Psychosocial Evaluation of Living Kidney Donors: A Survey of Current Practices in the United States.

BACKGROUND: Best practices in psychosocial evaluation and care of living donor candidates and donors are not well established. METHODS: We surveyed 195 living kidney donor (LKD) transplant centers in United States from October 2021 to April 2022 querying (1) composition of psychosocial teams, (2) evaluation processes including clinical tools and domains assessed, (3) selection criteria, and (4) psychosocial follow-up post-donation. RESULTS: We received 161 responses from 104 programs, representing 53% of active LKD programs and 67% of LKD transplant volume in 2019. Most respondents (63%) were social workers/independent living donor advocates. Over 90% of respondents indicated donor candidates with known mental health or substance use disorders were initially evaluated by the psychosocial team. Validated psychometric or transplant-specific tools were rarely utilized but domains assessed were consistent. Active suicidality, self-harm, and psychosis were considered absolute contraindications in >90% of programs. Active depression was absolute contraindication in 50% of programs; active anxiety disorder was excluded 27%. Conditions not contraindicated to donation include those in remission: anxiety (56%), depression (53%), and posttraumatic stress disorder (41%). There was acceptance of donor candidates using alcohol, tobacco, or cannabis recreationally, but not if pattern met criteria for active use disorder. Seventy-one percent of programs conducted post-donation psychosocial assessment and use local resources to support donors. CONCLUSIONS: There was variation in acceptance of donor candidates with mental health or substance use disorders. Although most programs conducted psychosocial screening post-donation, support is not standardized and unclear if adequate. Future studies are needed for consensus building among transplant centers to form guidelines for donor evaluation, acceptance, and support.

Consolidative Proton Radiotherapy for Pediatric Extramedullary Ocular Acute Myeloid Leukemia.

Purpose: Pediatric acute myeloid leukemia (AML) often involves extramedullary sites, which can be resistant to standard induction chemotherapy. Consolidative radiation therapy can be used in select cases to improve local control rates and help bridge patients to curative stem cell transplants. However, there is no previously published data to support the use of proton radiotherapy (PT) in this setting. We present radiographic findings and pathologic outcomes of the first reported patient with extramedullary ocular AML to be treated with PT. Patients and Methods: Details regarding diagnostic evaluation and treatment were obtained from the electronic medical records at the University of Florida Proton Therapy Institute, Nemours Children's Health, and St. Joseph's Children's Hospital. Results: This 7-month-old patient presented with biopsy-proven relapsed AML in the bilateral anterior chambers of the eyes, which did not resolve with induction chemotherapy. The patient then received PT to a dose of 24 cobalt gray equivalent to both eyes and was found to have no evidence of disease following treatment. Conclusion: This case provides further evidence that consolidative radiotherapy may be considered for select patients with extramedullary AML who have limited response to induction chemotherapy. Given the increased prevalence of extramedullary AML in pediatric patients, it is worth considering the utilization of PT to mitigate damage to nearby organs and the risk of secondary malignancies.

The role of donor type and pre-transplant immunosuppression on outcomes of hematopoietic stem cell transplantation in children and young adults with severe aplastic anemia.

BACKGROUND: The goal of this study was to assess the effect of donor type and pre-transplant immunotherapy (IST) on outcomes of hematopoietic stem cell transplantation (HSCT) for children and young adults with severe aplastic anemia (SAA). METHODS: This retrospective, multi-center study included 52 SAA patients, treated in 5 pediatric transplant programs in Florida, who received HSCT between 2010 and 2020 as the first- or second-line treatment. RESULTS: The median age at HSCT for all 52 patients was 15 years (range 1-25). The 3-year overall survival (OS) by donor type were as follows: 95% [95% CI 85.4-99] for matched related donors (MRD) (N = 24), 84% [95% CI 63.5-99] for haploidentical (N = 13), and 71% [95% CI 36-99] for matched unrelated donors (MUD) (N = 7). The 3-year OS was 81% [95% CI 69.7-99] for all patients, 90.5% [95% CI 79.5-99] for non-IST patients (N = 27), and 70% [95% CI 51-99] for IST patients (N = 24) (log-rank p = .04). Survival of haploidentical HSCT (haplo-HSCT) recipients with post-transplant cyclophosphamide (PTCy) (N = 13) was excellent for both groups: 100% for non-IST patients (N = 3) and 80% for IST patients (N = 10). The 3-year OS for patients with previous IST by donor type in groups where >5 patients were available was 78.8% [95% CI 52.3-99] for haplo-HSCT (N = 10) and 66.7% [95% CI 28.7-99] for MUD (N = 6). Although it appears that patients receiving HSCT ≥6 months after the start of IST had worse survival, the number of patients in each category was small and log-rank was not significant(p = .65). CONCLUSIONS: Patients receiving MUD and haplo-HSCT with PTCy had similar outcomes, suggesting that haplo-HSCT with PTCy could be included in randomized trials of upfront IST versus alternative donor HSCT.

