Safety, tolerability and immunogenicity of PRV-101, a multivalent vaccine targeting coxsackie B viruses (CVBs) associated with type 1 diabetes: a double-blind randomised placebo-controlled Phase I trial.

AIMS/HYPOTHESIS: Infection with coxsackie B viruses (CVBs) can cause diseases ranging from mild common cold-type symptoms to severe life-threatening conditions. CVB infections are considered to be prime candidates for environmental triggers of type 1 diabetes. This, together with the significant disease burden of acute CVB infections and their association with chronic diseases other than diabetes, has prompted the development of human CVB vaccines. The current study evaluated the safety and immunogenicity of the first human vaccine designed against CVBs associated with type 1 diabetes in a double-blind randomised placebo-controlled Phase I trial. METHODS: The main eligibility criteria for participants were good general health, age between 18 and 45 years, provision of written informed consent and willingness to comply with all trial procedures. Treatment allocation (PRV-101 or placebo) was based on a computer-generated randomisation schedule and people assessing the outcomes were masked to group assignment. In total, 32 participants (17 men, 15 women) aged 18-44 years were randomised to receive a low (n=12) or high (n=12) dose of a multivalent, formalin-inactivated vaccine including CVB serotypes 1-5 (PRV-101), or placebo (n=8), given by intramuscular injections at weeks 0, 4 and 8 at a single study site in Finland. The participants were followed for another 24 weeks. Safety and tolerability were the primary endpoints. Anti-CVB IgG and virus-neutralising titres were analysed using an ELISA and neutralising plaque reduction assays, respectively. RESULTS: Among the 32 participants (low dose, n=12; high dose, n=12; placebo, n=8) no serious adverse events or adverse events leading to study treatment discontinuation were observed. Treatment-emergent adverse events considered to be related to the study drug occurred in 37.5% of the participants in the placebo group and 62.5% in the PRV-101 group (injection site pain, headache, injection site discomfort and injection site pruritus being most common). PRV-101 induced dose-dependent neutralising antibody responses against all five CVB serotypes included in the vaccine in both the high- and low-dose groups. Protective titres ≥8 against all five serotypes were seen in >90% of participants over the entire follow-up period. CONCLUSIONS/INTERPRETATION: The results indicate that the tested multivalent CVB vaccine is well tolerated and immunogenic, supporting its further clinical development. TRIAL REGISTRATION: ClinicalTrials.gov NCT04690426. FUNDING: This trial was funded by Provention Bio, a Sanofi company.

Response to Letter to the Editor.

It is crucial to consider the possible influence of anesthetic agents on esophageal function testing. Dexmedetomidine has been shown to affect primary peristalsis during esophageal manometry. In the two case reports presented by Toaz et al., secondary peristalsis during FLIP panometry was also affected. This may be attributed to an alternate pharmacodynamic effect, with a transient direct α2-mediated effect on esophageal smooth muscle, associated with a high plasma concentration following bolus injection, prior to the onset of sympathetic inhibition.

Decreased Thalamic Activity Is a Correlate for Disconnectedness during Anesthesia with Propofol, Dexmedetomidine and Sevoflurane But Not S-Ketamine.

Establishing the neural mechanisms responsible for the altered global states of consciousness during anesthesia and dissociating these from other drug-related effects remains a challenge in consciousness research. We investigated differences in brain activity between connectedness and disconnectedness by administering various anesthetics at concentrations designed to render 50% of the subjects unresponsive. One hundred and sixty healthy male subjects were randomized to receive either propofol (1.7 µg/ml; n = 40), dexmedetomidine (1.5 ng/ml; n = 40), sevoflurane (0.9% end-tidal; n = 40), S-ketamine (0.75 µg/ml; n = 20), or saline placebo (n = 20) for 60 min using target-controlled infusions or vaporizer with end-tidal monitoring. Disconnectedness was defined as unresponsiveness to verbal commands probed at 2.5-min intervals and unawareness of external events in a postanesthesia interview. High-resolution positron emission tomography (PET) was used to quantify regional cerebral metabolic rates of glucose (CMRglu) utilization. Contrasting scans where the subjects were classified as connected and responsive versus disconnected and unresponsive revealed that for all anesthetics, except S-ketamine, the level of thalamic activity differed between these states. A conjunction analysis across the propofol, dexmedetomidine and sevoflurane groups confirmed the thalamus as the primary structure where reduced metabolic activity was related to disconnectedness. Widespread cortical metabolic suppression was observed when these subjects, classified as either connected or disconnected, were compared with the placebo group, suggesting that these findings may represent necessary but alone insufficient mechanisms for the change in the state of consciousness.SIGNIFICANCE STATEMENT Experimental anesthesia is commonly used in the search for measures of brain function which could distinguish between global states of consciousness. However, most previous studies have not been designed to separate effects related to consciousness from other effects related to drug exposure. We employed a novel study design to disentangle these effects by exposing subjects to predefined EC50 doses of four commonly used anesthetics or saline placebo. We demonstrate that state-related effects are remarkably limited compared with the widespread cortical effects related to drug exposure. In particular, decreased thalamic activity was associated with disconnectedness with all used anesthetics except for S-ketamine.

