Myocardial deformation assessment in patients with precapillary pulmonary hypertension: A cardiac magnetic resonance study

PurposeThe purpose of this study was to investigate right atrial and ventricular strain parameters on cardiac magnetic resonance (CMR) in patients with precapillary pulmonary hypertension (PPH) and whether they can aid in the assessment of PPH prognosis.Materials and methodsAdult patients with groups 1 and 4 PPH were invited to participate in the study. Age- and sex-matched healthy volunteers were also recruited as controls. At baseline, patients underwent clinical examination, N-terminal pro-B-type natriuretic peptide measurement and CMR with feature tracking post-processing (CMR-FT). Healthy controls underwent only CMR-FT. The study's primary endpoint was clinical failure, defined as death, hospitalization or demonstrable clinical deterioration during follow-up. Patients who were unable to perform 6-minute walking test due to musculoskeletal disorders were excluded from the study.ResultsThirty-six patients (8 men, 28 women; mean age, 50.6 ± 13.8 [SD] years [range: 18.6–78.5 years]) and 12 healthy control subjects (5 mean, 7 women; mean age, 40.6 ± 13.5 [SD] years [range: 23.1–64.4 years]) were recruited. Right ventricular global longitudinal strain (GLS) was significantly impaired in PPH patients (?20.2 ± 5.3 [SD] % [range: ?28.8 to ?9.1%] vs. ?28.4 ± 3.1% [?33.7 to ?22.7%] respectively, P < 0.001). The right atrial GLS was significantly impaired in PPH compared to healthy controls (?19.9 ± 4.5% [range: ?28.6 to ?3.6%] vs. ?26.5 ± 4.2% [range: ?32.8 to ?15.8%] respectively) (P < 0.001). Clinical failure occurred in 19 (19/36, 53%) of patients. Right ventricular GLS predicted clinical failure most reliably among CMR parameters (?22.6 ± 3.8 [SD] % [range: ?27.6 to ?12.7%] for patients without clinical failure vs. ?18 ± 5.6 [SD] % [range: ?28.8 to ?9.1%] for patients with clinical failure; hazard ratio [HR] = 1.85; P = 0.007; area under the AUC curve = 0.75). Lower absolute right atrial GLS was significantly associated with clinical failure (?22.7 ± 3.0 [SD] % [range: ?28.6 to ?17.7%] for patients without clinical failure vs. ?16.9 ± 5.8 [SD] % [range: ?24.2 to ?3.6%] for patients with clinical failure) (HR = 1.53; P = 0.035).ConclusionCMR feature tracking-derived myocardial strain parameters of both the right atrium and ventricle can assist clinicians in the prognosis of PPH.     

Effectiveness,Patient Satisfaction,and Cost Reduction of Virtual Joint Replacement Clinic Follow-Up of Hip and Knee Arthroplasty

BackgroundTotal hip and knee arthroplasties are increasingly performed operations, and routine follow-up places huge demands on orthopedic services. This study investigates the effectiveness, patients’ satisfaction, and cost reduction of Virtual Joint Replacement Clinic (VJRC) follow-up of total hip arthroplasty and total knee arthroplasty patients in a university hospital. VJRC is especially valuable when in-person appointments are not advised or feasible such as during the COVID-19 pandemic.MethodsA total of 1749 patients who were invited for VJRC follow-up for knee or hip arthroplasty from January 2017 to December 2018 were included in this retrospective study. Patients were referred to VJRC after their 6-week postoperative review. Routine VJRC postoperative review was undertaken at 1 and 7 years and then 3-yearly thereafter. We evaluated the VJRC patient response rate, acceptability, and outcome. Patient satisfaction was measured in a subgroup of patients using a satisfaction survey. VJRC costs were calculated compared to face-to-face follow-up.ResultsThe VJRC had a 92.05% overall response rate. Only 7.22% required further in-person appointments with only 3% being reviewed by an orthopedic consultant. VJRC resulted in an estimated saving of £42,644 per year at our institution. The patients’ satisfaction survey showed that 89.29% of the patients were either satisfied or very satisfied with VJRC follow-up.ConclusionVJRC follow-up for hip and knee arthroplasty patients is an effective alternative to in-person clinic assessment which is accepted by patients, has high patient satisfaction, and can reduce the cost to both health services and patients.     

