Population Of Healthy Volunteers Research Articles

Mild Systemic Inflammation Increases Erythrocyte Fragility.

There is growing evidence that inflammation impairs erythrocyte structure and function. We assessed the impact of mild systemic inflammation on erythrocyte fragility in three different settings. In order to investigate causation, erythrocyte osmotic fragility was measured in mice challenged with a live attenuated bacterial strain to induce low-grade systemic inflammation; a significant increase in erythrocyte osmotic fragility was observed. To gather evidence that systemic inflammation is associated with erythrocyte fragility in humans, two observational studies were conducted. First, using a retrospective study design, the relationship between reticulocyte-based surrogate markers of haemolysis and high-sensitivity C-reactive protein was investigated in 9292 healthy participants of the UK Biobank project. Secondly, we prospectively assessed the relationship between systemic inflammation (measured by the urinary neopterin/creatinine ratio) and erythrocyte osmotic fragility in a mixed population (n = 54) of healthy volunteers and individuals with long-term medical conditions. Both human studies were in keeping with a relationship between inflammation and erythrocyte fragility. Taken together, we conclude that mild systemic inflammation increases erythrocyte fragility and may contribute to haemolysis. Further research is needed to assess the molecular underpinnings of this pathway and the clinical implications in inflammatory conditions.

Semorinemab Pharmacokinetics and The Effect on Plasma Total Tau Pharmacodynamics in Clinical Studies.

Semorinemab is a monoclonal antibody that targets the N-terminal domain of the tau protein that is in clinical development for the treatment of Alzheimer's disease. To perform model-based evaluations of the observed pharmacokinetics in serum and the total plasma tau target-engagement dynamics from clinical studies evaluating semorinemab. The observed semorinemab pharmacokinetics and plasma tau target engagement from phase 1 and 2 clinical studies were modeled using a non-linear mixed effect target-mediated drug disposition model. The model was simulated to understand target engagement at clinical dose levels. The clinical studies testing semorinemab were evaluated in healthy volunteers, subjects with prodromal-to-mild Alzheimer's disease, and subjects with mild-to-moderate Alzheimer's disease. The data included a total of 8430 semorinemab serum concentrations and 4772 total tau protein plasma concentrations from 463 subjects treated with a range of single and multiple doses of semorinemab. Serum concentrations of semorinemab and the total plasma tau concentrations were measured after administration of a range of doses of semorinemab to subjects with Alzheimer's disease. A sensitivity analysis was performed wherein key target-mediated drug disposition model parameters were estimated separately between healthy volunteers, subjects with prodromal-to-mild Alzheimer's disease, and subjects with mild-to-moderate Alzheimer's disease. Serum concentrations of semorinemab were consistent across studies and showed a dose-proportional increase across the evaluated dose range. The pharmacokinetic profile was comparable between healthy volunteers and subjects with Alzheimer's disease. Total plasma tau concentrations increased in a dose-dependent non-linear manner upon semorinemab administration. The target-mediated drug disposition model adequately described the serum pharmacokinetics and protein dynamics with an estimated antibody-ligand binding strength, Kss, of 42.7 nM. The estimated values of clearance and central volume of distribution were 0.109 L/day/70 kg and 2.95 L/70 kg, respectively, and were consistent with typical values for IgG mAbs. In the sensitivity analysis, Kss (32 nM) and baseline tau protein (0.30 µM) were estimated to be lower for healthy volunteers compared to subjects with Alzheimer's disease but were comparable between subjects with Alzheimer's disease of different severities (Kss: 52-57 nM, baseline tau: 0.44-0.47 µM). The models suggested that peripheral target engagement was over 90% at the clinical doses in each of the diagnostic subgroups. Our target-mediated drug disposition model adequately described the serum pharmacokinetics and the peripheral non-linear increase with dose of the total tau. The model confirmed that these dose-response relationships were consistent across populations of healthy volunteers and subjects with different severities of Alzheimer's disease.

Serotype 3 Experimental Human Pneumococcal Challenge (EHPC) study protocol: dose ranging and reproducibility in a healthy volunteer population (challenge 3)

IntroductionSince the introduction of pneumococcal conjugate vaccines, pneumococcal disease rates have declined for many vaccine-type serotypes. However, serotype 3 (SPN3) continues to cause significant disease and is identified in colonisation...

