IL-18-secreting multiantigen targeting CAR T cells eliminate antigen-low myeloma in an immunocompetent mouse model.

ABSTRACT: Multiple myeloma is a plasma cell malignancy that is currently incurable with conventional therapies. Following the success of CD19-targeted chimeric antigen receptor (CAR) T cells in leukemia and lymphoma, CAR T cells targeting B-cell maturation antigen (BCMA) more recently demonstrated impressive activity in relapsed and refractory myeloma patients. However, BCMA-directed therapy can fail due to weak expression of BCMA on myeloma cells, suggesting that novel approaches to better address this antigen-low disease may improve patient outcomes. We hypothesized that engineered secretion of the proinflammatory cytokine interleukin-18 (IL-18) and multiantigen targeting could improve CAR T-cell activity against BCMA-low myeloma. In a syngeneic murine model of myeloma, CAR T cells targeting the myeloma-associated antigens BCMA and B-cell activating factor receptor (BAFF-R) failed to eliminate myeloma when these antigens were weakly expressed, whereas IL-18-secreting CAR T cells targeting these antigens promoted myeloma clearance. IL-18-secreting CAR T cells developed an effector-like T-cell phenotype, promoted interferon-gamma production, reprogrammed the myeloma bone marrow microenvironment through type-I/II interferon signaling, and activated macrophages to mediate antimyeloma activity. Simultaneous targeting of weakly-expressed BCMA and BAFF-R with dual-CAR T cells enhanced T-cell:target-cell avidity, increased overall CAR signal strength, and stimulated antimyeloma activity. Dual-antigen targeting augmented CAR T-cell secretion of engineered IL-18 and facilitated elimination of larger myeloma burdens in vivo. Our results demonstrate that combination of engineered IL-18 secretion and multiantigen targeting can eliminate myeloma with weak antigen expression through distinct mechanisms.

Recent advances in activated water systems for the postharvest management of quality and safety of fresh fruits and vegetables.

Over the last three decades, decontamination management of fresh fruits and vegetables (FFVs) in the packhouses and along the supply chains has been heavily dependent on chemical-based wash. This has resulted in the emergence of resistant foodborne pathogens and often the deposition of disinfectant byproducts on FFVs, rendering them unacceptable to consumers. The management of foodborne pathogens, microbial contaminants, and quality of FFVs are a major concern for the horticultural industries and public health. Activated water systems (AWS), such as electrolyzed water, plasma-activated water, and micro-nano bubbles, have gained significant attention from researchers over the last decade due to their nonthermal and nontoxic mode of action for microbial inactivation and preservation of FFVs quality. The aim of this review is to provide a comprehensive summary of recent progress on the application of AWS and their effects on quality attributes and microbial safety of FFVs. An overview of the different types of AWS and their properties is provided. Furthermore, the review highlights the chemistry behind generation of reactive species and the impact of AWS on the quality attributes of FFVs and on the inactivation/reduction of spoilage and pathogenic microbes (in vivo or in vitro). The mechanisms of action of microorganism inactivation are discussed. Finally, this work highlights challenges and limitations for commercialization and safety and regulation issues of AWS. The synergistic prospect on combining AWS for maximum microorganism inactivation effectiveness is also considered. AWS offers a potential alternative as nonchemical interventions to maintain quality attributes, inactivate spoilage and pathogenic microorganisms, and extend the shelf-life for FFVs.

Clinical and microbiological profiles in post-chemotherapy neutropenic fever in hematological malignancy: exploration of clinical phenotype patterns by two-step cluster analysis.

