Redox status regulates autophagy in thymic stromal cells and promotes T cell tolerance.

Thymic stromal cells (TSCs) are critical regulators of T cell tolerance, but their basic biology has remained under-characterized because they are relatively rare and difficult to isolate. Recent work has revealed that constitutive autophagy in TSCs is required for self-antigen presentation and central T cell tolerance induction; however, the mechanisms regulating constitutive autophagy in TSCs are not well understood. Hydrogen peroxide has been shown to increase autophagy flux in other tissues, and we previously identified conspicuously low expression of the hydrogen peroxide-quenching enzyme catalase in TSCs. We investigated whether the redox status of TSCs established by low catalase expression regulates their basal autophagy levels and their capacity to impose central T cell tolerance. Transgenic overexpression of catalase diminished autophagy in TSCs and impaired thymocyte clonal deletion, concomitant with increased frequencies of spontaneous lymphocytic infiltrates in lung and liver and of serum antinuclear antigen reactivity. Effects on clonal deletion and autoimmune indicators were diminished in catalase transgenic mice when autophagy was rescued by expression of the Becn1F121A/F121A knock-in allele. These results suggest a metabolic mechanism by which the redox status of TSCs may regulate central T cell tolerance.

Redox regulation of age-associated defects in generation and maintenance of T cell self-tolerance and immunity to foreign antigens.

Thymic atrophy reduces naive T cell production and contributes to increased susceptibility to viral infection with age. Expression of tissue-restricted antigen (TRA) genes also declines with age and has been thought to increase autoimmune disease susceptibility. We find that diminished expression of a model TRA gene in aged thymic stromal cells correlates with impaired clonal deletion of cognate T cells recognizing an autoantigen involved in atherosclerosis. Clonal deletion in the polyclonal thymocyte population is also perturbed. Distinct age-associated defects in the generation of antigen-specific T cells include a conspicuous decline in generation of T cells recognizing an immunodominant influenza epitope. Increased catalase activity delays thymic atrophy, and here, we show that it mitigates declining production of influenza-specific T cells and their frequency in lung after infection, but does not reverse declines in TRA expression or efficient negative selection. These results reveal important considerations for strategies to restore thymic function.

Impact of Clinical Decision Support on Azithromycin Prescribing in Primary Care Clinics.

BACKGROUND: Inappropriate use of antibiotics in the outpatient setting is a common problem, yet literature evaluating best practices for stewardship interventions in this setting is sparse. OBJECTIVE: To evaluate the impact of clinical decision support (CDS) order panels for azithromycin prescribing on the percentage of inappropriate azithromycin prescriptions in primary care clinics. DESIGN: Single-center, retrospective analysis of azithromycin prescribing within nine primary care clinics. Pre-intervention and post-intervention data included azithromycin prescriptions from November 2016 to April 2017 and February 2019 to July 2019, respectively. Key exclusion criteria included prescriptions for the treatment of a sexually transmitted infection or for prophylaxis against Mycobacterium avium complex. INTERVENTION: The azithromycin CDS panel was created to provide point-of-care information on appropriate use of azithromycin along with recommended alternatives based on indications. CDS panels were implemented on January 10, 2019. MAIN MEASURES: The primary composite outcome was the change in the percentage of inappropriate azithromycin prescribing before and after implementation of CDS panels. The composite outcome included prescriptions with inappropriate indications for azithromycin, unnecessary prescriptions, inappropriate treatment durations, and/or inappropriate dose. KEY RESULTS: There were 306 and 263 prescriptions for azithromycin prescriptions included for analysis in the pre- and post-intervention periods, respectively. Inappropriate prescriptions decreased by 12.6% from the pre- to post-intervention period (81.4% vs. 68.8%; P < 0.001). In both the pre- and post-intervention period, bronchitis and unspecified upper respiratory tract infections (URI) were the two most common indications where azithromycin was prescribed inappropriately. CONCLUSIONS: Implementation of CDS order panels resulted in a reduction in inappropriate azithromycin prescribing. However, additional improvement in azithromycin prescribing is needed especially for the indications of bronchitis and unspecified URI.

Risk Factors and Prevalence of QTc Prolongation in Adult Burn Patients Receiving Methadone.