Diastolic disfunction in systemic right ventricle: a cardiac magnetic resonance study on atrial function in congenital corrected transposition of great arteries patients

Abstract Background congenital corrected transposition of great arteries (ccTGA) leads to systemic position of the right ventricle (sRV). Patients with ccTGA are usually asymptomatic in the first decades of life but over time sRV will fail to support elevated systemic pressure, possibly leading to systolic heart failure (HF) in adulthood. Several factors have been associated with sRV failure and worse prognosis such as tricuspid valve dysfunction, conduction abnormalities, previous surgery due to associated lesions. However, little is known about diastolic function in sRV. We hypothesize that diastolic dysfunction characterizes sRV pathophysiology, therefore an accurate evaluation of diastolic function would allow a better assessment and risk stratification of patients. The present study aims to investigate the diastolic function in patients with ccTGA by assessing left atrial (LA) morpho-functional parameters. Methods we retrospectively examined Cardiac Magnetic Resonance (CMR) imaging of 33 ccTGA patients clinically referred to our Center between April 2014 and December 2022. ccTGA patients were matched based on sex and age with a healthy volunteer population (control group) and a group of patients with Hypertrophic Cardiomyopathy (HCM) diagnosed with HFpEF according to HF guidelines criteria. LA morpho-functional parameters were compared among the three groups: LA volumes (obtained by the length-area method), ejection fraction (EF) and, by means of feature tracking analysis, strain reservoir (εs), conduit (εe) and booster pump (εa). All patients were in sinus rhythm at the time of CMR. Results In comparison with the control group, ccTGA patients had a significant impairment in LA function (LA EF: 41,6 ± 15,1 vs 63,9 ± 7,8, p < 0,001, εs: 19,0 ± 8,3 vs 38,0 ± 10,3, p < 0,001, εe: 11,7 ± 5,9 vs 21,1 ± 8,3 p < 0,001, εa: 7,6 ± 4,1 vs 16,8 ± 6,1, p < 0,001). Conversely, no significant difference was found between ccTGA and HCM group regarding LA function (EF: 41,6 ± 15,1 vs 42,0 ± 10,1, εs: 19,0 ± 8,3 vs 22,6 ± 8,8, εe: 11,7 ± 5,9 vs 12,6 ± 7,0, εa: 7,6 ± 4,1 vs 10 ± 3,7). As for morphological parameters, ccTGA patients had an increase of LA volumes compared to both the control group and HCM patients. Conclusion ccTGA patients present an impaired LA function and a significative increase in LA volume consistent with the presence of diastolic disfunction. Further studies are needed to assess the clinical impact of morpho-functional LA impairment in ccTGA patients.

Menstrual Tampons Are Reliable and Acceptable Tools to Self-Collect Vaginal Microbiome Samples.

Many women report embarrassment as the cause for their avoidance of routine gynaecological screening appointments. Methods of self-collection of bio samples would perhaps encourage women to participate in routine screening programs. The vaginal microbiome plays a key role in women's health and reproductive function. Microbial disturbances can result in the loss of lactobacillus dominance, also known as dysbiosis, associated with an increased risk of contracting sexually transmitted infections (STIs), pregnancy complications and infertility. Our primary aim was to determine if vaginal microbiome screening results are comparable between two methods for self-collected sample acquisition: tampons and lower vaginal swabs (LVSs). Secondary aims included the assessment of the effect of pre-analytic storage on the data (to streamline processing), the prevalence of dysbiosis and the acceptability of the tampons to the participants. Statistical analysis revealed no significant difference in the microbiome data, from tampons versus LVSs or fresh versus frozen samples. The prevalence of dysbiosis in this population of healthy volunteers was 42.9%. The questionnaire data revealed that 52.4% of volunteers use tampons every period, and the majority of volunteers rated the tampons as 5 on a 1-5 Likert scale regarding their perceived comfort using tampons. All (100%) of volunteers were happy to provide a tampon as a sample for testing. The findings from this study show that tampons and LVSs were comparable when analysing the vaginal microbiome, with potential superiority of the tampon with regard to patient acceptability. Self-collection of vaginal secretions for gynaecological screening using tampons warrants further research as this could change the screening landscape, ensuring wider participation and increasing efficacy.

The reproducibility of breathing maneuvers as a vasoactive stimulus in the heart: an oxygenation-sensitive resonance imaging study

BackgroundEndothelial dysfunction and impaired oxygenation of the heart is a hallmark of several diseases, including coronary artery disease, hypertension, diabetes, and sleep apnea. Recent studies indicate that oxygenation-sensitive cardiovascular magnetic resonance (OS-CMR) imaging combined with breathing maneuvers may allow for assessing coronary vascular responsiveness as a marker for coronary vascular function in various clinical settings. However, despite the use of OS-CMR in evaluating tissue oxygenation, the reproducibility of these standardized, combined breathing maneuvers as a vasoactive stimulus has yet to be systematically assessed or validated. In this study, we aimed to assess the reproducibility of vasoactive breathing maneuvers to assess vascular function in a population of healthy volunteers. MethodsEighteen healthy volunteers were recruited for the study. Inclusion criteria were an age over 18 years and absence of any evidence or knowledge of cardiovascular, neurological, or pulmonary disease. MRI was performed on a clinical 3 T MRI system (MAGNETOM Skyra, Siemens Healthineers, Erlangen, Germany). The OS-CMR acquisition was performed as previously described (1 min hyperventilation followed by a maximal, voluntary breath-hold). Standard statistical tests were performed as appropriate. ResultsData from 18 healthy subjects was analyzed. The healthy volunteers had a mean age of 42 ± 15 years and a mean BMI of 25.4 ± 2.8 kg/m2, with an average heart rate of 72 ± 11 beats per minute, and ten of whom (56%) were female. There were no significant differences between global myocardial oxygenation (%Δ SI) after hyperventilation (HV1: − 7.82 ± 5.2; HV2: − 7.89 ± 6.4, p = 0.9) or breath-hold (BH1: 5.34 ± 3.1; BH2: 6.0 ± 3.3, p = 0.5) between the repeated breathing maneuvers. The Bland–Altman analysis showed good agreement (bias: 0.074, SD of bias: 2.93). ConclusionWe conclude that in healthy individuals, the myocardial oxygenation response to a standardized breathing maneuver with hyperventilation and a voluntary breath-hold is consistent and highly reproducible. These results corroborate previous evidence for breathing-enhanced OS-CMR as a robust test for coronary vascular function.

