The Paediatric Vault Score (PVS)-A Novel Scoring Tool for Prioritisation of Surgical Management of Craniosynostosis Patients.

Craniosynostosis is the premature fusion of the skull sutures, resulting in abnormal skull shape and volume. Timely management is a priority in avoiding raised intracranial pressure which can result in blindness and neurodevelopmental delay. Due to the COVID-19 pandemic, theater access was reduced. A risk stratification scoring system was thus devised to score patients attending surgery and aid in prioritization according to surgical need. The authors present the Paediatric Vault Score (PVS), which can also be customized to each unit's individual protocols. Ten patients on the waiting list were randomly selected and their clinical information was summarized in uniform anonymized reports. Six craniofacial consultants were selected as assessors and given 1 week to independently rank the patients from 1 to 10. Each scorer's ranking was verified against the PVS template and concordance was analyzed using the Kendall tau correlation coefficient (KT). Three cycles of the scoring process were carried out. Improvements were made to the scoring tool following cycle 1. Cycle 1 revealed 2 clinicians to be concordant with the PVS system and 4 to be discordant. Cycle 2 revealed all 6 clinicians to be concordant, with a mean KT score of 0.61. The final cycle revealed all 6 clinicians to be concordant, with a mean KT score of 0.70. Four scorers increased their concordance once the scoring sheet was introduced. Kendall's correlation of concordance calculated the interrater reliability to be 0.81. The PVS is the first known vault scoring system to aid in risk stratification and waiting list prioritization.

Pediatric ARDS phenotypes in critical COVID-19: implications for therapies and outcomes. (preprint)

Purpose: to describe lung mechanics in Pediatric Acute Respiratory Disease Syndrome (PARDS) associated with COVID-19. We hypothesize two phenotypes according to respiratory system mechanics and clinical diagnosis. Methods: a concurrent multicenter observational study was performed, analyzing clinical variables and pulmonary mechanics of PARDS associated with COVID-19 in 4 Pediatric intensive care units (PICUs) of Peru. Subgroup analysis included PARDS associated with multisystem inflammatory syndrome in children (MIS-C), MIS-PARDS, and PARDS with COVID-19 primary respiratory infection, C-PARDS. In addition, receiver operator curve analysis (ROC) for mortality was performed. Results: 30 patients were included. Age was 7.5(4-11) years, 60% male, and mortality 23%. 47% corresponded to MIS-PARDS and 53% to C-PARDS phenotypes. C-PARDS had positive RT-PCR in 67% and MIS-PARDS none (p<0.001). C-PARDS group had more profound hypoxemia (P/Fratio<100, 86%vs38%,p<0.01) and higher driving-pressure (DP) [14(10-22)vs10(10-12)cmH2O], and lower compliance of the respiratory system (CRS)[0.5(0.3-0.6)vs 0.7(0.6-0.8)ml/kg/cmH2O] compared to MIS-PARDS (all p<0.05). ROC-analysis for mortality showed that DP had the best performance [AUC 0.91(95%CI0.81-1.00), with the best cut-point of 15 cmH2O (100% sensitivity and 87% of specificity). Mortality in C-PARDS was 38% and 7% in MIS-PARDS(p=0.09). MV free-days were 12(0-23) in C-PARDS and 23(21-25) in MIS-PARDS(p=0.02) Conclusion: critical pediatric COVID-19 is heterogeneous in children. COVID-19 PARDS had two phenotypes with distinctive pulmonary mechanics features. Characteristics of C-PARDS are like a classic primary PARDS, while a decoupling between compliance and hypoxemia was more frequent in MIS-PARDS. In addition, C-PARDS had fewer MV free-days. DP [≥] 15 cmH2O had the best performance of the quasi-static calculations to discriminate for mortality. Standardized pulmonary mechanics measurements in PARDS might reveal essential information to tailor the ventilatory strategy in pediatric critical COVID-19.

Clinical and Non-clinical Proof of Concept Supporting the Development of RJX As an Adjunct to Standard of Care Against Severe COVID-19 (preprint)

