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BackgroundHIV remains a major public health issue, especially in Eastern and Southern Africa. Pre-exposure prophylaxis is highly effective when adhered to, but its effectiveness is limited by cost, user acceptability and uptake. The cost of a non-inferiority phase III trial is likely to be prohibitive, and thus, it is essential to select the best possible drug, dose and schedule in advance. The aim of this study, the Combined HIV Adolescent PrEP and Prevention Study (CHAPS), is to investigate the drug, dose and schedule of pre-exposure prophylaxis (PrEP) required for the protection against HIV and the acceptability of PrEP amongst young people in sub-Saharan Africa, and hence to inform the choice of intervention for future phase III PrEP studies and to improve strategies for PrEP implementation.MethodsWe propose a mixed-methods study amongst young people aged 13–24 years. The first component consists of qualitative research to identify the barriers and motivators towards the uptake of PrEP amongst young people in South Africa, Uganda and Zimbabwe. The second component is a randomised clinical trial (ClinicalTrials.gov NCT03986970, June 2019) using a novel ex vivo HIV challenge method to investigate the optimal PrEP treatment (FTC-TDF vs FTC-TAF), dose and schedule. We will recruit 144 amongst HIV-negative uncircumcised men aged 13–24 years from voluntary male medical circumcision clinics in two sites (South Africa and Uganda) and randomise them into one of nine arms. One group will receive no PrEP prior to surgery; the other arms will receive either FTC-TDF or FTC-TAF, over 1 or 2 days, and with the final dose given either 6 or 20 h prior to surgery. We will conduct an ex vivo HIV challenge on their resected foreskin tissue.DiscussionThis study will provide both qualitative and quantitative results to help decide the optimum drug, dose and schedule for a future phase III trial of PrEP. The study will also provide crucial information on successful strategies for providing PrEP to young people in sub-Saharan Africa.Trial registrationClinicalTrials.govNCT03986970. Registered on 14 June 2019

Background: Snakebites affect over 5 million people each year, and over 100,000 per year die as a result. The only available treatment is antivenom, which has many shortcomings including high cost, intravenous administration, and high risk of adverse events. One of the most abundant and harmful components of viper venoms are the zinc-dependent snake venom metalloproteinases (SVMPs). Unithiol is a chelating agent which is routinely used to treat heavy metal poisoning. In vivo experiments in small animal models have demonstrated that unithiol can prevent local tissue damage and death caused by a certain viper species. This phase I clinical trial will assess the safety of ascending doses of unithiol with a view for repurposing for snakebite indication. Methods: This open label, single agent, phase I clinical trial of a repurposed drug has a primary objective to evaluate the safety of escalating doses of unithiol, and a secondary objective to describe its pharmacokinetics. In total, 64 healthy Kenyan volunteers from Kilifi County will be dosed in consecutive groups of eight, with dose escalation decisions dependent on review of safety data by an independent data safety monitoring board. Four groups will receive ascending single oral doses, two will receive multiple oral doses, and two will receive single intravenous doses. Follow-up will be for 6-months and includes full adverse event reporting. Pharmacokinetic analysis will define the Cmax, Tmax, half-life and renal elimination. Conclusions: This clinical trial will assess the safety and tolerability of a promising oral therapeutic in a relevant setting where snakebites are prevalent. Unithiol is likely to be safer than antivenom, is easier to manufacture, has activity against diverse snake species, and can be administered orally, and thus shows promise for repurposing for tropical snakebite. Pan African Clinical Trials Registry: PACTR202103718625048 (3/3/2021)