Importance of Polymorphisms in the Gene of Paraoxonase-1 (SNP rs662) and Apolipoprotein A-I (SNP rs670 and rs5069) in Non-Smoking and Smoking Healthy Subjects and Patients with Acute Pancreatitis

Oxidative stress has been implicated in the initiation of acute pancreatitis (AP). HDL is considered to be a preventing factor against cell membrane oxidation, thanks to the presence on its surface of apolipoprotein A-I (apoA-I) and paraoxonase-1 (PON1), which activity can be modified by genetic and environmental factors. The impact of SNP rs662 in the PON1 gene and SNP rs670 and rs5069 in the APOAI gene on PON1 activities and its concentration in the population of AP patients and healthy volunteers was investigated. In the group of patients with AP, a decreased HDL concentration and PON1 activities were observed. A decrease in the aryloesterase and lactonase activities of PON1 in AP patients with the TT genotype for SNP rs662 (especially in smokers) was found. In the group of patients with the AA genotype (rs670), the highest concentrations of HDL and apoA-I were observed, which were gradually decreasing in the course of AP. Changes in the concentration of apoA-I were associated with the changes in the concentration and activities of PON1 in the AP patients with the AA genotype for SNP rs670. A decreasing apoA-I concentration contributing to lowering PON1 concentration and its activities during the hospitalization of AP patients with the CC genotype for SNP rs5069 were shown. Therefore, more susceptibility of persons with the CC genotype for SNP rs5069 to pro/antioxidative imbalance was shown. In this process, an important role was played by the HDL level and its interaction with PON1 and apoA-I.

PBPK perspective on alternative CYP3A4 inducers for rifampin.

PBPK perspective on alternative CYP3A4 inducers for rifampin.

Development of a Method and a Scheme for the Use of a Live Recombinant Vaccine "GamLPV". Safety and Tolerability of Double Intranasal Vaccination of Healthy Adult Volunteers

Introduction. The increase in the incidence of whooping cough in children and adults of different age groups justifies the need for their revaccination and the development of new, acceptable for these purposes. This work is devoted to substantiating the design of a clinical trial and describing the results of a comparative study of the safety and tolerability of the drug "GamLPV" with two-fold intranasal administration to healthy adult volunteers using two methods. The choice of the scheme and method of administration of the drug is justified. The serological structure of the population of adults aged 18–40 years living in Moscow and the Moscow region is characterized.Aim. Determination of the safety and tolerability of the drug with a double intranasal administration of the vaccine by drip method and spraying through an actuator.Materials and methods. A randomized placebo-controlled trial included 50 healthy male and female volunteers aged 18 to 40 years who met the inclusion criteria. The volunteers were divided into 2 groups of 25 people: a drip method of administration and spraying through an "actuator". By both methods, the drug was administered twice with an interval of 60 days.Results and discussion. Serological analysis of the population of healthy volunteers at the prescreening stage justified the inclusion in the study of volunteers containing anti-pertussis antibodies in the blood (IgG ≤40 Ed/ml). A comparison of the results of preclinical studies on an experimental model of non-human monkeys and the first phase of a clinical study of GamLPV allowed us to propose two methods of double administration of the drug as a promising vaccination scheme for volunteers. A comparative randomized study shows the safety of using the proposed scheme for vaccination of adult volunteers.Conclusions. Both proposed methods of double administration can be used to plan a multicenter study to research the immunogenicity and protective activity of GamLPV.

S-Ketamine oral thin film-Part 2: Population pharmacodynamics of S-ketamine, S-norketamine and S-hydroxynorketamine.

