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Miltefosine, an orally administered drug, is an important component of the therapeutic arsenal against visceral and mucosal forms of leishmaniasis. However, data regarding the safety and tolerability of miltefosine treatment for cutaneous leishmaniasis (CL) are relatively limited. The aim of this study was to evaluate the tolerability, safety, and adverse events (AEs) of miltefosine treatment in patients with CL. In this cohort study, we reviewed the medical records of all miltefosine-treated patients between 1 January 2016 and 31 December 2022, at Israel Defense Forces military dermatology clinics and the dermatology and Tropical Medicine Clinics at Chaim Sheba Medical Center, Ramat-Gan, Israel. A total of 68 patients (54 males, 79%) with a median age of 30.3 ± 15.6 years (range: 18–88) were included in this study. Leishmania species were identified as L. major (n = 37, 54.4%), L. tropica (n = 12, 17.6%), L. braziliensis (n = 18, 26.5%), and L. infantum (n = 1, 1.5%) using polymerase chain reaction (PCR). Miltefosine tablets were administered orally at a dose of 50 mg, three times daily, for 28 days. Overall, 44 patients (65%) completed the 28-day treatment, and the remaining patients required dose reduction or early discontinuation of treatment. AEs (of any degree) were common, reported in 91% of patients. Both previously reported and previously unreported AEs were documented. Gastrointestinal symptoms (66.1%) and malaise (23.5%) typically occurred during the first two weeks of treatment and tended to subside. Other AEs, including acute renal failure (20.6%), sudden and severe pleuritic chest pain (7.6%), acne exacerbation (11.8%), suppuration of CL lesions (17.8%), and AEs related to the male genitourinary system (39.6% of males), typically occurred towards the end of treatment. The latter included testicular pain, epididymitis, diminution or complete absence of ejaculate, inability to orgasm, and impotence. Severe AEs necessitated treatment discontinuation (29.4%) or hospitalization (10.3%). URTI-like symptoms, arthritis, cutaneous eruption, pruritus, and laboratory abnormalities were also observed. Overall, the cure rate (for all patients combined) evaluated 3 months after the completion of treatment was 60%. The tolerability of miltefosine treatment for CL is low. Close clinical and laboratory monitoring is required during treatment, as severe AEs are not uncommon. As new insights regarding its toxicities emerge, further studies are required to define the role of miltefosine in the treatment of CL.

Background: Youth with somatic symptom disorder (SSD) present unique behavioral characteristics. Aims: To develop and examine the psychometric properties of an observational measure of behavioral characteristics for youth with SSD (the Somatization Behavioral Characteristics Questionnaire, SBCQ). Methods: N = 80 youth with SSD and 31 with non-SSD impairments participated in this study (age = 13.91 ± 2.72, 14 ± 3.21, respectively; females: n = 61, 14, respectively). Symptom intensity (Children’s Somatization Inventory-24; CSI-24), functional disability (Six-Minute Walk Test, walking rate of perceived exertion), and the SBCQ were assessed. SBCQ reliability and validity were examined. Results: SBCQ had acceptable reliability in both groups (Cronbach’s α > 0.7). Exploratory factor analysis in the SSD group revealed a three-cluster solution. Significant associations were found between the SBCQ, CSI-24, and functional disability. Both groups differed in the prevalence of all SBCQ behaviors. The greatest differences were in the mismatch between etiology and clinical presentation, and in the exhibited lack of trust in the therapist and “la belle indifference”. Receiver operating characteristic analysis showed that the SBCQ has moderate accuracy in discriminating between the two groups (area under the curve = 0.80). Sensitivity and specificity were 82.5% and 73.3%, respectively. Conclusions: The SBCQ is psychometrically sound. Findings may aid in developing sensitive assessment tools for SSD and continuing education for therapists.

Purpose: Recovery after minimally invasive repair of pectus excavatum (MIRPE) is prolonged. The purpose of this prospective study was to enhance our understanding of post-MIRPE recovery by following patients' recovery through postoperative day (POD) 60 using wearable devices and determine if recovery rate is impacted by PE severity and preoperative physical activity (PA) level., Methods: Children ≤ 18 years who underwent MIRPE with cryoablation between 8/2023 and 1/2024 wore a Fitbit™ for ≥ 3 days preoperatively to determine preoperative PA and through POD 60. The recovery trajectory, defined by postoperative daily step count divided by mean preoperative daily step count, was fit by power function through POD 60 among patients with uncomplicated recovery. Subgroup analyses were performed to compare recovery by PE severity and preoperative PA level., Results: Sixteen patients met criteria (68.8% male, mean [SD] age 15.4 [1.6] years). Recovery trajectory analysis demonstrated recovery on POD 60 was 84.8% (95CI 79.0-90.6%). On subgroup analysis, patients with Correction Index > 40% and preoperative mean steps/day ≥ 10,000 had faster recovery., Conclusions: Patients undergoing MIRPE with cryotherapy who are more active preoperatively or have higher Correction Indices were found to have accelerated recovery trajectories. These results may provide insight for preoperative counselling and interventions to optimize post-MIRPE recovery., Competing Interests: Declarations Conflict of interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

A single gene may have multiple enhancers, but how they work in concert to regulate transcription is poorly understood. To analyze enhancer interactions throughout the genome, we developed a generalized linear modeling framework, GLiMMIRS, for interrogating enhancer effects from single-cell CRISPR experiments. We applied GLiMMIRS to a published dataset and tested for interactions between 46,166 enhancer pairs and corresponding genes, including 264 "high-confidence" enhancer pairs. We found that enhancer effects combine multiplicatively but with limited evidence for further interactions. Only 31 enhancer pairs exhibited significant interactions (false discovery rate <0.1), none of which came from the high-confidence set, and 20 were driven by outlier expression values. Additional analyses of a second CRISPR dataset and in silico enhancer perturbations with Enformer both support a multiplicative model of enhancer effects without interactions. Altogether, our results indicate that enhancer interactions are uncommon or have small effects that are difficult to detect., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

In deserts, sedimentation from frequent dust activities on solar cells poses a substantial technical challenge, reducing efficiency and necessitating advanced cost-inefficient cleaning mechanisms. Herein, a novel sandfish scale-inspired self-healing fluorinated copolymer-based triboelectric layer is directly incorporated on top of the polysilicon solar cell for sustained hybrid energy harvesting. The transparent biomimetic layer, with distinctive saw-tooth microstructured morphology, exhibits ultra-low sand adhesion and high abrasion-resistant properties, inhibits sedimentation deposition on solar cells, and concurrently harvests kinetic energy from wind-driven sand particles through triboelectric nanogenerator (TENG). The film exhibits a low friction coefficient (0.149), minimal sand adhesion force (27 nN), and a small wear area (327 µm 2 ). In addition, over 2 months, a solar cell with the sandfish scale-inspired structure demonstrates only a 16% decline in maximum power output compared to the bare solar cell, which experiences a 60% decline. Further, the sandfish scale-based TENG device's electrical output is fully restored to its original value after a 6-h self-healing cycle and maintains consistent stable outputs. These results highlight the exceptional advantages of employing biomimetic self-healing materials as robust triboelectric layers, showcasing sustained device stability and durability for prolonged use in harsh desert environments, ultimately contributing to a low cost-of-electricity generation paradigm., (© 2024 Wiley‐VCH GmbH.)