Effects of dexmedetomidine on pharyngeal swallowing and esophageal motility-A double-blind randomized cross-over study in healthy volunteers.

BACKGROUND: Sedative agents increase the risk of pulmonary aspiration, where an intact swallowing function is an important defense mechanism. Dexmedetomidine is an α2 -adrenoceptor agonist widely used during procedural sedation due to beneficial properties with minimal respiratory effects. The effects of dexmedetomidine on pharyngeal swallowing and esophageal motility are not known in detail. METHODS: To determine the effects of dexmedetomidine on pharyngeal swallowing and esophageal motility, nineteen volunteers were included in this double-blinded, randomized placebo-controlled cross-over study. Study participants received target-controlled dexmedetomidine and placebo infusions. Recordings of pressure and impedance data were acquired using a manometry and impedance solid-state catheter. Data were analyzed from three bolus swallows series: baseline, during dexmedetomidine/placebo infusion at target plasma concentrations 0.6 ng ml-1 and 1.2 ng ml-1 . Subjective swallowing difficulties were also recorded. KEY RESULTS: On pharyngeal swallowing, dexmedetomidine affected the upper esophageal sphincter with decreased pre- and post-swallow contractile pressures and an increase in residual pressure during swallow-related relaxation. On esophageal function, dexmedetomidine decreased contractile vigor of the proximal esophagus and increased velocity of the peristaltic contraction wave. Residual pressures during swallow-related esophagogastric junction (EGJ) relaxation decreased, as did basal EGJ resting pressure. The effects on the functional variables were not clearly dose-dependent, but mild subjective swallowing difficulties were more common at the higher dose level. CONCLUSIONS AND INFERENCES: Dexmedetomidine induces effects on pharyngeal swallowing and esophageal motility, which should be considered in clinical patient management and also when a sedative agent for procedural sedation or for manometric examination is to be chosen.

Success and failure factors of patient recruitment for industry-sponsored clinical trials and the role of the electronic health records-a qualitative interview study in the Nordic countries.

BACKGROUND: Patient recruitment for clinical trials is challenging-only approximately one third of all trials recruit their participants as planned. The pharmaceutical industry's views on recruitment success have not been comprehensively investigated, although the industry globally conducts almost one third of all clinical drug trials. This study explored patient recruitment success and failure factors and the role of electronic health records (EHR) in the recruitment of trial participants in the Nordic countries. METHODS: A descriptive qualitative interview study was conducted with 21 representatives of the pharmaceutical industry or contract research organizations operating in Finland, Sweden, Denmark, and Norway. The interviews covered 34 clinical pre-market drug trials. Qualitative data were analyzed using inductive content analysis. RESULTS: Four main categories were derived to represent both success and failure factors, whereas a fifth category represented only failure factors: (1) sponsor-related (protocol and trial preparation and feasibility evaluations), (2) site/investigator-related (access to patients, motivation, commitment and resources), (3) patient-related recruitment factors (medical need, patients' role in their care and attitudes towards trials), (4) Sponsor-sites-patients collaboration factors, and (5) start-up related factors. EHR was the most important source of recruitment, utilized in 29 out of 34 trials discussed. Revision of the legislation regulating the secondary use of EHR was highlighted as the most effective measure to facilitate the use of EHR in recruitment of trial participants. CONCLUSIONS: The industry representatives recognized quite well their own role in contributing to the success or failure of the recruitment: to facilitate recruitment of trial participants, many obstacles can be avoided with better trial preparation and proper feasibility evaluations. As access to patients represents one of the key success or failure factors of recruitment, and as the EHR is regarded the main source of searching for and finding patients, the development of EHR utilization appears to represent a powerful tool to improve patient recruitment.

A randomized pharmacokinetic-pharmacodynamic evaluation of the potential biosimilar interferon beta-1a product, CinnoVex®.

BACKGROUND: The objective of the trial was to evaluate the bioequivalence of the interferon beta-1a (IFN beta-1a) biosimilar product candidate CinnoVex® with the reference product Avonex® by comparing the pharmacokinetics/pharmacodynamics (PK/PD), safety and immunogenicity of the two products in healthy subjects. METHODS: A total of 41 healthy subjects were randomized in a two-stage design to receive single doses of CinnoVex® and Avonex®. The primary PK endpoint was the area under the concentration-time curve from time 0 to the last quantifiable concentration (AUC0-last). Additional PK parameters, safety and immunogenicity were evaluated as secondary endpoints. The main secondary PD endpoints were the areas under the concentration-time curves from time 0 to 168 hours (AUC0-168h) of the PD biomarkers. RESULTS: The two products demonstrated similar PK parameters, and the 90% confidence interval (CI) of the primary PK endpoint was within the bioequivalence acceptance limit. No serious adverse events were reported, and all adverse events (AE) were mild or moderate in severity. Anti-drug antibodies were not observed in any of the study participants. CONCLUSION: This study demonstrated PK/PD bioequivalence between CinnoVex® and Avonex®. The safety and tolerability profiles of both products were similar. CLINICAL TRIALS REGISTRATION: EudraCT Number 2016-000139-41.

