"Can you help me think this through?" How pediatric hospitalists learn from informal peer consultation.

Informal peer consultation (IPC), also called curbside consultation, is a common practice in medicine. Research has shown that physicians use IPC but how this learning occurs during the process has not been studied. This basic qualitative study describes how pediatric hospitalists learn during IPC, framed by Kolb's (2015) Experiential Learning Theory of Growth and Development. Eleven pediatric hospitalists were interviewed. Deidentified transcripts were coded for key themes using inductive methods. The main prompt for informal peer consultation was the perception of uncertainty. Three themes describe the learning process: "Eliciting Perspectives," "Thinking Aloud Together," and "Experiencing Validation. A fourth theme, "Acknowledging Value," described the importance of IPC for modeling how to manage uncertainty with patients' caregivers and medical trainees. By describing the learning process, the results have implications for physicians who engage in IPC and may inform faculty-level professional development initiatives to improve the IPC process.

Multidisciplinary Initiative to Increase Guideline-concordant Antibiotic Prescription at Discharge for Hospitalized Children with Uncomplicated Community-acquired Pneumonia.

Background: Clinical practice guidelines recommend using narrow-spectrum antibiotics to treat uncomplicated pneumonia in children. This quality improvement (QI) project aimed to evaluate if QI methods could improve guideline-concordant antibiotic prescribing at hospital discharge for children with uncomplicated pneumonia. Methods: For this single-center QI project, we implemented QI interventions in serial plan-do-study-act cycles, focusing on the key drivers targeting general pediatric inpatient resident teams. Interventions included: (1)Small bimonthly group didactic sessions, (2)Visual job aids posted in resident work areas, and (3) A noon conference session. Balancing measures included postdischarge emergency room visits, readmission and adverse drug reactions. Results: To establish a baseline rate, we conducted a chart review of 112 children diagnosed with uncomplicated community-acquired pneumonia during hospitalization from July 2017 through January 2019. The average monthly percentage of children discharged with guideline-concordant antibiotics was 67%. The intervention period was from February 2019 through February 2020, with 118 children meeting the criteria after a review of 262 charts. After our interventions, the average monthly percentage of children discharged with guideline-concordant antibiotics increased to 87%, with the increase persisting for at least 12 months. There were no significant differences in balancing measures pre- and post-interventions. Conclusions: Our QI initiative sustained increased rates of uncomplicated community-acquired pneumonia guideline-concordant antibiotic prescribing at discharge over 12 months without an increase in balancing measures. The enduring changes in prescribing behavior suggest a lasting impact of our interventions.

Clonal selection of hematopoietic stem cells after gene therapy for sickle cell disease.

Gene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD); however, the occurrence of myeloid malignancies in GT clinical trials has prompted concern, with several postulated mechanisms. Here, we used whole-genome sequencing to track hematopoietic stem cells (HSCs) from six patients with SCD at pre- and post-GT time points to map the somatic mutation and clonal landscape of gene-modified and unmodified HSCs. Pre-GT, phylogenetic trees were highly polyclonal and mutation burdens per cell were elevated in some, but not all, patients. Post-GT, no clonal expansions were identified among gene-modified or unmodified cells; however, an increased frequency of potential driver mutations associated with myeloid neoplasms or clonal hematopoiesis (DNMT3A- and EZH2-mutated clones in particular) was observed in both genetically modified and unmodified cells, suggesting positive selection of mutant clones during GT. This work sheds light on HSC clonal dynamics and the mutational landscape after GT in SCD, highlighting the enhanced fitness of some HSCs harboring pre-existing driver mutations. Future studies should define the long-term fate of mutant clones, including any contribution to expansions associated with myeloid neoplasms.

Diagnostic utility of whole genome sequencing in adults with B-other acute lymphoblastic leukemia.

Genomic profiling during the diagnosis of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) in adults is used to guide disease classification, risk stratification, and treatment decisions. Patients for whom diagnostic screening fails to identify disease-defining or risk-stratifying lesions are classified as having B-other ALL. We screened a cohort of 652 BCP-ALL cases enrolled in UKALL14 to identify and perform whole genome sequencing (WGS) of paired tumor-normal samples. For 52 patients with B-other, we compared the WGS findings with data from clinical and research cytogenetics. WGS identified a cancer-associated event in 51 of 52 patients, including an established subtype defining genetic alterations that were previously missed with standard-of-care (SoC) genetics in 5 of them. Of the 47 true B-other ALL, we identified a recurrent driver in 87% (41). A complex karyotype via cytogenetics emerges as a heterogeneous group, including distinct genetic alterations associated with either favorable (DUX4-r) or poor outcomes (MEF2D-r and IGK::BCL2). For a subset of 31 cases, we integrated the findings from RNA sequencing (RNA-seq) analysis to include fusion gene detection and classification based on gene expression. Compared with RNA-seq, WGS was sufficient to detect and resolve recurrent genetic subtypes; however, RNA-seq can provide orthogonal validation of findings. In conclusion, we demonstrated that WGS can identify clinically relevant genetic abnormalities missed with SoC testing as well as identify leukemia driver events in virtually all cases of B-other ALL.

