Combined HIV Adolescent Prevention Study (CHAPS): comparison of HIV pre-exposure prophylaxis regimens for adolescents in sub-Saharan Africa-study protocol for a mixed-methods study including a randomised controlled trial.

BACKGROUND: HIV 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. METHODS: We 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. DISCUSSION: This 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 REGISTRATION: ClinicalTrials.gov NCT03986970 . Registered on 14 June 2019.

Plasmid CDS5 influences infectivity and virulence in a mouse model of Chlamydia trachomatis urogenital infection.

The native plasmid of both Chlamydia muridarum and Chlamydia trachomatis has been shown to control virulence and infectivity in mice and in lower primates. We recently described the development of a plasmid-based genetic transformation protocol for Chlamydia trachomatis that for the first time provides a platform for the molecular dissection of the function of the chlamydial plasmid and its individual genes or coding sequences (CDS). In the present study, we transformed a plasmid-free lymphogranuloma venereum isolate of C. trachomatis, serovar L2, with either the original shuttle vector (pGFP::SW2) or a derivative of pGFP::SW2 carrying a deletion of the plasmid CDS5 gene (pCDS5KO). Female mice were inoculated with these strains either intravaginally or transcervically. We found that transformation of the plasmid-free isolate with the intact pGFP::SW2 vector significantly enhanced infectivity and induction of host inflammatory responses compared to the plasmid-free parental isolate. Transformation with pCDS5KO resulted in infection courses and inflammatory responses not significantly different from those observed in mice infected with the plasmid-free isolate. These results indicate a critical role of plasmid CDS5 in in vivo fitness and in induction of inflammatory responses. To our knowledge, these are the first in vivo observations ascribing infectivity and virulence to a specific plasmid gene.

Genome-wide profiling of methylation identifies novel targets with aberrant hypermethylation and reduced expression in low-risk myelodysplastic syndromes.

Gene expression profiling signatures may be used to classify the subtypes of Myelodysplastic syndrome (MDS) patients. However, there are few reports on the global methylation status in MDS. The integration of genome-wide epigenetic regulatory marks with gene expression levels would provide additional information regarding the biological differences between MDS and healthy controls. Gene expression and methylation status were measured using high-density microarrays. A total of 552 differentially methylated CpG loci were identified as being present in low-risk MDS; hypermethylated genes were more frequent than hypomethylated genes. In addition, mRNA expression profiling identified 1005 genes that significantly differed between low-risk MDS and the control group. Integrative analysis of the epigenetic and expression profiles revealed that 66.7% of the hypermethylated genes were underexpressed in low-risk MDS cases. Gene network analysis revealed molecular mechanisms associated with the low-risk MDS group, including altered apoptosis pathways. The two key apoptotic genes BCL2 and ETS1 were identified as silenced genes. In addition, the immune response and micro RNA biogenesis were affected by the hypermethylation and underexpression of IL27RA and DICER1. Our integrative analysis revealed that aberrant epigenetic regulation is a hallmark of low-risk MDS patients and could have a central role in these diseases.

AT1 receptor block does not affect arterial baroreflex during pregnancy in rabbits.

The role of ANG II in the arterial baroreflex control of renal sympathetic nerve activity (RSNA) in eight term-pregnant (P) and eight nonpregnant (NP) conscious rabbits was assessed using sequential intracerebroventricular and intravenous infusions of losartan, an AT1 receptor antagonist. The blood pressure (BP)-RSNA relationship was generated by sequential inflations of aortic and vena caval perivascular occluders. Pregnant rabbits exhibited a lower maximal RSNA reflex gain (-44%) that was primarily due to a reduction in the maximal sympathetic response to hypotension (P, 248 +/- 20% vs. NP, 357 +/- 41% of rest RSNA, P < 0.05). Intracerebroventricular losartan decreased resting BP in P (by 9 +/- 3 mmHg, P < 0.05) but not NP rabbits, and had no effect on the RSNA baroreflex in either group. Subsequent intravenous losartan decreased resting BP in NP and further decreased BP in P rabbits, but had no significant effect on the maximal RSNA reflex gain. ANG II may have an enhanced role in the tonic support of BP in pregnancy, but does not mediate the gestational depression in the arterial baroreflex control of RSNA in rabbits.

Cholangiocarcinoma: a nursing perspective.