A single gene may have multiple enhancers, but how they work in concert to regulate transcription is poorly understood. To analyze enhancer interactions throughout the genome, we developed a generalized linear modeling framework, GLiMMIRS, for interrogating enhancer effects from single-cell CRISPR experiments. We applied GLiMMIRS to a published dataset and tested for interactions between 46,166 enhancer pairs and corresponding genes, including 264 'high-confidence' enhancer pairs. We found that enhancer effects combine multiplicatively but with limited evidence for further interactions. Only 31 enhancer pairs exhibited significant interactions (FDR < 0.1), of which none came from the high confidence subset and 20 were driven by outlier expression values. Additional analyses of a second CRISPR dataset and in silico enhancer perturbations with Enformer both support a multiplicative model of enhancer effects without interactions. Altogether, our results indicate that enhancer interactions are uncommon or have small effects that are difficult to detect., Competing Interests: Declaration of interests The authors declare no competing interests.

Perioperative neurocognitive disorders (PND) are a cognitive impairment that occurs after anesthesia, especially in elderly patients and significantly affects their quality of life. The hippocampus, as a critical region for cognitive function and an important location in PND research, has recently attracted increasing attention. However, in the hippocampus the impact of anesthesia and its underlying mechanisms remain unclear. This review focuses on investigation of the effects of anesthesia on the hippocampal dopamine (DA) system and explores its potential association with PND. Through comprehensive review of existing studies, it was found that anesthesia affects the hippocampus through various pathways involved in metabolism, synaptic plasticity and oxygenation. Anesthesia may also influence the DA neurotransmitter system in the brain which plays a role in emotions, rewards, learning and memory functions. Specifically, anesthesia may participate in the pathogenesis of PND by affecting the DA system within the hippocampus. Future studies should explore the molecular mechanisms of these effects through techniques such as neuroimaging to study real-time effects to improve animal models to better simulate clinical observations. For clinical application, it is recommended that physicians exercise caution when selecting and managing anesthetic drugs by adopting comprehensive cognitive assessment methods to reduce post-anesthesia cognitive risk. Overall, this review provides a better understanding of the relationship between the hippocampal DA system and perioperative neurocognitive function and provides valuable guidance for prevention and treatment strategies for PND., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). Published by IMR Press.)

Background: Although electronic prescription cancellation such as via CancelRx can facilitate critical communication between prescribers and pharmacy staff about discontinued medications, there is little work that explores whether CancelRx meets the needs of pharmacy staff users., Objective: This study leverages qualitative interviews with pharmacy staff to address the following question: When medication changes are made by a prescriber using CancelRx, what information is needed by pharmacy staff to make correct and effective decisions in their roles in medication management?, Methods: We conducted an inductive thematic analysis of interviews with 11 pharmacy staff members (pharmacists and pharmacy technicians) across three outpatient community pharmacy sites within an academic health care system., Results: Three information needs themes were consistently identified by both pharmacists and pharmacy technicians: prescriber intent when initiating the CancelRx, clinical rationale for the medication change, and intended medication regimen. Notably, both pharmacists and pharmacy technicians often reported seeking multiple information needs not fully addressed by CancelRx in the electronic health record (EHR) to achieve the shared goals of correct dispensing of medications and supporting patient self-management., Conclusions: Our qualitative analysis reveals that outpatient community pharmacy staff in an academic health care system often seek additional information from the (EHR) following medication changes communicated by CancelRx to meet their information needs. Ideally, the prescriber would provide sufficient information through CancelRx to automatically identify all discontinued prescriptions. These limitations highlight the need for design features that support routine communication of needed information at the time of a medication change, such as structured data elements., Competing Interests: The authors have no competing interests to disclose., (© 2023 The Authors. Published by Elsevier Inc.)

Importance: An estimated 1.5% to nearly 5% of medications are dispensed after discontinuation in the electronic health record (EHR), with 34% meeting criteria for high risk of potential harm., Objective: To evaluate the association of the implementation of e-prescription cancellation messaging (CancelRx) with medication dispensing after discontinuation of e-prescriptions in the EHR., Design, Setting, and Participants: This case series with interrupted time series analysis included patients who had at least 1 medication e-prescribed in ambulatory care to a health system pharmacy and discontinued in the 2-year study period from 1 year prior to approximately 1 year after CancelRx implementation (January 15, 2018, to December 7, 2019). Prior to CancelRx implementation, changes to e-prescribed medications within the EHR were not electronically communicated to health system pharmacies, which used separate pharmacy management software. Statistical analysis was performed from November 2020 to June 2023 (primary analysis from March 2021 to May 2022)., Exposure: Implementation of CancelRx., Main Outcomes and Measures: The primary outcome was the proportion of e-prescribed medications dispensed and sold to patients by pharmacies within 6 months after discontinuation in the EHR. A medication was defined as dispensed after discontinuation if the timestamp of dispensing was at least 1 minute and less than 6 months after the timestamp of discontinuation in the EHR. A secondary outcome was the proportion of discontinued medications that was reordered within 120 days., Results: A total of 53 298 qualifying e-prescriptions that were discontinued were identified for 17 451 unique patients (mean [SD] age, 50.6 [18.2] years; 9332 women [53.5%]). After CancelRx implementation, 22 443 (85.9%) of the 26 127 discontinued e-prescriptions resulted in a CancelRx transaction. In interrupted time series analysis, the proportion of prescriptions dispensed after discontinuation decreased from a baseline of 8.0% (2162 of 27 171) to 1.4% (369 of 26 127; P < .001), without a significant week-to-week trend (β = 0.000158; P = .37)., Conclusions and Relevance: In this case series with interrupted time series analysis, findings suggest that CancelRx implementation was associated with an immediate and persistent reduction in the proportion of e-prescriptions sold after discontinuation in the EHR. Widespread implementation of CancelRx may significantly improve medication safety through the reduction of medication dispensing after discontinuation by prescribers.

