Search

COVID-19 prompted unprecedented disruptions to schools with challenges particularly severe for high-poverty remote rural schools. This case study recounts the story of a rural school that had participated in a research–practice partnership (RPP) multi-year improvement effort prior to the pandemic and documents the ways the RPP and the school-based improvement team worked to navigate pandemic-related disruptions. This case study provides educational leaders with insights into ways to surmount challenges and innovate especially during times of significant disruption and provides prompts to consider with regard to the use of RPP support and improvement science-based processes and tools.

Objectives/hypothesis Children who do not require oxygen beyond 3 hours after surgery and pass a sleep room air challenge (SRAC) are safe for discharge regardless of polysomnogram (PSG) results or comorbidities. Study design Cross-sectional prospective study. Methods All children observed overnight undergoing an adenotonsillectomy for obstructive sleep-disordered breathing were prospectively recruited. Demographic, clinical, and PSG characteristics were stratified by whether the patient had required oxygen beyond 3 hours postoperatively (prolonged oxygen requirement [POR]) and compared using t test, chi-squared test, or Fisher's exact test depending on distribution. Optimal cut points for predicting POR postsurgery were calculated using receiver operating characteristic curves. The primary analysis was performed on the full cohort via logistic regression using POR as the outcome. Significant characteristics were analyzed in a logistic regression model, with significance set at P Results A total of 484 participants met the inclusion criteria. The mean age was 5.65 (standard deviation = 4.02) years. Overall, 365 (75%) did not have a POR or any other adverse respiratory event. In multivariable logistic regression, risk factors for POR were an asthma diagnosis (P Conclusions In conclusion, all children in our study who are off oxygen within 3 hours of surgery and passed a SRAC were safe for discharge from a respiratory standpoint regardless of age, obesity status, asthma diagnosis, and obstructive apnea/hypopnea index. Additional investigations are necessary to confirm our findings. Level of evidence 3 Laryngoscope, 2021.

Background Risk prediction models for time-to-event outcomes play a vital role in personalized decision-making. A patient’s biomarker values, such as medical lab results, are often measured over time but traditional prediction models ignore their longitudinal nature, using only baseline information. Dynamic prediction incorporates longitudinal information to produce updated survival predictions during follow-up. Existing methods for dynamic prediction include joint modeling, which often suffers from computational complexity and poor performance under misspecification, and landmarking, which has a straightforward implementation but typically relies on a proportional hazards model. Random survival forests (RSF), a machine learning algorithm for time-to-event outcomes, can capture complex relationships between the predictors and survival without requiring prior specification and has been shown to have superior predictive performance. Methods We propose an alternative approach for dynamic prediction using random survival forests in a landmarking framework. With a simulation study, we compared the predictive performance of our proposed method with Cox landmarking and joint modeling in situations where the proportional hazards assumption does not hold and the longitudinal marker(s) have a complex relationship with the survival outcome. We illustrated the use of the RSF landmark approach in two clinical applications to assess the performance of various RSF model building decisions and to demonstrate its use in obtaining dynamic predictions. Results In simulation studies, RSF landmarking outperformed joint modeling and Cox landmarking when a complex relationship between the survival and longitudinal marker processes was present. It was also useful in application when there were several predictors for which the clinical relevance was unknown and multiple longitudinal biomarkers were present. Individualized dynamic predictions can be obtained from this method and the variable importance metric is useful for examining the changing predictive power of variables over time. In addition, RSF landmarking is easily implementable in standard software and using suggested specifications requires less computation time than joint modeling. Conclusions RSF landmarking is a nonparametric, machine learning alternative to current methods for obtaining dynamic predictions when there are complex or unknown relationships present. It requires little upfront decision-making and has comparable predictive performance and has preferable computational speed.

In the United States, advances in information technology and globalization present new social and political terrain for citizens to navigate. Preparing well-rounded young adults who are ready to me...

