Intraoperative Positioning in Maxillofacial Trauma Patients With Cervical Spine Injury – Is It Safe? Radiological Simulation in a Healthy Volunteer

Introduction Cervical spine (C-spine) injury is present in up to 10% of patients with maxillofacial fractures. Uncertainty over the status of the C-spine and permitted head movements may delay maxillofacial surgical intervention, resulting in prolonged patient discomfort and return to oral nutrition, reducing quality of life. This study aimed to investigate the effects on the C-spine of positioning patients for maxillofacial procedures by simulating intraoperative positions for common maxillofacial procedures. Methods Magnetic resonance imaging was used to assess the effects of head position in common intraoperative configurations – neutral (anterior mandible position), extended (tracheostomy position) and laterally rotated (mandibular condyle position) on the C-spine of a healthy volunteer. Results In the tracheostomy position, maximal movement occurred in the sagittal plane between the cervico-occipital junction and C4–C5, as well as at the cervico-thoracic junction. Minimal movement occurred at C2 (on C3), C5 (on C6) and C6 (on C7). In the mandibular condyle position, C-spine movements occurred in both rotational and sagittal planes. Maximal movement occurred above the level of C4, concentrated at atlanto-occipital and atlanto-axial (C1–2) joints. Conclusion Neck extension is likely to be relatively safe in injuries that are stable in flexion and extension, such as odontoid peg fracture and fractures between C5 and C7. Head rotation is likely to be relatively safe in fractures below C4, as well as vertebral body fractures, and laminar fractures without disc disruption. Early dialogue with the neurosurgical team remains a central tenet of safe management of patients with combined maxillofacial and C-spine injuries.

Exploring the Pharmacokinetics of Phenoxymethylpenicillin (Penicillin-V) in Adults: A Healthy Volunteer Study

This healthy volunteer study aimed to explore phenoxymethylpenicillin (penicillin-V) pharmacokinetics (PK) to support the planning of large dosing studies in adults. Volunteers were dosed with penicillin-V at steady state. Total and unbound penicillin-V serum concentrations were determined, and a base population PK model was fitted to the data.

Overlap phenotypes of the left ventricular noncompaction and hypertrophic cardiomyopathy with complex arrhythmias and heart failure induced by the novel truncated DSC2 mutation

Background The left ventricular noncompaction cardiomyopathy (LVNC) is a rare subtype of cardiomyopathy associated with a high risk of heart failure (HF), thromboembolism, arrhythmia, and sudden cardiac death. Methods The proband with overlap phenotypes of LVNC and hypertrophic cardiomyopathy (HCM) complicates atrial fibrillation (AF), ventricular tachycardia (VT), and HF due to the diffuse myocardial lesion, which were diagnosed by electrocardiogram, echocardiogram and cardiac magnetic resonance imaging. Peripheral blood was collected from the proband and his relatives. DNA was extracted from the peripheral blood of proband for high-throughput target capture sequencing. The Sanger sequence verified the variants. The protein was extracted from the skin of the proband and healthy volunteer. The expression difference of desmocollin2 was detected by Western blot. Results The novel heterozygous truncated mutation (p.K47Rfs*2) of the DSC2 gene encoding an important component of desmosomes was detected by targeted capture sequencing. The western blots showed that the expressing level of functional desmocollin2 protein (~ 94kd) was lower in the proband than that in the healthy volunteer, indicating that DSC2 p.K47Rfs*2 obviously reduced the functional desmocollin2 protein expression in the proband. Conclusion The heterozygous DSC2 p.K47Rfs*2 remarkably and abnormally reduced the functional desmocollin2 expression, which may potentially induce the overlap phenotypes of LVNC and HCM, complicating AF, VT, and HF.

No antidepressant-like acute effects of bright light on emotional information processing in healthy volunteers

Rationale Bright light treatment (BLT) is an efficacious antidepressant intervention, but its mechanism of action is not well understood. Antidepressant drugs acutely affect how emotional information is processed, pushing the brain to prioritise positive relative to negative input. Whether BLT could have a similar effect is not known to date. Objective To test whether BLT acutely influences emotional information processing similar to antidepressant drugs, using an established healthy volunteer assay. Methods Following a double-blind, parallel-group design, 49 healthy volunteers (18–65 years, 26 females) were randomly allocated to 60-min BLT (≥ 10,000 lux) or sham-placebo treatment early in the morning in autumn/winter. Immediately after treatment, emotional information processing was assessed using the Oxford Emotional Test Battery, a validated set of behavioural tasks tapping into emotional information processing in different cognitive domains. Participants also completed questionnaires before and after treatment to assess changes in subjective state. Results The BLT group did not show significantly more positively biased emotional information processing compared to the placebo group (p > 0.05 for all measures). After adjustment for pre-treatment scores, there were also no significant post-treatment differences between groups in subjective state (p > 0.05 for all measures). Conclusions BLT did not show immediate effects on emotional information processing in an established healthy volunteer assay. Thus, BLT might exert its clinical effects through a different (cognitive) mechanism than other antidepressant interventions. Future studies should corroborate this finding including clinical populations and more intensive treatment regimes, and control for potential chronobiological effects.