BACKGROUND: Epidemiology of infectious diseases causing febrile illness varies geographically with human attributes. Periodic institutional surveillance of clinical and microbiological profiles in adding data to updating trends, modulating pharmatherapeutics, signifying possible excessive treatments and risk of drug resistance in post-chemotherapy neutropenic fever (NF) in hematological malignancy (HM) is limited. We aimed to review institutional clinical and microbiological data and explore clinical phenotype pattern groups among data. METHODS: Available data from 372 NF episodes were included. Demographics, types of malignancies, laboratory data, antimicrobial treatments and febrile-related outcome data such as predominant pathogens and microbiological diagnosed infections (MDIs) were collected. Descriptive statistics, two-step cluster analysis and non-parametric tests were employed. RESULTS: The occurrences of microbiological diagnosed bacterial infections (MDBIs; 20.2%) and microbiological diagnosed fungal infections (MDFIs; 19.9%) were almost equal. Gram-negative pathogens (11.8%) were comparable with gram-positive pathogens (9.9%), with gram-negative being slightly predominant. Death rate was 7.5%. Two-step cluster analysis yielded four distinct clinical phenotype pattern (cluster) groups: cluster 1 'lymphomas without MDIs', cluster 2 'acute leukemias MDBIs', cluster 3 'acute leukemias MDFIs' and cluster 4 'acute leukemias without MDIs'. Considerable NF events with antibiotic prophylaxis being not identified as MDI might have cases in low-risk with non-infectious reasons causing febrile reactions that might possibly not require prophylaxis. CONCLUSIONS: Regular institutional surveillance with active parameter assessments to signify risk levels in the post-chemotherapy stage, even prior to the onset of fever, might be an evidence-based strategy in the management of NF in HM.

Octopamine neuron dependent aggression requires dVGLUT from dual-transmitting neurons.

Neuromodulators such as monoamines are often expressed in neurons that also release at least one fast-acting neurotransmitter. The release of a combination of transmitters provides both "classical" and "modulatory" signals that could produce diverse and/or complementary effects in associated circuits. Here, we establish that the majority of Drosophila octopamine (OA) neurons are also glutamatergic and identify the individual contributions of each neurotransmitter on sex-specific behaviors. Males without OA display low levels of aggression and high levels of inter-male courtship. Males deficient for dVGLUT solely in OA-glutamate neurons (OGNs) also exhibit a reduction in aggression, but without a concurrent increase in inter-male courtship. Within OGNs, a portion of VMAT and dVGLUT puncta differ in localization suggesting spatial differences in OA signaling. Our findings establish a previously undetermined role for dVGLUT in OA neurons and suggests that glutamate uncouples aggression from OA-dependent courtship-related behavior. These results indicate that dual neurotransmission can increase the efficacy of individual neurotransmitters while maintaining unique functions within a multi-functional social behavior neuronal network.

Management of esophageal button battery ingestions: resource utilization and outcomes.

PURPOSE: Institutions are adopting the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition (NASPGHAN) guidelines for pediatric esophageal button battery ingestion (EBBI). Our objective was to evaluate the guidelines' impact on in-hospital resource utilization and short-term clinical outcomes in hemodynamically stable patients after endoscopic battery removal. METHODS: A single-center retrospective review of all EBBI admissions from 2010 to 2020. Patients were divided into two groups based on adoption of national guidelines: pre-guideline (2010-2015) and post-guideline (2016-2020). RESULTS: Sixty-five patients were studied (pre-guideline n = 23; post-guideline n = 42). Compared with pre-guideline, post-guideline use of magnetic resonance imaging (MRI) increased (2/23 [8.7%]; 30/42 [71.4%]; p < 0.001). Post-guideline increases resulted for median days (IQR) receiving antibiotics (0 [0, 4]; 6 [3, 8]; p = 0.01), total pediatric intensive care unit admission (0 [0, 1]; 3 [0, 6]; p < 0.001), and total hospital length of stay (5 [2, 11]; 11.5 [4, 17]; p = 0.02). Two patients in the post-guideline group had delayed presentations despite normal imaging: one with TEF and one with aorto-esophageal fistula. All survived to discharge. CONCLUSION: In EBBI cases managed using the consensus based NASPHAGN guidelines, we report increased resource utilization without improved patient outcomes. Further research should evaluate post-guideline costs and resource utilization.

Survey of Current Institutional Practices in the Use of High-Flow Nasal Cannula for Pediatric Patients.