GATA3 is essential for T cell differentiation and is surrounded by genome-wide association study (GWAS) hits for immune traits. Interpretation of these GWAS hits is challenging because gene expression quantitative trait locus (eQTL) studies lack power to detect variants with small effects on gene expression in specific cell types and the genome region containing GATA3 contains dozens of potential regulatory sequences. To map regulatory sequences for GATA3, we performed a high-throughput tiling deletion screen of a 2 Mb genome region in Jurkat T cells. This revealed 23 candidate regulatory sequences, all but one of which is within the same topological-associating domain (TAD) as GATA3. We then performed a lower-throughput deletion screen to precisely map regulatory sequences in primary T helper 2 (Th2) cells. We tested 25 sequences with ∼100 bp deletions and validated five of the strongest hits with independent deletion experiments. Additionally, we fine-mapped GWAS hits for allergic diseases in a distal regulatory element, 1 Mb downstream of GATA3, and identified 14 candidate causal variants. Small deletions spanning the candidate variant rs725861 decreased GATA3 levels in Th2 cells, and luciferase reporter assays showed regulatory differences between its two alleles, suggesting a causal mechanism for this variant in allergic diseases. Our study demonstrates the power of integrating GWAS signals with deletion mapping and identifies critical regulatory sequences for GATA3., Competing Interests: Declaration of interests Electroporation experiments were performed with an ExPERT MaxCyte ATx instrument that was provided to the McVicker laboratory by MaxCyte, Inc. for technology development and evaluation purposes., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Study Design: A retrospective cohort study from a multisite academic medical center., Objective: To construct, evaluate, and interpret a series of machine learning models to predict outcomes related to inpatient health care resource utilization for patients undergoing anterior cervical discectomy and fusion (ACDF)., Summary of Background Data: Reducing postoperative health care utilization is an important goal for improving the delivery of surgical care and serves as a metric for quality assessment. Recent data has shown marked hospital resource utilization after ACDF surgery, including readmissions, and ED visits. The burden of postoperative health care use presents a potential application of machine learning techniques, which may be capable of accurately identifying at-risk patients using patient-specific predictors., Methods: Patients 18-88 years old who underwent ACDF from 2011 to 2021 at a multisite academic center and had preoperative lab values within 3 months of surgery were included. Outcomes analyzed included 90-day readmissions, postoperative length of stay, and nonhome discharge. Four machine learning models-Extreme Gradient Boosted Trees, Balanced Random Forest, Elastic-Net Penalized Logistic Regression, and a Neural Network-were trained and evaluated through the Area Under the Curve estimates. Feature importance scores were computed for the highest-performing model per outcome through model-specific metrics., Results: A total of 1026 cases were included in the analysis cohort. All machine learning models were predictive for outcomes of interest, with the Random Forest algorithm consistently demonstrating the strongest average area under the curve performance, with a peak performance of 0.84 for nonhome discharge. Important features varied per outcome, though age, body mass index, American Society of Anesthesiologists classification >2, and medical comorbidities were highly weighted in the studied outcomes., Conclusions: Machine learning models were successfully applied and predictive of postoperative health utilization after ACDF. Deployment of these tools can assist clinicians in determining high-risk patients., Level of Evidence: III., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Oncofertility is a developing field of increasing importance, particularly in pediatric oncology, where most patients are likely to survive long-term and have not yet had the opportunity to have children., Aims: We performed a quality improvement initiative to increase our rates of fertility preservation counseling and referral through the implementation of a pediatric oncofertility team, and we report outcomes 7 years following implementation of our initiative., Methods and Results: We compare our baseline oncofertility survey to 44 post-intervention survey respondents and electronic medical record documentation for 149 patients treated in 2019. Ninety-five percent of post-intervention survey respondents recalled fertility counseling (baseline 70%, p = .004) and 89.3% were appropriately referred for fertility preservation (baseline 50%, p = .017). Counseling was documented in 60.4% of charts; 81% of patients analyzed by chart review were appropriately referred for fertility preservation. Fertility preservation outcomes differed by sex assigned at birth., Conclusion: Creation of an oncofertility team produced improvements in fertility counseling and fertility preservation referral across an extended period of time., (© 2022 The Authors. Cancer Reports published by Wiley Periodicals LLC.)

Electronic communication of prescription discontinuation, or CancelRx, has the potential to improve medication safety. We aimed to describe the proportion of discontinued outpatient medications that would result in a CancelRx message to understand its impact on medication safety. We used a data report to identify all outpatient medications discontinued in the electronic health record (EHR) of an academic health system in 1 month (October 2018). Among all 63 485 medications discontinued, 23 118 (36.4%) were e-prescribed, 25 982 (40.9%) were patient-reported or reconciled, and the remainder prescribed nonelectronically. Discontinued high-risk medications were more likely to be e-prescribed (2768 of 5896, 47.0%). A discontinuation reason was specified in 37 353 (58.9%) of all discontinued medications. Approximately one-third to one-half of discontinued medications were e-prescribed within the same EHR and would result in a CancelRx message to the pharmacy. Extension of this functionality to medications reconciled in the EHR could significantly expand the impact of CancelRx on medication safety. In addition, complete and accurate discontinuation reasons are needed to optimize CancelRx implementation., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Medical Informatics Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: This study aimed to evaluate the impact of electronic communication of medication discontinuation from prescribers to pharmacies (CancelRx) on medication safety., Methods: We used electronic health record (EHR) data to identify medications that were e-prescribed from a pilot practice to a health system pharmacy and subsequently discontinued before or after CancelRx implementation (January 16-April 15, 2018 versus 2019). We matched these EHR data to pharmacy management software data to identify medications that were sold to patients in the 6 months after discontinuation. As a surrogate for unintended cancellation, we also identified medications refilled within 120 days of discontinuation. We conducted a medical record review to identify documentation of prescriber intent to discontinue these medications., Results: CancelRx implementation prevented prescriptions from being sold after discontinuation in the EHR (42 of 392 [10.7%] versus 0 of 387 [0.0%], P &lt; 0.0001), but only 15 of 42 (35.7%) had documented intent to discontinue the medication (15 of 392, or 3.8% overall). There was a nonsignificant increase in the proportion of discontinued medications reordered within 120 days (10.0% versus 12.7%, P = 0.23). Medical record review of reordered prescriptions after CancelRx implementation found that 10 of 49 (10 of 387, or 2.6% overall) might have been unintentionally canceled., Conclusions: Implementation of CancelRx eliminated the sale of e-prescribed medications after discontinuation in the EHR but might result in the unintentional cancellation of some prescriptions. Strategies to increase situational awareness of providers and pharmacy staff, including increased visibility of CancelRx, clear distinctions between active and expired prescriptions, and transmission of the reason for discontinuation, might reduce the risk of unintentional cancellations., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: Wrong-patient errors are common and have the potential to cause serious harm. The Office of the National Coordinator for Health Information Technology Patient Identification SAFER Guide recommends displaying patient photographs in electronic health record (EHR) systems to facilitate patient identification and reduce wrong-patient errors. A potential barrier to implementation is patient refusal; however, patients' perceptions about having their photograph captured during registration and integrated into the EHR are unknown., Methods: The study was conducted in an emergency department (ED) and primary care outpatient clinic within a large integrated health system in New York City. The study consisted of 2 components: (1) direct observation of the registration process to quantify the frequency of patient refusals and (2) semistructured interviews to elicit patients' feedback on perceived benefits and barriers to integrating their photograph into the EHR., Results: Of 172 registrations where patients were asked to take a photograph for patient identification, 0 refusals were observed (ED, 0 of 87; primary care outpatient clinic, 0 of 85). A convenience sample of 30 patients were interviewed (female, 70%; age ≥55 years, 43%; Hispanic/Latino, 67%; Black, 23%). Perceived benefits of integrating patient photographs into the EHR included improved security (40%), improved patient identification (23%), and ease of registration (17%). A small proportion of patients raised privacy concerns., Conclusions: Patient refusal was not found to be a barrier to implementation of patient photographs in the EHR. Efforts to identify and address other potential barriers would help ensure that the highest proportion of patients has photographs in their medical record., Competing Interests: The authors disclose no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Meaningful engagement in quality improvement (QI) projects by trainees is often challenging. A fellow-led QI project aimed to improve adherence to a blood culture clinical decision algorithm and reduce unnecessary cultures in pediatric oncology inpatients., Methods: We visualized preintervention rates of blood cultures drawn on pediatric oncology inpatients using a control chart. Following the introduction of the algorithm to our division, an Ishikawa fishbone diagram of cause-and-effect identified two areas for improvement: prescriber education on the algorithm and targeted feedback on its use. We developed two interventions to support algorithm awareness and use: (1) bundled educational interventions and (2) targeted chart review and feedback. Fellows reviewed >750 blood culture episodes and adjudicated each as "adherent" or "nonadherent" to the algorithm. In addition, fellows provided direct feedback to prescribers regarding nonadherent episodes and discussed strategies for algorithm adherence., Results: Blood culture rates in preintervention, intervention, and follow-up periods were 33.35, 25.24, and 22.67 cultures/100 patient-days, respectively. The proportion of nonadherent culture episodes decreased from 47.14% to 11.11%. The use of the algorithm did not prolong the time to cultures drawn on patients with new fever. Seventy-five percent of fellows provided feedback to inpatient teams on algorithm use. Following this project, trainees reported feeling more qualified to apply QI principles to patient care., Conclusions: Implementation of a clinical decision algorithm reduced the rate of cultures drawn on pediatric oncology inpatients. Fellow-led education of the care team decreased the proportion of nonadherent culture episodes and provided active engagement in QI., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Oncofertility counseling regarding the reproductive risks associated with cancer therapy is essential for quality cancer care. We aimed to increase the rate of oncofertility counseling for patients of reproductive age (18-40 years) with cancer who were initiating systemic therapy at the Johns Hopkins Cancer Center from a baseline rate of 37% (25 of 68, June 2019-January 2020) to 70% by February 2021., Methods: We formed an interprofessional, multidisciplinary team as part of the ASCO Quality Training Program. We obtained data from the electronic medical record and verified data with patients by phone. We surveyed patients, oncologists, and fertility specialists to identify barriers. After considering a prioritization matrix, we implemented Plan-Do-Study-Act (PDSA) cycles., Results: We identified the following improvement opportunities: (1) oncologist self-reported lack of knowledge about counseling and local fertility preservation options and (2) lack of a standardized referral mechanism to fertility services. During the first PDSA cycle (February 2020-August 2020, disrupted by COVID-19), we introduced the initiative to increase oncofertility counseling at faculty meetings. From September 2020 to November 2020, we implemented a second PDSA cycle: (1) educating and presenting the initiative at Oncology Grand Rounds, (2) distributing informative pamphlets to oncologists and patients, and (3) implementing an electronic medical record order set. In the third PDSA cycle (December 2020-February 2021), we redesigned the order set to add information (eg, contact information for fertility coordinator) to the patient after-visit summary. Postimplementation (September 2020-February 2021), counseling rates increased from 37% to 81% (38 of 47)., Conclusion: We demonstrate how a trainee-led, patient-centered initiative improved oncofertility care. Ongoing work focuses on ensuring sustainability and assessing the quality of counseling., Competing Interests: Amin S. HeratiConsulting or Advisory Role: Dadi, Teleflex Medical Adam F. BinderConsulting or Advisory Role: Genzyme, Oncopeptides Allen R. ChenOpen Payments Link: https://openpaymentsdata.cms.gov/physician/480762 Kristen A. MarroneHonoraria: AstraZenecaConsulting or Advisory Role: AstraZeneca, Amgen, Puma Biotechnology, Janssen, Mirati TherapeuticsResearch Funding: Bristol Myers Squibb, AstraZenecaNo other potential conflicts of interest were reported.