Psychosocial evaluation of living liver donors-State of current practices in the United States.

We surveyed living donor liver transplant programs in the United States to describe practices in the psychosocial evaluation of living donors focused on (1) composition of psychosocial team; (2) domains, workflow, and tools of the psychosocial assessment; (3) absolute and relative mental health-related contraindications to donation; and (4) postdonation psychosocial follow-up. We received 52 unique responses, representing 33 of 50 (66%) of active living donor liver transplant programs. Thirty-one (93.9%) provider teams included social workers, 22 (66.7%) psychiatrists, and 14 (42.4%) psychologists. Validated tools were rarely used, but domains assessed were consistent. Respondents rated active alcohol (93.8%), cocaine (96.8%), and opioid (96.8%) use disorder, as absolute contraindications to donation. Active suicidality (97%), self-injurious behavior (90.9%), eating disorders (87.9%), psychosis (84.8%), nonadherence (71.9%), and inability to cooperate with the evaluation team (78.1%) were absolute contraindications to donation. There were no statistically significant differences in absolute psychosocial contraindications to liver donation between geographical areas or between large and small programs. Programs conduct postdonation psychosocial follow-up (57.6%) or screening (39.4%), but routine follow-up of declined donors is rarely conducted (15.8%). Psychosocial evaluation of donor candidates is a multidisciplinary process. The structure of the psychosocial evaluation of donors is not uniform among programs though the domains assessed are consistent. Psychosocial contraindications to living liver donation vary among the transplant programs. Mental health follow-up of donor candidates is not standardized.

The Effect of Deuteration and Homologation of the Lactam Ring of Nirmatrelvir on Its Biochemical Properties and Oxidative Metabolism.

This study explores the relationship between structural alterations of nirmatrelvir, such as homologation and deuteration, and metabolic stability of newly synthesized derivatives. We developed a reliable synthetic protocol toward dideutero-nirmatrelvir and its homologated analogues with high isotopic incorporation. Deuteration of the primary metabolic site of nirmatrelvir provides a 3-fold improvement of its human microsomal stability but is accompanied by an increased metabolism rate at secondary sites. Homologation of the lactam ring allows the capping group modification to decrease and delocalize the molecule's lipophilicity, reducing the metabolic rate at secondary sites. The effect of deuteration was less pronounced for the 6-membered lactam than for its 5-membered analogue in human microsomes, but the trend is reversed in the case of mouse microsomes. X-ray data revealed that the homologation of the lactam ring favors the orientation of the drug's nitrile warhead for interaction with the catalytic sulfur of the SARS-CoV-2 Mpro, improving its binding. Comparable potency against SARS-CoV-2 Mpro from several variants of concern and selectivity over human cysteine proteases cathepsin B, L, and S was observed for the novel deuterated/homologated derivative and nirmatrelvir. Synthesized compounds displayed a large interspecies variability in hamster, rat, and human hepatocyte stability assays. Overall, we aimed to apply a rational approach in changing the physicochemical properties of the drug to refine its biochemical and biological parameters.

Multiplex Assays Enable Simultaneous Detection and Identification of SARS-CoV-2 Variants of Concern in Clinical and Wastewater Samples.