Objectives: To investigate whether adding carvedilol, a nonselective β- and selective α1-receptor blocking agent with antioxidant properties, to oxygenated blood cardioplegia improves myocardial function after weaning from bypass. Design: A randomized controlled study. Setting: A university laboratory. Participants: Twenty anesthetized pigs, Norwegian Landrace. Interventions: On cardiopulmonary bypass, cardiac arrest was induced with cold (12°C), oxygenated blood cardioplegia, enriched with carvedilol or vehicle, and repeated every 20 minutes. After 100 minutes, the heart was reperfused and weaned. Measurements and Main Results: Left ventricular function was evaluated with pressure-volume loops, local myocardial systolic strain, and strain rate from Speckle tracking analysis and multilayer short-axis tissue Doppler Imaging. In the carvedilol group, the load-independent logarithmic end-diastolic pressure volume relationship, β, decreased from 1 to 3 hours of reperfusion and was low, 0.028±0.004 v 0.042±0.007 (p

Background: ART initiation in the 3rd trimester of pregnancy is associated with failure to achieve viral suppression (VS) by delivery and increased transmission of HIV. We randomised 60 treatment naïve pregnant women at 28-36w gestation in Uganda and South Africa 1:1 to receive EFV or DTG+2NRTIs. The primary endpoint was pharmacokinetics (PK) of DTG in women and breastfed infants; secondary endpoints included VS. Methods: To comply with national guidelines, EFV+2NRTI was initiated on referral, with subjects randomized to DTG switched within 7 days. Viral load (VL) was collected at every visit; intensive maternal PK sampling (0-24h) was performed at 14 days on DTG, and 2 weeks post-partum, with paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. All infants were exclusively breastfed. Results: There was no significant pre-ART differences between DTG (n=29) and EFV (n=31) arms in maternal age, gestation at treatment initiation (30.8w), weight, obstetric history, VL (log 4 copies) and CD4 count (394 cells/mm3). Third trimester DTG exposures were low with Ctrough at or below target (MEC 324ng/mL) in 9/28 (32%) mothers. DTG transfer across the placenta (122%) and in breast milk (3%) coupled with delayed elimination resulted in significant infant exposures potentially persisting during breast-feeding. Both regimens were well-tolerated. A total of 10 SAEs were reported in 5 mothers and 3 infants, with no significant differences between arms. Superior VS was observed with DTG (Table 1) at the 2w post-partum visit (P=0.005). However, VL>1000 copies/mL near delivery was still observed with both DTG (3.7%) and EFV (7.4%). No HIV transmissions were observed Conclusions: HIV RNA suppression < 50 copies/mL was more rapid with DTG (despite low DTG exposures when started in the third trimester) which may translate to improved PMTCT for ART initiation in late pregnancy. The impact of significant infant DTG exposures related to intrauterine transfer, continued breastfeeding and delayed elimination is being evaluated in the DolPHIN-2 study.

Cardiopulmonary bypass (CPB) is associated with fluid overload. We examined how a continuous infusion of hypertonic saline/dextran (HSD) influenced fluid shifts during CPB.Fourteen animals were randomized to a control-group (CT-group) or a hypertonic saline/dextran-group (HSD-group). Ringer's solution was used as CPB-prime and as maintenance fluid at a rate of 5 ml/kg/h. In the HSD group, 1 ml/kg/h of the maintenance fluid was substituted with HSD. After 60 min of normothermic CPB, hypothermic CPB was initiated and continued for 90 min. Fluid was added to the CPB-circuit as needed to maintain a constant level in the venous reservoir. Fluid balance, plasma volume, total tissue water (TTW), intracranial pressure (ICP) and fluid extravasation rates (FER) were measured/calculated.In the HSD-group the fluid need was reduced with 60% during CPB compared with the CT-group. FER was 0.38(0.06) ml/kg/min in the HSD-group and 0.74 (0.16) ml/kg/min in the CT-group. TTW was significantly lower in the heart and some of the visceral organs in the HSD-group. In this group ICP remained stable during CPB, whereas an increase was observed in the CT-group (p0.01).A continuous infusion of HSD reduced the fluid extravasation rate and total fluid gain during CPB. TTW was reduced in the heart and some visceral organs. During CPB ICP remained normal in the HSD-group, whereas an increase was present in the CT-group. No adverse effects were observed.