Treatment of high-risk neuroblastoma typically incorporates multiagent chemotherapy, surgery, radiation therapy, autologous stem cell transplantation, immunotherapy, and differentiation therapy. The discovery of activating mutations in ALK receptor tyrosine kinase ( ALK ) in ∼8% of neuroblastomas opens the possibility of further improving outcomes for this subset of patients with the addition of ALK inhibitors. ALK inhibitors have shown efficacy in tumors such as non-small-cell lung cancer and anaplastic large cell lymphoma in which wild-type ALK overexpression is driven by translocation events. In contrast, ALK mutations driving neuroblastomas are missense mutations in the tyrosine kinase domain yielding constitutive activation and differing sensitivity to available ALK inhibitors. We describe a case of a patient with relapsed, refractory, metastatic ALK F1174L-mutated neuroblastoma who showed no response to the first-generation ALK inhibitor crizotinib but had a subsequent complete response to the ALK/ROS1 inhibitor lorlatinib. The patient's disease relapsed after 13 mo of treatment. Sequencing of cell-free DNA at the time of relapse pointed toward a potential mechanism of acquired lorlatinib resistance: amplification of CDK4 and FGFR1 and a NRAS Q61K mutation. We review the literature regarding differing sensitivity of ALK mutations found in neuroblastoma to current FDA-approved ALK inhibitors and known pathways of acquired resistance. Our report adds to the literature of important correlations between neuroblastoma ALK mutation status and clinical responsiveness to ALK inhibitors. It also highlights the importance of understanding acquired mechanisms of resistance., (© 2021 Liu et al.; Published by Cold Spring Harbor Laboratory Press.)

Ultrasonic vocalizations (USVs) are known to reflect emotional processing, brain neurochemistry, and brain function. Collecting and processing USV data is manual, time-intensive, and costly, creating a significant bottleneck by limiting researchers' ability to employ fully effective and nuanced experimental designs and serving as a barrier to entry for other researchers. In this report, we provide a snapshot of the current development and testing of Acoustilytix™, a web-based automated USV scoring tool. Acoustilytix implements machine learning methodology in the USV detection and classification process and is recording-environment-agnostic. We summarize the user features identified as desirable by USV researchers and how these were implemented. These include the ability to easily upload USV files, output a list of detected USVs with associated parameters in csv format, and the ability to manually verify or modify an automatically detected call. With no user intervention or tuning, Acoustilytix achieves 93% sensitivity (a measure of how accurately Acoustilytix detects true calls) and 73% precision (a measure of how accurately Acoustilytix avoids false positives) in call detection across four unique recording environments and was superior to the popular DeepSqueak algorithm (sensitivity = 88%; precision = 41%). Future work will include integration and implementation of machine-learning-based call type classification prediction that will recommend a call type to the user for each detected call. Call classification accuracy is currently in the 71-79% accuracy range, which will continue to improve as more USV files are scored by expert scorers, providing more training data for the classification model. We also describe a recently developed feature of Acoustilytix that offers a fast and effective way to train hand-scorers using automated learning principles without the need for an expert hand-scorer to be present and is built upon a foundation of learning science. The key is that trainees are given practice classifying hundreds of calls with immediate corrective feedback based on an expert's USV classification. We showed that this approach is highly effective with inter-rater reliability (i.e., kappa statistics) between trainees and the expert ranging from 0.30-0.75 (average = 0.55) after only 1000-2000 calls of training. We conclude with a brief discussion of future improvements to the Acoustilytix platform.