Primary cancer of the bile duct (cholangiocarcinoma [CC]) is a rare malignancy that presents many nursing challenges. This article focuses on disease presentation, treatment options, quality of life, and the nurse's unique role in caring for this patient population. Surgical resection is the only treatment modality that offers a potential cure and prolonged survival. In patients with unresectable disease, biliary bypass or nonoperative biliary drainage procedures can provide palliation. Other palliative treatment modalities include chemotherapy, radiation, and photodynamic therapy. The sudden onset, limited treatment options, and overall poor prognosis add to the challenge of caring for patients with CC.

Renal hemodynamic responses to dynamic exercise in rabbits.

Cardiovascular hemodynamics, including renal blood flow, were measured in rabbits with one intact and one denervated kidney during various intensities of treadmill exercise. Within the first 10 s of exercise, there was rapid vasoconstriction in the innervated kidney associated with decreases in renal blood flow (range -10 to -17%). The vasoconstriction in the innervated kidney was evident at all workloads and was intensity dependent. There was no significant vasoconstriction or change in renal blood flow (range 0.5 to -3.1%) in the denervated kidney at the onset of exercise. However, a slowly developing vasoconstriction occurred in the denervated kidney as exercise progressed to 2 min at all workloads. Examination of responses to exercise performed under alpha-adrenergic blockade with phentolamine (5 mg/kg iv) revealed that the vasoconstriction in the innervated kidney at the onset of exercise and the delayed vasoconstriction in the denervated kidney were due primarily to activation of alpha-adrenergic receptors. In addition, a residual vasoconstriction was also present in the innervated kidney after alpha-adrenergic blockade, suggesting that, during exercise, activation of other renal vasoconstrictor mechanisms occurs which is dependent on the presence of renal nerves.

Arterial baroreflex during pregnancy and renal sympathetic nerve activity during parturition in rabbits.

The arterial baroreflex control of renal sympathetic nerve activity (RSNA) was evaluated in nine term pregnant (P) and 12 nonpregnant (NP) conscious New Zealand White rabbits. In an additional four P rabbits, the RSNA response to spontaneous parturition was measured. The blood pressure (BP)-RSNA relationship was generated by sequential inflations of aortic and vena caval perivascular occluders. Rest BP (P: 61 +/- 2 vs. NP: 73 +/- 2 mmHg) and the centering point of the baroreflex (P: 57 +/- 2 vs. NP: 70 +/- 2 mmHg) were lower (P < 0.05) in term pregnancy. Baroreflex range (P: 246 +/- 14% vs. NP 263 +/- 24% of rest RSNA) was not affected by pregnancy. However, maximal reflex gain was moderately depressed (-44%) in P rabbits (P: -15 +/- 1 vs. NP: -27 +/- 4% of rest RSNA/mmHg; P < 0.05) due to a significant reduction in the slope coefficient. Delivery of a fetus was associated with strong renal sympatho-excitation. Peak RSNA averaged 80 +/- 37% of smoke-elicited RSNA or 1,221 +/- 288% of rest RSNA (mean +/- SD). These results suggest that, in contrast to rat pregnancy, depressed arterial baroreflex control of RSNA in rabbit pregnancy is due primarily to a reduction in maximal gain rather than a reduction in the maximal sympathetic response to hypotension.

Physiological effects of technique and rolling resistance in uphill roller skiing.

OBJECTIVE: The double pole technique (DP) has been shown to be more economical than the V1 skate technique (V1 ) on flat terrain. The objective of the present study was to compare these two techniques during uphill roller skiing. In addition, the physiological effects of changing roller ski rolling resistance was examined for V1. METHODS: Five female and five male competitive cross-country skiers roller skied 4-min bouts on a 5.2% incline while physiological measurements were made. RESULTS: Oxygen uptake (VO2) values averaged 8% greater (P = 0.0004) with V1, whereas rating of perceived exertion (RPE) and blood lactate concentrations were higher (P < or = 0.002) with DP. Doubling the dynamic friction coefficient of the roller skis, which increased external power output by 16-17%, resulted in VO2 values with V1 that averaged 13% higher (P = 0.0006). This magnitude of change in roller ski rolling resistance did not cause a statistical change in the relationship of VO2 with RPE. CONCLUSIONS: These findings suggest that 1) grade has little effect on relative economies of DP and V1, possibly because of a lower effectiveness of force application with V1 when going uphill, and 2) large differences in roller ski rolling resistance should have no effect on the cardiovascular training adaptations that result from uphill roller skiing with V1.

Muscle chemoreflex increases renal sympathetic nerve activity during exercise.