The targeted screening and sequencing approaches for COVID-19 surveillance need to be adjusted to fit the evolving surveillance objectives which necessarily change over time. We present the development of variant screening assays that can be applied to new targets in a timely manner and enable multiplexing of targets for efficient implementation in the laboratory. By targeting the HV69/70 deletion for Alpha, K417N for Beta, K417T for Gamma, and HV69/70 deletion plus K417N for sub-variants BA.1, BA.3, BA.4, and BA.5 of Omicron, we achieved simultaneous detection and differentiation of Alpha, Beta, Gamma, and Omicron in a single assay. Targeting both T478K and P681R mutations enabled specific detection of the Delta variant. The multiplex assays used in combination, targeting K417N and T478K, specifically detected the Omicron sub-variant BA.2. The limits of detection for the five variants of concern were 4-16 copies of the viral RNA per reaction. Both assays achieved 100% clinical sensitivity and 100% specificity. Analyses of 377 clinical samples and 24 wastewater samples revealed the Delta variant in 100 clinical samples (nasopharyngeal and throat swab) collected in November 2021. Omicron BA.1 was detected in 79 nasopharyngeal swab samples collected in January 2022. Alpha, Beta, and Gamma variants were detected in 24 wastewater samples collected in May-June 2021 from two major cities of Alberta (Canada), and the results were consistent with the clinical cases of multiple variants reported in the community.

Bovine Serum Albumin-Protected Gold Nanoclusters for Sensing of SARS-CoV-2 Antibodies and Virus.

An approach to assess severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (and past infection) was developed. For virus detection, the SARS-CoV-2 virus nucleocapsid protein (NP) was targeted. To detect the NP, antibodies were immobilized on magnetic beads to capture the NPs, which were subsequently detected using rabbit anti-SARS-CoV-2 nucleocapsid antibodies and alkaline phosphatase (AP)-conjugated anti-rabbit antibodies. A similar approach was used to assess SARS-CoV-2-neutralizing antibody levels by capturing spike receptor-binding domain (RBD)-specific antibodies utilizing RBD protein-modified magnetic beads and detecting them using AP-conjugated anti-human IgG antibodies. The sensing mechanism for both assays is based on cysteamine etching-induced fluorescence quenching of bovine serum albumin-protected gold nanoclusters where cysteamine is generated in proportion to the amount of either SARS-CoV-2 virus or anti-SARS-CoV-2 receptor-binding domain-specific immunoglobulin antibodies (anti-RBD IgG antibodies). High sensitivity can be achieved in 5 h 15 min for the anti-RBD IgG antibody detection and 6 h 15 min for virus detection, although the assay can be run in "rapid" mode, which takes 1 h 45 min for the anti-RBD IgG antibody detection and 3 h 15 min for the virus. By spiking the anti-RBD IgG antibodies and virus in serum and saliva, we demonstrate that the assay can detect the anti-RBD IgG antibodies with a limit of detection (LOD) of 4.0 and 2.0 ng/mL in serum and saliva, respectively. For the virus, we can achieve an LOD of 8.5 × 105 RNA copies/mL and 8.8 × 105 RNA copies/mL in serum and saliva, respectively. Interestingly, this assay can be easily modified to detect myriad analytes of interest.

Utilization of a Glucometer Test Strip and Enzymatic Reactions to Quantify Anti-SARS-CoV-2 Spike RBD IgG Antibody and SARS-CoV-2 Virus in Saliva and Serum.

A sensor capable of quantifying both anti-SARS-CoV-2 spike receptor-binding domain (RBD) antibody levels and the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus in saliva and serum was developed. This was accomplished by exploiting the enzymatic reaction of maltose and orthophosphate (PO43-) in the presence of maltose phosphorylase to generate an equivalent amount of glucose that was detected using a commercial glucometer test strip and a potentiostat. Important for this approach is the ability to generate PO43- in an amount that is directly related to the concentration of the analytes. RBD-modified magnetic microparticles were used to capture anti-SARS-CoV-2 spike RBD antibodies, while particles modified with anti-SARS-CoV-2 nucleocapsid antibodies were used to capture SARS-CoV-2 nucleocapsid protein from inactivated virus samples. A magnet was used to isolate and purify the magnetic microparticles (with analyte attached), and alkaline phosphatase-conjugated secondary antibodies were bound to the analytes attached to the respective magnetic microparticles. Finally, through enzymatic reactions, specific amounts of PO43- (and subsequently glucose) were generated in proportion to the analyte concentration, which was then quantified using a commercial glucometer test strip. Utilizing glucose test strips makes the sensor relatively inexpensive, with a cost per test of ∼US $7 and ∼US $12 for quantifying anti-SARS-CoV-2 spike RBD antibody and SARS-CoV-2, respectively. Our sensor exhibited a limit of detection of 0.42 ng/mL for anti-SARS-CoV-2 spike RBD antibody, which is sensitive enough to quantify typical concentrations of antibodies in COVID-19-infected or vaccinated individuals (>1 µg/mL). The limit of detection for the SARS-CoV-2 virus is 300 pfu/mL (5.4 × 106 RNA copies/mL), which exceeds the performance recommended by the WHO (500 pfu/mL). In addition, the sensor exhibited good selectivity when challenged with competing analytes and could be used to quantify analytes in saliva and serum matrices with an accuracy of >94% compared to RT-qPCR.