Development and Implementation of a Peer Curbside Consult Service for Pediatric Hospitalists.

OBJECTIVE: To describe the development and implementation of a Peer Curbside Consult Service (PCCS) for a pediatric hospital medicine (PHM) division. METHODS: We developed a pilot intervention with hospitalists at a freestanding children's hospital to provide peer consultation services for challenging clinical cases. Postconsultation surveys collected from both the requesting and consulting hospitalists provided feedback about the program. The 12-point Template for Intervention Description and Replication (TIDieR) checklist is used to describe the process for program creation and implementation. RESULTS: The PCCS has provided 60 consultations in the first 2 years since implementation in April 2020 and supports a large PHM division with >75 members who practice at a tertiary care, freestanding children's hospital and 7 affiliate sites. Hospitalists request peer consultation for challenging clinical cases. The consultations were typically conducted in person or via telephone. Currently, 11 PHM faculty members within the division volunteer as consultants, with 2 assigned per week. Electronic postconsultation experience surveys were received from 70% of requesting and 89% of consultant hospitalists. We also provide preliminary data from this pilot intervention in the Supplemental Information. CONCLUSIONS: We successfully established a peer consult service that provided just-in-time clinical decision support across the various practice sites. Through transparent reporting using the TIDieR checklist, other divisions may be able to replicate and adapt their own peer consult program.

A multicentre evaluation exploring the impact of an integrated health and social care intervention for the caregivers of ICU survivors.

BACKGROUND: Caregivers and family members of Intensive Care Unit (ICU) survivors can face emotional problems following patient discharge from hospital. We aimed to evaluate the impact of a multi-centre integrated health and social care intervention, on caregiver and family member outcomes. METHODS: This study evaluated the impact of the Intensive Care Syndrome: Promoting Independence and Return to Employment (InS:PIRE) programme across 9 sites in Scotland. InS:PIRE is an integrated health and social care intervention. We compared caregivers who attended this programme with a contemporary control group of ICU caregivers (usual care cohort), who did not attend. RESULTS: The primary outcome was anxiety measured via the Hospital Anxiety and Depression Scale at 12 months post-hospital discharge. Secondary outcome measures included depression, carer strain and clinical insomnia. A total of 170 caregivers had data available at 12 months for inclusion in this study; 81 caregivers attended the InS:PIRE intervention and completed outcome measures at 12 months post-hospital discharge. In the usual care cohort of caregivers, 89 completed measures. The two cohorts had similar baseline demographics. After adjustment, those caregivers who attended InS:PIRE demonstrated a significant improvement in symptoms of anxiety (OR: 0.42, 95% CI: 0.20-0.89, p = 0.02), carer strain (OR: 0.39; 95% CI: 0.16-0.98 p = 0.04) and clinical insomnia (OR: 0.40; 95% CI: 0.17-0.77 p < 0.001). There was no significant difference in symptoms of depression at 12 months. CONCLUSIONS: This multicentre evaluation has shown that caregivers who attended an integrated health and social care intervention reported improved emotional health and less symptoms of insomnia, 12 months after the delivery of the intervention.

Cricopharyngeal Achalasia Presenting as Acute Dysphagia in a Pediatric Patient.

OBJECTIVE: To describe a case of idiopathic cricopharyngeal achalasia (CPA) in a pediatric patient with acute onset of dysphagia managed conservatively with supportive care. METHODS: Sixteen-month-old boy presented with acute onset of gagging and coughing with feeding. His exam was notable for a well-appearing child with pooling of oral secretions and coarse breath sounds. Plain film series did not show radio-opaque foreign body (FB) and an esophagram demonstrated an endoluminal filling defect of the cervical esophagus and aspiration of contrast. He was taken to the operating room for urgent endoscopy but no FB or food impaction was observed. He had persistent symptoms that required further evaluation and a multidisciplinary team approach. Bedside laryngoscopy did not reveal any abnormalities. Modified barium swallow (MBS) study revealed upper esophageal sphincter (UES) dysfunction, consistent with cricopharyngeal achalasia. Repeat upper endoscopy with biopsies demonstrated mucosal irritation overlying the UES but histologic studies were negative for infectious causes. RESULTS: He was treated with supportive care, including nasogastric feedings for nutrition supplementation as he was unable to tolerate oral feedings without aspiration. Over the course of 3 months after discharge, his symptoms resolved and repeat MBS was normal. CONCLUSION: CPA is a rare cause of dysphagia in the pediatric population. Conservative management with supportive care is a reasonable approach in cases with acute onset in otherwise healthy children without underlying medical problems.