Activation of the muscle chemoreflex increases sympathetic drive to skeletal muscle in humans. This study investigated whether activation of the muscle chemoreflex augments the renal sympathetic nerve activity (RSNA) response to dynamic exercise in rabbits. The muscle chemoreflex was evoked by hindlimb ischemia during exercise on a motorized treadmill. Seven New Zealand White rabbits performed a nonischemic control protocol and a hindlimb ischemia protocol in which terminal aortic blood flow (Qta) was reduced to 51 +/- 2% of preocclusion Qta by partial aortic occlusion after 1.5 min of exercise. Mean arterial pressure (MAP), heart rate, RSNA and Qta increased in response to exercise and were similar between trials during the first 1.5 min of exercise. In the control trial, Qta, MAP, and RSNA were stable at an elevated level through an additional 3.5 min of exercise. Hindlimb ischemia produced a potent pressor response that plateaued after 2.5 min (delta + 17 +/- 4 mmHg, where delta designates change). RSNA began to increase after 1.5 min of ischemic exercise and was significantly elevated relative to preocclusion RSNA at 2.5 (delta + 25 +/- 9%) and 3.5 (delta + 47 +/- 12%) min of occlusion. These results suggest that the muscle chemoreflex can augment sympathoexcitatory drive to the kidney during dynamic exercise.

Muscle chemoreflex causes renal vascular constriction.

The purpose of this study was to investigate the effects of the muscle chemoreflex on vascular conductance in innervated and denervated kidneys. During each experiment, six dogs ran at 10 km/h for 8-16 min, and the muscle chemoreflex was stimulated by reducing hindlimb blood flow (HLBF) (0%-74%) at 4-min intervals. Small reductions in HLBF did not cause changes in arterial blood pressure or renal vascular conductance. However, further reductions of HLBF caused increases in arterial blood pressure and decreases in renal vascular conductance. Decreases in renal vascular conductance occurred in the denervated kidneys when the HLBF was reduced below 1,500 +/- 215 ml/min and occurred in the innervated kidneys when HLBF was reduced below 1,402 +/- 161 ml/min. There was not a significant difference between the reductions in HLBF required to cause a decrease in vascular conductance in the innervated and denervated kidneys. These results demonstrate that reductions in HLBF cause decreases in renal vascular conductance, which are not dependent on renal sympathetic nerve activity.

Delta efficiency of uphill roller skiing with the double pole and diagonal stride techniques.

Delta efficiencies for uphill roller skiing with the double pole (DP) and diagonal stride (DS) techniques were determined among 4 female and 4 male cross-country ski racers in order to examine for differences between techniques and between the sexes. Each skier roller-skied on a motorized ski-treadmill at 1.7% and 7.1% grades with both techniques at 2 to 4 different speeds. Steady-state oxygen uptake values were used to calculate the differences in metabolic requirements for roller skiing at the 2 grades (delta E). The differences in external work rates between the 2 grades (delta W) were calculated from the work rates for overcoming rolling resistance and elevating the transported mass against gravity. Delta efficiencies (delta W/ delta E) ranged from 14 to 36%, were significantly greater (p < 0.001) for DS than DP, and showed a significant (p < 0.01) velocity effect for DS. Delta efficiencies were 27% greater (p < 0.05) for the women compared with the men for DP, and significant (p < 0.05) correlations were found between efficiency for DP and body mass. This suggests that the higher efficiency with DP for female skiers is at least partially due to their lower body mass.

Lactate response to uphill roller skiing: diagonal stride versus double pole techniques.

The purpose of this experiment was to investigate the lactate responses to roller skiing with double pole and diagonal stride techniques in eight collegiate or national level cross-country ski racers. Four-minute exercise stages were performed on a ski treadmill at 67, 94, 121, 148, and 174 m.min-1 on a 1.7% grade and at 67, 94, and 121 m.min-1 on a 7.1% grade. Whole blood lactate concentration, heart rate, oxygen consumption (VO2) and rating of perceived exertion (RPE) were determined at each exercise stage. Blood lactate concentrations were not significantly different between double poling and diagonal striding at the 1.7% grade. However, the blood lactate concentrations were higher during double poling at the 7.1% grade for all speeds. Blood lactate concentrations were also higher for double poling at the 7.1% grade when compared with diagonal striding at 70% of technique specific peak VO2, a heart rate of 145 and a RPE of 12. We conclude that blood lactate concentrations do not offer physiological justification for choosing one technique over the other when skiing on low grades, but low blood lactate concentrations may provide a physiological advantage for diagonal striding on steep grades.

Phenyl biguanide does not inhibit locomotion in conscious rabbits.