Ketamine is a versatile drug used for many indications and is administered via various routes. Here, we report on the pharmacodynamics of sublingual and buccal fast-dissolving oral-thin-films that contain 50 mg of S-ketamine in a population of healthy male and female volunteers. Twenty volunteers received one or two 50 mg S-ketamine oral thin films in a crossover design, placed for 10 min sublingually (n = 15) or buccally (n = 5). The following measurements were made for 6 h following the film placement: antinociception using three distinct pain assay; electrical, pressure, and heat pain, and drug high on an 11-point visual analog scale. Blood samples were obtained for the measurement of plasma S-ketamine, S-norketamine, and S-hydroxynorketamine concentrations. A population pharmacodynamic analysis was performed in NONMEM to construct a pharmacodynamic model of S-ketamine and its metabolites. P-values < 0.01 were considered significant. The sublingual and buccal 50 and 100 mg S-ketamine oral thin films were antinociceptive and produced drug high with effects lasting 2–6 h, although a clear dose-response relationship for antinociception could not be established. The effects were solely related to the parent compound with no contribution from S-norketamine or S-hydroxynorketamine. S-ketamine potency was lower for antinociception (C50 ranging from 1.2 to 1.7 nmol/mL) than for drug high (C50 0.3 nmol/ml). The onset/offset of effect as defined by the blood-effect-site equilibration half-life did not differ among endpoints and ranged from 0 to 5 min. In conclusion, the 50-mg S-ketamine oral thin film was safe and produced long-term antinociception in all three nociceptive assays with side effects inherent to the use of ketamine. The study was registered at the trial register of the Dutch Cochrane Center (www.trialregister.nl) under identifier NL9267 and the European Union Drug Regulating Authorities Clinical Trials (EudraCT) database under number 2020-005185-33.

S-Ketamine Oral Thin Film-Part 1: Population Pharmacokinetics of S-Ketamine, S-Norketamine and S-Hydroxynorketamine.

Ketamine is administered predominantly via the intravenous route for the various indications, including anesthesia, pain relief and treatment of depression. Here we report on the pharmacokinetics of sublingual and buccal fast-dissolving oral-thin-films that contain 50 mg of S-ketamine in a population of healthy male and female volunteers. Twenty volunteers received one or two oral thin films on separate occasions in a randomized crossover design. The oral thin films were placed sublingually (n = 15) or buccally (n = 5) and left to dissolve for 10 min in the mouth during which the subjects were not allowed to swallow. For 6 subsequent hours, pharmacokinetic blood samples were obtained after which 20 mg S-ketamine was infused intravenously and blood sampling continued for another 2-hours. A population pharmacokinetic analysis was performed in NONMEM pharmacokinetic model of S-ketamine and its metabolites S-norketamine and S-hydroxynorketamine; p < 0.01 were considered significant. S-ketamine bioavailability was 26 ± 1% (estimate ± standard error of the estimate) with a 20% lower bioavailability of the 100 mg oral thin film relative to the 50 mg film, although this difference did not reach the level of significance. Due to the large first pass-effect, 80% of S-ketamine was metabolized into S-norketamine leading to high plasma levels of S-norketamine following the oral thin film application with 56% of S-ketamine finally metabolized into S-hydroxynorketamine. No differences in pharmacokinetics were observed for the sublingual and buccal administration routes. The S-ketamine oral thin film is a safe and practical alternative to intravenous S-ketamine administration that results in relatively high plasma levels of S-ketamine and its two metabolites.

Oxygen efficient respiratory Aid (OxEraTM) device: A safety study.

Severe Coronavirus Disease 2019 (COVID-19) can develop pneumonia with severe complications. The Oxygen Efficient Respiratory Aid (OxEraTM) device has been granted SAPHRA approval for emergency COVID-19 pandemic use. The device has the potential to be used widely in the healthcare sector due to its efficient oxygen supply and adjustable wall positive expiratory pressure (PEP). We assessed whether the OxEraTM device was safe to use in a healthy adult volunteer population. Our primary objective was to ensure there was no asphyxiation, as assessed by changes observed from baseline End Tidal Carbon Dioxide (ETCO2) exceeding 6.3mmHg and above the 45mmHg threshold. We also monitored changes in vital organ signs and assessed the pain and comfort of the participant at various intervals with changes in PEPs. This was an experimental safety study of the OxEraTM Device on 30 healthy participants at the ICU training centre of Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa. Each participant had basic vital-signs, ETCO2, and Oxygen saturation percentages (SpO2%) taken at baseline until the end of 2h. In the first 20min, the PEP was increased by 5cmH20 until 20min, then continued for the rest of the time on a PEP of 5cmH20. At each interval, vital signs, subjective comfort, pain, and visual scores were measured. Thirty healthy participants were enrolled. There was no significant difference in ETCO2 from baseline until 2h. No participant experienced an increase in measured ETCO2 greater than 45mmHg and no increase in ETCO2 from baseline was greater than 6.3mmHg. The median increase in ETCO2 over the study period was 2mmHg. There were no significant changes in respiratory rate and blood pressure. The heart rate decreased significantly (73-68bpm). The VAS and comfort score had a significant increase over the 2h from baseline of 0-2 at maximum; however, the PAS scores showed no significant increase. Overall the OxEraTM device achieved the safety endpoints set out. There was no sign of asphyxiation and there were appropriate physiological responses to changes in PEP once applied. The comfort of the mask did worsen over the 2h; however, the scores were minimally worse on PEP application but improved once-off PEP. No adverse event was recorded at all.