Uptake of 18F-rhPSMA-7.3 in Positron Emission Tomography Imaging of Prostate Cancer: A Phase 1 Proof-of-Concept Study.

Background: This study evaluated tracer uptake and lesion detectability with the novel radiopharmaceutical 18F-radiohybrid (rh)PSMA-7.3 in patients with prostate cancer (PCa). Materials and Methods: Ten patients (three with high-risk primary localized PCa [Cohort A], three with hormone-sensitive metastatic PCa [Cohort B], and four with castration-resistant metastatic PCa [Cohort C]) underwent whole-body 18F-rhPSMA-7.3 positron emission tomography (PET)/computed tomography (CT) and findings were correlated with standard-of-care imaging. 18F-rhPSMA-7.3 maximum standardized uptake value (SUVmax) and its possible association with Gleason score (GS)/International Society of Urological Pathology (ISUP) grade group (GG) and serum PSA levels were evaluated. Cohort A 18F-rhPSMA-7.3 findings were also correlated with histopathology, including prostate-specific membrane antigen (PSMA) staining. Results: 18F-rhPSMA-7.3 identified the primary tumor in 3/3 Cohort A patients and lymph node (LN) and/or bone lesions in 7/7 metastatic patients. All prostate lesions with GS ≥4 + 3/GG ≥3 were identified, but only 1/4 GS ≤3 + 4/GG ≤2 lesions. Prostate lesion SUVmax appeared positively associated with GS/GGs. Among metastatic patients, 18F-rhPSMA-7.3 identified all known pelvic and extrapelvic LN metastases and all known bone lesions. 18F-rhPSMA-7.3 detected possible additional nodal and bone lesions not reported in standard-of-care imaging in all metastatic patients. No association existed between bone or LN uptake and either GS/GG or PSA. Conclusions: 18F-rhPSMA-7.3 PET/CT showed good detection of primary and metastatic PCa lesions. In this small patient population, 18F-rhPSMA-7.3 identified intraprostatic lesions with GS ≥4 + 3/GG ≥3 with good accuracy.

Nitrogen Balance after the Administration of a Prolonged-Release Protein Substitute for Phenylketonuria as a Single Dose in Healthy Volunteers.

Nitrogen balance is the difference between nitrogen excreted as urea and nitrogen ingested, mainly in proteins. Increased circulating concentrations of amino acids (AA) in the bloodstream are usually associated with proportional increases in the production and excretion of urea. Previously, we reported results from a randomized, controlled, single-dose, crossover trial in healthy adult volunteers (n = 30) (Trial Registration: ISRCTN11016729), in which a Test product (prolonged-release AA mixture formulated with Physiomimic Technology™ (PT™)) significantly slowed down the release and reduced the peak plasma concentrations of essential AAs compared with a free AA mixture (Reference product) while maintaining essential AA bioavailability. Here, we report an assessment of the nitrogen balance from the same study. The amount of nitrogen contained in plasma AAs, levels of blood urea nitrogen (BUN) (p < 0.0001) and changes in BUN (p < 0.0001) were smaller after the Test product compared with the Reference product. These findings suggest that the production of urea in proportion to systemic AA availability was significantly smaller after the administration of the Test product compared with the Reference product and that the test product conferred the increased utilization of AAs for protein synthesis and reduced their oxidation and conversion to urea. In the clinical setting, it is possible that the effects of PT™ observed on the disposition of free AAs in this study may translate to health benefits in terms of physiological body composition and growth if used for the treatment of subjects with phenylketonuria (PKU). Further investigation in patients with PKU is warranted.

Clinical trial site identification practices and the use of electronic health records in feasibility evaluations: An interview study in the Nordic countries.

INTRODUCTION: Feasibility evaluations are performed to create the best possible starting point for the set-up and execution of a clinical trial, and to identify any obstacles for successful trial conduct. New digital technologies can provide various types of data for use in feasibility evaluations. There is a need to identify and compare such data sources for trial site identification and for evaluating the sites' patient recruitment potential. Especially, information is needed on the use of electronic health records. We investigated how different data sources are used by pharmaceutical companies operating in the Nordic countries for identifying trial sites and for evaluating their potential to recruit trial participants. METHODS: This was a semi-structured qualitative interview study with 21 participants from pharmaceutical companies and contract research organizations operating in Finland, Sweden, Denmark and Norway. Qualitative content analysis was applied. RESULTS: For identifying countries and trial sites on a global level, the trial sponsors mostly used databases on previous trial performance. The use of electronic health record data was very limited. Sites' and investigators' visibility in various databases was seen as fundamental for their countries becoming selected into new clinical trials. For estimating the sites' recruitment projections, most sites were seen to base their patient count estimates solely on their previous experience. Some sites had reviewed their electronic health record data, which was considered to increase the accuracy of their recruitment estimates and these sites' attractivity. Along with dialogs with investigators, the sponsors used various data sources to validate the investigators' estimates. Legislative obstacles were seen to hinder the use of electronic health record queries for estimation of patient counts. CONCLUSION: Visibility in the databases used by trial sponsors is crucial for the countries and sites to be identified. Site selection appears to be based on trust and relationships built from experience, but electronic data provide the support upon which the trust is based. Estimation of the number of potential trial participants is a complex and time-consuming process for both investigators and sponsors. Sponsors seem to favour sites who could support their patient count estimates with electronic health record data as they were quicker in providing the estimates and more reliable than sites with no electronic health record evidence. The patient count evaluation process could be simplified, accelerated and made more reliable with more systematic use of electronic health record evidence in the feasibility evaluation phase. This would increase the accuracy of the patient count estimates and, on its part, contribute to improved recruitment success.

