Outcomes for Pediatric Oncology and Hematopoietic Stem Cell Transplantation Patients Who Undergo Tracheostomy Placement: A Pediatric Health information System Database Cohort Study, 2009-2020.

OBJECTIVES: To describe the epidemiology, surgical complications, and long-term outcomes after tracheostomy in pediatric oncology and/or hematopoietic stem cell transplantation (HSCT) patients in U.S. Children's Hospitals. DESIGN: Retrospective cohort from the Pediatric Health information System (PHIS) database, 2009-2020. SETTING: The PHIS dataset incorporates data from 48 pediatric hospitals in the Children's Hospital Association. PATIENTS: Patients 0-21 years old with an oncologic diagnosis and/or underwent HSCT, received a tracheostomy, and were discharged from hospital between January 1, 2009, and December 31, 2020. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 1061 patients included in the dataset, and 217 (20.5%) had undergone HSCT. The annual prevalence in tracheostomy usage did not change over the study period. The majority of patients (62.2%) underwent tracheostomy early (< 30 d) in the admission and those who underwent the procedure later (> 90 d) had a significant increase in mortality (52.6% vs. 17.6%; p < 0.001) and mechanical ventilation (MV) at discharge (51.9% vs. 24.5%; p < 0.001) compared with the early tracheostomy patients. Complications reported included tracheostomy site bleeding (< 1%) and infection (24%). The overall rate of MV at discharge was 32.6% and significantly associated with chronic lung (adjusted odds ratio [OR], 1.54; 95% CI, 1.03-2.32) and acute lung disease (OR, 2.18; 95% CI, 1.19-3.98). The overall rate of mortality was 19.6% within the cohort and significantly associated with HSCT (OR, 5.45; 95% CI, 3.88-7.70), diagnosis of sepsis (OR, 2.09; 95% CI, 1.28-3.41), and requirement for renal replacement therapy (OR, 2.76; 95% CI, 1.58-4,83). CONCLUSIONS: This study demonstrated a static prevalence of tracheostomy placement in the cohort population relative to the increasing trends in other reported groups. Regardless of underlying diagnosis, the study patients incurred substantial morbidity and mortality. However, tracheostomy specific complication rates were comparable with that of the general pediatric population and were not associated with increased odds of mortality within this population.

Safety of the immediate use of nonsteroidal anti-inflammatory drugs after adult craniotomy for tumor.

OBJECTIVE: Poor pain control has a negative impact on postoperative recovery and patient satisfaction. However, overzealous pain management, particularly with opioids, can confound serial neurological assessments, increase morbidity, and predispose patients to long-term dependence. Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in treating postoperative pain and can limit opioid intake, but their use has been limited in patients undergoing craniotomy for brain tumor resection due to concerns of an increased hemorrhage risk. Herein, the authors aim to 1) address the safety of NSAID use in the immediate postoperative setting and 2) determine whether NSAID administration decreases opioid use following craniotomy for tumor resection in adult patients. METHODS: The authors conducted a retrospective cohort study of patients 18 years and older with an estimated glomerular filtration rate ≥ 60 ml/min/body surface area who had undergone craniotomy for tumor resection at their institution between 2019 and 2021. NSAID use in the first 48 hours following surgery was recorded. Primary outcomes were postoperative hemorrhage requiring a return to the operating room before hospital discharge and within 30 days of surgery. Secondary outcomes were more-than-minimal hemorrhage that did not require reoperation, acute kidney injury, and total opioid use within 48 hours after craniotomy. RESULTS: Among 1765 reviewed patient records, 1182 were eligible for inclusion in this analysis. Amid these records were 114 patients (9.6%) who had received at least one dose of an NSAID within 48 hours of their craniotomy. Four (0.3%) patients experienced bleeding requiring a return to operating room, one of whom was from the NSAID-treated group (RR 3.12, 95% CI 0.33-29.77, p = 0.30). No significant difference in nonoperative intracranial hemorrhage (RR 1.34, 95% CI 0.54-3.35, p = 0.53), postoperative acute kidney injury, or clinically significant extracranial bleeding was found between the NSAID and no-NSAID groups. Patients in the NSAID group had significantly higher oral morphine equivalent use (median 68 vs 30, p < 0.001). CONCLUSIONS: Postoperative NSAID use following craniotomy for tumor resection was not associated with an increased risk of hemorrhage requiring a return to the operating room. The authors noted higher opioid use in the patients treated with NSAIDs, which may reflect underlying reasons for the decision to treat patients with NSAIDs in the immediate postoperative period. These data warrant further investigation of NSAIDs as a safe, opioid-sparing postoperative pain management strategy in patients with normal kidney function who are undergoing intracranial tumor resection.