Advanced magnetic resonance imaging of chronic whiplash patients: a clinical practice-based feasibility study

BackgroundWhiplash injury is common following road traffic crashes affecting millions worldwide, with up to 50% of the injured developing chronic symptoms and 15% having a reduced working capability due to ongoing disability. Many of these patients receive treatment in primary care settings based upon clinical and diagnostic imaging findings. Despite the identification of different types of injuries in the whiplash patients, clinically significant relationships between injuries and chronic symptoms remains to be fully established. This study investigated the feasibility of magnetic resonance imaging (MRI) techniques including quantitative diffusion weighted imaging and measurements of cerebrospinal fluid (CSF) flow as novel non-invasive biomarkers in a population of healthy volunteers and chronic whiplash patients recruited from a chiropractic clinic for the purpose of improving our understanding of whiplash injury.MethodsTwenty chronic whiplash patients and 18 healthy age- and gender matched control subjects were included [mean age ± SD (sex ratio; females/males), case group: 37.8 years ± 9.1 (1.22), control group: 35.1 years ± 9.2 (1.25)]. Data was collected from May 2019 to July 2020. Data from questionnaires pertaining to the car crash, acute and current symptoms were retrieved and findings from clinical examination and MRI including morphologic, diffusion weighted and phase-contrast images were recorded. The apparent diffusion coefficient and fractional anisotropy were calculated, and measurement and analysis of CSF flow was conducted. Statistical analyses included Fisher’s exact test, Mann Whitney U test and analysis of variance between groups.ResultsThe studied population was described in detail using readily available clinical tools. No statistically significant differences were found between the groups on MRI.ConclusionsThis study did not show that MRI‐based measures of morphology, spinal cord and nerve root diffusion or cerebrospinal fluid flow are sensitive biomarkers to distinguish between chronic whiplash patients and healthy controls. The detailed description of the chronic whiplash patients using readily available clinical tools may be of great relevance to the clinician. In the context of feasibility, clinical practice-based advanced imaging studies with a technical setup similar to the presented can be expected to have a high likelihood of successful completion.

761 Echocardiographic evaluation in patients recovered from COVID-19

AimsCOVID-19 has a wide spectrum of clinical presentation, from severe forms that require hospitalization to less severe forms that can be managed at home. An acute myocardial involvement was demonstrated in a large proportion of patients admitted for COVID-19 and may persist in the long term. We evaluated the possible cardiac involvement using echocardiography, comprehensive of right and left ventricular strain, in patients who recovered from SARS-CoV-2 infection (hospitalized or home-treated) comparing them with a population of healthy volunteers.Methods and resultsForty-one patients with COVID-19, of which fifteen hospitalized, with no prior heart disease, were compared with 13 healthy volunteers. COVID-19 diagnosis was made by a positive molecular swab. Patients with history of pre-existing heart disease were excluded. The median time from infection to outpatient follow-up was 5.9 months. Numerous echocardiographic parameters were compared by unpaired t-test including left ventricular EF, left ventricular GLS, RV free wall strain, FAC, TAPSE, PAPS, TAPSE/PAPS ratio, RA area, and RV thickness. There was a significant difference in RV free wall strain between hospitalized patients and control (−14.6 ± 2.8% vs. −22 ± 0.7%; P-value 0.03) and between hospitalized and home-treated patients (−14.6 ± 2.8% vs. −19.8 ± 0.9%; P-value 0.03), the difference was not significant between control and home-treated patients (−22 ± 0.7% vs. −19.8 ± 0.8%; P-value 0.09). Between hospitalized and not hospitalized group there was a significant reduction in FAC (38.5 ± 3.2% vs. 44.7 ± 1.3%; P-value 0.03) with an increase of RV end diastolic area (19.9 ± 1.3 cm2 vs. 16.8 ± 0.7 cm2; P-value 0.037) and also of end systolic right atrium area (18.2 ± 1.3 cm2 vs. 15.4 ± 0.5 cm2; P-value 0.01). No difference was observed between hospitalized and home-treated patients in TAPSE (22.38 ± 1.26 mm vs. 23.02 ± 0.68 mm; P-value 0.6) and PAPS (24.3 ± 1.6 mmHg vs. 20.2 ± 1.4 mmHg; P-value 0.07) but there was a borderline significant decrease in right ventricular coupling evaluated with TAPSE/PAPS ratio (0.97 ± 0.08 mm/mmHg vs. 1.29 ± 0.10 mm/mmHg; P-value 0.056) and a significant increase in RV thickness in hospitalized patients (5.32 ± 0.45 mm vs. 3.69 ± 0.24 mm; P-value 0.0014). No significant differences were found between hospitalized and not hospitalized group in left ventricular EF (57.8 ± 1.9% vs. 59.9 ± 1.0%; P-value 0.3) and left ventricular GLS (−15.2 ± 0.6% vs. −16.4 ± 0.4%; P-value 0.1).ConclusionsPatients hospitalized for COVID-19 showed a dysfunction in RV parameters at 6 months follow-up compared to non-hospitalized patients. No difference in RV function was found between home treated patients and healthy volunteers. No significant differences in LV function were found among the three groups. These preliminary data confirm a decrease in RV function in more severe COVID-19 infection requiring hospital admission, possibly related to increased pulmonary afterload.

