Pharmacokinetic Modelling of Efavirenz, Atazanavir, Lamivudine and Tenofovir in the Female Genital Tract of HIV-Infected Pre-Menopausal Women

A previously published study of antiretroviral pharmacokinetics in the female genital tract of HIV-infected women demonstrated differing degrees of female genital tract penetration among antiretrovirals. These blood plasma (BP) and cervicovaginal fluid (CVF) data were co-modelled for four antiretrovirals with varying CVF exposures

Expression of Six Drug Transporters in Vaginal, Cervical, and Colorectal Tissues: Implications for Drug Disposition in HIV Prevention

Effective antiretroviral (ARV)-based HIV prevention strategies require optimizing drug exposure in mucosal tissues; yet factors influencing mucosal tissue disposition remain unknown. We hypothesized drug transporter expression in vaginal, cervical, and colorectal tissues is a contributing factor and selected 3 efflux (ABCB1/MDR1, ABCC2/MRP2, ABCC4/MRP4) and 3 uptake (SLC22A6/OAT1, SLC22A8/OAT3, SLCO1B1/OATP1B1) transporters to further investigate based on their affinity for 2 ARVs central to prevention (tenofovir, maraviroc). Tissue was collected from 98 donors. mRNA and protein expression were quantified using qPCR and immunohistochemistry (IHC). Hundred percent of tissues expressed efflux transporter mRNA. IHC localized them to the epithelium and/or submucosa. Multivariable analysis adjusted for age, smoking, and co-medications revealed significant (P  colorectal; vaginal ABCC2 2.9-fold > colorectal; colorectal ABCC4 2.0-fold > cervical). In contrast, uptake transporter mRNA was expressed in <25% of tissues. OAT1 protein was detected in 0% of female genital tissues and in 100% of colorectal tissues, but only in rare epithelial cells. These data support clinical findings of higher maraviroc and tenofovir concentrations in rectal tissue compared to vaginal or cervical tissue after oral dosing. Quantifying mucosal transporter expression and localization can facilitate ARV selection to target these tissues

Models for Predicting Effective HIV Chemoprevention in Women

Model systems which rapidly identify tissue drug concentrations protective of HIV infection could streamline the development of chemoprevention strategies. Tissue models are promising, but limited concentration targets exist, and no systematic comparison to cell models or clinical studies has been performed

Does physiotherapy reduce the incidence of postoperative complications in patients following pulmonary resection via thoracotomy? a protocol for a randomised controlled trial

Background: Postoperative pulmonary and shoulder complications are important causes of postoperative morbidity following thoracotomy. While physiotherapy aims to prevent or minimise these complications, currently there are no randomised controlled trials to support or refute effectiveness of physiotherapy in this setting. Methods/Design: This single blind randomised controlled trial aims to recruit 184 patients following lung resection via open thoracotomy. All subjects will receive a preoperative physiotherapy information booklet and following surgery will be randomly allocated to a Treatment Group receiving postoperative physiotherapy or a Control Group receiving standard care nursing and medical interventions but no physiotherapy. The Treatment Group will receive a standardised daily physiotherapy programme to prevent respiratory and musculoskeletal complications. On discharge Treatment Group subjects will receive an exercise programme and exercise diary to complete. The primary outcome measure is the incidence of postoperative pulmonary complications, which will be determined on a daily basis whilst the patient is in hospital by a blinded assessor. Secondary outcome measures are the length of postoperative hospital stay, severity of pain, shoulder function as measured by the self-reported shoulder pain and disability index, and quality of life measured by the Medical Outcomes Study Short Form 36 v2 New Zealand standard version. Pain, shoulder function and quality of life will be measured at baseline, on discharge from hospital, one month and three months postoperatively. Additionally a subgroup of subjects will have measurement of shoulder range of movement and muscle strength by a blinded assessor. Discussion: Results from this study will contribute to the increasing volume of evidence regarding the effectiveness of physiotherapy following major surgery and will guide physiotherapists in their interventions for patients following thoracotomy. Trial registration: The study protocol is registered with the Australian and New Zealand Clinical Trials registry (ANZCTRN12605000201673)

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

A postoperative shoulder exercise program improves function and decreases pain following open thoracotomy: a randomised trial

