Phase 1 Open-Label Study of Omigapil in Patients With LAMA2- or COL6-Related Dystrophy.

Background and Objectives: Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dyw/dyw) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy2J/dy2J) LAMA2-RD mouse model and the (Col6a1-/-) COL6-RD mouse model demonstrated decreased apoptosis. Methods: A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data. Results: Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC0-24h) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study. Discussion: This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations. Classification of Evidence: This study provides Class IV evidence of omigapil in a dose-finding phase 1 study. Trial Registration Information: Clinical Trials NCT01805024.

Neuromuscular problems of the critically Ill neonate and child.

Acute neuromuscular disorders occasionally occur in the Pediatric Neurologic Intensive Care Unit. Many of these are primary disorders of the motor unit that may present acutely or exacerbate during an intercurrent illness. Additionally, acute neuromuscular disorders may develop during an acute systemic illness requiring intensive care management that predispose the child to another set of acute motor unit disorders. This chapter discusses acute neuromuscular crises in the infant, toddler, and adolescent, as well as neuromuscular disorders resulting from critical illness.

Hereditary Neuropathies.

OBJECTIVE: This article provides an overview of hereditary neuropathies, describes the different hereditary neuropathy subtypes and the clinical approach to differentiating between them, and summarizes their clinical management. LATEST DEVELOPMENTS: Increasingly available clinical genetic testing has broadened the clinical spectrum of hereditary neuropathy subtypes and demonstrated a significant overlap of phenotypes associated with a single gene. New subtypes such as SORD -related neuropathy and CANVAS (cerebellar ataxia, neuropathy, vestibular areflexia syndrome) have emerged. The optimization of clinical management has improved gait and motor function in the adult and pediatric populations. Novel therapeutic approaches are entering clinical trials. ESSENTIAL POINTS: Hereditary neuropathies constitute a spectrum of peripheral nerve disorders with variable degrees of motor and sensory symptoms, patterns of involvement, and clinical courses.

Performance of Cornell Assessment of Pediatric Delirium Scale in Mechanically Ventilated Children.

Accuracy of delirium diagnosis in mechanically ventilated children is often limited by their varying developmental abilities. The purpose of this study was to examine the performance of the Cornell Assessment of Pediatric Delirium (CAPD) scale in these patients. This is a single-center, prospective, observational study of patients requiring sedation and mechanical ventilation for 2 days or more. CAPD scale was implemented in our unit for delirium screening. Each CAPD assessment was accompanied by a physician assessment using Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria. Sensitivity analysis was performed to determine the best cut-off score in our target population. We also evaluated ways to improve the accuracy of this scale in patients with and without developmental delay. A total of 837 paired assessments were performed. Prevalence of delirium was 19%. Overall, CAPD score ≥ 9 had sensitivity of 81.8% and specificity of 44.8%. Among typically developed patients, the sensitivity and specificity were 76.7 and 65.4%, respectively, whereas specificity was only 16.5% for developmentally delayed patients. The best cut-off value for CAPD was 9 for typically developed children and 17 for those with developmental delay (sensitivity 74.4%, specificity 63.2%). Some CAPD questions do not apply to patients with sensory and neurocognitive deficits; upon excluding those questions, the best cut-off values were 5 for typically developed and 6 for developmentally delayed children. In mechanically ventilated patients with developmental delay, CAPD ≥ 9 led to a high false-positive rate. This emphasizes the need for either a different cut-off score or development of a delirium scale specific to this patient population.

Challenges in the Clinical Recognition of Acute Flaccid Myelitis and its Implications.

OBJECTIVES: To explore the challenges in diagnosing acute flaccid myelitis (AFM) and evaluate clinical features and treatment paradigms associated with under recognition. STUDY DESIGN: This was a retrospective multicenter study of pediatric patients (≤18 years) who were diagnosed with AFM from 2014 to 2018 using the Centers for Disease Control and Prevention's case definition. RESULTS: In 72% of the cases (126 of 175), AFM was not considered in the initial differential diagnosis (n = 108; 61.7%) and/or the patient was not referred for acute care (n = 90; 51.4%) at the initial clinical encounter, and this did not improve over time. Although many features of the presentation were similar in those initially diagnosed with AFM and those who were not; preceding illness, constipation, and reflexes differed significantly between the 2 groups. Patients with a non-AFM initial diagnosis more often required ventilatory support (26.2% vs 12.2%; OR, 0.4; 95% CI, 0.2-1.0; P = .05). These patients received immunomodulatory treatment later (3 days vs 2 days after neurologic symptom onset; 95% CI, -2 to 0; P = .05), particularly intravenous immunoglobulin (5 days vs 2 days; 95% CI, -4 to -2; P < .001). CONCLUSIONS: Delayed recognition of AFM is concerning because of the risk for respiratory decompensation and need for intensive care monitoring. A non-AFM initial diagnosis was associated with delayed treatment that could have a clinical impact, particularly as new treatment options emerge.