Mechanical hyperalgesia and neuropathic pain qualities impart risk for chronic postoperative pain after total knee replacement.

Total knee replacement (TKR) is the gold-standard treatment for end-stage chronic osteoarthritis pain, yet many patients report chronic postoperative pain after TKR. The search for preoperative predictors for chronic postoperative pain following TKR has been studied with inconsistent findings. This study investigates the predictive value of quantitative sensory testing (QST) and PainDETECT for postoperative pain 3, 6, and 12 months post-TKR. We assessed baseline and postoperative (3- and 6-months) QST measures in 77 patients with knee OA (KOA) and 41 healthy controls, along with neuropathic pain scores in patients (PainDETECT). QST parameters included pressure pain pressure threshold (PPT), pain tolerance threshold (PTT), conditioned pain modulation (CPM), and temporal summation (TS) using cuff algometry, alongside mechanical hyperalgesia, and mechanical temporal summation to repeated pinprick stimulation. Compared to healthy controls, KOA patients at baseline demonstrated hyperalgesia to pinprick stimulation at the medial OA-affected knee and cuff pressure on the ipsilateral calf. Lower cuff algometry PTT and mechanical pinprick hyperalgesia were associated with baseline KOA pain intensity. Moreover, baseline pinprick pain hyperalgesia explained 25% of variance in pain intensity 12 months post-TKR and preoperative neuropathic pain scores also captured 30% and 20% of the variance in postoperative pain at 6- and 12-months, respectively. A decrease in mechanical pinprick hyperalgesia from before surgery to 3 months after TKR was associated with lower postoperative pain at the 12 months post-TKR follow-up, and vice-versa. Our findings suggest that preoperative pinprick hyperalgesia and PainDETECT neuropathic-like pain symptoms show predictive value for the development of chronic post-TKR pain.

An ERK5-PFKFB3 axis regulates glycolysis and represents a therapeutic vulnerability in pediatric diffuse midline glioma.

Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

Surgical resection of recurrent intramedullary subependymoma of the cervical spinal cord.

Spinal subependymomas (SE) are rare, often indolent benign tumors presenting most frequently as intramedullary tumors in the cervical spine or cervicothoracic junction. When symptomatic, patients often present with years of sensory changes, weakness, paresthesias, or bowel and bladder dysfunction. Preoperatively, SE are difficult to distinguish radiographically from ependymomas or astrocytomas; however, it is important to make the distinction intraoperatively as complete resection can be curative. Here the authors present a rare case of recurrent, symptomatic cervical subependymoma which underwent gross-total resection and discussion of management strategies and outcomes of all SE at their institution.

Operative Outcomes After Cervical Diffuse Idiopathic Skeletal Hyperostosis Fracture in the Elderly.

BACKGROUND: Cervical diffuse idiopathic skeletal hyperostosis (DISH) fractures are frequently unstable and carry significant risk of neurologic injury and death. Most patients with DISH fractures are elderly (>70 years) with significant comorbidities. We assessed factors that contribute to outcomes in elderly patients with cervical DISH fractures. METHODS: Elderly patients with cervical DISH fractures from 2008 to 2017 were included in this retrospective multi-institutional cohort study. Predictor variables included injury level, surgical approach, preinjury comorbidities, American Society of Anesthesiologists (ASA) score, American Spinal Injury Association (ASIA) impairment scale grade, preoperative anticoagulation status, and the subaxial cervical spine injury classification system (SLIC) score. Univariate and multivariate analyses were utilized to identify factors associated with 30-day mortality and ambulatory status at discharge. RESULTS: A total of 48 patients, mean age 74.7 years old (range 60-96), underwent cervical fixation for DISH fractures. Average SLIC score was 6.30 ± 1.2 (range 5-8), and most frequent fracture level was at C6 to -C7 (31.3%) followed by C7-T1 (25.0%). Forty (83.3%) patients underwent posterior fixation, 7 (14.6%) with anterior fixation, and 1 (2.1%) had combined approach. Ten (20.4%) patients died within 30 days of surgery. Multivariate analysis demonstrated that poorer preoperative ASIA grade (OR 2.35, P = 0.003, CI = 1.33-4.14) and ASA score >3 (P = 0.027) had increased risk of being nonambulatory at discharge. Higher SLIC score was associated with increased 30-day mortality (P = 0.021, CI = 1.20-9.60). CONCLUSIONS: Cervical DISH fractures can be highly unstable, for which instrumentation and fixation are indicated. Surgical decision-making should focus on preoperative ASIA grade, SLIC score, and ASA score. CLINICAL RELEVANCE: The study is relevant due to an aging poulation predisposed to cervical DISH fractures.