Methadone is an opioid commonly used for acute pain management in burn patients. One adverse effect of methadone is QTc interval prolongation, which may be associated with adverse cardiac outcomes. There is currently a paucity of data regarding risk of QTc prolongation in burn patients taking methadone and a lack of evidence-based recommendations for monitoring strategies in this population. The study objective was to determine the prevalence, risk factors, and cardiac outcomes related to methadone-associated QTc prolongation in adult burn patients. A total of 91 patients were included and were divided into groups according to maximum QTc. QTc prolongation was defined as greater than or equal to 470 ms (males) or 480 ms (females). There were no differences between groups regarding patient-specific risk factors, baseline QTc, or time to longest QTc. Patients in the prolonged QTc group had a higher rate of cardiac events (44% vs 9%; P < .001), higher median (IQR) change from baseline to longest QTc (61 ms [18,88] vs 23 ms [13,38]; P < .001), higher median (IQR) total daily dose of methadone (90 mg [53,98] vs 53 mg [30,75]; P = .004), and longer median (IQR) length of stay (53 [33,82] vs 35 [26,52] days; P = .008). QTc prolongation in burn patients was associated with increased methadone dose and resulted in a higher rate of cardiac events. This study was the first of its kind to look at risk factors and cardiac outcomes associated with methadone use in burn patients.

Cancer Anorexia and Cachexia: Screening in an Ambulatory Infusion Service and Nutrition Consultation
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BACKGROUND: Cancer anorexia-cachexia syndrome compromises physical function and nutritional and emotional well-being. Systematic screening followed by nutrition referral for appropriate interventions is rare.
. OBJECTIVES: The purpose of this study was to pilot a screening process followed by nutritional assessment and intervention when warranted for patients with lung malignancies.
. METHODS: Adult patients with lung malignancies were invited to complete the 12-item Anorexia/Cachexia Scale (A/CS-12) on the day of chemotherapy initiation in ambulatory infusion. Those who scored at a preset threshold were referred to nutrition services for a comprehensive assessment and intervention plan. Those who scored better than the threshold completed the A/CS-12 at each infusion visit for as many as 16 weeks. 
. FINDINGS: 90 participants enrolled, and 46 scored in a moderate-to-severe-risk category; of those, 42 were referred to nutrition services.

Prenatal cannabis exposure - The "first hit" to the endocannabinoid system.

As more states and countries legalize medical and/or adult recreational marijuana use, the incidences of prenatal cannabis exposure (PCE) will likely increase. While young people increasingly view marijuana as innocuous, marijuana preparations have been growing in potency in recent years, potentially creating global clinical, public health, and workforce concerns. Unlike fetal alcohol spectrum disorder, there is no phenotypic syndrome associated with PCE. There is also no preponderance of evidence that PCE causes lifelong cognitive, behavioral, or functional abnormalities, and/or susceptibility to subsequent addiction. However, there is compelling circumstantial evidence, based on the principles of teratology and fetal malprogramming, suggesting that pregnant women should refrain from smoking marijuana. The usage of marijuana during pregnancy perturbs the fetal endogenous cannabinoid signaling system (ECSS), which is present and active from the early embryonic stage, modulating neurodevelopment and continuing this role into adulthood. The ECSS is present in virtually every brain structure and organ system, and there is also evidence that this system is important in the regulation of cardiovascular processes. Endocannabinoids (eCBs) undergird a broad spectrum of processes, including the early stages of fetal neurodevelopment and uterine implantation. Delta-9-tetrahydrocannabinol (THC), the psychoactive chemical in cannabis, enters maternal circulation, and readily crosses the placental membrane. THC binds to CB receptors of the fetal ECSS, altering neurodevelopment and possibly rewiring ECSS circuitry. In this review, we discuss the Double-Hit Hypothesis as it relates to PCE. We contend that PCE, similar to a neurodevelopmental teratogen, delivers the first hit to the ECSS, which is compromised in such a way that a second hit (i.e., postnatal stressors) will precipitate the emergence of a specific phenotype. In summary, we conclude that perturbations of the intrauterine milieu via the introduction of exogenous CBs alter the fetal ECSS, predisposing the offspring to abnormalities in cognition and altered emotionality. Based on recent experimental evidence that we will review here, we argue that young women who become pregnant should immediately take a "pregnant pause" from using marijuana.