Patients who have undergone Fontan palliation have reduced exercise tolerance measured by maximal oxygen consumption (VO2 max). Declining exercise capacity is associated with increased morbidity and mortality. The impact of hemodynamics and other variables on this population’s functional status is not well understood. This study sought to identify variables that predict low VO2 max in Fontan patients living at moderate altitude (5,000–8,000 feet). We performed a retrospective cohort study of 44 adult Fontan patients living at moderate altitude who had undergone cardiopulmonary exercise testing (CPET) and cardiac catheterization. We evaluated hemodynamic parameters measured during catheterization, imaging results, and laboratory studies for correlation with VO2 max measured during CPET. Our study cohort (median age 30 years, 52% female) had exercise impairment with mean VO2 max of 21.6 mL/kg/min. Higher trans-pulmonary gradient (TPG) (p

Background:Milrinone is a phosphodiesterase type 3 inhibitor that results in a positive inotropic effect in the heart through an increase in cyclic adenosine monophosphate. The purpose of this study was to evaluate circulating cyclic adenosine monophosphate and milrinone concentrations in milrinone treated paediatric patients undergoing congenital heart surgery.Methods:Single-centre prospective observational pilot study from January 2015 to December 2017 including children aged birth to 18 years. Milrinone and circulating cyclic adenosine monophosphate concentrations were measured at four time points through the first post-operative day and compared between patients with and without low cardiac output syndrome, defined using clinical and laboratory criteria.Results:Fifty patients were included. Nine (18%) developed low cardiac output syndrome. For all patients, 22% had single ventricle heart disease. The density and distribution of cyclic adenosine monophosphate concentrations varied between those with and without low cardiac output syndrome but were not significantly different. Milrinone concentrations increased in all patients. Paired t-tests demonstrated an increase in circulating cyclic adenosine monophosphate concentrations during the post-operative period among patients without low cardiac output syndrome.Conclusions:In this prospective observational study, circulating cyclic adenosine monophosphate concentrations increased in those without low cardiac output syndrome during the first 24 post-operative hours and milrinone concentrations increased in all patients. Further study of the utility of cyclic adenosine monophosphate concentrations in milrinone treated patients is necessary.

Clinicians have few tools to predict the risk of alloimmune injury that would guide immunosuppression management in renal transplant patients. We evaluated human leukocyte antigen (HLA)-DR/DQ molecular mismatch to predict de novo donor-specific antibodies (DSAs) during the first year of transplant and explored how differences in tacrolimus exposure may modulate this risk. HLA-DR and -DQ eplet mismatches were determined between 444 donor-recipient pairs in Denver, Colorado between 2007 and 2013. Previously defined mismatch thresholds stratified recipients into low- (N = 119), intermediate- (N = 153), and high- (N = 172) risk categories. The area under the curve for DSA at 1 year was 0.84 and 0.82 for HLA-DR and HLA-DQ eplet mismatches, respectively. Compared to low-risk patients, there was a graded increase in risk of DR/DQ DSA in intermediate (HR 15.39, 95% CI 2.01-118.09, p = .009) and high-risk (HR 23.81, 95% CI 3.17-178.66, p = 0.002) categories. Intermediate- and high-risk patients with a mean tacrolimus6 ng/ml versus8 ng/ml had increased risk of DR/DQ DSA at 1 year (HR 2.34, 95% CI 1.05-5.22, p = .04). HLA molecular mismatch represents a reproducible, objective, and clinically relevant tool to stratify patients by alloimmune risk and may help guide personalized immunosuppression management.

Survivors of palliative surgery for single ventricle heart disease (SVHD) are at risk of poor neurodevelopmental outcomes and reduced exercise capacity. In healthy populations, reduced exercise capacity is related to decreased cognition suggesting a possible relationship between exercise capacity and neurodevelopment. Using cardiopulmonary exercise testing (CPET) and neuropsychological testing (NPT) as indicators of exercise capacity and neurodevelopment, respectively, we hypothesized that in SVHD, higher CPET measures are related to better NPT performance. Patients were retrospectively identified. CPET variables included VO2max, anaerobic threshold, peak heart rate, ventilatory efficiency, and respiratory exchange ratio. NPT instruments were divided into domains measuring attention, executive functioning, adaptive functioning, and emotional functioning. Linear regression was used to test for associations between CPET and NPT. 23 subjects with SVHD met inclusion criteria. On both CPET and NPT, the cohort scored worse than healthy, age-matched subjects. Higher VO2max and anaerobic threshold were associated with better parent-rated overall adaptive functioning (p = 0.01 and p = 0.02, respectively). Higher peak heart rate was related to better sustained visual attention (p = 0.01). In SVHD, CPET measures indicating better exercise capacity were positively associated with a subset of scores on NPT. Larger, multisite studies implementing cardiorespiratory fitness intervention and incorporating cognitive outcome measures will be needed to better characterize the relationship between neurodevelopment and functional capacity in this population. Results may assist in providing anticipatory guidance and optimizing post-Fontan developmental trajectories.