BackgroundThe identification of effective strategies capable of reducing the case mortality rate of high-risk COVID-19 is an urgent and unmet medical need. We recently reported the clinical safety profile of RJX, a well-defined intravenous GMP-grade pharmaceutical formulation of anti-oxidant and anti-inflammatory vitamins as active ingredients, in a Phase 1 study in healthy volunteers (ClinicalTrials.gov Identifier: NCT03680105) (Uckun et al., Front. Pharmacol. 11, 594321. 10.3389/fphar.2020.594321). Here we report data from a pilot clinical study (RPI-015) which examined the safety, tolerability, and feasibility of using RJX in combination with clinical standard of care (SOC) in hospitalized COVID-19 patients with pneumonia (ClinicalTrials.gov Identifier: NCT04708340). In addition to our early clinical proof of concept (POC) data, we also present non-clinical POC from a mouse model of CRS and ARDS that informed the design of the reported clinical study. Methods13 patients, who were hospitalized with COVID-19 pneumonia and abnormally elevated serum inflammatory biomarkers markers [≥]3 months prior to the identification of the first confirmed U.S case of the Omicron variant, were treated with IV RJX (daily x 7 days) plus SOC. Non-clinical POC study examined the ability of RJX plus dexamethasone (DEX) to improve the survival outcome in the lipopolysaccharide (LPS)-Galactosamine (GalN) mouse model of fatal cytokine release syndrome (CRS), sepsis and acute respiratory distress syndrome (ARDS). FindingsIn the Phase 1 clinical study, none of the 13 patients developed a treatment-related DLT, SAE, or Grade 3-5 AEs. Nine (9) of the 12 evaluable patients, including 3 patients with hypoxemic respiratory failure, showed rapid clinical recovery. In the non-clinical POC study in LPS-GalN challenged mice, the combination of RJX plus DEX was more effective than RJX alone or DEX alone, reversed the CRS as well as inflammatory tissue damage in the lungs and liver, and improved the survival outcome. Taken together, these findings provide the early clinical and non-clinical POC for the development of RJX as an adjunct to the SOC in the multi-modality management of high-risk COVID-19.

Mathematical model of a cytokine storm (preprint)

Cytokine storm is a life-threatening inflammatory response that is characterized by hyperactivation of the immune system, and which can be caused by various therapies, auto-immune conditions, or pathogens, such as respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease COVID-19. While initial causes of cytokine storms can vary, late-stage clinical manifestations of cytokine storm converge and often overlap, and therefore a better understanding of how normal immune response turns pathological is warranted. Here we propose a theoretical framework, where cytokine storm phenomenology is captured using a conceptual mathematical model, where cytokines can both activate and regulate the immune system. We simulate normal immune response to infection, and through variation of system parameters identify conditions where, within the frameworks of this model, cytokine storm can arise. We demonstrate that cytokine storm is a transitional regime, and identify three main factors that must converge to result in storm-like dynamics, two of which represent individual-specific characteristics, thereby providing a possible explanation for why some people develop CRS, while others may not. We also discuss possible ecological insights into cytokine-immune interactions and provide mathematical analysis for the underlying regimes. We conclude with a discussion of how results of this analysis can be used in future research.

Where Are We Headed? Diagnosing Abnormal Head Shapes Through Virtual Care Visits.

PURPOSE: Since the beginning of the coronavirus disease 2019 pandemic in early March, there has been a push to expand virtual patient care visits instead of in-person clinic visits. Studies have found that telemedicine can provide efficient triaging, reduction in emergency room visits, and conservation of health care resources and personnel. Although virtual patient care has been implicated in providing similar outcomes to traditional face-to-face care in patients affected with coronavirus disease 2019, there are a lack of studies on the effectiveness of virtual care visits (VCVs) for patients with craniosynostosis or deformational plagiocephaly. This study aims to develop an understanding of whether physicians can accurately diagnose pediatric patients with craniosynostosis or deformational plagiocephaly via VCVs, and whether they can determine if affected patients will benefit from helmet correction or if surgical treatment is required. METHODS: An Institutional Review Board-approved retrospective chart analysis over a 4-month period (March 1, 2020 to June 30, 2020) was performed analyzing all pediatric patients (<18 years old) who underwent virtual care calls for diagnosis and treatment of abnormal head shape. Patients were referred to UT Physicians Pediatric Surgery clinic for evaluation by a member of the Texas Cleft-Craniofacial Team (2 surgeons or 1 physician's assistant). Variables such as patient demographics, diagnosis, and need for confirmation were pulled and recorded from Allscripts Electronic Medical Records software. RESULTS: Thirty-five patients were identified who fit our search criteria. Out of these patients, eleven (31.43%) cases were diagnosed with craniosynostosis, twenty-two (62.86%) cases were diagnosed with deformational plagiocephaly, and 2 (5.71%) cases were diagnosed as being normocephalic. Median age at virtual care evaluation was 14.10 months (Interquartile Range [IQR] 5.729, 27.542) for patients diagnosed with craniosynostosis and 6.51 months (IQR 4.669, 7.068) for patients diagnosed with deformational plagiocephaly. All eleven (100%) patients diagnosed with craniosynostosis were referred for a confirmatory computed tomography scan before undergoing surgical intervention and saw an alleviation in head shape postoperatively. Eighteen (81.82%) of patients diagnosed with deformational plagiocephaly were recommended to undergo conservative treatment and the remaining 4 (18.18%) were recommended for helmet therapy. Two cases were unable to be diagnosed virtually. These patients needed a follow-up visit in person to establish a diagnosis and plan of treatment. CONCLUSIONS: Virtual care visits are increasing in frequency and this includes consultations for abnormal head shapes. Our experience demonstrates that the majority of patients can be evaluated safely in this modality, with only 5.71% requiring additional imaging or in-person visits to confirm the diagnosis. Our study underscores the feasibility of virtually diagnosing and recommending a plan for treatment in pediatric patients with abnormal head shapes. This information can be implemented to further our knowledge on the accuracy of diagnosis and treatment options for patients with craniosynostosis and deformational plagiocephaly. Further analyses are needed to quantify the financial and patient-reported outcomes of VCVs for these patients.