Stimulation of cardiopulmonary vagal C fibers with phenyl biguanide (PBG) reflexly inhibits locomotion in addition to causing depression of blood pressure (BP), heart rate (HR), and respiration in cats and rats. We investigated whether PBG caused somatomotor inhibition during exercise in the rabbit, a species in which it is known that the hemodynamic and respiratory responses to PBG are mediated by cardiac rather than by pulmonary receptors. In eight New Zealand White rabbits, BP, HR, and hindlimb electromyographic (EMG) responses to 60 and 120 micrograms/kg PBG and saline vehicle were evaluated during two separate 3-min exercise bouts at 10 m/min at 0% grade. During exercise, 60 micrograms/kg PBG decreased BP (-27 +/- 4 mmHg) and HR (-95 +/- 16 beats/min) but did not inhibit locomotion as suggested by the EMG response (+112 +/- 8% of preinfusion EMG). Hemodynamic and EMG responses to 120 micrograms/kg PBG were similar to 60 micrograms/kg PBG. Saline infusion during exercise had no effect on HR, BP, or locomotion (+114 +/- 8% of preinfusion EMG). Locomotion is not inhibited by PBG in rabbits, which suggests that PBG-induced reflex somatomotor inhibition observed in other species is primarily mediated by pulmonary rather than by cardiac receptors.

Effects of pulmonary denervation on renal sympathetic and heart rate responses to hypoxia.

We hypothesized that the renal sympathetic nerve activity (RSNA) response to hypoxia is attenuated because of stimulation of pulmonary receptors by the increase in ventilation. RSNA was measured during 20 min of severe hypoxia (8% O2) in conscious New Zealand White rabbits with intact lung innervation and in rabbits with surgical denervation of the lungs (LDX). LDX decreased resting breathing frequency but had no effect on resting mean arterial pressure (MAP), heart rate (HR), or RSNA. In intact rabbits, 4 min of hypoxia resulted in elevated RSNA (from 14 +/- 2 to 29 +/- 3% of smoke-elicited maximum), bradycardia (delta-65 +/- 12 beats/min), and no change in MAP (delta 2 +/- 2 mmHg). Bradycardia diminished with time, but elevated RSNA was maintained throughout the 20-min exposure. LDX enhanced the initial bradycardia (delta-113 +/- 11 beats/min, P < 0.01) but had no effect on the RSNA response (35 +/- 2% of maximum) to hypoxia. LDX did not alter steady-state responses of HR or RSNA, but MAP declined over time (-11 +/- 2 mmHg). These results suggest that in conscious rabbits pulmonary receptors have a minor influence on control of sympathetic activity to viscera during severe hypoxemia.

Effect of an abdominal binder during wheelchair exercise.

The purpose of this study was to determine whether use of an abdominal binder would affect oxygen uptake, trunk range of motion, and duration of the stroke phase during wheelchair propulsion. The subjects were six paraplegic wheelchair athletes with T1-T6 injuries and no abdominal muscle function. Each subject performed two trials, one while wearing the binder and one without the binder. Each trial consisted of submaximal and maximal exercise tests conducted on wheelchair rollers. Oxygen uptake was determined by open circuit spirometry while heart rate was determined by telemetry. Max VO2 values averaged 2.51 l.min-1 while average maximum heart rate values were 190 b.min-1. A 3-D video-based motion analysis system was used to obtain kinematic parameters of wheelchair propulsion. In general, 30% of the cycle time was comprised of the stroke phase, while 70% was comprised of the recovery phase across speeds. There were no statistically significant effects of the abdominal binder on any of the cardiovascular or kinematic variables at submaximal or maximal levels of exercise. Under the conditions of this laboratory investigation, it appears that an abdominal binder does not alter physiological or selected biomechanical measures in highly trained athletes.

Emotional and psychological abuse: problems of definition.

Defining "emotional abuse" and "psychological abuse" is a task made difficult by uncertainty as to whether or not such terms are synonomous and/or interchangeable. There is an increasing tendency in child protection literature to regard them as synonomous, or at least, to make little distinction between them. The purpose of this paper is to explore the origins of this tendency, and to provide an alternative view, namely, that the terms are not synonomous, and there should be different definitions for each. Existing commonly used definitions are reviewed. The definitions that this paper provides stem from important concepts in emotional and psychological development.

Muscle chemoreflex alters vascular conductance in nonischemic exercising skeletal muscle.