Background/Context In the field of education, the lens of agency has provided a valuable conceptual alternative to deterministic portrayals of schools as oppressive institutions where teachers and students have little power over the conditions in which they teach and learn. A number of studies have investigated teacher and student agency, but few have explored the relationships between the two, particularly in regard to how teacher and student agency relate in high-need and high-diversity contexts with exemplary student graduation outcomes. Purpose/Focus of the Study In an effort to address the paucity of research investigating the relationships of teacher and student agency, this analysis draws on seven qualitative case studies of secondary schools achieving a trend of above-predicted (i.e., odds-beating) graduation outcomes. We pursued the overarching research question: What are the relationships between teacher and student agency in odds-beating schools? Setting The study took place in a purposeful sample of odds-beating secondary schools identified through multiple regression analyses. The sample included schools in rural, suburban, and more urban communities and were distributed across various geographic regions in the state of New York. All schools shared a pattern of above-predicted graduation outcomes, taking into account student demographic factors (percentage of students economically disadvantaged, African American/Black, Hispanic/Latinx, and English language learners). All schools met the criteria of being within the normal range for wealth ratio as well. Research Design This qualitative multiple case study focused on data generated from interviews and focus groups with 302 participants, including teachers, student support specialists, and school and district leaders, as well as field notes gathered during guided school tours, and documents. These data were analyzed using qualitative comparative analysis methods in multiple phases of deductive and inductive coding. Conclusions Study findings indicate that when teachers are offered opportunities to act as agents, they tend to offer opportunities to their students similarly. This research also suggests that affordances for teachers to assert agency can mitigate the constraining effects of state accountability system compliance-oriented practices. We conclude that teacher and student reciprocal agency merits further study and offers theoretical insights of particular import in high-needs and high-diversity school contexts.

Despite recent gains, Latinx students still lag behind other subgroups on measures of academic attainment. Explanations for this gap have ranged from pernicious deficit ideologies to deterministic ...

Low-grade glioma (LGG) represent the most common pediatric central nervous system tumor. When total surgical resection is not feasible, chemotherapy is first-line therapy in children. Multiple pediatric LGG chemotherapy regimens have been investigated with variable 2-year event free survival (EFS) rates of 39–69%. To date, treatment of pediatric LGG with a carboplatin and vinblastine (C/VBL) chemotherapy regimen has only been evaluated in a phase 1 dose-finding study. A retrospective review of pediatric patients with LGG who were treated with C/VBL at Children’s Hospital of Colorado or Akron Children’s Hospital from 2011 to 2017 was conducted. Data collected included patient demographics, tumor location, disease response, neurofibromatosis 1 (NF1) status, therapy duration and toxicities. Response to therapy was determined by objective findings on imaging and treating physicians' evaluation. Forty-six patients were identified for analysis, all of whom were chemotherapy-naive. Only five patients treated in this cohort had NF1. BRAF fusion was identified in 65% (22/34) of tested tumors. Best therapy response was partial response in nine patients and stable disease in twenty-five patients. Twelve patients had progressive disease. One-year, 3-year, and 5-year EFS probabilities for all patients were 69.6%, 39.4%, and 34.5%, respectively. Nine patients had admissions for febrile neutropenia and seven patients experienced one delay in chemotherapy due to neutropenia. Only two patients had to discontinue this chemotherapy regimen because of treatment-related toxicities [carboplatin allergy (n = 1) and vinblastine neuropathy (n = 1)]. C/VBL achieves similar EFS rates to other single-agent and combination cytotoxic chemotherapy regimens for pediatric LGG with manageable toxicities.

This multiple case study examines practices of educators in high schools called “odds-beaters”. These schools are exemplary in that they consistently achieve better-than-predicted graduation outcom...

Patients with congenital heart disease (CHD) who undergo cardiac procedures may become hemodynamically unstable. Predictive algorithms that utilize dense physiologic data may be useful. The compensatory reserve index (CRI) trends beat-to-beat progression from normovolemia (CRI = 1) to decompensation (CRI = 0) in hemorrhagic shock by continuously analyzing unique sets of features in the changing pulse photoplethysmogram (PPG) waveform. We sought to understand if the CRI accurately reflects changing hemodynamics during and after a cardiac procedure for patients with CHD. A transcatheter pulmonary valve replacement (TcPVR) model was used because left ventricular stroke volume decreases upon sizing balloon occlusion of the right ventricular outflow tract (RVOT) and increases after successful valve placement. A single-center, prospective cohort study was performed. The CRI was continuously measured to determine the change in CRI before and after RVOT occlusion and successful TcPVR. Twenty-six subjects were enrolled with a median age of 19 (interquartile range (IQR) 13-29) years. The mean (± standard deviation) CRI decreased from 0.66 ± 0.15 1-min before balloon inflation to 0.53 ± 0.16 (p = 0.03) 1-min after balloon deflation. The mean CRI increased from a pre-valve mean CRI of 0.63 [95% confidence interval (CI) 0.56-0.70] to 0.77 (95% CI 0.71-0.83) after successful TcPVR. In this study, the CRI accurately reflected acute hemodynamic changes associated with TcPVR. Further research is justified to determine if the CRI can be useful as an early warning tool in patients with CHD at risk for decompensation during and after cardiac procedures.