Interferon regulatory factor 3 mediates effective antiviral responses to human coronavirus 229E and OC43 infection.

Interferon regulatory factors (IRFs) are key elements of antiviral innate responses that regulate the transcription of interferons (IFNs) and IFN-stimulated genes (ISGs). While the sensitivity of human coronaviruses to IFNs has been characterized, antiviral roles of IRFs during human coronavirus infection are not fully understood. Type I or II IFN treatment protected MRC5 cells from human coronavirus 229E infection, but not OC43. Cells infected with 229E or OC43 upregulated ISGs, indicating that antiviral transcription is not suppressed. Antiviral IRFs, IRF1, IRF3 and IRF7, were activated in cells infected with 229E, OC43 or severe acute respiratory syndrome-associated coronavirus 2 (SARS-CoV-2). RNAi knockdown and overexpression of IRFs demonstrated that IRF1 and IRF3 have antiviral properties against OC43, while IRF3 and IRF7 are effective in restricting 229E infection. IRF3 activation effectively promotes transcription of antiviral genes during OC43 or 229E infection. Our study suggests that IRFs may be effective antiviral regulators against human coronavirus infection.

Thoracic point-of-care ultrasound is an accurate diagnostic modality for clinically significant traumatic pneumothorax.

OBJECTIVE: There are conflicting data regarding the accuracy of thoracic point-of-care ultrasound (POCUS) in detecting traumatic pneumothorax (PTX). The purpose of our study was to determine the accuracy of thoracic POCUS performed by emergency physicians for the detection of clinically significant PTX in blunt and penetrating trauma patients. METHODS: We conducted a retrospective institutional review board-approved study of trauma patients 15 years or older presenting to our urban Level I academic trauma center from December 2021 to June 2022. All study patients were imaged with single-view chest radiography (CXR) and thoracic POCUS. The presence or absence of PTX was determined by multidetector computed tomography (CT) or CXR and ultrasound (US) with tube thoracostomy placement. RESULTS: A total of 846 patients were included, with 803 (95%) sustaining blunt trauma. POCUS identified 13/15 clinically significant PTXs (defined as ≥35 mm of pleural separation on a blinded overread or placement of a tube thoracostomy prior to CT) with a sensitivity of 87% (95% confidence interval [CI] 58-97), specificity of 100% (95% CI 99-100), positive predictive value of 81% (95% CI 54%-95%), and negative predictive value of 100% (95% CI 99%-100%). The positive likelihood ratio was 484 and the negative likelihood ratio was 0.1. CXR identified eight (53%) clinically significant PTXs, with a sensitivity of 53% (95% CI 27%-78%) and a specificity of 100%, when correlated with the CT. The most common reason for a missed PTX identified on expert-blinded overread was failure to recognize a lung point sign that was present on US. CONCLUSIONS: Thoracic POCUS accurately identifies the majority of clinically significant PTXs in both blunt and penetrating trauma patients. Common themes for false-negative thoracic US in the expert-blinded overread process identified key gaps in training to inspire US education and medical education research.

A diagnostic classifier for pediatric chronic graft-versus-host disease: results of the ABLE/PBMTC 1202 study.

