterol were analyzed using homogeneous enzymatic methods. Concentration results for each variable were plotted in histograms and the type of distribution established. Summary statistics were then calculated non- parametrically to set reference values. RESULTS: Empirical ranges were: Cholesterol 2.1–7.2 mmol/L; triacylglycerols 0.4–6.87 mmol/L; HDLC 0.09–2.13 mmol/L; LDLC 0.95–5.38 mmol/L and capillary blood glucose 2.72–9.21 mmol/L. The reference ranges covering the central 95 percentile were: Cholesterol 2.65–5.15 mmol/L, triacylglycerols 0.61–4.03 mmol/L; HDLC 0.58–1.97 mmol/L; LDLC 1.25–3.57 mmol/L and capillary blood glucose 3.11–7.55 mmol/L. CONCLUSION: The established reference values for the age group 20–26 years were: Total Cholesterol 2.65–5.15 mmol/L, LDL 1.25–3.57 mmol/L, HDL 0.58–1.97 mmol/L, TG 0.61–4.03 mmol/L and capillary blood glucose 3.11–7.55 mmol/L which differed from set international values. RECOMMENDATIONS: We recommend the establishment of indices for the indigenous populations, conscientiously planned diets, and regular exercise

An ex Vivo

Transurothelial drug delivery continues to be an attractive treatment option for a range of urological conditions; however, dosing regimens remain largely empirical. Recently, intravesical delivery of the nonsteroidal anti-inflammatory ketorolac has been shown to significantly reduce ureteral stent-related pain. While this latest development provides an opportunity for advancing the management of stent-related pain, clinical translation will undoubtedly require an understanding of the rate and extent of delivery of ketorolac into the bladder wall. Using an ex vivo porcine model, we evaluate the urothelial permeability and bladder wall distribution of ketorolac. The subsequent application of a pharmacokinetic (PK) model enables prediction of concentrations achieved in vivo. Ketorolac was applied to the urothelium and a transurothelial permeability coefficient (Kp) calculated. Relative drug distribution into the bladder wall after 90 min was determined. Ketorolac was able to permeate the urothelium (Kp = 2.63 × 10–6 cm s–1), and after 90 min average concentrations of 400, 141 and 21 μg g–1 were achieved in the urothelium, lamina propria and detrusor respectively. An average concentration of 87 μg g–1 was achieved across the whole bladder wall. PK simulations (STELLA) were then carried out, using ex vivo values for Kp and muscle/saline partition coefficient (providing an estimation of vascular clearance), to predict 90 min in vivo ketorolac tissue concentrations. When dilution of the drug solution with urine and vascular clearance were taken into account, a reduced ketorolac concentration of 37 μg g–1 across the whole bladder wall was predicted. These studies reveal crucial information about the urothelium’s permeability to agents such as ketorolac and the concentrations achievable in the bladder wall. It would appear that levels of ketorolac delivered to the bladder wall intravesically would be sufficient to provide an anti-inflammatory effect. The combination of such ex vivo data and PK modeling provides an insight into the likelihood of achieving clinically relevant concentrations of drug following intravesical administration