Predictors of first pass effect and effect on outcomes in mechanical thrombectomy for basilar artery occlusion.

INTRODUCTION: For patients undergoing endovascular thrombectomy (EVT), those who are recanalized with a successful single pass (first pass effect, FPE) have better functional outcomes than those who do not. There is a scarcity of data regarding predictors of FPE in basilar artery occlusion (BAO). We aim to determine what characteristics may predict FPE for posterior circulation thrombectomies in a cohort of patients undergoing EVT for BAO. METHODS: We reviewed prospectively-collected data for patients presenting to a comprehensive stroke center with BAO between December 2015 and April 2019. Patients were included in this study if they underwent manual aspiration thrombectomy for BAO. Patients were excluded if they had occlusions of the posterior cerebral or vertebral arteries or if they had tandem lesions. Patients were stratified by whether FPE or modified FPE (mFPE) was achieved, and multivariate logistic regression analyses were performed to identify predictors of FPE and the effect of FPE on clinical outcome. RESULTS: 100 patients with BAO underwent thrombectomy. Mean age was 64.7 ± 16.7, 42% were female, and median NIHSS was 20 (IQR 11-27). 33% met criteria for FPE and 60% for mFPE. Univariate analysis identified female gender, lack of IV-tPA use, pcASPECTS, atrial fibrillation, and hyperlipidemia as possible predictors of FPE. On multivariate analysis, age, pcASPECTs, atrial fibrillation, hyperlipidemia and IV-tPA use were not independent predictors of FPE or mFPE. Female gender was an independent predictor of mFPE (p = 0.02), but not FPE (p = 0.18). FPE was a predictor of mRS 0-2 at 90 days (p = 0.04). Predictors of mortality were age (p < 0.01), baseline NIHSS (p < 0.01) and mFPE (p = 0.01). CONCLUSION: In this cohort analysis of 100 patients with basilar artery occlusion undergoing manual aspiration thrombectomy, female gender was associated with mFPE but not FPE. Previously-reported anterior circulation FPE predictors including age, ASPECTS and atrial fibrillation were not predictors of FPE in this cohort of patients with BAO.

Outcomes for Children With Pulmonary Hypertension Undergoing Tracheostomy Placement: A Multi-Institutional Analysis.

OBJECTIVES: To describe epidemiology, interventions, outcomes, and the health services experience for a cohort of children with pulmonary hypertension (PH) who underwent tracheostomy placement and to identify risk factors for inhospital mortality and 30-day readmissions. DESIGN: Retrospective cohort study of the Pediatric Health Information System database. SETTING: Thirty-seven freestanding U.S. children's hospitals. PATIENTS: Patients 31 days to 21 years old who were discharged from the hospital between January 1, 2009, and December 31, 2017, with a diagnosis of primary or secondary PH, and who underwent tracheostomy placement. Outcomes were examined over a 2-year period from the time of discharge from the index encounter. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were 793 patients with PH who underwent tracheostomy placement. The overall inhospital mortality rate was 23.7%. Secondary PH due to congenital heart disease (CHD) was significantly associated with overall inhospital mortality (adjusted odds ratio [OR], 2.36; 95% CI, 1.38-4.04). The rate of 30-day readmissions for patients over the 2-year follow-up period was 33.3%. Tracheostomy during the index encounter and the diagnosis of secondary PH due to CHD were significantly associated with lower rates of 30-day readmissions (adjusted OR, 0.34; 95% CI, 0.19-0.61; and adjusted OR, 0.43; 95% CI, 0.24-0.77, respectively). CONCLUSIONS: In the context of expanding utilization of tracheostomy and long-term ventilation, children with PH are among the highest risk cohorts for extended and repeated hospitalization and death. Tracheostomy placement during the index encounter was associated with fewer 30-day readmissions over the 2-year follow-up period. Further understanding of which subgroups may benefit from earlier intervention and which subgroups are at highest risk may offer important clinical insight when considering optimal timing of tracheostomy and may enhance informed decision-making for all stakeholders.

Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome.

Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.

Results in clinical practice in the treatment of severe eosinophilic asthma with mepolizumab: a real-life study.

OBJECTIVE: Add-on therapy with monoclonal antibodies is the recommended therapy for severe asthmatic patients refractory to maintenance treatment. In randomized control trials, mepolizumab reduced the number of exacerbations, the need of oral corticosteroids (OCS), increased asthma control, and lung function in a population of uncontrolled severe eosinophilic asthmatic patients. In this piece of work, we aimed to assess mepolizumab efficacy and safety in a cohort of patients with severe eosinophilic asthma in real-life conditions. METHODS: A retrospective study was carried out at eight hospitals from Asturias (Spain). The sample included patients treated with mepolizumab from 1 January 2016 to 31 March 2019. Demographic and clinical variables were collected, including OCS use, asthma control, lung function, and exacerbation rate. RESULTS: Sixty-nine patients (72% women) with mean age 56 ± 13 years were included. Annual exacerbation rate decreased from 4.7 (SD 3.7) to 1.3 (SD 2.5) (p < 0.001). The number of patients requiring OCS treatment decreased from 25 patients (36%, mean prednisone dose = 18 mg/day) to 13 patients (19%, mean prednisone dose = 9 mg/day) (p < 0.001). Twelve patients (48%) stopped OCS treatment. Forced expired volume in one second (FEV1) as percentage increased from 68% (SD 20) to 76% (SD 21) (p < 0.001). Fifty-six patients (81%) were considered responders to mepolizumab. No serious adverse events were detected during the study period. CONCLUSIONS: Overall, this study demonstrates mepolizumab efficacy and safety in a cohort of patients with uncontrolled severe eosinophilic asthma in routine clinical practice.

Seven-year follow-up of durability and safety of AAV CNS gene therapy for a lysosomal storage disorder in a large animal.

Delivery of adeno-associated viral vectors (AAVs) to cerebrospinal fluid (CSF) has emerged as a promising approach to achieve widespread transduction of the central nervous system (CNS) and peripheral nervous system (PNS), with direct applicability to the treatment of a wide range of neurological diseases, particularly lysosomal storage diseases. Although studies in small animal models have provided proof of concept and experiments in large animals demonstrated feasibility in bigger brains, there is not much information on long-term safety or durability of the effect. Here, we report a 7-year study in healthy beagle dogs after intra-CSF delivery of a single, clinically relevant dose (2 × 1013 vg/dog) of AAV9 vectors carrying the canine sulfamidase, the enzyme deficient in mucopolysaccharidosis type IIIA. Periodic monitoring of CSF and blood, clinical and neurological evaluations, and magnetic resonance and ultrasound imaging of target organs demonstrated no toxicity related to treatment. AAV9-mediated gene transfer resulted in detection of sulfamidase activity in CSF throughout the study. Analysis at tissue level showed widespread sulfamidase expression and activity in the absence of histological findings in any region of encephalon, spinal cord, or dorsal root ganglia. Altogether, these results provide proof of durability of expression and long-term safety for intra-CSF delivery of AAV-based gene transfer vectors encoding therapeutic proteins to the CNS.

Treatment of skeletal and non-skeletal alterations of Mucopolysaccharidosis type IVA by AAV-mediated gene therapy.

Mucopolysaccharidosis type IVA (MPSIVA) or Morquio A disease, a lysosomal storage disorder, is caused by N-acetylgalactosamine-6-sulfate sulfatase (GALNS) deficiency, resulting in keratan sulfate (KS) and chondroitin-6-sulfate accumulation. Patients develop severe skeletal dysplasia, early cartilage deterioration and life-threatening heart and tracheal complications. There is no cure and enzyme replacement therapy cannot correct skeletal abnormalities. Here, using CRISPR/Cas9 technology, we generate the first MPSIVA rat model recapitulating all skeletal and non-skeletal alterations experienced by patients. Treatment of MPSIVA rats with adeno-associated viral vector serotype 9 encoding Galns (AAV9-Galns) results in widespread transduction of bones, cartilage and peripheral tissues. This led to long-term (1 year) increase of GALNS activity and whole-body correction of KS levels, thus preventing body size reduction and severe alterations of bones, teeth, joints, trachea and heart. This study demonstrates the potential of AAV9-Galns gene therapy to correct the disabling MPSIVA pathology, providing strong rationale for future clinical translation to MPSIVA patients.