Background: The aim of this study was to evaluate how a continuous infusion of a hyperosmolar/hyperoncotic solution influences fluid shifts and intracranial pressure during cardiopulmonary bypass in piglets. Methods: Fourteen animals, randomized to the control (CT) group or the hypertonic saline/hydroxyethyl starch (HyperHaes®) (HSH) group, received acetated Ringer’s solution as prime and supplemental fluid. The HSH group received, in addition, HyperHaes® 1 ml/kg/h. After 1 h of normothermic cardiopulmonary bypass, hypothermic cardiopulmonary bypass (28 °C) was initiated and continued for 90 min. Fluid balance, plasma volume, tissue water content, acid–base parameters and intracranial pressure were recorded, and protein masses and fluid extravasation rates were calculated. Results: At the start of normothermic cardiopulmonary bypass, the fluid extravasation rates (ml/kg/min) increased from 0.19 (0.06) to 1.57 (0.71) and 0.19 (0.09) to 0.82 (0.14) in the CT and HSH groups, respectively, with no between-group differences (P = 0.081) During hypothermic cardiopulmonary bypass, the fluid extravasation rates (ml/kg/min) increased from 0.19 (0.14) to 0.51 (0.10) (P < 0.01) and 0.15 (0.08) to 0.33 (0.08) (P < 0.05), respectively, with significantly lower extravasation rates in the HSH group (P < 0.01). In the HSH group, the total fluid gain during cardiopulmonary bypass decreased by about 50% (P < 0.05) and the tissue water content was significantly lower in the left and right heart as well as in the lungs. The intracranial pressure remained stable in the HSH group, but increased in the CT group. Conclusions: A continuous infusion of HSH (HyperHaes®) during cardiopulmonary bypass reduced the fluid extravasation rate and the total fluid gain during bypass. No electrolyte or acid–base disturbances were present. The intracranial pressure remained stable in the HSH group.

Cardiopulmonary bypass(CPB) is associated with fluid overload. We hypothesized that fluid gain during CPB could be reduced by substituting parts of a crystalloid prime with 7.2% hypertonic saline and 6% poly(O-2-hydroxyethyl) starch solution (HyperHaes®). 14 animals were randomized to a control group (Group C) or to Group H. CPB-prime in Group C was Ringer’s solution. In group H, 4 ml/kg of Ringer’s solution was replaced by the hypertonic saline / hydroxyethyl starch solution. After 60 min stabilization, CPB was initiated and continued for 120 min. All animals were allowed drifting of normal temperature (39.0°C) to about 35.0°C. Fluid was added to the CPB circuit as needed to maintain a 300-ml level in the venous reservoir. Blood chemistry, hemodynamic parameters, fluid balance, plasma volume, fluid extravasation rate (FER), tissue water content and acid-base parameters were measured/calculated. Total fluid need during 120 min CPB was reduced by 60% when hypertonic saline/hydroxyethyl starch solution was added to the CPB prime (p

Objective--Evaluation of the centrifugal pump vs roller pump concerning effects upon platelet function, hemolysis and clinical outcome in elective coronary artery bypass surgery. Design--Thirty-four patients were randomized to centrifugal or roller pump. Platelet activation was studied by flow cytometry before, during and up to 3 days after bypass. Results--Duration of bypass, ischemic period, peripheral anastomoses, hospital stay and mortality did not differ. In roller pump patients, platelet aggregates increased by 250% between end of bypass and 3 h postoperatively (p < 0.001). A secondary, fivefold increase in number of platelet aggregates was found on the 3rd postoperative day (p < 0.001). In the centrifugal pump group, these changes were not significant. Hemolysis increased (20%) at end of bypass and 3 h postoperatively (p < 0.005), and decreased to preoperative levels the next day without group difference. Conclusion--Platelet aggregation was significantly increased in roller compared with centrifugal pump patients, indicating higher susceptibility to postoperative thrombotic complications with the roller pump. Otherwise, there was no clinical evidence for superiority of the centrifugal pump.