OBJECTIVES: High-flow nasal cannula (HFNC) is an oxygen delivery device that provides heated humidified air with higher flow rates. The purpose of this survey is to look at institutional practice patterns of HFNC initiation, weaning, and disposition for pediatric patients across the United States. METHODS: Survey was sent via electronic listservs to pediatric physicians in emergency medicine, hospital medicine, critical care, and urgent care. The questionnaire was divided into demographics and HFNC practices (initiation, management, and weaning). One response per institution was included in the analysis. RESULTS: Two hundred twenty-four responses were included in the analysis, composed of 40% pediatric emergency medicine physicians, 46% pediatric hospitalists, 13% pediatric intensive care unit (PICU) physicians, and 1% pediatric urgent care physicians. Ninety-eight percent of the participants have HFNC at their institution. Thirty-seven percent of the respondents had a formal guideline for HFNC initiation. Nearly all guideline and nonguideline institutions report HFNC use in bronchiolitis. Guideline cohort is more likely to have exclusion criteria for HFNC (42% in the guideline cohort vs 17% in the nonguideline cohort; P < 0.001) and less frequently mandates PICU admissions once on HFNC (11% in the guideline cohort vs 56% in the nonguideline cohort; P < 0.001). Forty-six percent of guideline cohort had an objective scoring system to help determine the need for HFNC, and 73% had a weaning guideline. CONCLUSIONS: Although there is general agreement to use HFNC in bronchiolitis, great practice variation remains in the initiation, management, and weaning of HFNC across the United States. There is also a discordance on PICU use when a patient is using HFNC.

Liver complications of haemoglobin H disease in adults.

Haemoglobin H (HbH) disease is a type of non-transfusion-dependent thalassaemia. This cross-sectional study aimed at determining the prevalence and severity of liver iron overload and liver fibrosis in patients with HbH disease. Risk factors for advanced liver fibrosis were also identified. A total of 80 patients were evaluated [median (range) age 53 (24-79) years, male 34%, non-deletional HbH disease 24%]. Patients underwent 'observed' T2-weighted magnetic resonance imaging examination for liver iron concentration (LIC) quantification, and transient elastography for liver stiffness measurement (LSM) and fibrosis staging. In all, 25 patients (31%) had moderate-to-severe liver iron overload (LIC ≥7 mg/g dry weight). The median LIC was higher in non-deletional than in deletional HbH disease (7·8 vs. 2.9 mg/g dry weight, P = 0·002). In all, 16 patients (20%) had advanced liver fibrosis (LSM >7.9 kPa) and seven (9%) out of them had probable cirrhosis (LSM >11.9 kPa). LSM positively correlated with age (R = 0·24, P = 0·03), serum ferritin (R = 0·36, P = 0·001) and LIC (R = 0·28, P = 0·01). In multivariable regression, age ≥65 years [odds ratio (OR) 4·97, 95% confidence interval (CI) 1·52-17·50; P = 0·047] and moderate-to-severe liver iron overload (OR 3·47, 95% CI 1·01-12·14; P = 0·01) were independently associated with advanced liver fibrosis. The findings suggest that regular screening for liver complications should be considered in the management of HbH disease.

Association of Clinical Guidelines and Decision Support with Computed Tomography Use in Pediatric Mild Traumatic Brain Injury.

OBJECTIVE: To examine whether the presence of clinical guidelines and clinical decision support (CDS) for mild traumatic brain injury (mTBI) are associated with lower use of head computed tomography (CT). STUDY DESIGN: We conducted a cross-sectional study of 45 pediatric emergency departments (EDs) in the Pediatric Hospital Information System from 2015 through 2019. We included children discharged with mTBI and surveyed ED clinical directors to ascertain the presence and implementation year of clinical guidelines and CDS. The association of clinical guidelines and CDS with CT use was assessed, adjusting for relevant confounders. As secondary outcomes, we evaluated ED length of stay and rates of 3-day ED revisits and admissions after revisits. RESULTS: There were 216 789 children discharged with mTBI, and CT was performed during 20.3% (44 114/216 789) of ED visits. Adjusted hospital-specific CT rates ranged from 11.8% to 34.7% (median 20.5%, IQR 17.3%, 24.3%). Of the 45 EDs, 17 (37.8%) had a clinical guideline, 9 (20.0%) had CDS, and 19 (42.2%) had neither. Compared with EDs with neither a clinical guideline nor CDS, visits to EDs with CDS (aOR 0.52 [0.47, 0.58]) or a clinical guideline (aOR 0.83 [0.78, 0.89]) had lower odds of including a CT for mTBI. ED length of stay and revisit rates did not differ based on the presence of a clinical guideline or CDS. CONCLUSIONS: Clinical guidelines for mTBI, and particularly CDS, were associated with lower rates of head CT use without adverse clinical outcomes.