Safety, Pharmacokinetics, Pharmacodynamics, and Formulation of Liver‐Distributed Farnesoid X‐Receptor Agonist TERN‐101 in Healthy Volunteers

TERN-101 is a nonsteroidal farnesoid X-receptor agonist being developed for the treatment of nonalcoholic steatohepatitis (NASH). We assessed the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of TERN-101 capsule and tablet formulations in healthy volunteers. In a randomized, double-blind, placebo-controlled study, 38 participants were enrolled and randomized to receive placebo or 25-, 75-, or 150-mg TERN-101 capsules orally once daily for 7 days. In a separate open-label PK and formulation-bridging study, 16 participants received single doses of TERN-101 tablets (5 and 25 mg) or capsules (25 mg). TERN-101 was overall well-tolerated in this healthy volunteer population; no pruritus was reported. TERN-101 capsule administration over 7 days resulted in decreases in serum 7α-hydroxy-4-cholesten-3-one that were sustained for 24 hours after the last dose (maximum suppression 91% from baseline), indicating target engagement in the liver. TERN-101 capsules exhibited less than dose-proportional PK. Relative to capsules, TERN-101 tablets showed increased bioavailability, with 24-hour plasma exposure of the 5-mg tablet similar to that of the 25-mg capsule. There was no significant effect of food on exposure. The overall safety, PK, and PD profiles of TERN-101 support its further evaluation for the treatment of NASH.

Low Carotid Flow Pulsatility Index Correlates With the Presence of Unruptured Intracranial Aneurysms.

BackgroundWe assessed cases of incidental unruptured intracranial aneurysm (UIA) discovered on screening magnetic resonance angiography to identify hemodynamic and atherosclerotic risk factors.Methods and ResultsThe data of 1376 healthy older subjects (age range, 31–91 years) without cerebro‐ or cardiovascular diseases who underwent brain magnetic resonance angiography as part of a medical checkup program at a health screening center were examined retrospectively. We looked for an increase in classical risk factors for UIAs (age, sex, hypertension, and smoking) and laboratory data related to lifestyle diseases among subjects with UIAs. Brachial‐ankle pulse wave velocity, central systolic blood pressure, radial augmentation index, and carotid flow pulsatility index were also compared between those with and without UIAs. We found UIAs in 79 (5.7%) of the subjects. Mean age was 67.1±9.0 years, and 55 (70%) were women. Of the 79 aneurysms, 75 (95%) were in the anterior circulation, with a mean diameter of 3.1 mm (range, 2.0–8.0 mm). Subjects with UIAs were significantly older and had more severe hypertension. The carotid flow pulsatility index was significantly lower in subjects with UIAs and negatively and independently correlated with UIAs. Tertile analysis stratified by carotid flow pulsatility index revealed that subjects with lower indices had higher levels of low‐density lipoprotein cholesterol.ConclusionsThe presence of UIAs correlated with lower carotid flow pulsatility index and elevated low‐density lipoprotein cholesterol in the data from a population of healthy older volunteers. A reduced carotid flow pulsatility index may affect low‐density lipoprotein cholesterol elevation by some molecular pathways and influence the development of cerebral aneurysms. This may guide aneurysm screening indications for institutions where magnetic resonance angiography is not routine.

Cortisol as biomarker for CYP17 inhibition in mCRPC patients treated with abiraterone acetate.

5035 Background: Abiraterone acetate is an effective metastatic castration resistant prostate cancer (mCRPC) treatment, however, there is a high variability in response. It inhibits CYP17, thereby preventing the production of androgens. Abiraterone trough concentrations (Cmin) &gt; 8.4 ng/mL have been associated with an increased progression free survival (PFS) (Eur J Cancer. 2017;72:54-61; Prostate Cancer Prostatic Dis. 2020;23(2):244-251). However, plasma levels do not directly provide information on the level of CYP17 inhibition. Ideally, testosterone levels should be measured, but these levels are below the detection limit of available assays. The synthesis of cortisol is also inhibited by abiraterone via CYP17 inhibition and might therefore be a biomarker for CYP17 inhibition. The objective of this study was to investigate if cortisol levels are related to abiraterone levels and to clinical response. Methods: An observational study was performed in mCRPC patients treated with abiraterone acetate. At the outpatient clinic, plasma samples were collected for pharmacokinetic (PK) monitoring at each hospital visit. Reference populations of healthy volunteers and mCRPC patients using enzalutamide were included to investigate the influence of mCRPC and abiraterone treatment on the circadian rhythm of cortisol. Abiraterone and cortisol levels were measured using validated liquid chromatography-mass spectrometry (LC-MS/MS) assays. Clinical (prostate specific antigen (PSA) independent) PFS and PSA response were evaluated. Results: In total, 117 mCRPC patients using abiraterone acetate, 100 mCRPC patients using enzalutamide and 12 healthy volunteers were included. A clear circadian rhythm of cortisol was described in healthy volunteers and unaffected in mCRPC patients using enzalutamide. Contrarily, a circadian rhythm of cortisol could not be identified in mCRPC patients using abiraterone acetate, due to continuous suppression throughout the day. Patients with an abiraterone Cmin &gt; 8.4 ng/mL (n = 77) had a median cortisol concentration of 1.03 ng/mL vs. 2.59 ng/mL in patients with an abiraterone Cmin ≤8.4 ng/mL (n = 40) (p = 0.020). The median cortisol concentration in PSA responders (n = 63) was 1.02 ng/mL vs. 2.59 ng/mL for PSA non responders (n = 54) (p = 0.037). Patients in the highest cortisol tertile ( &gt; 3.03 ng/mL) had a median PFS of 3.7 months (n = 39) vs. 13.8 months in patients with cortisol levels ≤3.03 ng/mL (n = 78) (p = 0.007). The median PFS was 16.3 months in patients with an abiraterone Cmin &gt; 8.4 ng/mL and cortisol concentration &lt; 3.03 ng/ml vs. 5.3 months in patients with an abiraterone Cmin &gt; 8.4 ng/mL and cortisol concentration &gt; 3.03 ng/ml (p = 0.02). Conclusions: This study demonstrates that cortisol levels are of additional value to abiraterone concentrations as a marker for abiraterone acetate efficacy. This might help be helpful to assess efficacy of abiraterone treatment.