"Sick or not sick?" A mixed methods study evaluating the rapid determination of illness severity in a pediatric emergency department.

OBJECTIVES: Experienced physicians must rapidly identify ill pediatric patients. We evaluated the ability of an illness rating score (IRS) to predict admission to a pediatric hospital and explored the underlying clinical reasoning of the gestalt assessment of illness. METHODS: We used mixed-methods to study pediatric emergency medicine physicians at an academic children's hospital emergency department (ED). Physicians rated patients' illness severity with the IRS, anchored by 0 (totally well) and 10 (critically ill), and shared their rationale with concurrent think-aloud responses. The association between IRS and need for hospitalization, respiratory support, parenteral antibiotics, and resuscitative intravenous (IV) fluids were analyzed with mixed effects linear regression. Area under the curve (AUC) receiver operator characteristic (ROC) curve and test characteristics at different cut-points were calculated for IRS as a predictor of admission. Think-aloud responses were qualitatively analyzed via inductive process. RESULTS: A total of 141 IRS were analyzed (mean 3.56, SD 2.30, range 0-9). Mean IRS were significantly higher for patients requiring admission (4.32 vs. 3.13, p<0.001), respiratory support (6.15 vs. 3.98, p = 0.033), IV fluids (4.53 vs. 3.14, p < 0.001), and parenteral antibiotics (4.68 vs. 3.32, p = 0.009). AUC for IRS as a predictor of admission was 0.635 (95% CI: 0.534-0.737). Analysis of 95 think-aloud responses yielded eight categories that describe the underlying clinical reasoning. CONCLUSIONS: Rapid assessments as captured by the IRS differentiated pediatric patients who required admission and medical interventions. Think-aloud responses for the rationale for rapid assessments may form the basis for teaching the skill of identifying ill pediatric patients.

The mutational landscape of human somatic and germline cells.

Over the course of an individual's lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.

Development, maturation, and maintenance of human prostate inferred from somatic mutations.

Clonal dynamics and mutation burden in healthy human prostate epithelium are relevant to prostate cancer. We sequenced whole genomes from 409 microdissections of normal prostate epithelium across 8 donors, using phylogenetic reconstruction with spatial mapping in a 59-year-old man's prostate to reconstruct tissue dynamics across the lifespan. Somatic mutations accumulate steadily at ∼16 mutations/year/clone, with higher rates in peripheral than peri-urethral regions. The 24-30 independent glandular subunits are established as rudimentary ductal structures during fetal development by 5-10 embryonic cells each. Puberty induces formation of further side and terminal branches by local stem cells disseminated throughout the rudimentary ducts during development. During adult tissue maintenance, clonal expansions have limited geographic scope and minimal migration. Driver mutations are rare in aging prostate epithelium, but the one driver we did observe generated a sizable intraepithelial clonal expansion. Leveraging unbiased clock-like mutations, we define prostate stem cell dynamics through fetal development, puberty, and aging.

Extensive heterogeneity in somatic mutation and selection in the human bladder.

The extent of somatic mutation and clonal selection in the human bladder remains unknown. We sequenced 2097 bladder microbiopsies from 20 individuals using targeted (n = 1914 microbiopsies), whole-exome (n = 655), and whole-genome (n = 88) sequencing. We found widespread positive selection in 17 genes. Chromatin remodeling genes were frequently mutated, whereas mutations were absent in several major bladder cancer genes. There was extensive interindividual variation in selection, with different driver genes dominating the clonal landscape across individuals. Mutational signatures were heterogeneous across clones and individuals, which suggests differential exposure to mutagens in the urine. Evidence of APOBEC mutagenesis was found in 22% of the microbiopsies. Sequencing multiple microbiopsies from five patients with bladder cancer enabled comparisons with cancer-free individuals and across histological features. This study reveals a rich landscape of mutational processes and selection in normal urothelium with large heterogeneity across clones and individuals.

Feasibility of behavioral activation group therapy in reducing depressive symptoms and improving quality of life in patients with depression: the BRAVE pilot trial.