Phylogenetics of mud snakes (Squamata: Serpentes: Homalopsidae): A paradox of both undescribed diversity and taxonomic inflation.

Mud snakes (Serpentes: Homalopsidae) are a family of 55 described, mainly aquatic, species primarily distributed throughout mainland Southeast Asia and the Indo-Australian Archipelago. Although they have been the focus of prior research, the basic relationships amongst genera and species remain poorly known. We used a combined mitochondrial and nuclear gene dataset to infer their phylogenetic relationships, using the highest levels of taxon and geographic sampling for any homalopsid phylogeny to date (62% generic and 62% species coverage; 140 individuals). Our results recover two reciprocally monophyletic groups: the fangless Brachyorrhos and its sister clade comprised of all rear-fanged homalopsids. Most genera and interspecific relationships were monophyletic and strongly supported, but intergeneric relationships and intraspecific population structure lack support. We find evidence of both undescribed diversity as well as cases of taxonomic inflation within several species. Tree-based species delimitation approaches (mPTP) support potential new candidate species as distinct from their conspecifics and also suggest that many named taxa may not be distinct species. Divergence date estimation and lineage-through-time analyses indicate lower levels of speciation in the Eocene, with a subsequent burst in diversification in the Miocene. Homalopsids may have diversified most rapidly during the Pliocene and Pleistocene, possibly in relation to tectonic shifts and sea-level fluctuations that took place in Sundaland and the Sahul Shelf. Our analyses provide new insights on homalopsid taxonomy, a baseline phylogeny for the family, and further biogeographic implications demonstrating how dynamic tectonics and Quaternary sea level changes may have shaped a widespread, diverse family of snakes.

New option for improving hematological recovery: suppression of luteinizing hormone.

Not available.

Long-term evidence of neonatal anaesthesia neurotoxicity linked to behavioural phenotypes in monkeys: where do we go from here?

Whether anaesthesia exposure early in life leads to brain damage with long-lasting structural and behavioural consequences in primates has not been conclusively determined. A study in the British Journal of Anaesthesia by Neudecker and colleagues found that 2 yr after early anaesthesia exposure, monkeys exhibited signs of chronic astrogliosis which correlate with behavioural deficits. Given the increasing frequency of exposure to anaesthetics in infancy in humans, clinical trials are greatly needed to understand how sedative/anaesthetic agents may be impacting brain and behaviour development.

Antimicrobial prophylaxis and post-chemotherapy neutropenic fever in patients with leukemia: comparisons of C-reactive protein, procalcitonin and immediate fever outcome measures between those with and without prophylaxis, and the implications for practice.

PURPOSE: The efficacy of prophylactic antimicrobial treatment renders challenges in patients with leukemias receiving chemotherapy. The study aimed to compare differences in C-reactive protein (CRP) and procalcitonin (PCT) at presentation and the immediate outcome measures of post-chemotherapy NF between patients with and without antimicrobial prophylaxis. METHODS: A 5-year observational study included 282 NF episodes in 133 leukemia patients requiring hospital care from January 2014 to May 2019. We collected demographic characteristics, laboratory data of blood cell counts and inflammatory biomarkers, and immediate outcome measures of NF, including microbiologically diagnosed infections, presence of predominant pathogens, required modification of antibiotics during NF, adverse medical complications, total fever duration, and deaths. We evaluated data between patients with and without prophylaxis. RESULTS: Of patients, 77.3%, 68.4%, and 20.6% had antibiotic prophylaxis, antifungal prophylaxis, and no prophylaxis, respectively. There were totally 15 deaths-13 with antibiotic prophylaxis and 10 with antifungal prophylaxis. CRP, PCT, and immediate outcome measures of NF did not show significant differences between those with and without antimicrobial prophylaxis. Although between-group differences showed no statistical significance, higher median fever duration, CRP and PTC values, and higher proportions of NF requiring modification of antibiotics were found more frequently in those with antimicrobial prophylaxis than in those without. CONCLUSION: The benefits of using antimicrobial prophylaxis were less supported. Enhancing diagnostic laboratory and medical complication surveillance and periodic evaluation of institutional data during post-chemotherapy neutropenia and NF in relation to antimicrobial prophylaxis is promising in providing insights to redefine the risk-benefit accounts of using prophylaxis.