Phenotypic Spectrum of DNM2-Related Centronuclear Myopathy.

Background and Objectives: Centronuclear myopathy (CNM) due to mutations in the dynamin 2 gene, DNM2, is a rare neuromuscular disease about which little is known. The objective of this study was to describe the range of clinical presentations and subsequent natural history of DNM2-related CNM. Methods: Pediatric and adult patients with suspicion for a CNM diagnosis and confirmed heterozygous pathogenic variants in DNM2 were ascertained between December 8, 2000, and May 1, 2019. Data were collected through a retrospective review of genetic testing results, clinical records, and pathology slides combined with patient-reported clinical findings via questionnaires. Results: Forty-two patients with DNM2-related CNM, whose ages ranged from 0.95 to 75.76 years at most recent contact, were enrolled from 34 families in North or South America and Europe. There were 8 different DNM2 pathogenic variants within the cohort. Of the 32 biopsied patients, all had histologic features of CNM. The disease onset was in infancy or childhood in 81% of the cohort, and more than half of the patients had high arched palates, indicative of weakness in utero. Ambulation was affected in nearly all (92%) the patients, and while the rapidity of progression was variable, most (67%) reported a "deteriorating course." Ptosis, ophthalmoparesis, facial weakness, dysphagia, and respiratory insufficiency were commonly reported. One-third of the patients experienced restricted jaw mobility. Certain pathogenic variants appear to correlate with a more severe phenotype. Discussion: DNM2-related CNM has a predominantly early-onset, often congenital, myopathy resulting in progressive difficulty with ambulation and occasionally bulbar and respiratory dysfunction. This detailed characterization of the phenotype provides important information to support clinical trial readiness for future disease-modifying therapies.

Educating health professionals about COVID-19 with ECHO telementoring.

BACKGROUND: When the COVID-19 pandemic began, primary care clinicians had almost no knowledge regarding best practices COVID-19 treatment. Project ECHO developed a COVID-19 Infectious Disease Office Hours (Office Hours) program to respond to the needs of clinicians seeking COVID-19 information. METHODS: This mixed-methods evaluation analyzed weekly post-session data and focus group results from the weekly Office Hours ECHO sessions during June 1, 2020- May 31, 2021. RESULTS: A total of 1,421 participants attended an average of 4.9 sessions during the 45 Office Hours sessions studied. The most common specialties included: nurses= 530 (37%), physicians= 284 (20%), and 493 (34%) having other degrees. The participants stated that they were definitely (68.2%) or probably (22.0%) going to use what they learned in their work, especially vaccination information. Focus group results identified these themes: 1) quality information, 2) community of practice, 3) interprofessional learning, and 4) increased knowledge, confidence, and practice change. CONCLUSIONS: This evaluation demonstrates that the Office Hours program was successful in bringing a large group of health professionals together each week in a virtual community of practice. The participants acknowledged their plans to use the information gained with their patients. This diffusion of knowledge from clinician to patient amplifies the response of the program, changes practice behavior and may improve patient care.

Reduction of Central-line-Associated Bloodstream Infections in a Tertiary Neonatal Intensive Care Unit through Simulation Education.

Introduction: Critically ill neonates and those with complex medical conditions frequently require the use of central venous lines. Unfortunately, central line-associated bloodstream infections (CLABSIs) result in significant morbidity and mortality, and the cost and increased length of stay burden the healthcare system. Previous studies have demonstrated that standardized care bundles can decrease CLABSI rates, but achieving sustained improvement has proven difficult. Methods: All patients admitted to the Neonatal Intensive Care Unit between 2014 and 2020 who had a CVL were included in this study. First, we recorded all CLABSI events and total CVL days according to defined criteria. Then, in late 2016, we instituted simulation-based nursing training for CVL care. Results: Job Instruction Sheets were initially introduced to Neonatal Intensive Care Unit nursing staff simultaneously with one-on-one teaching sessions between instructors and bedside nurses. Intermittent performance audits and re-education for identified deficiencies did not improve the CLABSI rate per 1000 line days. After instituting simulation-based CVL training in 2016, there was a decreased rate of CLABSI events per 1000 line days sustained over time (x = 0.692). Conclusions: Standardized care bundles and Hospital-acquired Condition interactor audits were insufficient to reduce the CLABSI rate. However, combining care bundles and education with simulation-based training significantly decreased CLABSI rates. One-on-one intensive training and continued ongoing monitoring were critical to producing a sustained reduction. This experience demonstrates that supervised, interactive education combined with simulation can significantly impact patient outcomes.