Telehealth Applied to Deliver In Situ Behavioral Skills Training to Reduce Car Seat Misuse During the CovidAcc19 Pandemic (preprint)

Objective The use of telehealth has been a common approach to deliver health education before and during the COVID-19 pandemic. However, its ability to apply behavioral skills training (BST) for CRS education has been undocumented. This study assessed the efficacy of telehealth to deliver in-situ behavioral skills training (BST) to teach expectant parents how to install and use their child restraint system (CRS) to reduce misuse and improve retention during the COVID-19 pandemic. Method A repeated measures group design was used to evaluate 171 individual participants, in a 37-step CRS task analysis for baseline, BST, and follow-up. Performance across all participants was aggregated for each task analysis. Participants were recruited from National Highway Traffic Safety Administration car seat fitting stations during the Covid-19 pandemic between March through July, 2020. Results Baseline results identified significant critical misuse across participants. With BST, delivered with telehealth, misuse decreased by 97% among 37 task objectives. A 2-week follow-up evaluation concluded that 100% of participants retained the skills they mastered during BST. Conclusions This study suggests the use of telehealth, as a method of BST delivery for CRS education, is an effective approach to reduce CRS misuse and the burden of child occupant motor vehicle injury. It was found to empower participants and improve their self-confidence, while ensuring the safety of their child occupant. While it was found to be an effective approach for expectant parents during the COVID-19 pandemic, it also has broader child passenger safety program and train-the-trainer implications beyond the COVID-19 pandemic.

An Appraisal of Respiratory System Compliance In Mechanically Ventilated Covid-19 Patients (preprint)

Background Heterogeneous respiratory system static compliance (CRS) values and levels of hypoxemia in patients with novel coronavirus disease (COVID-19) requiring mechanical ventilation have been reported in previous small-case series or studies conducted at a national level.Methods We designed a retrospective observational cohort study with rapid data gathering from the international COVID-19 Critical Care Consortium study to comprehensively describe the impact of CRS on the ventilatory management and outcomes of COVID-19 patients on mechanical ventilation (MV), admitted to intensive care units (ICU) worldwide.Results We enrolled 318 COVID-19 patients enrolled into the study from January 14th through September 31th, 2020 in 19 countries and stratified into two CRS groups. CRS was calculated as: tidal volume/[airway plateau pressure-positive end-expiratory pressure (PEEP)] and available within 48 h from commencement of MV in 318 patients. Patients were mean ± SD of 58.0 ± 12.2, predominantly from Europe (54%) and males (68%). Median CRS (IQR) was 34.1 mL/cmH2O (26.5–45.5) and PaO2/FiO2 was 119 mmHg (87.1–164) and was not correlated with CRS. Female sex presented lower CRS than in males (95% CI: -13.8 to -8.5 P < 0.001) and higher body mass index (34.7 ± 10.9 vs 29.1 ± 6.0, p < 0.001). Median (IQR) PEEP was 12 cmH2O (10–15), throughout the range of CRS, while median (IQR) driving pressure was 12.3 (10–15) cmH2O and significantly decreased as CRS improved (p < 0.001). No differences were found in comorbidities and clinical management between CRS strata. In addition, 28-day ICU mortality and hospital mortality did not differ between CRS groups.Conclusions This multicentre report provides a comprehensive account of CRS in COVID-19 patients on MV – predominantly males or overweight females, in their late 50 s – admitted to ICU during the first international outbreaks. Phenotypes associated with different CRS upon commencement of MV could not be identified. Trial documentation: Available at https://www.covid-critical.com/study.Trial registration ACTRN12620000421932.