Sorafenib and omacetaxine mepesuccinate as a safe and effective treatment for acute myeloid leukemia carrying internal tandem duplication of Fms-like tyrosine kinase 3.

BACKGROUND: Omacetaxine mepesuccinate (OME) has antileukemic effects against acute myeloid leukemia (AML) carrying an internal tandem duplication of Fms-like tyrosine kinase 3 (FLT3-ITD). A phase 2 clinical trial was conducted to evaluate a combination treatment of sorafenib and omacetaxine mepesuccinate (SOME). METHODS: Relapsed or refractory (R/R) or newly diagnosed patients were treated with sorafenib (200-400 mg twice daily) and OME (2 mg daily) for 7 (first course) or 5 days (second course onward) every 21 days until disease progression or allogeneic hematopoietic stem cell transplantation (HSCT). The primary endpoint was composite complete remission, which was defined as complete remission (CR) plus complete remission with incomplete hematologic recovery (CRi). Secondary endpoints were leukemia-free survival (LFS) and overall survival (OS). RESULTS: Thirty-nine R/R patients and 5 newly diagnosed patients were recruited. Among the R/R patients, 28 achieved CR or CRi. Two patients showed partial remission, and 9 patients did not respond. Among the 5 newly diagnosed patients, 4 achieved CR, and 1 achieved CRi. The median LFS and OS were 5.6 and 10.9 months, respectively. Prior Fms-like tyrosine kinase 3 (FLT3) inhibitor exposure (P = .007), 2 or more inductions (P = .001), and coexisting IDH2 (P = .008) and RUNX1 mutations (P = .003) were associated with lower CR/CRi rates. HSCT consolidation and deep molecular responses (defined as an FLT3-ITD variant allelic frequency [VAF] ≤ 0.1% or a nucleophosmin 1 [NPM1] mutant VAF ≤ 0.01%) were associated with better OS and LFS. Prior FLT3 inhibitor exposure and 2 or more inductions were associated with inferior LFS. CONCLUSIONS: SOME was safe and effective for R/R and newly diagnosed FLT3-ITD AML.

Utility of Point-of-Care Lung Ultrasonography for Evaluating Acute Chest Syndrome in Young Patients With Sickle Cell Disease.

STUDY OBJECTIVE: Acute chest syndrome is a leading cause of mortality in patients with sickle cell disease (SCD). Because early detection of acute chest syndrome is directly tied to prognosis, young patients with SCD undergo countless chest radiography screenings throughout their lifetime for commonly occurring acute chest syndrome risk factors such as fever, chest pain, or cough. Chest radiography is not an ideal screening method because it is associated with radiation exposure, which accumulates with repeated imaging. Point-of-care lung ultrasonography is a nonradiating imaging modality that has been used to identify other lung pathology and may have a role in SCD. The goal of this study was to determine the accuracy of point-of-care lung ultrasound to identify an infiltrate suggestive of acute chest syndrome in patients with SCD compared to chest radiography as the gold standard. METHODS: This was a prospective observational study in 2 urban pediatric emergency departments to evaluate the accuracy of point-of-care lung ultrasonography in identifying patients with SCD who were aged 0 to 21 years and had an infiltrate suggestive of acute chest syndrome compared with chest radiography. Clinicians and trainees with point-of-care lung ultrasonographic training obtained informed consent and performed investigational point-of-care lung ultrasonography to evaluate for lung consolidation. A blinded point-of-care lung ultrasonographic expert reviewed results for quality assurance and agreement. Accuracy, sensitivity, specificity, likelihood ratios, and positive and negative predictive value were calculated for point-of-care lung ultrasonography test performance characteristics, with chest radiography as a reference standard. RESULTS: Point-of-care lung ultrasonography was performed on 191 SCD patients with a mean age of 8 years; 41% were female patients, and there was a 17% prevalence of acute chest syndrome. Accuracy of point-of-care lung ultrasonography to detected acute chest syndrome was 92%, sensitivity was 88%, and specificity was 93% compared with that for chest radiography. CONCLUSION: Point-of-care lung ultrasonography is a feasible alternative to chest radiography for screening for acute chest syndrome in young patients with SCD. Further studies are needed to determine how this test performs within clinical practice.