Examining the Feasibility of Early Mobilization With Virtual Reality Gaming Using Head-Mounted Display and Adaptive Software With Adolescents in the Pediatric Intensive Care Unit: Case Report.

BACKGROUND: Early rehabilitative mobilization for adolescents is safe and feasible. However, there is a lack of published rehabilitation strategies and treatments that can maximize engagement and outcomes among adolescents in the pediatric intensive care unit (PICU). Virtual reality (VR) gaming using a head-mounted display (HMD) and adaptive software can allow active and nonactive gameplay at the bedside for people with limited arm mobility, making it a potentially inclusive and enjoyable treatment modality for adolescents in the PICU. OBJECTIVE: The purpose of this brief case study is to report on the preliminary feasibility of incorporating adaptive VR gaming using an HMD with 2 adolescents who received early mobility treatment within the PICU. METHODS: This study was a mini-ethnographic investigation of 2 adolescents (a 15-year-old male and a 13-year old male) in the PICU who underwent VR gaming sessions as part of their early mobilization care, using an Oculus Rift HMD and adaptive software (WalkinVR) that promoted full gameplay in bed. The Rift was plugged into a gaming laptop that was set up on a table within the patient's room before each session. The intervention was delivered by an adapted exercise professional and supervised by a physical therapist. Patients had access to a variety of active games (eg, boxing, rhythmic movement to music, and exploratory adventure) and nonactive games (eg, racing and narrative adventure). Gaming sessions were scheduled between usual care, when tolerable and requested by the participant. The interventionist and therapists took audio-recorded and written notes after completing each gaming session. These data were analyzed and presented in a narrative format from the perspective of the research team. RESULTS: Case 1 participated in 4 gaming sessions, with an average of 18 minutes (SD 11) per session. Case 2 participated in 2 sessions, with an average of 35 minutes (SD 7) per session. Both cases were capable of performing active gaming at a moderate level of exercise intensity, as indicated by their heart rate. However, their health and symptoms fluctuated on a daily basis, which prompted the gameplay of adventure or nonactive games. Gameplay appeared to improve participants' affect and alertness and motivate them to be more engaged in early mobilization therapy. Gameplay without the WalkinVR software caused several usability issues. There were no serious adverse events, but both cases experienced symptoms based on their condition. CONCLUSIONS: The findings of this study suggest that VR gaming with HMDs and adaptive software is likely a feasible supplement to usual care for adolescents within the PICU, and these findings warrant further investigation. Recommendations for future studies aimed at incorporating VR gaming during early mobilization are presented herein.

Ending the Chase: Experiences of Rural Individuals with Opioid Use Disorder.

BACKGROUND: The US remains in the midst of an opioid overdose epidemic. Given that rural populations have higher rates of opioid-related morbidity and mortality, it is important to understand the factors that perpetuate opioid use and facilitate recovery in rural communities. Purpose: To explore experiences of individuals living with opioid use disorder (OUD) and to analyze these experiences within a broader sociocultural context. Methods: Using a descriptive, qualitative design, we interviewed twenty purposefully sampled participants. We used thematic content analysis to identify themes and patterns. Results: As participants became dependent, the chase for opioids was to avoid the pain of withdrawal. Waking up sick became an everyday experience, leading to a lifestyle of hustling. The pursuit of opioids resulted in physical, social, emotional, and legal consequences that fed a cycle of stigmatization. In recovery, participants learned to embrace a new way of thinking, allowing them to make new choices. The strong influence of family and community in their lives was a key factor in their resiliency and opioid use experiences. Conclusions: Individuals with OUD are impacted by intersecting social, physical, economic and policy factors that reinforce the expansion of the opioid epidemic rurally. This study provided a voice to rural individuals with opioid use disorder, a group often underrepresented in the literature, providing an understanding of their struggles and the unique sociocultural dynamics that exist in rural northern New Mexico. The complex sociocultural relationships to family and community represent important adaptive factors that could support individual healing and community transformation.