A prospective, multi-institutional study of pediatric all-terrain vehicle crashes.

BACKGROUND: Pediatric all-terrain vehicle (ATV) injuries have been increasing annually for more than a decade. The purpose of this study was to prospectively evaluate crash circumstances and clinical outcomes resulting from pediatric ATV crashes. METHODS: Three pediatric trauma centers prospectively collected data from patients during their hospitalization for injuries sustained in ATV crashes from July 2007 through June 2012. Patients completed a 35-item questionnaire describing the crash circumstances (ATV engine size, safety equipment use, and training/experience). Clinical data (injuries, surgical procedures, etc.) were collected for each patient. RESULTS: Eighty-four patients were enrolled, with a mean (SD) age of 13.0 (3.1) years, and were predominantly male (n = 55, 65%). Injuries were musculoskeletal (42%), central nervous system (39%), abdominal (20%), thoracic (16%), and genitourinary (4%). Multisystem injuries were prevalent (27%), and two patients died. Thirty-three patients (43%) required operative intervention. Most children were riding for recreation (96%) and ignored ATV manufacturers' recommendation that children younger than 16 years ride ATVs with smaller (≤90 cc) engines (71%). Dangerous riding practices were widespread: no helmet (70%), no adult supervision (56%), double riding (50%), riding on paved roads (23%), and nighttime riding (16%). Lack of helmet use was significantly associated with head injury (53% vs. 25%, p = 0.03). Rollover crashes were most common (44%), followed by collision with a stationary object (25%) or another vehicle (12%). Half (51%) of children said that they would ride an ATV again. CONCLUSION: These data demonstrate a relationship between dangerous ATV riding behaviors and severe injuries in children who crash. Children younger than 16 years should not operate ATVs, and legislation that effectively restricts ATV use in children is urgently needed. LEVEL OF EVIDENCE: Epidemiologic study, level III.

Early vs interval appendectomy for children with perforated appendicitis.

OBJECTIVE: To compare the effectiveness and adverse event rates of early vs interval appendectomy in children with perforated appendicitis. DESIGN: Nonblinded randomized trial. SETTING: A tertiary-referral urban children's hospital. PATIENTS: A total of 131 patients younger than 18 years with a preoperative diagnosis of perforated appendicitis. INTERVENTIONS: Early appendectomy (within 24 hours of admission) vs interval appendectomy (6-8 weeks after diagnosis). MAIN OUTCOME MEASURES: Time away from normal activities (days). Secondary outcomes included the overall adverse event rates and the rate of predefined specific adverse events (eg, intra-abdominal abscess, surgical site infection, unplanned readmission). RESULTS: Early appendectomy, compared with interval appendectomy, significantly reduced the time away from normal activities (mean, 13.8 vs 19.4 days; P < .001). The overall adverse event rate was 30% for early appendectomy vs 55% for interval appendectomy (relative risk with interval appendectomy, 1.86; 95% confidence interval, 1.21-2.87; P = .003). Of the patients randomized to interval appendectomy, 23 (34%) had an appendectomy earlier than planned owing to failure to improve (n = 17), recurrent appendicitis (n = 5), or other reasons (n = 1). CONCLUSIONS: Early appendectomy significantly reduced the time away from normal activities. The overall adverse event rate after early appendectomy was significantly lower compared with interval appendectomy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00435032.

Late effects of pelvic rhabdomyosarcoma and its treatment in female survivors.