Effects of remifentanil on pharyngeal swallowing and esophageal motility: no impact of different bolus volumes and partial antagonism by methylnaltrexone.

Remifentanil impairs swallowing, and disturbed accommodation to bolus volume may be one of the underlying causes. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms. So, this study aimed to investigate if remifentanil-induced swallowing dysfunction is dependent on the bolus volume and whether the effect of remifentanil could be counteracted by methylnaltrexone, a peripherally acting opioid antagonist. Nineteen healthy volunteers were included in this double-blinded, randomized, placebo-controlled, crossover study. Study participants received target-controlled remifentanil infusions and placebo infusions in a randomized order. Methylnaltrexone was administered by intravenous injection of doses of 0.3 mg/kg. Recordings of pressure and impedance data were acquired using a combined manometry and impedance solid-state catheter. Data were analyzed from three series of bolus swallows, baseline, during study medication exposure, and 15 min after methylnaltrexone. Remifentanil induced significant effects on multiple pharyngeal and esophageal function parameters. No significant differences in remifentanil-induced swallowing dysfunction related to different bolus volumes were found. Pharyngeal effects of remifentanil were not significantly counteracted by methylnaltrexone, whereas on the distal esophageal level, effects on distension pressures were counteracted. Changes in pharyngeal and esophageal pressure flow variables were consistent with previous results on remifentanil-induced swallowing dysfunction and uniform across all bolus volumes. The effects of remifentanil on the pharyngeal level and on the proximal esophagus appear to be predominantly centrally mediated, whereas the effects of remifentanil on the distal esophagus may be mediated by both central and peripheral mechanisms.NEW & NOTEWORTHY In this randomized controlled trial, we used the "Swallow Gateway" online platform to analyze the effects of remifentanil on pharyngeal and esophageal swallowing. It is not fully understood whether remifentanil-induced swallowing dysfunction is mediated by peripheral or central mechanisms. By using methylnaltrexone, we demonstrated that effects of remifentanil on pharyngeal swallowing were predominantly centrally mediated, whereas its effects on the distal esophagus may be mediated by both central and peripheral mechanisms.

A Randomized Trial of a Transglutaminase 2 Inhibitor for Celiac Disease.

BACKGROUND: In celiac disease, small intestinal transglutaminase 2 causes deamidation of glutamine residues in gluten peptides, which enhances stimulation of T cells and leads to mucosal injury. Inhibition of transglutaminase 2 is a potential treatment for celiac disease. METHODS: In a proof-of-concept trial, we assessed the efficacy and safety of a 6-week treatment with ZED1227, a selective oral transglutaminase 2 inhibitor, at three dose levels as compared with placebo, in adults with well-controlled celiac disease who underwent a daily gluten challenge. The primary end point was the attenuation of gluten-induced mucosal damage, as measured by the ratio of villus height to crypt depth. Secondary end points included intraepithelial lymphocyte density, the Celiac Symptom Index score, and the Celiac Disease Questionnaire score (for assessment of health-related quality of life). RESULTS: Of the 41 patients assigned to the 10-mg ZED1227 group, the 41 assigned to the 50-mg group, the 41 assigned to the 100-mg group, and the 40 assigned to the placebo group, 35, 39, 38, and 30 patients, respectively, had adequate duodenal-biopsy samples for the assessment of the primary end point. Treatment with ZED1227 at all three dose levels attenuated gluten-induced duodenal mucosal injury. The estimated difference from placebo in the change in the mean ratio of villus height to crypt depth from baseline to week 6 was 0.44 (95% confidence interval [CI], 0.15 to 0.73) in the 10-mg group (P = 0.001), 0.49 (95% CI, 0.20 to 0.77) in the 50-mg group (P<0.001), and 0.48 (95% CI, 0.20 to 0.77) in the 100-mg group (P<0.001). The estimated differences from placebo in the change in intraepithelial lymphocyte density were -2.7 cells per 100 epithelial cells (95% CI, -7.6 to 2.2) in the 10-mg group, -4.2 cells per 100 epithelial cells (95% CI, -8.9 to 0.6) in the 50-mg group, and -9.6 cells per 100 epithelial cells (95% CI, -14.4 to -4.8) in the 100-mg group. Use of the 100-mg dose may have improved symptom and quality-of-life scores. The most common adverse events, the incidences of which were similar across all groups, were headache, nausea, diarrhea, vomiting, and abdominal pain. Rash developed in 3 of 40 patients (8%) in the 100-mg group. CONCLUSIONS: In this preliminary trial, treatment with ZED1227 attenuated gluten-induced duodenal mucosal damage in patients with celiac disease. (Funded by Dr. Falk Pharma; CEC-3 EudraCT number, 2017-002241-30.).