QuestionDoes a postoperative physiotherapy exercise program incorporating shoulder exercises improve shoulder function, pain, range of motion, muscle strength, and health-related quality of life in patients undergoing elective pulmonary resection via open thoracotomy?DesignRandomised trial with concealed allocation, assessor blinding, and intention-to-treat analysis.Participants76 patients who underwent pulmonary resection via open thoracotomy.InterventionAll participants received standard medical and nursing care involving a clinical pathway. The experimental group also received physiotherapy interventions that included daily supervised, progressive exercises until discharge and a postoperative exercise booklet on discharge.Outcome measuresPreoperatively and up to 3 months postoperatively pain was measured with a numerical rating scale, shoulder function with the Shoulder Pain and Disability Index, and quality of life with the Short Form-36. Shoulder range of motion and muscle strength were measured in a subgroup.ResultsThe experimental group had 1.3 units (95% CI 0.3 to 2.2) less shoulder pain (scored /10) and 2.2 units (95% CI 0.2 to 4.3) less total pain (scored /30) at discharge, and 7.6% (95% CI 1.7 to 13.6) better function at 3 months. The Short Form-36 physical component score was 4.8 points (95% CI –0.3 to 10.0) better for the experimental group than the control group at 3 months. Differences between groups in all range of motion and strength measures were small and statistically non-significant.ConclusionA physiotherapist-directed postoperative exercise program resulted in significant benefits in pain and shoulder function over usual care for patients following open thoracotomy.Trial registrationANZCTRN 12605000201673

Expression of six drug transporters in vaginal, cervical, and colorectal tissues: Implications for drug disposition in HIV prevention.

Effective antiretroviral (ARV)-based HIV prevention strategies require optimizing drug exposure in mucosal tissues; yet factors influencing mucosal tissue disposition remain unknown. We hypothesized drug transporter expression in vaginal, cervical, and colorectal tissues is a contributing factor and selected 3 efflux (ABCB1/MDR1, ABCC2/MRP2, ABCC4/MRP4) and 3 uptake (SLC22A6/OAT1, SLC22A8/OAT3, SLCO1B1/OATP1B1) transporters to further investigate based on their affinity for 2 ARVs central to prevention (tenofovir, maraviroc). Tissue was collected from 98 donors. mRNA and protein expression were quantified using qPCR and immunohistochemistry (IHC). Hundred percent of tissues expressed efflux transporter mRNA. IHC localized them to the epithelium and/or submucosa. Multivariable analysis adjusted for age, smoking, and co-medications revealed significant (P &lt; 0.05) differences in efflux transporter mRNA between tissue types (vaginal ABCB1 3.9-fold &gt; colorectal; vaginal ABCC2 2.9-fold &gt; colorectal; colorectal ABCC4 2.0-fold &gt; cervical). In contrast, uptake transporter mRNA was expressed in &lt;25% of tissues. OAT1 protein was detected in 0% of female genital tissues and in 100% of colorectal tissues, but only in rare epithelial cells. These data support clinical findings of higher maraviroc and tenofovir concentrations in rectal tissue compared to vaginal or cervical tissue after oral dosing. Quantifying mucosal transporter expression and localization can facilitate ARV selection to target these tissues

Pharmacokinetic Modelling of Efavirenz, Atazanavir, Lamivudine and Tenofovir in the Female Genital Tract of HIV-Infected Pre-Menopausal Women

BACKGROUND AND OBJECTIVES: A previously published study of antiretroviral pharmacokinetics in the female genital tract of HIV-infected women demonstrated differing degrees of female genital tract penetration among antiretrovirals. These blood plasma (BP) and cervicovaginal fluid (CVF) data were co-modelled for four antiretrovirals with varying CVF exposures. METHODS: Six paired BP and CVF samples were collected over 24 h, and antiretroviral concentrations determined using validated liquid chromatography (LC) with UV detection or LC-mass spectrometry analytical methods. For each antiretroviral, a BP model was fit using Bayesian estimation (ADAPT5), followed by addition of a CVF model. The final model was chosen based on graphical and statistical output, and then non-linear mixed-effects modelling using S-ADAPT was performed. Population mean parameters and their variability are reported. Model-predicated area under the concentration-time curve during the dosing interval (AUC(τ)) and exposure ratios of CVF AUC(τ):BP AUC(τ) were calculated for each drug. RESULTS: The base model uses first-order absorption with a lag time, a two-compartment model, and a series of transit compartments that transfer the drug from BP to CVF. Protein-unbound drug transfers into CVF for efavirenz and atazanavir; total drug transfers for lamivudine and tenofovir. CVF follows a one-compartment model for efavirenz and atazanavir, and a two-compartment model for lamivudine and tenofovir. As expected, inter-individual variability was high. Model-predicted CVF AUC(τ):BP AUC(τ) ratios are consistent with published results. CONCLUSIONS: This is the first pharmacokinetic modelling of antiretroviral disposition in BP and CVF. These models will be further refined with tissue data, and used in clinical trials simulations to inform future studies of HIV pre-exposure prophylaxis in women