BACKGROUND: Depression impacts the lives of millions of people worldwide. Behavioral activation (BA), derived from cognitive behavioral therapy, has the potential for improving depressive symptoms in patients with depression. Studies evaluating the effectiveness of BA specifically in the context of group therapy programs in a hospital setting for patients with depression are limited. In this study, we report findings from a pilot trial evaluating group BA for major depressive disorder. OBJECTIVE: The objectives of this pilot trial are to assess the potential of a full trial of BA group therapy in a large-scale tertiary care setting and to provide preliminary information about possible results regarding mood symptoms and quality of life in adults with depression. METHODS: Using a parallel single-cohort pragmatic pilot randomized controlled trial design, we evaluated the potential of conducting a large trial of BA effectiveness among adults with depression. Participants were randomized to the intervention (BA in addition to usual care) or control (support group in addition to usual care) groups and were assessed weekly for 18 consecutive weeks. Participants randomized to intervention underwent 28 2-h group BA therapy visits administered by trained therapists and completed assessments to examine treatment outcomes. Feasibility was measured in terms of enrollment rates (min. 20%), completion rates of study (min. 80%), and completion rates of weekly measurement scales (min. 80%). The reporting of this pilot trial is in accordance with the CONSORT extension for randomized pilot and feasibility trials. RESULTS: We randomized 20 individuals of mean age of 48.8 years (standard deviation = 9.7) with a DSM-5 diagnosis of major depressive disorder to intervention (n = 10) or control (n = 10) groups. Based on our feasibility criteria, our recruitment rate was excellent (20/27; 74%), study completion was found to be a moderate (80% of the total participants in both arms completed the study; BA = 100%, control = 60%), and completeness of measurements on a weekly basis was adequate overall (82%; BA = 86%, control = 79%). CONCLUSIONS: The study has demonstrated the potential feasibility to perform a larger scale trial upon modifications to the control group to avoid the low rate of study completion (60%) in this group. TRIAL REGISTRATION: ClinicalTrials NCT02045771, Registered January 22, 2014.

Analysis of Histone Modifications in Rodent Pancreatic Islets by Native Chromatin Immunoprecipitation.

The islets of Langerhans are clusters of cells dispersed throughout the pancreas that produce several hormones essential for controlling a variety of metabolic processes, including glucose homeostasis and lipid metabolism. Studying the transcriptional control of pancreatic islet cells has important implications for understanding the mechanisms that control their normal development, as well as the pathogenesis of metabolic diseases such as diabetes. Histones represent the main protein components of the chromatin and undergo diverse covalent modifications that are very important for gene regulation. Here we describe the isolation of pancreatic islets from rodents and subsequently outline the methods used to immunoprecipitate and analyze the native chromatin obtained from these cells.

The landscape of somatic mutation in normal colorectal epithelial cells.

The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer1. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.

Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis.

Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.

Population dynamics of normal human blood inferred from somatic mutations.

Haematopoietic stem cells drive blood production, but their population size and lifetime dynamics have not been quantified directly in humans. Here we identified 129,582 spontaneous, genome-wide somatic mutations in 140 single-cell-derived haematopoietic stem and progenitor colonies from a healthy 59-year-old man and applied population-genetics approaches to reconstruct clonal dynamics. Cell divisions from early embryogenesis were evident in the phylogenetic tree; all blood cells were derived from a common ancestor that preceded gastrulation. The size of the stem cell population grew steadily in early life, reaching a stable plateau by adolescence. We estimate the numbers of haematopoietic stem cells that are actively making white blood cells at any one time to be in the range of 50,000-200,000. We observed adult haematopoietic stem cell clones that generate multilineage outputs, including granulocytes and B lymphocytes. Harnessing naturally occurring mutations to report the clonal architecture of an organ enables the high-resolution reconstruction of somatic cell dynamics in humans.

Acceptability of the Fitbit in behavioural activation therapy for depression: a qualitative study.