Oral arsenic trioxide incorporation into frontline treatment with all-trans retinoic acid and chemotherapy in newly diagnosed acute promyelocytic leukemia: A 5-year prospective study.

BACKGROUND: Strategies using oral arsenic trioxide (As2 O3 ) are efficacious in relapsed acute promyelocytic leukemia (APL), but they have not been examined in newly diagnosed cases. METHODS: Sixty-two consecutive patients (24 men and 38 women) with a median age of 52 years (range, 22-85 years), 36% of whom had high-risk features, underwent induction with all-trans retinoic acid at 45 mg/m2 /d, oral As2 O3 at 10 mg/d, and ascorbic acid at 1 g/d (the all-trans retinoic acid-arsenic trioxide-ascorbic acid [AAA] regimen) for 6 weeks (with patients younger than 70 years additionally receiving daunorubicin at 50 mg/m2 /d × 3); they then underwent consolidation with 2 monthly cycles of daunorubicin (50 mg/m2 /d × 2) and cytarabine (100 mg/m2 /d × 5) and received AAA maintenance (2 weeks every 8 weeks) for 2 years. A contemporaneous cohort of 37 newly diagnosed patients (15 men and 22 women) with a median age of 51 years (range, 23-78 years), not consenting to oral As2 O3 induction but receiving similar induction, consolidation, and AAA maintenance, served as a comparator group; 46% of these patients had high-risk features. RESULTS: The oral As2 O3 induction cohort showed a complete remission (CR) rate of 100%. After a median of 37 months (range, 13-82 months), there were no relapses, so conventional risks (age, leukocyte and platelet counts, and Fms-like tyrosine kinase 3 [FLT3] mutations) were not relevant. The leukemia-free survival (LFS) and overall survival (OS) rates were 100% at 3 years and 94.1% at 5 years. The non-As2 O3 induction cohort showed a CR rate of 100%. After a median of 52 months (range, 14-77 months), there were 3 relapses (8%). Comparable patients in the oral As2 O3 induction and non-As2 O3 induction cohorts showed similar OS, but LFS was significantly superior in the oral As2 O3 induction cohort. CONCLUSIONS: The incorporation of oral As2 O3 into induction for newly diagnosed APL was safe and decreased relapses.

Distinct mutation spectrum, clinical outcome and therapeutic responses of typical complex/monosomy karyotype acute myeloid leukemia carrying TP53 mutations.

The present study aimed to define a subtype of complex/monosomal karyotype (CK/MK) acute myeloid leukemia (AML) by its distinct clinical features, p53 signaling and responses to p53 targeting agents. Ninety-eight young adults (range: 21-60 years; median: 49 years) with CK/MK AML were studied. They received standard induction, consolidation and allogeneic hematopoietic stem cell transplantation from siblings or matched unrelated donors if available. Chromosomal abnormalities most commonly affected chromosome 5 (30%), 7 (22%) and 17 (21%). Next generation sequencing of a 54-myeloid gene panel were available in 76 patients. Tumor protein 53 (TP53) mutations were most common (49%) and associated with the presence of -5/5q- (P < .001) and -17/17p- (P < .001), but not -7/7q- (P = .370). This "typical" CK/MK AML subtype was associated with significantly lower presenting white cell counts, higher number of karyotypic abnormalities, and inferior leukemia-free and overall survivals, compared with CK/MK AML without the typical features. Blood or bone marrow samples from typical CK/MK AML patients showed defective p53 signaling upon induction by etoposide. In vitro drug sensitivity analysis showed that they were sensitive to APR-246 that targeted mutant p53, but resistant to MDM2 antagonist MI-77301. Novel therapeutic strategies targeting TP53 mutations in CK/MK AML should be developed and tested in clinical trials.