CD3-directed T cell engagers provide clinical benefit in a variety of hematologic cancers, but it remains unclear whether γδ T cells (GDT) are present at sufficient numbers to be similarly harnessed because they represent only 1-5% of the total T cell pool. The Vγ9Vδ2 T cell receptor is activated by a butyrophilin 2A1 and 3A1 (2A1/3A1) heterodimer as “signal 1”, together with costimulatory signaling through CD28 or NKG2D as “signal 2”. Here we evaluated the ability of a GDT engager (GADLEN) comprising the extracellular domains of 2A1/3A1 adjoined via an Fc to an antibody fragment targeting the CD20 antigen, to mediate target-cell depletion in vivo at physiologically relevant frequencies of GDT. A humanized mouse model was developed wherein human peripheral blood mononuclear cells (PBMC) were engrafted to NSG-IL15 mice and a high degree of human chimerism persisted for over 3 weeks, including a circulating pool of human GDT comprising 0.5 to 3% of total T cells. Across different human donors, the GDT effector to target B cell ratio varied from 1:1 to 1:46. Following treatment with a B cell-targeted GADLEN, rapid and dose-dependent depletion of over 95% of human B cells was achieved in the peripheral blood and spleen, even at E:T ratios of 1:46. Based on these data, a repeat-dose toxicology study was conducted in cynomolgus macaques across a dose range of 0.1 to 25 mg/kg with the CD20-targeted GADLEN. This study also demonstrated dose-dependent B cell depletion within 2 hours of infusion. Durable receptor occupancy was observed on CD20+ cells for over 7 days, whereas transient occupancy was observed on circulating cynomolgus Vγ9Vδ2 T cells. GDT represented approximately 1-3% of total T cells in cynomolgus macaques, and E:T ratios ranged from 1:7 to 1:49. All treatments were well tolerated, and no evidence of cytokine release syndrome nor any other toxicities were observed. Interestingly, in both humanized mice and non-human primates, the proliferation of GDT was not required to achieve B cell depletion. In fact, over several weeks, the circulating frequencies of cynomolgus Vγ9Vδ2 T cells remained stable, and no evidence of either proliferation or migration out of the blood was observed. These observations, together with the speed at which B cell depletion occurred, suggest that the Vγ9Vδ2 T cells eliminated the B cell pool by serial killing following treatment with the GADLEN. Despite a GDT frequency of less than 5% of total T cells in all these studies, Vγ9Vδ2 T cells achieved rapid depletion of target cells following treatment with the GADLEN, without evidence of toxicity, even at high doses. Collectively, these results indicate that low frequencies of GDT can be harnessed to achieve similar target-cell killing potential as the broader CD3+ T cell pool but with potentially less toxicity. Citation Format: Anne Y. Lai, Louis E. Gonzalez, Noah Murr, Karen Lenz, Derek Franklin, Kristen Campbell, Faraha Brewer, Arpita Patel, Kinsley Evans, Mahmud Hussein, Keith Wilson, George Fromm, Taylor H. Schreiber, Suresh de Silva. Rapid serial killing of target cells by Vγ9Vδ2 T Cells in cynomolgus macaques and humanized mice treated with a CD20-directed heterodimeric butyrophilin 2A1/3A1 fusion protein [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1815.