Quality Improvement Methodology to Optimize Safe Early Mobility in a Pediatric Intensive Care Unit.

Utilization of robust quality improvement methodology in conjunction with traditional interventions to enhance an Early Mobility program (EMP) in a tertiary pediatric intensive care unit (PICU). METHODS: EMP was implemented in our PICU in May 2017. The percentage of appropriate physical and occupational therapist consults were determined. We also evaluated the activity levels received by the patient and the levels for which they qualified based on their medical condition. Failure Modes and Effects Analysis (FMEA) was performed to identify potential complications related to the mobilization of critically ill children. We created 4 simulation scenarios based on FMEA prioritized results. RESULTS: After the implementation of EMP, appropriate physical and occupational therapist consults significantly increased (P < 0.0001). However, most patients still failed to receive the optimal level of activity recommended by protocol. This failure was partly due to concern for safety events during mobilization. FMEA identified vital sign changes [Risk Priority Number (RPN) 97.8], staff injury (RPN 64), and pain/anxiety (RPN 60.5) as potential safety events. We performed various in-situ simulation sessions based on these potential events. In post-simulation evaluations, 100% of participants agreed that the simulation experience would improve their performance in the actual clinical setting. Feedback from simulations led to the development of an EM patient safety checklist and clinical pathway. CONCLUSIONS: We describe a novel technique of using FMEA to develop scenarios that simulate potential adverse events to optimize safe EM in PICU. An EM checklist and pathway can guide in the implementation of safe EMP.

Opioid use is Associated with ICU Delirium in Mechanically Ventilated Children.

INTRODUCTION: Pediatric delirium is a significant problem when encounterd in an intensive care unit (ICU). The pathophysiology of pediatric delirium is complex and the etiology is typically multifactorial. Even though various risk factors associated with pediatric delirium in a pediatric ICU have been identified, there is still a paucity of literature associated with the condition, especially in extremely critically ill children, sedated and mechanically ventilated. AIM OF THE STUDY: To identify factors associated with delirium in mechanically ventilated children in an ICU. MATERIAL AND METHODS: This is a single-center study conducted at a tertiary care pediatric ICU. Patients admitted to the pediatric ICU requiring sedation and mechanical ventilation for >48 hours were included. Cornell Assessment of Pediatric Delirium scale was used to screen patients with delirium. Baseline demographic and clinical factors as well as daily and cumulative doses of medications were compared between patients with and without delirium. Firth's penalized maximum likelihood logistic regression was used on a priori set of variables to examine the association of potential factors with delirium. Two regression models were created to assess the effect of daily medication doses (Model 1) as well as cumulative medication doses (Model 2) of opioids and benzodiazepines. RESULTS: 95 patient visits met the inclusion criteria. 19 patients (20%) were diagnosed with delirium. Older patients (>12 years) had higher odds of developing delirium. Every 1mg/kg/day increase in daily doses of opioids was associated with an increased risk of delirium (OR=1.977, p=0.017). Likewise, 1 mg/kg increase in the cumulative opioid dose was associated with a higher odds of developing delirium (OR=1.035, p=0.022). Duration of mechanical ventilation was associated with the development of delirium in Model 1 (p=0.007). CONCLUSIONS: Age, daily and cumulative opioid dosage and the duration of mechanical ventilation are associated with the development of delirium in mechanically ventilated children.

Overcoming Barriers: Individual Experiences Obtaining Medication-Assisted Treatment for Opioid Use Disorder.

Medication-assisted treatment (MAT) for opioid use disorder (OUD) is accessed half as often in rural versus urban areas in the United States. To better understand this disparity, we used a qualitative descriptive approach to explore the experiences of individuals with OUD seeking MAT in rural New Mexico. Guided interviews were conducted with 20 participants. The frameworks of critical social theory, intersectionality theory, and the brain opioid theory of social attachment were used to guide data analysis and interpretation. Thematic content analysis derived five major themes which identified novel barriers and facilitators to MAT success, including a perceived gender disparity in obtaining MAT, challenges in building a recovery-oriented support system, and the importance of navigating a new normal social identity. This deeper knowledge of the experiences and perspectives of rural individuals with OUD could serve to address the rural-urban MAT disparity, leading to enhanced recovery capacity and transformative policies.