Effects of Bifidobacterium animalis ssp. lactis 420 on gastrointestinal inflammation induced by a nonsteroidal anti-inflammatory drug: A randomized, placebo-controlled, double-blind clinical trial.

AIMS: Use of nonsteroidal anti-inflammatory drugs (NSAIDs) can cause damage to the gastric and duodenal mucosa. Some probiotics have proven useful in ameliorating the harmful side-effects of NSAIDs. Our aim was to evaluate whether oral administration of Bifidobacterium animalis ssp. lactis 420 (B420) can attenuate the increase of calprotectin excretion into faeces induced by intake of diclofenac sustained-release tablets. METHODS: A double-blind, parallel-group, placebo-controlled and randomized clinical study was performed in 50 healthy male and female volunteers aged 20-40 years, in Finland. Study participation consisted of 4 phases: run-in, intervention with B420 or placebo, B420 or placebo + NSAID treatment, and follow-up. The primary outcome was the concentration of calprotectin in faeces. Secondary outcomes were haemoglobin and microbial DNA in faeces and blood haemoglobin levels. RESULTS: Intake of diclofenac increased the faecal excretion of calprotectin in both groups. The observed increases were 48.19 ± 61.55 µg/g faeces (mean ± standard deviation) in the B420 group and 31.30 ± 39.56 µg/g in the placebo group (difference estimate 16.90; 95% confidence interval: -14.00, 47.77; P = .276). There were no significant differences between the treatment groups in changes of faecal or blood haemoglobin. Faecal B. lactis DNA was much more abundant in the B420 group compared to the placebo group (ANOVA estimate for treatment difference 0.85 × 109 /g faeces; 95% confidence interval: 0.50 × 109 , 1.21 × 109 ; P < .0001). CONCLUSIONS: Short-term administration of the probiotic B420 did not protect the healthy adult study participants from diclofenac-induced gastrointestinal inflammation as determined by analysis of faecal calprotectin levels.

Kinetic analysis and optimisation of 18F-rhPSMA-7.3 PET imaging of prostate cancer.

PURPOSE: This phase 1 open-label study evaluated the uptake kinetics of a novel theranostic PET radiopharmaceutical, 18F-rhPSMA-7.3, to optimise its use for imaging of prostate cancer. METHODS: Nine men, three with high-risk localised prostate cancer, three with treatment-naïve hormone-sensitive metastatic disease and three with castration-resistant metastatic disease, underwent dynamic 45-min PET scanning of a target area immediately post-injection of 300 MBq 18F-rhPSMA-7.3, followed by two whole-body PET/CT scans acquired from 60 and 90 min post-injection. Volumes of interest (VoIs) corresponding to prostate cancer lesions and reference tissues were recorded. Standardised uptake values (SUV) and lesion-to-reference ratios were calculated for 3 time frames: 35-45, 60-88 and 90-118 min. Net influx rates (Ki) were calculated using Patlak plots. RESULTS: Altogether, 44 lesions from the target area were identified. Optimal visual lesion detection started 60 min post-injection. The 18F-rhPSMA-7.3 signal from prostate cancer lesions increased over time, while reference tissue signals remained stable or decreased. The mean (SD) SUV (g/mL) at the 3 time frames were 8.4 (5.6), 10.1 (7) and 10.6 (7.5), respectively, for prostate lesions, 11.2 (4.3), 13 (4.8) and 14 (5.2) for lymph node metastases, and 4.6 (2.6), 5.7 (3.1) and 6.4 (3.5) for bone metastases. The mean (SD) lesion-to-reference ratio increases from the earliest to the 2 later time frames were 40% (10) and 59% (9), respectively, for the prostate, 65% (27) and 125% (47) for metastatic lymph nodes and 25% (19) and 32% (30) for bone lesions. Patlak plots from lesion VoIs signified almost irreversible uptake kinetics. Ki, SUV and lesion-to-reference ratio estimates showed good agreement. CONCLUSION: 18F-rhPSMA-7.3 uptake in prostate cancer lesions was high. Lesion-to-background ratios increased over time, with optimal visual detection starting from 60 min post-injection. Thus, 18F-rhPSMA-7.3 emerges as a very promising PET radiopharmaceutical for diagnostic imaging of prostate cancer. TRIAL REGISTRATION: NCT03995888 (24 June 2019).

Assessing an Electronic Health Record research platform for identification of clinical trial participants.