The National Institutes of Health Consensus criteria for chronic graft-versus-host disease (cGVHD) diagnosis can be challenging to apply in children, making pediatric cGVHD diagnosis difficult. We aimed to identify diagnostic pediatric cGVHD biomarkers that would complement the current clinical criteria and help differentiate cGVHD from non-cGVHD. The Applied Biomarkers of Late Effects of Childhood Cancer (ABLE) study, open at 27 transplant centers, prospectively evaluated 302 pediatric patients after hematopoietic cell transplant (234 evaluable). Forty-four patients developed cGVHD. Mixed and fixed effect regression analyses were performed on diagnostic cGVHD onset blood samples for cellular and plasma biomarkers, with individual markers declared relevant if they met 3 criteria: an effect ratio ≥1.3 or ≤0.75; an area under the curve (AUC) of ≥0.60; and a P value <5.814 × 10-4 (Bonferroni correction) (mixed effect) or <.05 (fixed effect). To address the complexity of cGVHD diagnosis in children, we built a machine learning-based classifier that combined multiple cellular and plasma biomarkers with clinical factors. Decreases in regulatory natural killer cells, naïve CD4 T helper cells, and naïve regulatory T cells, and elevated levels of CXCL9, CXCL10, CXCL11, ST2, ICAM-1, and soluble CD13 (sCD13) characterize the onset of cGVHD. Evaluation of the time dependence revealed that sCD13, ST2, and ICAM-1 levels varied with the timing of cGVHD onset. The cGVHD diagnostic classifier achieved an AUC of 0.89, with a positive predictive value of 82% and a negative predictive value of 80% for diagnosing cGVHD. Our polyomic approach to building a diagnostic classifier could help improve the diagnosis of cGVHD in children but requires validation in future prospective studies. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Two DNA vaccines protect against severe disease and pathology due to SARS-CoV-2 in Syrian hamsters.

The SARS-CoV-2 pandemic is an ongoing threat to global health, and wide-scale vaccination is an efficient method to reduce morbidity and mortality. We designed and evaluated two DNA plasmid vaccines, based on the pIDV-II system, expressing the SARS-CoV-2 spike gene, with or without an immunogenic peptide, in mice, and in a Syrian hamster model of infection. Both vaccines demonstrated robust immunogenicity in BALB/c and C57BL/6 mice. Additionally, the shedding of infectious virus and the viral burden in the lungs was reduced in immunized hamsters. Moreover, high-titers of neutralizing antibodies with activity against multiple SARS-CoV-2 variants were generated in immunized animals. Vaccination also protected animals from weight loss during infection. Additionally, both vaccines were effective at reducing both pulmonary and extrapulmonary pathology in vaccinated animals. These data show the potential of a DNA vaccine for SARS-CoV-2 and suggest further investigation in large animal and human studies could be pursued.

Ruptured Tubo-Ovarian Pregnancy Presenting at 15 Weeks' Gestation.

Ectopic pregnancies develop outside of the uterus and lead to significant maternal morbidity and mortality if they rupture. As the primary diagnostic tool for these presentations, ultrasound has a growing list of signs and measurements that help distinguish between intrauterine and ectopic pregnancies, the latter being exceedingly rare once a woman has entered her second trimester. The present case reports a series of Emergency Department visits by a woman carrying a second-trimester pregnancy-deemed intrauterine on transabdominal ultrasound due to gestational age and location-who developed massive hemoperitoneum and was diagnosed with a ruptured 15-week tubo-ovarian pregnancy on laparotomy. The discussion describes the sonographic findings that could have helped make the proper diagnosis, most notably mantle distance-the thickness of the myometrium surrounding the gestational sac-which would have correctly identified this pregnancy as ectopic.

Efficacy of a Standardized Premedication and Therapeutic Drug Monitoring Protocol for Pegaspargase to Prevent Hypersensitivity Reactions.