Hypoglycemia in patients with congenital muscle disease.

BACKGROUND: Only a few small studies have previously reported episodes of hypoglycemia in children with neuromuscular diseases; however, there has been no broader investigation into the occurrence of hypoglycemia in children with congenital muscle disease (CMD). METHODS: Pediatric patients enrolled in the CMD International Registry (CMDIR) with a history of hypoglycemia were included in this retrospective review. Hypoglycemic episodes and associated clinical and biochemical characteristics were characterized. RESULTS: Ten patients with CMD (5 with LAMA2-related muscular dystrophy) reported at least one episode of hypoglycemia beginning at an average age of 3.5 years. Predominant symptoms included altered mental status and nausea/vomiting, and laboratory studies demonstrated metabolic acidosis and ketonuria, consistent with ketotic hypoglycemia. CONCLUSION: Patients with CMD may have an increased risk of hypoglycemia during fasting, illness, or stress due to their relatively low muscle mass and hence, paucity of gluconeogenic substrate. Clinicians should therefore maintain a high index of suspicion for hypoglycemia in this high-risk patient population and caregivers should routinely be trained to recognize and treat hypoglycemia.

Introduction to "health informatics, healthcare quality and safety, and healthcare simulation: the new triad to advance healthcare operations".

This special themed international issue explores the multiple facets of health informatics, healthcare quality and safety, and healthcare simulation from different parts of the world. The papers in this issue fall into two broad themes. The first theme uses the intersection to address better management of care including physical design layout. The second theme examines innovative uses of the triad to prevent critical and non-critical safety events. The collection of papers culminates with a position paper reporting on the interdependence that is emerging as an important triad for research and practice within medical education, system development and testing, and teamwork and communication and concludes with reducing imprecision and factual errors in handoffs. Findings from the special collection of papers can inform managers and leaders on advancing operations in healthcare settings.

Development of a computerized paediatric intensive care unit septic shock pathway: improving user experience.

The purpose of this study was to understand the user experience with a computerized septic shock protocol relative to the workflow of Paediatric Intensive Care Unit clinicians. The need for data-driven, condition-specific, computerized protocols in the intensive care unit helps improve decision-making at the bedside. PICU clinicians were interviewed and given pre-and post-implementation surveys asking their opinions on the current PICU septic shock protocol, as well as the current electronic health record being used at [Paediatric Academic Medical Center]. User preferences guided adjustments toward improved usability of the septic shock protocol. Computerized Physician Order Entry, a critical component of the septic shock protocol, allows for more streamlined processes, more complete records, and more time to care for patients. This study revealed that although clinicians had an unfavorable view of the EHR in general, the computerized septic shock protocol was very well-received with an overall usability score of 82.

Optimization of Orthopedic Surgical Instrument Trays: Lean Principles to Reduce Fixed Operating Room Expenses.

BACKGROUND: Optimization of surgical instrument trays improves efficiency and reduces cost. The purpose of this study is to assess the economic impact of optimizing orthopedic instrument trays at a tertiary medical center. METHODS: Twenty-three independent orthopedic surgical instrument trays at a single academic hospital were reviewed from 2017 to 2018. Using Lean methodology, surgeons agreed upon the fewest number of instruments needed for each of the procedure trays. Instrument usage counts, cleaning times, room turnover times, tray weight, holes in tray wrapping, wet trays, and time invested to optimize each tray were tracked. Cost savings were calculated. Student's t-test was used to determine statistical significance, with P < .05 considered significant. RESULTS: The mean instrument usage before and after Lean optimization was 23.4% and 54.2% (P < .0001). By Lean methods, 433 of 792 instruments (55%) were removed from 11 unique instrument trays (102 total trays), resulting in a reduction of 3520 instruments. Total weight reduction was 574.3 pounds (22%), ranging from 2.1-16.2 pounds per tray. The number of trays with wrapping holes decreased from 13 to 1 (P < .0001). The process of examining and removing instruments took an average of 7 minutes 35 seconds per tray. The calculated total annual savings was $270,976 (20% overall cost reduction). CONCLUSION: In addition to substantial cost savings, tray optimization decreases tray weights and cleaning times without negatively impacting turnover times. Lean methodology improves efficiency in instrument tray usage, and reduces hospital cost while encouraging surgeon and staff participation through continuous process improvement. LEVEL OF EVIDENCE: Economic Quality Improvement, Level III.