Opioid use disorder (OUD) is a major public health emergency in the United States. In 2020, 2.7 million individuals had an OUD. Medication for opioid use disorder is the evidence-based, standard of care for treating OUD in outpatient settings, especially buprenorphine because it is effective and has low toxicity. Buprenorphine is increasingly prescribed in primary care, a setting that provides greater anonymity and convenience than substance use disorder treatment centers. Yet two-thirds of people who begin buprenorphine treatment discontinue within the first six months. Treatment dropout elevates the risks of return to use, infections, higher levels of medical care and related costs, justice system involvement, and death. One promising form of retention support is peer service programs. Peers combine their lived experience of substance use and recovery with formal training to help patients engage and persist in OUD treatment. They provide a range of services, including health education, encouragement and empathy, coping skills, recovery modeling, and concrete assistance in overcoming the situational barriers to retention. However, guidance is needed to define the peer role in primary care, the specific tasks peers should perform, the competencies those tasks require, training and professional development needs, and peer performance standards. Guidance also is needed to integrate peers into the care team, allocate and coordinate responsibilities among care team members, manage peer operations and workflow, and facilitate effective team communication. Here we describe a peer support program in the University of Pennsylvania Health System (UPHS or Penn Medicine) network of primary care practices. This paper details the program’s core components, values, and activities. We also report the organizational challenges, unresolved questions, and lessons for the field in administering a peer support program to meet the needs of patients served by a large, urban medical system with an extensive suburban and rural catchment area. CLINICAL TRIALS REGISTRATION: www.clinicaltrials.gov registration: NCT04245423.

Coinhibition of TIGIT (T cell immunoreceptor with Ig and ITIM domains) and PD-1/PD-L1 (PD-1/L1) may improve response rates compared with monotherapy PD-1/L1 blockade in checkpoint naive non–small cell lung cancer with PD-L1 expression >50%. TIGIT mAbs with an effector-competent Fc can induce myeloid cell activation, and some have demonstrated effector T cell depletion, which carries a clinical liability of unknown significance. TIGIT Ab blockade translates to antitumor activity by enabling PVR signaling through CD226 (DNAM-1), which can be directly inhibited by PD-1. Furthermore, DNAM-1 is downregulated on tumor-infiltrating lymphocytes (TILs) in advanced and checkpoint inhibition–resistant cancers. Therefore, broadening clinical responses from TIGIT blockade into PD-L1low or checkpoint inhibition–resistant tumors, may be induced by immune costimulation that operates independently from PD-1/L1 inhibition. TNFSF14 (LIGHT) was identified through genomic screens, in vitro functional analysis, and immune profiling of TILs as a TNF ligand that could provide broad immune activation. Accordingly, murine and human bifunctional fusion proteins were engineered linking the extracellular domain of TIGIT to the extracellular domain of LIGHT, yielding TIGIT-Fc-LIGHT. TIGIT competitively inhibited binding to all PVR ligands. LIGHT directly activated myeloid cells through interactions with LTβR (lymphotoxin β receptor), without the requirement for a competent Fc domain to engage Fcγ receptors. LIGHT costimulated CD8+ T and NK cells through HVEM (herpes virus entry mediator A). Importantly, HVEM was more widely expressed than DNAM-1 on T memory stem cells and TILs across a range of tumor types. Taken together, the mechanisms of TIGIT-Fc-LIGHT promoted strong antitumor activity in preclinical tumor models of primary and acquired resistance to PD-1 blockade, suggesting that immune costimulation mediated by LIGHT may broaden the clinical utility of TIGIT blockade.

PURPOSE: To estimate the rate and magnitude of neurologic symptom change during radiation therapy (RT) and impact of symptom change on survival outcomes in patients with diffuse intrinsic pontine glioma (DIPG). METHODS: From 2006 to 2014, 108 patients with newly diagnosed DIPG were treated with conventionally fractionated radiation therapy (RT) to 54 Gy (median) at our institution. The presence and severity of neurologic symptoms related to cranial neuropathy (CN) and cerebellar (CB) and long-tract (LT) signs was reviewed before and weekly during RT for each patient. The rate and magnitude of change for each symptom category was evaluated according to accumulated RT dose. The impact of clinical factors and radiation dose-volume parameters was determined using Cox proportional hazards models. RESULTS: Median dose to first sign of symptomatic improvement was 16.2 Gy (CN), 19.8 Gy (LT) and 21.6 Gy (CB). Most patients showed an improvement by 20 Gy. Larger uninvolved brainstem volume, alone or normalized to total brain (TB) or posterior fossa volume (PF), was associated with shorter time to LT sign improvement (P = 0.044, P = 0.033, and P = 0.05, respectively). Patients with any improvement in CN experienced significantly, yet modestly, prolonged progression-free survival (PFS) and overall survival (OS) (P = 0.002 and P = 0.008, respectively). Tumor volume, with or without normalization to TB or PF, was not significantly associated with PFS or OS. CONCLUSIONS: Low cumulative RT doses resulted in neurologic improvement in most patients with DIPG. The volume of brainstem spared by tumor influenced time to symptomatic improvement. Neurologic improvement during RT was associated with superior survival.