OBJECTIVE: The purpose of this study was to evaluate the efficacy of a standardized premedication and therapeutic drug monitoring (TDM) protocol to prevent hypersensitivity reactions from pegaspargase infusions. Pegaspargase is an essential therapeutic agent used for the treatment of acute lymphoblastic leukemia (ALL) in pediatric patients. METHODS: This study was a retrospective cohort study conducted at Wolfson Children's Hospital, Jacksonville, Florida, and included pediatric ALL patients 0 to 21 years old. Patients were excluded if they had not received the appropriate premedication after protocol implementation or had received premedication before protocol implementation. Patients were separated into 2 groups: those who received premedication before pegaspargase infusion and those who did not. The primary endpoint was the incidence of documented hypersensitivity reactions. Observational data endpoints included incidence of silent inactivation and cost savings from reducing complicated drug substitutions. RESULTS: A total of 38 patients (50 doses in no premedication group; 80 doses in premedication group) were evaluated. There was not a significant reduction in the incidence of hypersensitivity reactions for patients receiving premedication and TDM (5.3% vs 6.4%, p = 1.0). A trend towards patients reacting earlier with more severe reactions in the post-implementation group was observed. There were no incidences of silent inactivation. Observational cost analysis predicts potential drug cost savings of $106,550.45. CONCLUSIONS: A standardized premedication protocol did not reduce the incidence of hypersensitivity reactions. Premedication to prevent hypersensitivity reactions may provide a potential drug cost savings. Further investigation is warranted to assess the efficacy of a standardized premedication and TDM protocol to prevent hypersensitivity reactions.

Inter-rater reliability of optic nerve sheath diameter measurement using real-time ultrasonography.

OBJECTIVES: Ultrasound measurement of the optic nerve sheath diameter (ONSD) is a rapid, non-invasive means to indirectly assess intracranial pressure. Previous research has demonstrated the ability of emergency physicians to measure ONSD accurately with bedside ultrasound when compared to CT scan or MRI, however the reliability of this measurement between two or more operators has been called into question (Hassen et al. in J Emerg Med 48:450-457, 2015; Shirodkar et al. in Ind J Crit Care Med 19:466-470, 2015). Given the need for accurate and precise measurement to use this as a screening exam, we sought to determine the inter-rater reliability between ONSD measurements obtained in real time by fellowship-trained emergency ultrasound physicians. METHODS: Three ultrasound fellowship-trained emergency physicians measured bilateral ONSD of 10 healthy volunteers using a high-frequency linear transducer. The physicians were blinded to the other scanners' measurements, and no instructions were given other than to obtain the ONSD. Each sonographer measured the ONSD in real time and it was recorded by a research coordinator. All measurements were recorded in millimeters. Intraclass correlation coefficients (ICCs) were calculated to estimate the inter-rater reliability. RESULTS: A total of 60 measurements of ONSD were obtained. The average measurement was 4.3 mm (3.83-4.77). Very little variation was found between the three physicians, with a calculated ICC of 0.82 (95% confidence interval 0.63-0.92). CONCLUSIONS: ONSD measurement obtained by ultrasound fellowship-trained emergency medicine physicians is a reliable measurement with a high degree of correlation between scanners.

Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability.

Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against a broad spectrum of coronaviruses. Described in this Article are novel α-acyloxymethylketone warhead peptidomimetic compounds with a six-membered lactam glutamine mimic in P1. Compounds with potent SARS-CoV-2 3CL protease and in vitro viral replication inhibition were identified with low cytotoxicity and good plasma and glutathione stability. Compounds 15e, 15h, and 15l displayed selectivity for SARS-CoV-2 3CL protease over CatB and CatS and superior in vitro SARS-CoV-2 antiviral replication inhibition compared with the reported peptidomimetic inhibitors with other warheads. The cocrystallization of 15l with SARS-CoV-2 3CL protease confirmed the formation of a covalent adduct. α-Acyloxymethylketone compounds also exhibited antiviral activity against an alphacoronavirus and non-SARS betacoronavirus strains with similar potency and a better selectivity index than remdesivir. These findings demonstrate the potential of the substituted heteroaromatic and aliphatic α-acyloxymethylketone warheads as coronavirus inhibitors, and the described results provide a basis for further optimization.

Metabolomic identification of α-ketoglutaric acid elevation in pediatric chronic graft-versus-host disease.