Investigation of an Opioid Prescribing Protocol After Third Molar Extraction Procedures.

PURPOSE: The United States is experiencing an epidemic of opioid overdoses and deaths. The relation between prescription opioids and opioid abuse is well documented. Oral and maxillofacial surgeons and other dentists are proportionately among the most prevalent prescribers of opioids. Practitioners are looking for evidence-based ways to decrease excess opioid prescriptions and adequately manage postoperative pain. The authors recently analyzed the impact of a mandated nonopioid prescribing protocol at their institution. Although broad guidelines have been useful for treating postoperative pain, there are no procedure-specific guidelines for managing pain after third molar extraction. The purpose of this study was to determine whether an opioid prescribing protocol was sufficient to decrease opioid prescribing after third molar extractions. MATERIALS AND METHODS: This retrospective study compared the use of opioids prescribed for patients undergoing third molar extraction before introducing and after implementing a postoperative opioid prescribing protocol. The inclusion criterion was third molar extraction performed at the Division of Oral and Maxillofacial Surgery at the University of Minnesota (Minneapolis, MN) during the fourth quarters of 2015 and 2017 with complete records. RESULTS: The number of opioid prescriptions decreased and the number of nonopioid analgesics prescribed increased for all procedure codes after implementation of the protocol. Higher Current Dental Terminology (CDT) codes were associated with increased opioid prescriptions, indicating increased surgical difficulty was a rationale for opioid prescriptions. The mean number of opioid tablets per prescription was 15.9 in 2015 and decreased to 11.5 in 2017. No statistical difference was observed for average tablets for various CDT codes. CONCLUSION: Data from this study suggest an acute postoperative pain opioid prescribing protocol leads to fewer opioid prescriptions after third molar extraction procedures, less variance in opioid prescribing among practitioners, a decreased number of opioid tablets prescribed per patient, and safe and effective management of acute postoperative pain.

Radiologic Imaging in Trauma Patients with Cervical Spine Immobilization at a Pediatric Trauma Center.

BACKGROUND: Pediatric trauma patients with cervical spine (CS) immobilization using a cervical collar often require procedural sedation (PS) for radiologic imaging. The limited ability to perform airway maneuvers while CS immobilized with a cervical collar is a concern for emergency department (ED) staff providing PS. OBJECTIVE: To describe the use of PS and analgesia for radiologic imaging acquisition in pediatric trauma patients with CS immobilization. METHODS: Retrospective medical record review of all trauma patients with CS immobilization at a high-volume pediatric trauma center was performed. Patient demographics, imaging modality, PS success, sedative and analgesia medications, and adverse events were analyzed. Patients intubated prior to arrival to the ED were excluded. RESULTS: A total of 1417 patients with 1898 imaging encounters met our inclusion criteria. A total of 398 patients required more than one radiographic imaging procedure. The median age was 8 years (range 3.8-12.75 years). Computed tomography of the head was used in 974 of the 1898 patients (51.3%). A total of 956 of the 1898 patients (50.4%) required sedatives or analgesics for their radiographic imaging, with 875 (91.5%) requiring a single sedative or analgesic agent, and 81 (8.5%) requiring more than one medication. Airway obstruction was the most common adverse event, occurring in 5 of 956 patients (0.3%). All imaging procedures were successfully completed. CONCLUSION: Only 50% of CS immobilized, nonintubated patients required a single sedative or analgesic medication for their radiologic imaging. Procedural success was high, with few adverse events.

Long-term outcome of relapsed acute promyelocytic leukemia treated with oral arsenic trioxide-based reinduction and maintenance regimens: A 15-year prospective study.