Previous studies have shown that the muscle chemoreflex causes an augmented blood pressure response to exercise and partially restores blood flow to ischemic muscle. The purpose of this study was to investigate the effects of the muscle chemoreflex on blood flow to nonischemic exercising skeletal muscle. During each experiment, dogs ran at 10 kph for 8-16 min and the muscle chemoreflex was evoked by reducing hindlimb blood flow at 4-min intervals (0-80%). Arterial blood pressure, hindlimb blood flow, forelimb blood flow, and forelimb vascular conductance were averaged over the last minute at each level of occlusion. Stimulation of the muscle chemoreflex caused increases in arterial blood pressure and forelimb blood flow and decreases in forelimb vascular conductance. The decrease in forelimb vascular conductance demonstrates that the muscle chemoreflex causes vasoconstriction in the nonischemic exercising forelimb. Despite the decrease in vascular conductance, the increased driving pressure caused by the pressor response was large enough to produce an increased forelimb blood flow.

Physiological comparison of uphill roller skiing: diagonal stride versus double pole.

The physiological responses to treadmill roller skiing with the double pole (DP) and diagonal stride (DS) techniques were compared at 1.7% and 7.1% grades among eight cross-country ski racers. Oxygen uptake (VO2) requirements were found to be lower (P < 0.05) for DP at the 1.7% grade, but similar at the 7.1% grade. In contrast, ratings of perceived exertion (RPE) and percentages of technique-specific peak VO2 were similar between techniques at the 1.7% grade, and lower (P < 0.05) for DS at the 7.1% grade. RPE and percentages of technique-specific peak VO2 were strongly correlated (r = 0.89). The primary findings indicate that 1) the economies for DP and DS are dependent upon the incline, 2) it is possible for the economy of DP to be greater than DS although the percentages of technique-specific peak VO2 are similar, and 3) the perceived effort associated with the use of DP and DS reflects the percentage of technique-specific peak VO2.

Intrapericardial blocking agents have extracardiac effects in dogs.

The purpose of this study was to determine if intrapericardial infusion of hexamethonium, propranolol, or atropine affected extracardiac receptors in anesthetized dogs. Intrapericardial hexamethonium (> or = 25 mg) decreased renal sympathetic nerve activity (RSNA) in a dose-dependent fashion. After 250 mg, RSNA began to decrease in 65 +/- 7 s. Whereas vagal stimulation caused a muscarinic receptor-mediated increase in tracheal smooth muscle tone (as indicated by a 9.6 +/- 1.1 mmHg increase in endotracheal cuff pressure), the increase in cuff pressure (1.8 +/- 0.4 mmHg) was attenuated after intrapericardial tropine (4 mg). When the ansa and vagus were stimulated simultaneously, beta-adrenergic receptor-mediated smooth muscle relaxation opposed the muscarinic receptor-mediated constriction resulting in an increase in cuff pressure of only 3.6 +/- 0.9 mmHg. After intrapericardial propranolol (8 mg), simultaneous ansa and vagal stimulation caused a 7.0 +/- 1.6 mmHg increase in cuff pressure, demonstrating that intrapericardial propranolol blocked beta-adrenergic receptor-mediated relaxation of tracheal smooth muscle. These results show that hexamethonium, atropine, and propranolol infused intrapericardially have extracardiac effects.

Cardiac receptors modulate the renal sympathetic response to dynamic exercise in rabbits.

Activation of cardiac sensory receptors with vagal afferents can result in inhibition of sympathetic outflow to the peripheral circulation. This study investigated whether the regulation of renal sympathetic nerve activity (RSNA) during dynamic exercise was modulated by cardiac sensory receptors. RSNA, blood pressure, and heart rate were measured in seven New Zealand White rabbits during treadmill exercise while cardiac receptors were intact (saline), during cardiac neural block with 2% procaine (2% PCN), and during cardiac efferent receptor block with methscopolamine and atenolol (M + A). Drugs were infused into the pericardial space via a chronic catheter. Two exercise protocols were used: 7 m/min (5 min) and 12 m/min (2 min) at 0% grade. The increases in HR during exercise at 7 and 12 m/min were attenuated with 2% PCN or M + A. At 12 m/min, blood pressure was significantly lower with 2% PCN (76 +/- 4 mmHg) or M + A (76 +/- 3 mmHg) than with saline (86 +/- 2 mmHg). Abolition of cardiac afferent input with 2% PCN resulted in a potentiated RSNA response to exercise at 7 m/min (+134 +/- 37%) and 12 m/min (+234 +/- 45%) relative to saline (+62 +/- 24 and +101 +/- 28%) or M + A (+19 +/- 9 and +52 +/- 19%, P < 0.05). These results suggest that cardiac sensory receptors attenuate sympathetic drive to the kidney during dynamic exercise in conscious rabbits.