Microbial sharing between humans and animals has been demonstrated in a variety of settings. However, the extent of microbial sharing that occurs within the healthcare setting during animal-assisted intervention programs is unknown. Understanding microbial transmission between patients and therapy dogs can provide important insights into potential health benefits for patients, in addition to addressing concerns regarding potential pathogen transmission that limits program utilization. This study evaluated for potential microbial sharing between pediatric patients and therapy dogs and tested whether patient-dog contact level and a dog decolonization protocol modified this sharing. Patients, therapy dogs, and the hospital environment were sampled before and after every group therapy session and samples underwent 16S rRNA sequencing to characterize microbial communities. Both patients and dogs experienced changes in the relative abundance and overall diversity of their nasal microbiome, suggesting that the exchange of microorganisms had occurred. Increased contact was associated with greater sharing between patients and therapy dogs, as well as between patients. A topical chlorhexidine-based dog decolonization was associated with decreased microbial sharing between therapy dogs and patients but did not significantly affect sharing between patients. These data suggest that the therapy dog is both a potential source of and a vehicle for the transfer of microorganisms to patients but not necessarily the only source. The relative contribution of other potential sources (e.g., other patients, the hospital environment) should be further explored to determine their relative importance.

CRISPR screens are a powerful technology for the identification of genome sequences that affect cellular phenotypes such as gene expression, survival, and proliferation. By targeting non-coding sequences for perturbation, CRISPR screens have the potential to systematically discover novel functional sequences, however, a lack of purpose-built analysis tools limits the effectiveness of this approach. Here we describe RELICS, a Bayesian hierarchical model for the discovery of functional sequences from CRISPR screens. RELICS specifically addresses many of the challenges of non-coding CRISPR screens such as the unknown locations of functional sequences, overdispersion in the observed single guide RNA counts, and the need to combine information across multiple pools in an experiment. RELICS outperforms existing methods with higher precision, higher recall, and finer-resolution predictions on simulated datasets. We apply RELICS to published CRISPR interference and CRISPR activation screens to predict and experimentally validate novel regulatory sequences that are missed by other analysis methods. In summary, RELICS is a powerful new analysis method for CRISPR screens that enables the discovery of functional sequences with unprecedented resolution and accuracy., Competing Interests: The authors have declared that no competing interests exist.

Objectives High-dose methotrexate (HDMTX) is an important chemotherapeutic agent in the treatment of many cancers. Identification of the predictors of poor clearance during HDMTX infusions could advance the introduction of improved supportive care to prevent toxicities and reduce hospital length of stay. The purpose of this study was to identify relationships between patient physical characteristics and HDMTX clearance in the treatment of pediatric acute lymphoblastic leukemia (ALL). At our hospital, patients who have delayed methotrexate (MTX) clearance during a cycle of HDMTX receive an increased rate of hydration with subsequent cycles. This increase in hydration rate was examined for its potential to mitigate predictors of poor clearance and to prevent nephrotoxicity. Methods This study retrospectively examined the treatment records of 87 pediatric patients diagnosed with ALL who were treated on or according to Children's Oncology Group (COG) protocols AALL0232, AALL0434, AALL1131, and AALL1231. Each patient received four cycles of HDMTX (5 g/m 2  over 24 hours) at two-week intervals. Patients received either 125 ml/m 2 /hour (standard) or 200 ml/m 2 /hour (delayed clearance protocol) hydration before, with, and after each infusion. MTX levels taken at 24-, 42-, and 48-hour time points were used as an indirect measure of drug clearance. Two-tailed inference for ordinary least squares regression and both heteroskedastic and paired two-tailed t-tests were performed to identify physical characteristics associated with delayed MTX clearance and the effects of hydration rate on MTX clearance, respectively. Results Patient age and body surface area (BSA) were found to have statistically significant (p<0.05) positive associations with the serum MTX levels at 24, 42, and 48 hours in cycle 1. Age and BSA were significant only at the 24-hour time point in cycles 2 and 4. Weight alone was not associated with delayed MTX clearance. For patients who had delayed MTX clearance once and thus received the delayed clearance protocol in subsequent cycles, increasing the hydration rate from 125 to 200 ml/m 2 /hour was associated with a statistically significant decrease in average MTX levels as well as serum creatinine levels at the 24-, 42-, and 48-hour time points. Once patients with delayed clearance received the 200 ml/m 2 /hour rate of hydration, the history of prior poor clearance lost its predictive value for serum MTX levels and delayed clearance. Conclusions These results suggest that patient age and BSA are significant predictors of MTX clearance if all patients receive the same rate of hydration. Age and BSA affect the distribution phase of MTX kinetics, with downstream effects in the elimination phase. Increased hydration mitigates the effects of these physical characteristics on the elimination phase kinetics by improving renal elimination of MTX, causing a loss of significance of age and BSA as predictors of MTX levels in subsequent cycles at the 42- and 48-hour time points, but with less effect at 24 hours. Thus, hyperhydration regimens prior to cycle 1 of HDMTX could be considered for patients presenting with risk factors of advanced age or high BSA to avoid delayed clearance., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Chen et al.)

Detection of minimal residual disease (MRD) pre- and post-hematopoietic cell transplantation (HCT) for pediatric acute lymphoblastic leukemia (ALL) has been associated with relapse and poor survival. Published studies have had insufficient numbers to: (1) compare the prognostic value of pre-HCT and post-HCT MRD; (2) determine clinical factors post-HCT associated with better outcomes in MRD+ patients; and (3) use MRD and other clinical factors to develop and validate a prognostic model for relapse in pediatric patients with ALL who undergo allogeneic HCT. To address these issues, we assembled an international database including sibling (n = 191), unrelated (n = 259), mismatched (n = 56), and cord blood (n = 110) grafts given after myeloablative conditioning. Although high and very high MRD pre-HCT were significant predictors in univariate analysis, with bivariate analysis using MRD pre-HCT and post-HCT, MRD pre-HCT at any level was less predictive than even low-level MRD post-HCT. Patients with MRD pre-HCT must become MRD low/negative at 1 to 2 months and negative within 3 to 6 months after HCT for successful therapy. Factors associated with improved outcome of patients with detectable MRD post-HCT included acute graft-versus-host disease. We derived a risk score with an MRD cohort from Europe, North America, and Australia using negative predictive characteristics (late disease status, non-total body irradiation regimen, and MRD [high, very high]) defining good, intermediate, and poor risk groups with 2-year cumulative incidences of relapse of 21%, 38%, and 47%, respectively. We validated the score in a second, more contemporaneous cohort and noted 2-year cumulative incidences of relapse of 13%, 26%, and 47% (P < .001) for the defined risk groups.