BACKGROUND: For patients who have acute promyelocytic leukemia (APL) in second complete remission (CR2), optimal postremission strategies remain undefined. METHODS: The role of an oral arsenic trioxide (As2 O3 )-based regimen in the management of patients who had APL in CR2 was examined. RESULTS: Seventy-three patients with APL in first relapse (R1) were studied. Oral As2 O3 -based reinduction resulted uniformly in CR2, irrespective of previous As2 O3 exposure. All patients received oral As2 O3 -based maintenance in CR2. At a median follow-up of 94 months (range, 9-205 months), 43 patients (58.9%) were still in CR2, and 49 (67.1%) had finished the planned 2-year CR2 maintenance with all-trans retinoic acid, oral As2 O3 , and ascorbic acid. Reinduction and maintenance treatments were well tolerated. Grade 1 and 2 headache occurred in 20 patients (27.4%). Hepatotoxicity, all in the form of transaminitis, occurred in 35 patients (47.9%; grade 1 and 2, n = 26; grade 3 and 4, n = 9). Three patients had self-limiting QTc prolongation. The 10-year leukemia-free survival rate was 56.8%. Thirty patients developed R2. Oral As2 O3 -based reinduction led to CR3 in 27 patients (90%). Post-CR3 strategies included autologous hematopoietic stem cell transplantation and oral As2 O3 maintenance. At a post-CR3 follow-up of 30 months (range, 3-166 months), 11 patients were still in CR3. The 5-year and 10-year overall survival rates in the R1 cohort were 79.5% and 67.3%, respectively. Prior receipt of oral As2 O3 maintenance in CR1 was the only risk factor for inferior leukemia-free survival. Central nervous system involvement occurred in 15 patients, including 5 who remained alive. Relapse during oral As2 O3 therapy was the only significant risk factor for central nervous system involvement. CONCLUSIONS: For patients with relapsed APL, As2 O3 remained effective despite repeated As2 O3 exposures. Oral As2 O3 maintenance was an effective postremission strategy for CR2. Cancer 2018;124:2316-26. © 2018 American Cancer Society.

Deletion of Interleukin-6 Attenuates Pressure Overload-Induced Left Ventricular Hypertrophy and Dysfunction.

RATIONALE: The role of interleukin (IL)-6 in the pathogenesis of cardiac myocyte hypertrophy remains controversial. OBJECTIVE: To conclusively determine whether IL-6 signaling is essential for the development of pressure overload-induced left ventricular (LV) hypertrophy and to elucidate the underlying molecular pathways. METHODS AND RESULTS: Wild-type and IL-6 knockout (IL-6(-/-)) mice underwent sham surgery or transverse aortic constriction (TAC) to induce pressure overload. Serial echocardiograms and terminal hemodynamic studies revealed attenuated LV hypertrophy and superior preservation of LV function in IL-6(-/-) mice after TAC. The extents of LV remodeling, fibrosis, and apoptosis were reduced in IL-6(-/-) hearts after TAC. Transcriptional and protein assays of myocardial tissue identified Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) and signal transducer and activator of transcription 3 (STAT3) activation as important underlying mechanisms during cardiac hypertrophy induced by TAC. The involvement of these pathways in myocyte hypertrophy was verified in isolated cardiac myocytes from wild-type and IL-6(-/-) mice exposed to prohypertrophy agents. Furthermore, overexpression of CaMKII in H9c2 cells increased STAT3 phosphorylation, and exposure of H9c2 cells to IL-6 resulted in STAT3 activation that was attenuated by CaMKII inhibition. Together, these results identify the importance of CaMKII-dependent activation of STAT3 during cardiac myocyte hypertrophy via IL-6 signaling. CONCLUSIONS: Genetic deletion of IL-6 attenuates TAC-induced LV hypertrophy and dysfunction, indicating a critical role played by IL-6 in the pathogenesis of LV hypertrophy in response to pressure overload. CaMKII plays an important role in IL-6-induced STAT3 activation and consequent cardiac myocyte hypertrophy. These findings may have significant therapeutic implications for LV hypertrophy and failure in patients with hypertension.