Dose Escalation and Safety of Capsaicin for Cerebral Perfusion Augmentation: A Pilot Study.

Sphenopalatine ganglion (SPG) electrical stimulation has been studied in the setting of acute ischemic stroke to enhance collateral flow. Capsaicin poses an alternative to chemically stimulate the sphenopalatine ganglion. Therefore, the objective of this study was to determine the safety and effect of increasing doses of capsaicin upon serial transcranial Doppler markers of cerebral blood flow. We performed serial transcranial Doppler testing in 30 healthy volunteers divided into 5 equal groups. Capsaicin doses ranged from 33 to 165 μMol. We recorded peak systolic and end-diastolic velocities in the middle cerebral artery, arterial pressure, and perceived pungency in 5-minute intervals up to 20 minutes. We then calculated the mean velocity, the pulsatility index, and the cerebral blood flow index. The participants’ median age was 21 years (range, 5 years); all reported consumption of capsaicin in their diets. After and during the study, none reported side effects. Perceived pungency peaked at 5 minutes, and by the 20-minute mark, none perceived any pungency. All the tested doses produced the same pattern, consisting of augmentation of the middle cerebral artery mean velocity with the pulsatility index’s diminution. The effects peaked between the 5- and the 10-minute measurements and then returned to basal levels except for the 66-μMol doses, which produced a sustained effect. We found no correlation between perceived pungency and dose, but the middle cerebral artery mean velocity was strongly correlated with the dose administered. This study provides evidence supporting the safety and tolerability of oral capsaicin in a population of healthy volunteers. Capsaicin appears to produce effects similar to those of sphenopalatine ganglion electrical stimulation. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04545892.

Effect of Active Cancer on the Cardiac Phenotype: A Cardiac Magnetic Resonance Imaging‐Based Study of Myocardial Tissue Health and Deformation in Patients With Chemotherapy‐Naïve Cancer

BackgroundThe overlap between cancer and cardiovascular care continues to expand, with intersections emerging before, during, and following cancer therapies. To date, emphasis has been placed on how cancer therapeutics influence downstream cardiac health. However, whether active malignancy itself influences chamber volumes, function, or overall myocardial tissue health remains uncertain. We sought to perform a comprehensive cardiovascular magnetic resonance‐based evaluation of cardiac health in patients with chemotherapy‐naïve cancer with comparison with a healthy volunteer population.Methods and ResultsThree‐hundred and eighty‐one patients with active breast cancer or lymphoma before cardiotoxic chemotherapy exposure were recruited in addition to 102 healthy volunteers. Both cohorts underwent standardized cardiovascular magnetic resonance imaging with quantification of chamber volumes, ejection fraction, and native myocardial T1. Left ventricular mechanics were incrementally assessed using three‐dimensional myocardial deformation analysis, providing global longitudinal, circumferential, radial, and principal peak‐systolic strain amplitude and systolic strain rate. The mean age of patients with cancer was 53.8±13.4 years; 79% being women. Despite similar left ventricular ejection fraction, patients with cancer showed smaller chambers, increased strain amplitude, and systolic strain rate in both conventional and principal directions, and elevated native T1 versus sex‐matched healthy volunteers. Adjusting for age, sex, hypertension, and diabetes mellitus, the presence of cancer remained associated with these cardiovascular magnetic resonance parameters.ConclusionsThe presence of cancer is independently associated with alterations in cardiac chamber size, function, and objective markers of tissue health. Dedicated research is warranted to elucidate pathophysiologic mechanisms underlying these findings and to explore their relevance to the management of patients with cancer referred for cardiotoxic therapies.