Background: CancelRx allows prescribers to send electronic cancellation messages to pharmacies when medications are discontinued. Little is known about its functionality and impact on clinical workflows., Objectives: To understand CancelRx functionality, its potential impact on workflows and medication safety risks, and to develop mitigating strategies for risks introduced by implementation., Methods: We conducted direct observations and semi-structured interviews to develop CancelRx use cases and assessed CancelRx in an end-to-end test environment, proactive risk assessment, and pilot implementation from April 16 to July 15, 2018., Results: E-cancellations were sent upon discontinuation of e-prescriptions written within the electronic health record (EHR), but not other medications (e.g., printed prescriptions) and could be initiated by nonprescribers. In our proactive risk assessment, CancelRx implementation eliminated five of seven failure modes in outpatient prescribing to Johns Hopkins pharmacies, but introduced new risks, including (1) failure to act if an e-cancellation was not sent or was unsuccessful; (2) failure to cancel all prescriptions for a medication; (3) errors in manual matching; and (4) erroneous medication cancellations. We identified potential mitigation strategies for these risks. During pilot implementation, 92.4% (428/463) of e-cancellations had confirmed approval by the receiving pharmacy, while 4.5% (21/463) were denied, and 3.0% (14/463) had no e-cancellation response. Among e-cancellations received by the pilot pharmacy, 1.7% (7/408) required manual matching by pharmacy staff. Based on performance in testing, 73.4% (340/463) of completed e-cancellations would be expected to generate an in-basket message, including 21 (6.2%) denials and 319/340 (93.8%) approvals with a note from the pharmacy., Conclusion: CancelRx is an important functionality with the potential to decrease adverse events due to medication errors. However, changes in implementation in our EHR and pharmacy software and enhancements in the CancelRx standard are needed to maximize safety and usability. Further studies are needed to evaluate the impact of e-cancellation on medication safety., Competing Interests: None declared., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Relapsed and refractory sarcomas continue to have poor survival rates. The cancer stem cell (CSC) theory provides a tractable explanation for the observation that recurrences occur despite dramatic responses to upfront chemotherapy. Preclinical studies demonstrated that inhibition of the mechanistic target of rapamycin (mTOR) sensitizes the CSC population to chemotherapy., Methods: Here we present the results of the Phase II portion of a Phase I/II clinical trial that aimed to overcome the chemoresistance of sarcoma CSC by combining the mTOR inhibitor temsirolimus (20 mg/m 2 weekly) with the chemotherapeutic agent liposomal doxorubicin (30 mg/m 2 monthly)., Results: Fifteen patients with relapsed/refractory sarcoma were evaluable at this recommended Phase 2 dose level. The median progression free survival was 315 days (range 27-799). Response rate, defined as stable disease or better for 60 days, was 53%. Nine of the patients had been previously treated with doxorubicin. Therapy was well tolerated. In a small number of patients, pre- and post- treatment tumor biopsies were available for assessment of ALDH expression as a marker of CSCs and showed a correlation between response and decreased ALDH expression. We also found a correlation between biopsy-proven inhibition of mTOR and response., Conclusions: Our study adds to the literature supporting the addition of mTOR inhibition to chemotherapy agents for the treatment of sarcomas, and proposes that a mechanism by which mTOR inhibition enhances the efficacy of chemotherapy may be through sensitizing the chemoresistant CSC population. Further study, ideally with pre- and post-therapy assessment of ALDH expression in tumor cells, is warranted. Trial registration The trial was registered on clinicaltrials.gov (NCT00949325) on 30 July 2009. http://www.editorialmanager.com/csrj/default.aspx.

We enrolled 150 patients in a prospective multicenter study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplantation (HSCT) to compare the detection of measurable residual disease (MRD) by a "difference from normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients screened for HSCT had detectable residual disease by ΔN (.04% to 53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (.04% to 14%) by ΔN. The disease-free survival of this group was 10% (0 to 35%) compared with 55% (46% to 64%, P < .001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 patients who had confirmation of tumor detection relapsed, whereas the 2 patients with suspicious phenotype cells lacking this confirmation did not. The phenotype of the relapse specimen was then used retrospectively to assess the pre-HSCT specimen, allowing identification of additional samples with low levels of MRD involvement that were previously undetected. Quantitative assessment of WT1 gene expression was not predictive of relapse or other outcomes in either pre- or post-transplant specimens. MRD detected by ΔN was highly specific, but did not identify most relapsing patients. The application of the assay was limited by poor quality among one-third of the specimens and lack of a diagnostic phenotype for comparison., (Copyright © 2018. Published by Elsevier Inc.)

Introduction: Medication reconciliation can reduce medication discrepancies, errors, and patient harm. After a large academic hospital introduced a medication reconciliation software program, there was low compliance with electronic health record documentation of home medication reconciliation. This quality improvement project aimed to improve medication reconciliation on admission in 4 pediatric inpatient units by 50% over 3 months., Methods: We used Lean Sigma methodology to observe medication reconciliation processes; interview residents, nurses, pharmacists, and families; and perform swim lane process mapping and Ishikawa Cause and Effect analysis. The improvement plan included education and automated e-mails sent to admitting residents who had not completed medication reconciliation within 24 hours of admission. The daily percentage of patients without medication reconciliation within 24 hours of admission, indicated by the presence of old prescriptions in Sunrise Prescription Writer (RxWriter) (Allscripts Healthcare Solutions, Chicago, Ill.) from prior admissions, was assessed from March 2015-June 2016. We constructed statistical process control charts and identified special causes., Results: Key barriers included lack of knowledge about RxWriter and lack of accountability for completing medication reconciliation. The percentage of patients without medication reconciliation decreased from 32% at baseline to 22% with education ( P < 0.001), to 15% with the use of automated e-mail reminders ( P < 0.001). We sustained improvement over the following year. Statistical process control testing indicated shifts aligning with each stage of the study., Conclusion: Provider-tailored, automated e-mail reminders linked to electronic health record with educational training significantly improved resident compliance with use of an electronic tool for documentation of home medication reconciliation on hospital admission.

High-risk, recurrent, or refractory solid tumors in pediatric, adolescent, and young adult (AYA) patients have an extremely poor prognosis despite current intensive treatment regimens. We piloted an allogeneic bone marrow transplant platform using reduced-intensity conditioning (RIC) and partially HLA-mismatched (haploidentical) related donors for this population of pediatric and AYA solid tumor patients. Sixteen patients received fludarabine, cyclophosphamide, melphalan, and low-dose total body irradiation RIC haploidentical BMT (haploBMT) followed by post-transplantation cyclophosphamide (PTCy), mycophenolate mofetil, and sirolimus. All assessable patients were full donor chimeras on day 30 with a median neutrophil recovery of 19 days and platelet recovery of 21 days. One patient (7%) exhibited secondary graft failure associated with concomitant infection. The median follow-up time was 15 months. Overall survival was 88%, 56%, and 21% at 6, 12, and 24 months, respectively. Median survival from transplant date was 14 months with a median progression-free survival 7 months. We observed limited graft-versus-host disease in 3 patients and nonrelapse mortality in 1 patient. We demonstrated that RIC haploBMT with PTCy is feasible and has acceptable toxicities in patients with incurable pediatric and AYA solid tumors; thus, this approach serves as a platform for post-transplant strategies to prevent relapse and optimize progression-free survival., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

As quality improvement and patient safety come to play a larger role in health care, academic medical centers and health systems are poised to take a leadership role in addressing these issues. Academic medical centers can leverage their large integrated footprint and have the ability to innovate in this field. However, a robust quality management infrastructure is needed to support these efforts. In this context, quality and safety are often described at the executive level and at the unit level. Yet, the role of individual departments, which are often the dominant functional unit within a hospital, in realizing health system quality and safety goals has not been addressed. Developing a departmental quality management infrastructure is challenging because departments are diverse in composition, size, resources, and needs.In this article, the authors describe the model of departmental quality management infrastructure that has been implemented at the Johns Hopkins Hospital. This model leverages the fractal approach, linking departments horizontally to support peer and organizational learning and connecting departments vertically to support accountability to the hospital, health system, and board of trustees. This model also provides both structure and flexibility to meet individual departmental needs, recognizing that independence and interdependence are needed for large academic medical centers. The authors describe the structure, function, and support system for this model as well as the practical and essential steps for its implementation. They also provide examples of its early success.