Interim Analysis of an Open-Label, Ascending-Dose, Phase 1 Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single Doses of the Subcutaneously Administered Human Monoclonal Antibody Pozelimab in Combination with Single Doses of the Subcutaneously Administered siRNA Cemdisiran in Healthy Volunteers

Introduction. Pozelimab (REGN3918) and cemdisiran (ALN-CC5) are C5 inhibitors under development for the treatment of paroxysmal nocturnal hemoglobinuria (PNH), myasthenia gravis (MG), and other diseases in which tissue damage is mediated by terminal complement pathway activity. Pozelimab is a fully human monoclonal immunoglobulin G4P (IgG4P) antibody directed against C5, and cemdisiran is a synthetic small interfering RNA (siRNA) targeting C5 mRNA. Both agents can be administered via subcutaneous (SC) injection. Pharmacokinetic (PK)/pharmacodynamic (PD) modeling based on observed data from both pozelimab and cemdisiran healthy volunteer studies (NCT03115996, NCT02352493) suggests that, by combining cemdisiran and pozelimab, the dose of both agents may be significantly reduced and the interval for SC dosing of pozelimab may be significantly increased. Objectives. To provide initial safety and tolerability data for a SC cemdisiran/pozelimab combination approach. Methods. This is an ongoing phase 1, open-label, parallel-dose cohort combination study (NCT04601844) assessing the safety and tolerability of ascending doses of SC pozelimab in combination with SC cemdisiran when administered on the same day or sequentially, on different days, in healthy subjects. Cohort Descriptions. Three parallel ascending-dose cohorts, consisting of six subjects each, were selected based on PK/PD modeling using observed data from both pozelimab and cemdisiran non-combination healthy volunteer studies: Cohort 1: Cemdisiran low dose SC followed by pozelimab low dose SC, administered on different days Cohort 2: Cemdisiran high dose SC followed by pozelimab low dose SC, administered on different days Cohort 3: Cemdisiran high dose SC and pozelimab high dose SC, both administered on the same day Dose regimens were designed to limit the duration of >50% complement inhibition for no longer than 8 weeks, to mitigate risk in the enrolled healthy subjects. An optional additional Cohort 4 was included in the study design and this interim analysis was planned to review safety data to guide the decision regarding whether to enroll this cohort and to inform its dose selection. Interim Analysis: An interim safety analysis was performed with a data cut-off corresponding to study day 127 for Cohort 1, study day 85 for Cohort 2, and study day 71 for Cohort 3. Eighteen healthy volunteer subjects, nine female and nine male, with a mean age of 36 years (standard deviation 9.5 years), were randomized to one of the three cohorts. Demographic and baseline characteristics were comparable for subjects in each cohort. A total of 47 treatment emergent adverse events (TEAEs) were reported, with comparable distribution across cohorts, all mild to moderate in severity with no severe TEAEs. "Nervous system disorders" was the TEAE System Organ Class with the most subjects for all three cohorts, occurring in 12 (66.7%) of the 18 subjects. "Headache" was the most frequent MedDRA Preferred Term for all three cohorts, occurring in 11 (61.1%) of the 18 subjects. All TEAEs were recovered or recovering at the time of data cut-off, and there were no study drug discontinuations or interruptions of treatment due to TEAEs. There were no serious TEAEs or deaths. There were no clinically meaningful findings or treatment-emergent changes reported on the vital signs or laboratory safety tests. Conclusions: The combined SC administration of pozelimab and cemdisiran represents a promising approach to achieve therapeutically significant complement inhibition for extended durations. An interim safety analysis demonstrated that the combined administration was generally safe and well tolerated. Final PK/PD analysis from this healthy volunteer study will allow for assessment of agreement between modeling predictions and observed data, and further inform combination dose regimens for studies in target patient populations. Disclosures van Zyl: Regeneron Pharmaceuticals, Inc.: Current Employment. Weyne: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chaudhari: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Harari: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Levy: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Miller: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Chen: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Meagher: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Rodgers: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Perlee: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Morton: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Weinreich: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Yancopoulos: Regeneron Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company.

Deploying a rapid point of care polymerase chain reaction test for SARS-CoV-2 in a clinical research unit to ensure healthy volunteer safety

The entire world was severely affected by the outbreak of the SARS-CoV-2 virus. Early phase clinical research was no exception and clinical healthy volunteer trials were halted across the globe. To enable continuation of development of new drugs, we developed a testing strategy for nonsymptomatic trial participants in an early stage of the outbreak. A point-of-care polymerase chain reaction test combined with a gold standard polymerase chain reaction test and strict social distancing and hygiene measures limited the number of infected subjects entering our clinical research units and reduced further spread for the duration of the clinical trial. Thus, proving efficacy of this strategy to allow safe and effective continuation of early phase clinical trials during the COVID-19 pandemic.