Examining the Immunological Effects of COVID-19 Vaccination in Patients with Conditions Potentially Leading to Diminished Immune Response Capacity – The OCTAVE Trial

SARS-COV-2 vaccines have been shown to be efficacious primarily in healthy volunteer populations and population level studies. Immune responses following SARS-CoV-2 vaccination are less well characterised in potentially immune vulnerable patient groups, including those with immune-mediated inflammatory and chronic diseases (inflammatory arthritis [IA] incorporating rheumatoid arthritis [RA] and psoriatic arthritis [PsA]; ANCA-Associated Vasculitis [AAV]; inflammatory bowel disease [IBD]); hepatic disease (HepD), end stage kidney disease requiring haemodialysis (HD) without or with immunosuppression (HDIS); solid cancers (SC) and haematological malignancies (HM), and those that have undergone haemopoietic stem cell transplant (HSCT). The OCTAVE trial is a multi-centre, multi-disease, prospective cohort that will comprehensively assess SARS-CoV-2 vaccine responses within and between the abovementioned disease cohorts using common analytical platforms in patients recruited across the United Kingdom (UK). The majority of subjects received either COVID-19 mRNA Vaccine BNT162b2 (Pfizer/BioNTech) or ChAdOx1 Vaccine (AstraZeneca formerly AZD1222) as part of the UK National COVID19 vaccination programme. As of 13 th August 2021; 2,583 patients have been recruited. We report herein the humoral and T cell immune response results from the first 600 participants recruited where serology data are available at baseline, pre-second vaccine dose (boost) and/or 4 weeks post second dose. We also include in the analysis, data obtained from 231 healthy individuals from the PITCH (Protective Immunity from T cells in Healthcare workers) study. Overall, in comparison to PITCH where 100% of tested individuals (n=93) generated anti-Spike antibodies after vaccine doses, 89% of patients within OCTAVE seroconverted 4 weeks after second vaccine dose. By corollary, approximately 11% of patients across all disease cohorts fail to generate antibodies that react to SARS-CoV-2 spike 4 weeks after two vaccines. Failure to generate spike reactive antibodies was found at a higher proportion in some specific patient subgroups, particularly AAV (72.4%), HD-IS (16.7%) and HepD (16.7%). Importantly, all recruited AAV patients had received Rituximab; a targeted B cell depletion therapy. Furthermore, even in those who seroconverted, 40% of patients across disease cohorts generate lower levels of SARS-CoV-2 antibody reactivity compared to healthy subjects after two SARS-CoV-2 vaccines; the functional significance of these findings in providing protection from subsequent SARS-CoV-2 exposure is not currently known. In contrast to the observed serological response, evaluation of the Spike-specific T cell response revealed that across all patient sub-groups (including AAV) a response similar to healthy individuals was generated. Our data argue strongly for further vaccination strategies to optimise humoral immune responses against SARS-CoV-2 in patients with chronic diseases and/or patients on immune suppressive therapies. Trial Registration: The trial is registered on ISRCTN 12821688.Funding: This work was supported by the Medical Research Council COVID-19 Immunity – National Core Study (IMM-NCS) [grant number MC-PC-20031]. Staff at the Cancer Research UK Clinical Trials Unit (CRCTU) are supported by a core funding grant from Cancer Research UK (C22436/A25354). PK and EB are supported by the NIHR Birmingham Biomedical Research Centres at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham Biomedical Research Centres. EB and PK are supported by an NIHR Senior Investigator award. PK is funded by WT109965MA. SJD is funded by an NIHR Global Research Professorship (NIHR300791). TdS is funded by a Wellcome Trust Intermediate Clinical Fellowship (110058/Z/15/Z). DS is supported by the NIHR Academic Clinical Lecturer programme in Oxford. LT is supported by the Wellcome Trust (grant number 205228/Z/16/Z), the U.S. Food and Drug Administration Medical Countermeasures Initiative contract 75F40120C00085. and the National Institute for Health Research Health Protection Research Unit (NIHR HPRU) in Emerging and Zoonotic Infections (NIHR200907) at University of Liverpool in partnership with Public Health England (PHE), in collaboration with Liverpool School of Tropical Medicine and the University of Oxford. The PITCH (Protective Immunity from T cells to Covid-19 in Health workers) Consortium, is funded by the UK Department of Health and Social Care with contributions from UKRI/NIHR through the UK Coronavirus Immunology Consortium (UKCIC), the Huo Family Foundation and The National Institute for Health Research (UKRIDHSC COVID-19 Rapid Response Rolling Call, Grant Reference Number COV19-RECPLAS).Declaration of Interest: None to declare. Ethical Approval: This study was approved by the UK Medicines and Healthcare Products Regulatory Agency on the 5th February 2021 and the London and Chelsea Research Ethics Committee (REC Ref:21/HRA/0489) on 12th February 2021, with subsequent amendments approved on 3rd March 2021, 19th April 2021 and 26th April 2021).