To date, there has been a lack of pediatric experience regarding the efficacy and tolerability of immune checkpoint inhibitors after haploidentical hematopoietic stem cell transplant (HSCT). We present the case of a 22-year-old female with multiple-relapsed Hodgkin lymphoma (HL) who presented with a new relapse after haploidentical (post-haplo) HSCT. Anti-PD-1 therapy with nivolumab resulted in significant objective disease response and clinical improvement without notable side effects, including the absence of a graft-versus-host disease (GVHD). This case report suggests that immune checkpoint inhibition may be safely tolerated even in the setting of haploidentical HSCT, without triggering overt GVHD., (© 2016 Wiley Periodicals, Inc.)

Lower-intensity conditioning regimens for haploidentical blood or marrow transplantation (BMT) are safe and efficacious for adult patients with hematologic malignancies. We report data for pediatric/young adult patients with high-risk hematologic malignancies (n = 40) treated with nonmyeloablative haploidentical BMT with post-transplantation cyclophosphamide from 2003 to 2015. Patients received a preparative regimen of fludarabine, cyclophosphamide, and total body irradiation. Post-transplantation immunosuppression consisted of cyclophosphamide, mycophenolate mofetil, and tacrolimus. Donor engraftment occurred in 29 of 32 (91%), with median time to engraftment of neutrophils >500/µL of 16 days (range, 13 to 22) and for platelets >20,000/µL without transfusion of 18 days (range, 12 to 62). Cumulative incidences of acute graft-versus-host disease (GVHD) grades II to IV and grades III and IV at day 100 were 33% and 5%, respectively. The cumulative incidence of chronic GVHD was 23%, with 7% moderate-to-severe chronic GVHD, according to National Institutes of Health consensus criteria. Transplantation-related mortality (TRM) at 1 year was 13%. The cumulative incidence of relapse at 2 years was 52%. With a median follow-up of 20 months (range, 3 to 148), 1-year actuarial overall and event-free survival were 56% and 43%, respectively. Thus, we demonstrate excellent rates of engraftment, GVHD, and TRM in pediatric/young adult patients treated with this regimen. This approach is a widely available, safe, and feasible option for pediatric and young adult patients with high-risk hematologic malignancies, including those with a prior history of myeloablative BMT and/or those with comorbidities or organ dysfunction that preclude eligibility for myeloablative BMT., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Objective: Use of high-dose cyclophosphamide without hematopoietic stem cell transplant to treat severe aplastic anemia (SAA) has been controversial due to concern for increased infectious toxicity as compared with antithymocyte globulin and cyclosporine A. As children often tolerate dose-intensive therapy better than adults, we sought to perform a detailed retrospective analysis of both treatment response and toxicity in 28 patients younger than 22 years of age treated with 29 courses of high-dose cyclophosphamide as the sole form of immunosuppression., Study Design: Children and adolescents with SAA who lacked an human leukocyte antigen-matched sibling donor were treated with cyclophosphamide 50 mg/kg/d for 4 consecutive days then received daily granulocyte colony stimulating factor until neutrophil recovery, transfusion support, and antimicrobial prophylaxis., Results: Overall survival was 85%, with hematologic response of 79% and complete response of 66%. Cumulative incidences of bacterial infection (86%) and fungal infection (62%) were high but deaths due to infection were rare, as were clonal evolution (1/28), clinically relevant paroxysmal nocturnal (1/28), and relapse (2/28)., Conclusions: Response rates and survival following high-dose cyclophosphamide in pediatric patients with SAA exceed those seen in adults and compare favorably to antithymocyte globulin/cyclosporine A with manageable infectious toxicity., Competing Interests: The authors have no conflicts of interest to disclose.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD) is a rare, generally progressive, and potentially fatal syndrome of unclear etiology. The syndrome is characterized by normal development followed by a sudden, rapid hyperphagic weight gain beginning during the preschool period, hypothalamic dysfunction, and central hypoventilation, and is often accompanied by personality changes and developmental regression, leading to substantial morbidity and mortality. We describe 2 children who had symptomatic and neuropsychological improvement after high-dose cyclophosphamide treatment. Our experience supports an autoimmune pathogenesis and provides the first neuropsychological profile of patients with rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation., (Copyright © 2016 by the American Academy of Pediatrics.)

There are few therapeutic options for patients with T-cell acute lymphoblastic leukemia (T-ALL) who have recurrent disease after initial matched sibling hematopoietic stem cell transplantation. While a second hematopoietic stem cell transplant (HSCT) from a haploidentical donor offers the conceptual possibility of greater graft versus leukemia effect, there is minimal literature to describe the efficacy of this approach in recurrent pediatric T-ALL. We present the case of a now 9-year-old female in whom second haploidentical HSCT, followed by successive donor lymphocyte infusions in response to minimal residual disease reemergence, has led to 3+ years of ongoing disease control without graft versus host disease and excellent quality of life., (© 2016 Wiley Periodicals, Inc.)

Background: Automated functional imaging (AFI) was introduced to two-dimensional speckle-tracking echocardiography to facilitate strain assessment in the clinical settings. In patients treated with cardiotoxic anthracyclines, AFI may be helpful in the detection of early myocardial injury when left ventricular ejection fraction (LVEF) remains normal., Methods: We retrospectively assessed feasibility of AFI in 143 echocardiograms on 102 subjects aged 0.4-22 years (mean 12.3) obtained over a 12-month period. We computed a Z-score for apical four-chamber longitudinal strain using published normal data to assess for abnormal strain in patients with and without previous exposure to anthracyclines., Results: AFI was feasible in 95.1% of echocardiograms, with low inter- and intraobserver variability. There was a statistically significant association between abnormal longitudinal strain Z-score (SZ < -2.0) and depressed LVEF (<55%, P < 0.001). However, 46% of echocardiograms with normal LVEF had abnormal SZ; half of which had no prior anthracycline exposure. The correlation between SZ and LVEF was strongest in subjects exposed to anthracyclines (r(2) = 0.12, P < 0.01). Increasing age was associated with decreasing SZ. Total cumulative dose, after adjusting for age, was inversely associated with SZ (r(2) = 0.42, P < 0.001). Time from last dose of anthracycline had no significant association with SZ., Conclusions: AFI is highly feasible in the clinical settings. The observed high prevalence of abnormal longitudinal strain in our cohort emphasizes the importance of obtaining baseline measurements prior to anthracycline treatment. The effects of anthracycline on longitudinal strain may be dose and age dependent, with younger children less likely to show abnormalities., (© 2016 Wiley Periodicals, Inc.)

Allogeneic hematopoietic stem cell transplantation (HSCT) is curative for many nonmalignant pediatric disorders, including hemoglobinopathies, bone marrow failure syndromes, and immunodeficiencies. There is great success using HLA-matched related donors for these patients; however, the use of alternative donors has been associated with increased graft failure, graft-versus-host disease (GVHD), and transplant-related mortality (TRM). HSCT using alternative donors with post-transplantation cyclophosphamide (PT/Cy) for GVHD prophylaxis has been performed for hematologic malignancies with engraftment, GVHD, and TRM comparable with that seen with HLA-matched related donors. There are limited reports of HSCT in nonmalignant pediatric disorders other than hemoglobinopathies using alternative donors and PT/Cy. We transplanted 11 pediatric patients with life-threatening nonmalignant conditions using reduced-intensity conditioning, alternative donors, and PT/Cy alone or in combination with tacrolimus and mycophenolate mofetil. We observed limited GVHD, no TRM, and successful engraftment sufficient to eliminate manifestations of disease in all patients. Allogeneic HSCT using alternative donors and PT/Cy shows promise for curing nonmalignant disorders; development of prospective clinical trials to confirm these observations is warranted., (Copyright © 2016 American Society for Blood and Marrow Transplantation. All rights reserved.)