Retrospective Analysis Using Pharmacokinetic/Pharmacodynamic Modeling and Simulation Offers Improvements in Efficiency of the Design of Volunteer Infection Studies for Antimalarial Drug Development

Volunteer infection studies using the induced blood stage malaria (IBSM) model have been shown to facilitate antimalarial drug development. Such studies have traditionally been undertaken in single‐dose cohorts, as many as necessary to obtain the dose‐response relationship. To enhance ethical and logistic aspects of such studies, and to reduce the number of cohorts needed to establish the dose‐response relationship, we undertook a retrospective in silico analysis of previously accrued data to improve study design. A pharmacokinetic (PK)/pharmacodynamic (PD) model was developed from initial fictive‐cohort data for OZ439 (mixing the data of the three single‐dose cohorts as: n = 2 on 100 mg, 2 on 200 mg, and 4 on 500 mg). A three‐compartment model described OZ439 PKs. Net growth of parasites was modeled using a Gompertz function and drug‐induced parasite death using a Hill function. Parameter estimates for the PK and PD models were comparable for the multidose single‐cohort vs. the pooled analysis of all cohorts. Simulations based on the multidose single‐cohort design described the complete data from the original IBSM study. The novel design allows for the ascertainment of the PK/PD relationship early in the study, providing a basis for rational dose selection for subsequent cohorts and studies.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Volunteer infection studies are routinely used in antimalarial drug development to generate early pharmacokinetic/pharmacodynamic data for compounds.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ Can in silico analyses be used to suggest improvements to volunteer infection study designs?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Multiple dose adaptive trial designs can potentially reduce the number of cohorts needed to establish the dose‐response relationship in volunteer infection studies.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Real time data analyses can be used to recommend doses for adaptive volunteer infection studies.

Volunteer infection studies using the induced blood stage malaria (IBSM) model have been recognized as a valuable system for defining the key pharmacokinetic (PK) and pharmacodynamic (PD) relationships for dose selection in antimalarial drug development. ¹ , ² , ³ , ⁴ , ⁵ , ⁶ , ⁷ In such studies, healthy volunteers are inoculated intravenously with a given quantity (with small variability) of Plasmodium‐infected red cells. Parasitemia is then followed by quantitative polymerase chain reaction until a prespecified treatment threshold is reached when the test drug is administered. Parasite and drug concentrations are then measured. These studies are conducted prior to phase II dose‐response (D‐R) trials and can be included in an integrated first‐in‐human study protocol, or after completion of the first‐in‐human PK and safety study. IBSM studies have been typically designed as flexible multiple cohort studies where each volunteer of one cohort receives a single dose of the same amount of drug (“single dose per cohort”). ² , ³ , ⁴ , ⁵ After each cohort, a decision is made to stop or to add a cohort to test a lower or higher dose based on the response observed in the previous cohorts.For the multiple single‐dose‐per‐cohort design, the starting dose is typically selected based on safety and PK information from a phase I single ascending dose (SAD) study and, more recently, on preclinical data from a severe combined immunodeficient mouse model, with the dose selected on the basis of being best able to inform the D‐R relationship, rather than aiming for cure. This approach, where a single dose is tested in all subjects of the initial cohort, risks missing the dose likely to be most informative for defining the PK/PD relationship.An alternative approach is to spread a range of doses across a smaller number of subjects within the initial cohort and use PK/PD models developed based on data from this cohort to support dose selections of subsequent cohorts and studies. Using data from a previous study, ² we undertook an in silico investigation of such an adaptive study design, aiming to reduce the number of subjects exposed to inefficacious doses, and to establish a D‐R relationship. This multiple‐dose‐groups‐per‐cohort design, referred to as the “2‐2‐4” design, is contrasted with the already implemented study design depicted in Figure  1 .Open in a separate windowFigure 1Comparison of standard and adaptive designs of IBSM studies. A/B/C, dose levels to be selected during the progress of the study based on pharmacokinetic/pharmacodynamic results of the initial cohort; CHMI, controlled human malaria infection; D‐R, dose‐response; IBSM, induced blood stage malaria infection; n, number of subjects at each dose.The objectives of this retrospective analysis were to: (i) compare PK/PD parameter estimates from the initial cohort of the 2‐2‐4 study design with the prior results from the data of the full study and (ii) propose a preliminary workflow to establish D‐R early in an IBSM study, and use modeling and simulation (M&S) to support dose selections for subsequent cohorts and later phase clinical trials.