Electronic health records (EHR) are a potential resource for identification of clinical trial participants. We evaluated how accurately a commercially available EHR Research Platform, InSite, is able to identify potential trial participants from the EHR system of a large tertiary care hospital. Patient counts were compared with results obtained in a conventional manual search performed for a reference study that investigated the associations of atrial fibrillation (AF) and cerebrovascular incidents. The Clinical Data Warehouse (CDW) of Turku University Hospital was used to verify the capabilities of the EHR Research Platform. The EHR query resulted in a larger patient count than the manual query (EHR Research Platform 5859 patients, manual selection 2166 patients). This was due to the different search logic and some exclusion criteria that were not addressable in structured digital format. The EHR Research Platform (5859 patients) and the CDW search (5840 patients) employed the same search logic. The temporal relationship between the two diagnoses could be identified when they were available in structured format and the time difference was longer than a single hospital visit. Searching for patients with the EHR Research Platform can help to identify potential trial participants from a hospital's EHR system by limiting the number of records to be manually reviewed. EHR query tools can best be utilized in trials where the selection criteria are expressed in structured digital format.

Hydroxychloroquine in the treatment of adult patients with Covid-19 infection in a primary care setting (LIBERTY): A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: The primary objective of this study is to evaluate the therapeutic potential of hydroxychloroquine (HCQ) in the treatment of adult patients with PCR-confirmed Covid-19 infection in a primary open-care setting, as compared to placebo. The study hypothesis is that treatment with HCQ will reduce the risk of hospitalization because of Covid-19 infection, and the sample size estimate of the study is based on the need to test this hypothesis. The secondary objectives of the study are: to evaluate the safety and tolerability of HCQ in the treatment of adult patients with PCR-confirmed Covid-19 infection in a primary open-care setting, as compared to placebo; to collect experience of the use of HCQ in the treatment of Covid-19 infection in outpatients, in order to be able to identify patient characteristics that predict specific treatment responses (favourable or unfavourable); this objective will also be addressed by post-hoc subgroup analysis of the study results and by meta-analysis of pooled patient data from other clinical trials of HCQ in outpatients; and to evaluate the impact of Covid-19 infection and its treatment on the mental health and well-being of the study participants. In addition, if the data allow, the study has the following exploratory objectives: to evaluate the extent and duration of SARS-CoV-2 viral shedding by PCR testing of nasopharyngeal swab samples in study subjects treated with HCQ, as compared to placebo; to evaluate the extent and time course of SARS-CoV-2 virus-specific antibody responses in serum of study subjects treated with HCQ, as compared to placebo; to evaluate other possible biomarker changes in blood in study subjects treated with HCQ, as compared to placebo; to explore the possible effects of genetic variation in drug metabolizing enzymes on HCQ-related outcomes in the study population; to explore the associations of HCQ-related outcome variables with other patient characteristics, e.g. HLA haplotypes, HCQ concentrations, demographic variables, disease history and concomitant medications. TRIAL DESIGN: This is a phase 2, placebo-controlled, double-blind, randomized, parallel-group treatment trial comparing HCQ with placebo in outpatients with Covid-19 infection. Participants will be randomized in a 1:1 ratio to the two treatment arms. PARTICIPANTS: Main inclusion criteria: 1. Males and females >40 years of age, or 18-40 years of age with one or both of the following: i. diabetes mellitus (type 1 or type 2); ii. BMI > 35 kg/m2; 2. Valid independent informed consent obtained; 3. Symptoms typical of Covid-19 infection, according to criteria specified in the study protocol. The onset of symptoms must be within 5 days of enrolment; 4. Positive SARS-CoV-2 PCR test result of a nasopharyngeal swab sample. Main exclusion criteria: 1. Suspected severe or moderately severe pneumonia, presenting with any of the following: respiratory rate > 26 breaths/min; significant respiratory distress; or SpO2 ≤94% on room air; 2. Requiring treatment in the hospital, according to the treating physician's judgement; 3. Any contraindication to treatment with HCQ; 4. Pregnancy or lactation. The trial will be conducted at seven study sites in a primary public health care setting in the region of Satakunta, Finland. INTERVENTION AND COMPARATOR: Participants will be randomized to receive either HCQ capsules at 300 mg twice a day for one day and then 200 mg twice a day for 6 days, or placebo capsules for 7 days. MAIN OUTCOMES: The primary endpoint of the study is the number of hospitalizations due to Covid-19 infection within four weeks of entry into the study. The secondary endpoints of the study include the following: duration and severity of Covid-19-related symptoms, as reported by daily self-assessments; number of Intensive Care Unit treatment episodes due to Covid-19 infection within four weeks of entry into the study; number of deaths due to Covid-19 infection within four weeks of entry into the study; number of treatment-related adverse events (AEs) and serious AEs (SAEs); all-cause hospitalizations and mortality within six months of entry into the study; and self-assessed symptoms of anxiety, as assessed with repeated administration of the Generalized Anxiety Disorder 7-item scale (GAD-7). The exploratory endpoints of the study include the following: extent and duration of SARS-CoV-2 viral shedding and virus-specific antibody responses in serum; and possible other blood biomarker changes. RANDOMISATION: Eligible study participants are randomly allocated into two treatment arms (1:1 ratio). The randomization list has been generated using Viedoc™ (Viedoc Technologies AB, Uppsala, Sweden) that is used as an electronic data capture system for this study. BLINDING (MASKING): The participants and all study personnel remain blinded to the treatment allocation by having both IMPs packed in identical containers. Masking of the treatments was performed by re-formulation of the IMPs so that the HCQ capsules and the placebo capsules have identical appearance. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): 600 participants are to be randomised with 300 in each arm. TRIAL STATUS: Protocol version 2, dated 14 July 2020; recruitment is expected to start in December, 2020, and to be completed in June, 2021. TRIAL REGISTRATION: EudraCT 2020-002038-33 , registered 26 June 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). The protocol has been redacted to conform with privacy regulations by deleting the names and contact information of individuals mentioned in the protocol but not listed as authors in this communication. In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Speech is special: The stress effects of speech, noise, and silence during tasks requiring concentration.