INTRODUCTION: Major depressive disorder is characterised by low mood and poor motivation. Literature suggests that increased physical activity has positive effects on alleviating depression. Fitness-tracking devices may complement behavioural activation (BA) therapy to improve physical activity and mental health in patients with depression. OBJECTIVES: To understand patients' perceived benefit from the Fitbit and explore themes associated with patient experiences. To compare perceived benefit, patient factors, Fitbit usage and Beck's Depression Inventory (BDI) scores. METHODS: Semistructured interviews were conducted with patients (n=36) who completed a 28-week BA group programme in a mood disorders outpatient clinic. All patients were asked to carry a Fitbit One device. We conducted thematic analyses on the interviews and exploratory quantitative analyses on patient characteristics, Fitbit usage, steps recorded, perceived benefit and BDI scores. FINDINGS: Twenty-three patients found the Fitbit helpful for their physical activity. Themes of positive experiences included self-awareness, peer motivation and goal-setting opportunities. Negative themes included inconvenience, inaccuracies and disinterest. Age, baseline and change in BDI scores, prior physical activity goals and familiarity with technology were not associated with perceived benefit from the Fitbit or usage. Perceived benefit was significantly (p<0.01) associated with usage. CONCLUSIONS: Overall, the Fitbit is an acceptable tool to complement BA therapy for patients with depression. Many positive themes were concordant with current literature; however, patients also reported negative aspects that may affect use. CLINICAL IMPLICATIONS: Clinicians and researchers should consider both strengths and limitations of activity trackers when implementing them to motivate patients with depression. TRIAL REGISTRATION NUMBER: NCT02045771; Pre-results.

Behavioral activation group therapy for reducing depressive symptoms and improving quality of life: a feasibility study.

BACKGROUND: Depression is associated with a loss of productivity and noticeable personal, social, and economic decline; it affects more than 350 million people worldwide. Behavioral activation (BA), derived from cognitive behavioral therapy, has drawn increasingly more interest as a means of treatment for major depressive disorder due to its relative cost-effectiveness and efficacy. In this study, we disseminate findings from a feasibility study evaluating barriers to implementing a group BA program for major depressive disorder. The purpose of this feasibility study is to assess both patient and clinician perceptions on components of a group-based behavioral activation (BA) program. In particular, this feasibility study provides in-depth evaluation of the acceptability of BA prior to the design and implementation of a randomized trial to investigate BA effectiveness. Findings from this study directly informed decisions regarding the design and implementation of BA during the pilot trial. Specific components of BA were assessed and modified based on the results of this study. METHODS: This qualitative study was completed through the Mood Disorders Program at St. Joseph's Healthcare Hamilton. The authors of this study used data from two focus group sessions, one consisting of an interdisciplinary group of clinicians working in the Mood Disorders Program, and the other of registered outpatients of the Mood Disorders Program with a confirmed clinical diagnosis of depression. The benefits of offering this program in a group format, mainly social skill development opportunities and the use of technology such as activity tracking device, smart phones, and tablets during the therapy sessions, are a major focus of both the clinician and patient groups. Both groups emphasized the importance of offering sustainable activation. RESULTS: Differences in opinions existed between staff and patient groups regarding the use of technology in the program, though ultimately it was agreed upon that technology could be useful as a therapeutic aid. All participants agreed that behavioral activation was essential to the development of positive habits and routines necessary for recovery from depression. Patients agreed the program looked sustainable and stressed the potential benefit for improving depressive symptoms. CONCLUSIONS: Discussions from clinician and patient-centered focus groups directly informed decisions regarding the design and implementation of BA during the pilot trial. Specific components of BA were assessed and modified based on the results of this study. These findings provide insight for clinicians providing behavioral activation programming, and will serve as a framework for the development of the Out of the Blues program, a group-based BA program to be piloted in the Mood Disorders Program at St. Joseph's Healthcare Hamilton. TRIAL REGISTRATION: Clinical Trials registration number NCT02045771.

Regulation of the Flt3 Gene in Haematopoietic Stem and Early Progenitor Cells.

The MYB transcription factor plays critical roles in normal and malignant haematopoiesis. We previously showed that MYB was a direct activator of FLT3 expression within the context of acute myeloid leukaemia. During normal haematopoiesis, increasing levels of FLT3 expression determine a strict hierarchy within the haematopoietic stem and early progenitor compartment, which associates with lymphoid and myeloid commitment potential. We use the conditional deletion of the Myb gene to investigate the influence of MYB in Flt3 transcriptional regulation within the haematopoietic stem cell (HSC) hierarchy. In accordance with previous report, in vivo deletion of Myb resulted in rapid biased differentiation of HSC with concomitant loss of proliferation capacity. We find that loss of MYB activity also coincided with decreased FLT3 expression. At the chromatin level, the Flt3 promoter is primed in immature HSC, but occupancy of further intronic elements determines expression. Binding to these locations, MYB and C/EBPα need functional cooperation to activate transcription of the locus. This cooperation is cell context dependent and indicates that MYB and C/EBPα activities are inter-dependent in controlling Flt3 expression to influence lineage commitment of multipotential progenitors.