Safety and Efficacy of Balloon Kyphoplasty for Vertebral Fractures With Posterior Wall Disruption.

BACKGROUND: Percutaneous balloon kyphoplasty (BK) is widely accepted as both a safe and effective method for the treatment of symptomatic benign vertebral compression fractures (VCFs) of the thoracic and lumbar spines. A disruption in the posterior wall of the affected vertebra is often considered to be a relative or an absolute contraindication to BK. This study was performed to determine the safety as well as the efficacy of BK for vertebral body compression fractures associated with posterior wall disruption. METHODS: This was a retrospective, nonrandomized clinical cohort investigation of patients with VCF and posterior wall disruption treated with BK between 2010 and 2018. All cases were performed using a bipedicular technique. Each case was examined for cement leakage, anterior vertebral body height restoration, improvement in pain (determined by VAS) from baseline and 6-week postprocedure, and clinical sequelae from cement leakage. RESULTS: Ninety-eight consecutive patients with 157 VCF levels who underwent BK were evaluated. There was a significant improvement in anterior vertebral height, vertebral wedge angle, and local kyphotic angle in all cases. The mean preoperative VAS improved from 8.7 preprocedure to 2.5 postprocedure (P = .001). There were 14 (9%) cases with asymptomatic cement leakage outside of the vertebral body, and no patients experienced postprocedure neurological symptoms at the 6-week follow up. CONCLUSIONS: BK in the setting of posterior wall disruption was found to be a safe and highly effective treatment for patients with benign compression fractures. Posterior wall disruption should not be considered an absolute contraindication to BK.

The Evolution of Telehealth From Pre-COVID-19 Pandemic Through A Hybrid Virtual Care Delivery Model: A Pediatric Hospital's Journey.

The COVID-19 pandemic transformed care delivery and influenced telehealth adoption by rehabilitation professionals and their patients. The purpose of this paper is to describe a pediatric health system's telehealth services pre-pandemic and how those services were scaled during the pandemic. A secondary aim is to provide a roadmap for the operational delivery of telehealth and rehabilitation services, including transition to a hybrid care delivery model. Findings suggested that telehealth can be rapidly scaled to address patient healthcare needs for an early intervention population during a pandemic. Telehealth use during the pandemic helped ensure continuity of care and likely reduced the risk of exposure to patients and staff to the virus. Benefits included enhanced access to care, and savings in time and money for families. Interestingly, as the pandemic declined, the use of telehealth services declined due to patient preference, with many families opting to request a return to in-person care.

'The face of the programme': How local clinicians shape decisions about eligibility for a national caregiver support programme in the USA.

OBJECTIVE: To examine the causes of variation for determining clinical eligibility for a national caregiver programme in the US Veterans Health Administration (VHA) and so help inform standardization of clinical eligibility assessment for support and establish conditions for more consistent caregiver experiences across the USA. METHODS: We used mixed methods, including a national survey of caregiver support coordinators (CSCs) across VHA medical centres, semi-structured interviews with a purposive sample of 53 CSCs and interdisciplinary team members, and observations of four VHA medical centre sites. RESULTS: A majority (70%) of CSCs across VHA medical centres reported that they used interdisciplinary teams to conduct assessments. Interdisciplinary teams were seen to help mitigate potential harm to therapeutic relationships from eligibility decisions. Survey respondents reported using a range of assessment tools provided by the national VHA Caregiver Support Program office, but participants expressed concerns that the tools did not necessarily effectively assess clinical need. Some local sites had developed innovative person-centered approaches, in which the assessment process provided an opportunity to assess veterans' holistic clinical needs, in contrast to a programme-centered approach, which focused on assessing whether veterans/their caregivers meet eligibility criteria. CONCLUSION: Discretion by those involved in making decisions on programme eligiblity is important for implementing a national social services programme based on clinical need. Interdisciplinary teams can help mitigate potential harm to therapeutic relationships. Discretion allows for innovation. This work has implications for setting policy in other programme contexts in which applying eligibility criteria requires clinical judgement.