Effects of noise on people depend on sound level but also on other sound properties. A systematic comparison of the stress effects of speech and noise with the same frequency content is missing. This study compared stress reactions under sound conditions speech (sound level 65 dB LAeq ), noise (65 dB), and silence (35 dB), all having similar relative frequency contents. Fifty-nine participants were exposed to one out of three sound conditions on average for 48 minutes while performing tasks requiring concentration. Acute physiological stress was estimated by measuring stress hormone concentrations in plasma (cortisol and noradrenaline), heart rate variability (HRV), and blood pressure. Psychological stress measures were subjective noise annoyance, workload, and fatigue. Compared to silence and noise, working during speech was more annoying, loading, but less tiring, and led to elevated HRV LF/HF ratio with time. Speech also raised cortisol levels compared with silence. Although noise was more annoying, and raised cortisol levels compared with silence, working during speech was more loading and caused more physiological stress than other sound conditions. Special care should be paid to noise control in workplaces requiring concentration because already exposure to moderate sound level sounds caused clear physiological effects on people.

Foundations of Human Consciousness: Imaging the Twilight Zone.

What happens in the brain when conscious awareness of the surrounding world fades? We manipulated consciousness in two experiments in a group of healthy males and measured brain activity with positron emission tomography. Measurements were made during wakefulness, escalating and constant levels of two anesthetic agents (experiment 1, n = 39), and during sleep-deprived wakefulness and non-rapid eye movement sleep (experiment 2, n = 37). In experiment 1, the subjects were randomized to receive either propofol or dexmedetomidine until unresponsiveness. In both experiments, forced awakenings were applied to achieve rapid recovery from an unresponsive to a responsive state, followed by immediate and detailed interviews of subjective experiences during the preceding unresponsive condition. Unresponsiveness rarely denoted unconsciousness, as the majority of the subjects had internally generated experiences. Unresponsive anesthetic states and verified sleep stages, where a subsequent report of mental content included no signs of awareness of the surrounding world, indicated a disconnected state. Functional brain imaging comparing responsive and connected versus unresponsive and disconnected states of consciousness during constant anesthetic exposure revealed that activity of the thalamus, cingulate cortices, and angular gyri are fundamental for human consciousness. These brain structures were affected independent from the pharmacologic agent, drug concentration, and direction of change in the state of consciousness. Analogous findings were obtained when consciousness was regulated by physiological sleep. State-specific findings were distinct and separable from the overall effects of the interventions, which included widespread depression of brain activity across cortical areas. These findings identify a central core brain network critical for human consciousness.SIGNIFICANCE STATEMENT Trying to understand the biological basis of human consciousness is currently one of the greatest challenges of neuroscience. While the loss and return of consciousness regulated by anesthetic drugs and physiological sleep are used as model systems in experimental studies on consciousness, previous research results have been confounded by drug effects, by confusing behavioral "unresponsiveness" and internally generated consciousness, and by comparing brain activity levels across states that differ in several other respects than only consciousness. Here, we present carefully designed studies that overcome many previous confounders and for the first time reveal the neural mechanisms underlying human consciousness and its disconnection from behavioral responsiveness, both during anesthesia and during normal sleep, and in the same study subjects.

Safety, Biodistribution, and Radiation Dosimetry of 18F-rhPSMA-7.3 in Healthy Adult Volunteers.

This first-in-humans study investigated the safety, biodistribution, and radiation dosimetry of a novel 18F-labeled radiohybrid prostate-specific membrane antigen (rhPSMA) PET imaging agent, 18F-rhPSMA-7.3. Methods: Six healthy volunteers (3 men, 3 women) underwent multiple whole-body PET acquisitions at scheduled time points up to 248 min after the administration of 18F-rhPSMA-7.3 (mean activity, 220; range, 210-228 MBq). PET scans were conducted in 3 separate sessions, and subjects were encouraged to void between sessions. Blood and urine samples were collected for up to 4 h after injection to assess metabolite-corrected radioactivity in whole blood, plasma, and urine. Quantitative measurements of 18F radioactivity in volumes of interest over target organs were determined directly from the PET images at 8 time points, and normalized time-activity concentration curves were generated. These normalized cumulated activities were then inputted into the OLINDA/EXM package to calculate the internal radiation dosimetry and the subjects' effective dose. Results:18F-rhPSMA-7.3 was well tolerated. One adverse event (mild headache, not requiring medication) was considered possibly related to 18F-rhPSMA-7.3. The calculated effective dose was 0.0141 mSv/MBq when using a 3.5-h voiding interval. The organs with the highest mean absorbed dose per unit of administered radioactivity were the adrenals (0.1835 mSv/MBq), the kidneys (0.1722 mSv/MBq), the submandibular glands (0.1479 mSv), and the parotid glands (0.1137 mSv/MBq). At the end of the first scanning session (mean time, 111 min after injection), an average of 7.2% (range, 4.4%-9.0%) of the injected radioactivity of 18F-rhPSMA-7.3 was excreted into urine. Conclusion: The safety, biodistribution, and internal radiation dosimetry of 18F-rhPSMA-7.3 are considered favorable for PET imaging.