PURPOSE: To document the spectrum and severity of late effects in female survivors of pelvic rhabdomyosarcoma. PATIENTS AND METHODS: We reviewed the demographic, diagnostic, treatment, and outcome data of the 26 females treated for pelvic rhabdomyosarcoma at our institution between March 1962 and December 1996 who survived free of disease for 5 or more years. Adverse effects that occurred 5 or more years after diagnosis were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. RESULTS: The most common tumor sites were vagina (n = 7), pelvis/retroperitoneum (n = 6), and bladder (n = 4). All patients received chemotherapy (alkylating agent, n = 23; doxorubicin, n = 16); 22 received radiotherapy (median dose, 46 Gy). Median follow-up of the 23 survivors was 20.3 years. Late effects occurred in 24 patients, 23 of whom had grade 3/4 late effects (median grade 3/4 late effects per patient, three; range, zero to 14). Fourteen patients (54%) required surgery for late complications. The 22 patients who had received radiotherapy had a greater median number of late effects per patient than did the remaining four (9.5 v one; P = .002). The median number of late effects per patient was higher in the 12 patients treated during or after 1984 than in the 14 treated earlier (12.5 v 6.5; P = .041). CONCLUSION: The burden of late effects in girls treated for pelvic rhabdomyosarcoma is significant and does not seem to be diminishing with advances in treatment. Prospective studies are needed to better assess the impact of these late effects on quality of life and functional outcome, and to refine the treatment approach to pelvic rhabdomyosarcoma.

Development of risk-based guidelines for pediatric cancer survivors: the Children's Oncology Group Long-Term Follow-Up Guidelines from the Children's Oncology Group Late Effects Committee and Nursing Discipline.

The Children's Oncology Group Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers are risk-based, exposure-related clinical practice guidelines intended to promote earlier detection of and intervention for complications that may potentially arise as a result of treatment for pediatric malignancies. Developed through the collaborative efforts of the Children's Oncology Group Late Effects Committee, Nursing Discipline, and Patient Advocacy Committee, these guidelines represent a statement of consensus from a multidisciplinary panel of experts in the late effects of pediatric cancer treatment. The guidelines are both evidence-based (utilizing established associations between therapeutic exposures and late effects to identify high-risk categories) and grounded in the collective clinical experience of experts (matching the magnitude of risk with the intensity of screening recommendations). They are intended for use beginning 2 or more years following the completion of cancer therapy; however, they are not intended to provide guidance for follow-up of the survivor's primary disease. A complementary set of patient education materials ("Health Links") was developed to enhance follow-up care and broaden the application of the guidelines. The information provided in these guidelines is important for health care providers in the fields of pediatrics, oncology, internal medicine, family practice, and gynecology, as well as subspecialists in many fields. Implementation of these guidelines is intended to increase awareness of potential late effects and to standardize and enhance follow-up care provided to survivors of pediatric cancer throughout the lifespan. The Guidelines, and related Health Links, can be downloaded in their entirety at www.survivorshipguidelines.org.

Facilitating care for childhood cancer survivors: integrating children's oncology group long-term follow-up guidelines and health links in clinical practice.

Childhood cancer survivors are a growing, vulnerable group with health care needs unique to their cancer treatments. They may experience many late physical and psychological complications (late effects) of treatment including organ dysfunction, infertility, second neoplasms, chronic hepatitis, musculoskeletal problems, alterations in cognitive function, and myriad psychosocial problems. Health care providers may be unaware of actual or potential survivor problems. Until recently, there were no clearly defined, easily accessible risk-based guidelines for cancer survivor follow-up care. This article will use a case-study approach to demonstrate how the newly developed Children's Oncology Group Long-term Follow-up Guidelines and Health Links can be used in clinical practice to improve awareness about late effects and the importance of follow-up care for childhood cancer survivors. The Children's Oncology Group Guidelines and Health Links were created by a multidisciplinary team of health care experts and patient advocates to provide a systematic plan for pediatric cancer survivor follow-up care and health education across the cancer continuum.

A model of care for childhood cancer survivors that facilitates research.

The majority of children and adolescents diagnosed with cancer will achieve long-term survival after contemporary therapy. Consequent to this success are challenges inherent in coordinating lifelong health care for a group predisposed to a variety of cancer-related complications. With increasing numbers of aging adult survivors of childhood cancer, clinicians now face the additional challenge of studying delayed effects of childhood cancer in the context of organ senescence. Clinicians must also address the transition of survivor health care from the pediatric oncology setting to the adult community. Salient issues influencing health care of long-term childhood cancer survivors are summarized, and a model for monitoring late treatment effects used at a pediatric cancer facility is presented. This model is remarkable for its ability to enhance optimal delivery of long-term survivor care, facilitate the transition of survivor care from the pediatric treatment center to community, providers, and support investigations of late cancer-related morbidity and mortality.