Chronic graft-versus-host disease (cGVHD) is the most common cause for non-relapse mortality postallogeneic hematopoietic stem cell transplant (HSCT). However, there are no well-defined biomarkers for cGVHD or late acute GVHD (aGVHD). This study is a longitudinal evaluation of metabolomic patterns of cGVHD and late aGVHD in pediatric HSCT recipients. A quantitative analysis of plasma metabolites was performed on 222 evaluable pediatric subjects from the ABLE/PBMTC1202 study. We performed a risk-assignment analysis at day + 100 (D100) on subjects who later developed either cGVHD or late aGVHD after day 114 to non-cGVHD controls. A second analysis at diagnosis used fixed and mixed multiple regression to compare cGVHD at onset to time-matched non-cGVHD controls. A metabolomic biomarker was considered biologically relevant only if it met all 3 selection criteria: (1) P ≤ .05; (2) effect ratio of ≥1.3 or ≤0.75; and (3) receiver operator characteristic AUC ≥0.60. We found a consistent elevation in plasma α-ketoglutaric acid before (D100) and at the onset of cGVHD, not impacted by cGVHD severity, pubertal status, or previous aGVHD. In addition, late aGVHD had a unique metabolomic pattern at D100 compared with cGVHD. Additional metabolomic correlation patterns were seen with the clinical presentation of pulmonary, de novo, and progressive cGVHD. α-ketoglutaric acid emerged as the single most significant metabolite associated with cGVHD, both in the D100 risk-assignment and later diagnostic onset analysis. These distinctive metabolic patterns may lead to improved subclassification of cGVHD. Future validation of these exploratory results is needed. This trial was registered at www.clinicaltrials.gov as #NCT02067832.

Novel Approach to Ultrasound-Guided Thoracostomy.

OBJECTIVES: Thoracostomy is often a required treatment in patients with thoracic trauma; however, performing a thoracostomy using traditional techniques can have complications. Ultrasound can be a beneficial tool for identifying the correct thoracostomy insertion site. We designed a randomized prospective study to assess if ultrasound guidance can improve thoracostomy site identification over traditional techniques. METHODS: Emergency medicine residents were randomly assigned to use palpation or ultrasound to identify a safe insertion site for thoracostomy placement. The target population comprised of hemodynamically stable trauma patients who received an extended focused assessment with sonography for trauma (EFAST) and a chest computed tomography (CT) exam. The resident placed a radiopaque marker on the skin of the patient where a safe intercostal space was believed to be located, either by palpation or ultrasound. Clinical ultrasound faculty reviewed the CT to confirm marker placement relative to the diaphragm. A Fischer's exact test was used to analyze the groups. RESULTS: One hundred and forty-seven patients were enrolled in the study, 75 in the ultrasound group and 72 in the landmark group. This resulted in the placement of 271 total thoracostomy site markers, 142 by ultrasound and 129 by palpation and landmarks. The ultrasound group correctly identified thoracostomy insertion sites above the diaphragm in 97.2% (138/142) of patients, while the palpation group identified a safe insertion site in 88.4% (114/129) of patients (P = .0073). CONCLUSION: This study found that emergency medicine residents are more likely to identify a safe tube thoracostomy insertion site in trauma patients by using ultrasound, as compared to using landmarks and palpation.

Super-refractory status epilepticus during blinatumomab initiation for B-cell acute lymphoblastic leukemia.

Seizures have been reported as an adverse effect of blinatumomab, a bispecific T-cell engager monoclonal antibody, which is mainly used for the treatment of pediatric relapsed/refractory leukemia. Here, we present the first reported case of super-refractory status epilepticus in an 11-year-old boy with B-cell acute lymphoblastic leukemia (B-ALL) while receiving blinatumomab. Our patient had a complete return to baseline despite enduring encephalopathy, refractory subclinical seizures requiring prolonged therapeutic burst suppression and MRI signal changes. This case demonstrates that super-refractory status epilepticus is a possible neurotoxic adverse effect of blinatumomab treatment, which responds well to conventional protocols for acute refractory seizures.

Seizures are a known side effect of blinatumomab, a relatively new immunotherapy drug, which is mainly used for the treatment of relapsed leukemia in children. Here, we present the first reported case of seizure continuing for more than 24 h despite appropriate antiseizure treatment while also receiving blinatumomab. Despite an extended period of altered mental status, new abnormalities on imaging of the brain and a medication-induced coma to treat unrelenting seizures, our patient returned completely to his healthy brain function. This case demonstrates that seizures, which are especially difficult to treat, can be associated with blinatumomab immunotherapy for pediatric refractory B-ALL; however, standard-tiered seizure treatments can be effective.