Pneumocystis jiroveci pneumonia (PJP) is associated with high morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Little is known about PJP infections after HSCT because of the rarity of disease given routine prophylaxis. We report the results of a Center for International Blood and Marrow Transplant Research study evaluating the incidence, timing, prophylaxis agents, risk factors and mortality of PJP after autologous (auto) and allogeneic (allo) HSCT. Between 1995 and 2005, 0.63% allo recipients and 0.28% auto recipients of first HSCT developed PJP. Cases occurred as early as 30 days to beyond a year after allo HSCT. A nested case cohort analysis with supplemental data (n=68 allo cases, n=111 allo controls) revealed that risk factors for PJP infection included lymphopenia and mismatch after HSCT. After allo or auto HSCT, overall survival was significantly poorer among cases vs controls (P=0.0004). After controlling for significant variables, the proportional hazards model revealed that PJP cases were 6.87 times more likely to die vs matched controls (P<0.0001). We conclude PJP infection is rare after HSCT but is associated with high mortality. Factors associated with GVHD and with poor immune reconstitution are among the risk factors for PJP and suggest that protracted prophylaxis for PJP in high-risk HSCT recipients may improve outcomes.

Background: Telomere syndromes have their most common manifestation in idiopathic pulmonary fibrosis and emphysema. The short telomere defect in these patients may manifest systemically as bone marrow failure and liver disease. We sought to understand the causes of dyspnea in telomerase and telomere gene mutation carriers who have no parenchymal lung disease., Methods: Clinical and pathologic data were reviewed as part of a Johns Hopkins-based natural history study of short telomere syndromes including dyskeratosis congenita., Results: Hepatopulmonary syndrome (HPS) was diagnosed in nine of 42 cases (21%). Their age at presentation was significantly younger than that of cases initially presenting with pulmonary fibrosis and emphysema (median, 25 years vs 55 years; P < .001). Cases had evidence of intra- and extrapulmonary arteriovascular malformations that caused shunt physiology. Nodular regenerative hyperplasia was the most frequent histopathologic abnormality, and it was seen in the absence of cirrhosis. Dyspnea and portal hypertension were progressive, and the median time to death or liver transplantation was 6 years (range, 4-10 years; n = 6). In cases that underwent liver transplantation, dyspnea and hypoxia improved, but pulmonary fibrosis subsequently developed., Conclusions: This report identifies HPS as a frequent cause of dyspnea in telomerase and telomere gene mutation carriers. While it usually precedes the development of parenchymal lung disease, HPS may also co-occur with pulmonary fibrosis and emphysema. Recognizing this genetic diagnosis is critical for management, especially in the lung and liver transplantation setting.

Forest floor food webs play pivotal roles in carbon cycling, but they are rarely considered in models of carbon fluxes, including soil carbon dioxide emissions (respiration), under climatic warming. The indirect effects of invertebrates on heterotrophic (microbial and invertebrate) respiration through interactions with microbial communities are significant and will be altered by warming. However, the interactive effects of invertebrates and warming on heterotrophic respiration in the field are poorly understood. In this study we combined field and common garden laboratory approaches to examine relationships between warming, forest floor food web structure, and heterotrophic respiration. We found that soil animals can overwhelm the effects of warming (to 5 degrees Celsius above ambient) on heterotrophic respiration. In particular, the presence of higher trophic levels and burrowing detritivores strongly determined heterotrophic respiration rates in temperate forest soils. These effects were, however, context-dependent, with greater effects in a lower-latitude site. Without isolating and including the significant impact of invertebrates, climate models will be incomplete, hindering well-informed policy decisions.

Background: A study was conducted to investigate (1) the extent to which best-practice central line maintenance practices were employed in the homes of pediatric oncology patients and by whom, (2) caregiver beliefs about central line care and central line-associated blood stream infection (CLABSI) risk, (3) barriers to optimal central line care by families, and (4) educational experiences and preferences regarding central line care., Methods: Researchers administered a survey to patients and families in a tertiary care pediatric oncology clinic that engaged in rigorous ambulatory and inpatient CLABSI prevention efforts., Results: Of 110 invited patients and caregivers, 105 participated (95% response rate) in the survey (March-May 2012). Of the 50 respondents reporting that they or another caregiver change central line dressings, 48% changed a dressing whenever it was soiled as per protocol (many who did not change dressings per protocol also never personally changed dressings); 67% reported the oncology clinic primarily cares for their child's central line, while 29% reported that an adult caregiver or the patient primarily cares for the central line. Eight patients performed their own line care "always" or "most of the time." Some 13% of respondents believed that it was "slightly likely" or "not at all likely" that their child will get an infection if caregivers do not perform line care practices perfectly every time. Dressing change practices were the most difficult to comply with at home. Some 18% of respondents wished they learned more about line care, and 12% received contradictory training. Respondents cited a variety of preferences regarding line care teaching, although the majority looked to clinic nurses for modeling line care., Conclusions: Interventions aimed at reducing ambulatory CLABSIs should target appropriate educational experiences for adult caregivers and patients and identify ways to improve compliance with best-practice care.

Purpose: The Children's Oncology Group study AHOD0031, a randomized phase III study, was designed to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. To avoid treatment-associated risks that compromise long-term health and to maintain high cure rates, dose-intensive chemotherapy with limited cumulative doses was used., Patients and Methods: Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone (ABVE-PC) followed by response evaluation. Rapid early responders (RERs) received two additional ABVE-PC cycles, followed by complete response (CR) evaluation. RERs with CR were randomly assigned to involved-field radiotherapy (IFRT) or no additional therapy; RERs with less than CR were nonrandomly assigned to IFRT. Slow early responders (SERs) were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). All SERs were assigned to receive IFRT., Results: Among 1,712 eligible patients, 4-year event-free survival (EFS) was 85.0%: 86.9% for RERs and 77.4% for SERs (P < .001). Four-year overall survival was 97.8%: 98.5% for RERs and 95.3% for SERs (P < .001). Four-year EFS was 87.9% versus 84.3% (P = .11) for RERs with CR who were randomly assigned to IFRT versus no IFRT, and 86.7% versus 87.3% (P = .87) for RERs with positron emission tomography (PET) -negative results at response assessment. Four-year EFS was 79.3% versus 75.2% (P = .11) for SERs who were randomly assigned to DECA versus no DECA, and 70.7% versus 54.6% (P = .05) for SERs with PET-positive results at response assessment., Conclusion: This trial demonstrated that early response assessment supported therapeutic titration (omitting radiotherapy in RERs with CR; augmenting chemotherapy in SERs with PET-positive disease). Strategies directed toward improved response assessment and risk stratification may enhance tailoring of treatment to patient characteristics and response., (© 2014 by American Society of Clinical Oncology.)