Application of the PET ligand [11C]ORM-13070 to examine receptor occupancy by the α2C-adrenoceptor antagonist ORM-12741: translational validation of target engagement in rat and human brain.

BACKGROUND: Availability of the α2C-adrenoceptor (α2C-AR) positron emission tomography (PET) tracer, [11C]ORM-13070, and the α2C-AR antagonist ORM-12741 allows probing of the roles of this G-protein coupled receptor subtype in brain function, both in healthy humans and in patients with various brain disorders. This translational study employed [11C]ORM-13070 autoradiography and PET to determine α2C-AR occupancy by ORM-12741 in rat and human brain, respectively. RESULTS: ORM-12741 has high affinity (Ki: 0.08 nM) and potent antagonist activity (Kb: 0.04 nM) as well as selectivity (Ki estimates for the human α2A-AR and α2B-AR were 8.3 nM and 0.8 nM, respectively) for the human α2C-AR subtype. [11C]ORM-13070 had highest uptake in the basal ganglia of rat and human brain. Pretreatment with ORM-12741 inhibited [11C]ORM-13070 binding in rat striatum in a time- and dose-dependent manner at 10 and 50 µg/kg (s.c.) with an EC50 estimate of 1.42 ng/mL in rat plasma, corresponding to protein-free drug concentration of 0.23 nM. In the living human brain, time- and dose-related α2C-AR occupancy was detected with EC50 estimates of 24 ng/mL and 31 ng/mL for the caudate nucleus and putamen, respectively, corresponding to protein-free concentrations in plasma of 0.07 nM and 0.1 nM. Modelling-based maximum α2C-AR occupancy estimates were 63% and 52% in the caudate nucleus and the putamen, respectively. CONCLUSIONS: ORM-12741 is a selective α2C-AR antagonist which penetrates the rat and human brain to occupy α2C-ARs in a manner consistent with its receptor pharmacology. Trial registration number and date of registration: ClinicalTrial.cov NCT00829907. Registered 11 December 2008. https://clinicaltrials.gov/ .

Effects of intramuscular vatinoxan (MK-467), co-administered with medetomidine and butorphanol, on cardiopulmonary and anaesthetic effects of intravenous ketamine in dogs.

OBJECTIVE: To investigate the impact of intramuscular (IM) co-administration of the peripheral α2-adrenoceptor agonist vatinoxan (MK-467) with medetomidine and butorphanol prior to intravenous (IV) ketamine on the cardiopulmonary and anaesthetic effects in dogs, followed by atipamezole reversal. STUDY DESIGN: Randomized, masked crossover study. ANIMALS: A total of eight purpose-bred Beagle dogs aged 3 years. METHODS: Each dog was instrumented and administered two treatments 2 weeks apart: medetomidine (20 µg kg-1) and butorphanol (100 µg kg-1) premedication with vatinoxan (500 µg kg-1; treatment MVB) or without vatinoxan (treatment MB) IM 20 minutes before IV ketamine (4 mg kg-1). Atipamezole (100 µg kg-1) was administered IM 60 minutes after ketamine. Heart rate (HR), mean arterial (MAP) and central venous (CVP) pressures and cardiac output (CO) were measured; cardiac (CI) and systemic vascular resistance (SVRI) indices were calculated before and 10 minutes after MVB or MB, and 10, 25, 40, 55, 70 and 100 minutes after ketamine. Data were analysed with repeated measures analysis of covariance models. A p-value <0.05 was considered statistically significant. Sedation, induction, intubation and recovery scores were assessed. RESULTS: At most time points, HR and CI were significantly higher, and SVRI and CVP significantly lower with MVB than with MB. With both treatments, SVRI and MAP decreased after ketamine, whereas HR and CI increased. MAP was significantly lower with MVB than with MB; mild hypotension (57-59 mmHg) was recorded in two dogs with MVB prior to atipamezole administration. Sedation, induction, intubation and recovery scores were not different between treatments, but intolerance to the endotracheal tube was observed earlier with MVB. CONCLUSIONS AND CLINICAL RELEVANCE: Haemodynamic performance was improved by vatinoxan co-administration with medetomidine-butorphanol, before and after ketamine administration. However, vatinoxan was associated with mild hypotension after ketamine with the dose used in this study. Vatinoxan shortened the duration of anaesthesia.