Diaphragmatic Ultrasound in Children With Asthma Exacerbations.

OBJECTIVES: Asthma is a leading cause of pediatric emergency department visits, yet few tools exist to objectively measure asthma severity. Diaphragmatic ultrasound (DUS) is a novel method of assessing respiratory distress; however, data are lacking for children.Our primary aim was to determine if diaphragmatic excursion (DE), diaphragmatic thickening (DT), or diaphragmatic thickening fraction (TF) correlated with asthma severity as determined by the Pediatric Respiratory Assessment Measure (PRAM) score. Secondarily, we examined if these parameters correlated with need for respiratory support and evaluated interrater reliability. METHODS: We conducted a prospective study of children 5-18 years presenting to a pediatric emergency department with an asthma exacerbation. Diaphragmatic ultrasound was performed by a trained pediatric emergency medicine sonologist in subcostal (DE) and midaxillary (DT). Thickening fraction was calculated from DT values as previously described in literature. To evaluate interrater reliability, a subset of subjects had DUS performed by a second sonologist. RESULTS: We enrolled 47 subjects for a total of 51 encounters. The mean age was 9.1 ± 3.7 years. Twenty-five (49%) had mild, 24 (47%) had moderate, and 2 (4%) had severe asthma. There was a significant difference in midaxillary DT and TF between children with mild and moderate asthma (P = 0.02; mean difference, 0.2 mm; 95% confidence interval [CI], 0.03-0.4 and P = 0.02; mean difference, 0.11 mm; 95% CI, 0.02-0.2, respectively). No difference was found in subcostal DE (P = 0.43; mean difference, 1.4 mm; 95% CI, -2.1 to 4.8). No association was found between use of positive pressure and DUS parameters. Fourteen encounters had 2 sonologists perform DUS, with strong interrater reliability found for midaxillary DT (Pearson correlation, 0.56) and poor association for subcostal DE (Pearson correlation, 0.18). CONCLUSIONS: In this pilot study, we conclude that DUS may be helpful in assessing severity of asthma. The midaxillary view assessment for DT and TF had the best correlation with asthma severity and the best interrater reliability. Future studies may benefit from focusing on the midaxillary view for DT and TF.

Efficacy of emicizumab therapy in two adult patients with type 3 von Willebrand disease.

Type 3 von Willebrand disease (T3VWD) is a rare inherited bleeding disorder caused by the absence of von Willebrand factor (VWF). The traditional treatment for T3VWD has been VWF concentrates, but their effectiveness may be limited due to the development of alloantibodies. Emicizumab, a bispecific mAb, has shown promise in treating hemophilia A and is being studied as prophylaxis for T3VWD. In this case series, two patients with T3VWD received emicizumab prophylaxis and experienced a significant reduction in bleeding episodes and improved quality of life with fewer healthcare encounters. Although breakthrough bleeding was rare, one patient experienced a terminal intracranial bleed. Despite limited clinical experience with emicizumab in T3VWD, these cases suggest that emicizumab may be a valuable prophylactic option for patients with T3VWD. Further research is needed to determine the long-term efficacy and safety profile of emicizumab and optimal therapy for breakthrough bleeds in this patient population.

Point-of-Care Ultrasound of a Pediatric Gastric Trichobezoar: A Case Report.

ABSTRACT: This case report describes a previously healthy pediatric patient with acute onset of abdominal pain and distention who was found to have an epigastric mass on physical examination. Point-of-care ultrasound (POCUS) demonstrated a large gastric mass with ultrasonographic features consistent with a trichobezoar. After POCUS was performed, trichophagia was confirmed on history, and the patient went to the operating room for removal of a large trichobezoar. We conclude POCUS may be helpful for evaluation of epigastric masses and diagnosis of gastric trichobezoars. We review the ultrasound technique, sonographic findings, and literature regarding ultrasound diagnosis of trichobezoars.

Cerebral Infarction due to Severe ADAMTS-13 Deficiency with Normal Hematological Parameters: A Cause of Cryptogenic Stroke.

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) is a microangiopathy resulting from an inherited or acquired severe deficiency in a disintegrin and metalloproteinase called ADAMTS-13. Acquired or immune TTP is classically described as a pentad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, renal insufficiency and neurological symptoms. Thrombotic thrombocytopenic purpura has been linked to stroke with the presence of hematologic abnormalities but whether or not severe ADAMTS-13 deficiency can cause stroke without hematological abnormalities is unknown. MATERIALS AND METHODS: As part of routine clinical care, we identified four cases of recurrent stroke attributed to severe deficiency of ADAMTS-13. We also conducted a search of a centralized electronic health record database including all inpatients and outpatient charts at a single academic medical center over the last ten years in an attempt to identify additional cases. RESULTS: Here we present four cases of stroke and severe ADAMTS-13 deficiency where stroke episodes occurred without microangiopathic hemolytic anemia or severe thrombocytopenia. These cases show the need to consider severe ADAMTS-13 deficiency in the setting of recurrent cryptogenic stroke in young patients. CONCLUSIONS AND RELEVANCE: TTP directed therapies may be considered for patients with recurrent stroke who have extremely low ADAMTS-13 levels, even when platelet and hemoglobin values are normal.

Assessment of physiological responses of bacteria to chlorine and UV disinfection using a plate count method, flow cytometry and viability PCR.

AIMS: This study aimed to investigate the physiological responses of two gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and two gram-positive bacteria (Enterococcus faecalis and Bacillus sphaericus) to ultraviolet (UV) and chlorine disinfection. METHODS AND RESULTS: Bacterial inactivation by UV and chlorine disinfection were evaluated with a plate count method for culturability, FCM and PMA-qPCR for membrane integrity and DyeTox13-qPCR for enzymatic activity, respectively. Both UV and chorine disinfection caused complete loss of culturability while membrane integrity remained intact after UV disinfection. Both DyeTox13-qPCR and PMA-qPCR showed high ΔCt values up to 8.9 after chlorine disinfection, indicating that both methods were able to distinguish non-treated from chlorine-treated cells. Although PMA-qPCR could not differentiate membrane integrity of cells on UV exposure, DyeTox13-qPCR showed significant differences in ΔCt values of 5.05 and 10.4 for gram-negative (E. coli) and gram-positive (Enterococcus) bacteria, respectively. However, DyeTox13-qPCR for gram-negative bacteria displayed relatively small differences in ΔCt values compared with gram-positive bacteria. CONCLUSION: UV and chlorine disinfection led to changes in physiological state of gram-negative and gram-positive bacteria. Particularly, UV disinfection could induce active but non-culturable (ABNC) for gram-negative bacteria and dormant cell for gram-positive bacteria where intact cells no longer showed the enzymatic activity. SIGNIFICANCE AND IMPACT OF THE STUDY: UV and chlorine are commonly used to disinfect water, food and fomites to inactivate pathogenic bacteria. However, a viable but non-culturable (VBNC) state of bacteria induced by disinfection may underestimate the health risks because of the potential resuscitation of VBNC cells. This study highlighted that bacteria could undergo different physiological (ABNC or dormant) states during UV and chlorine disinfection. In addition, viability PCR techniques could provide insight into the changes in physiological states during disinfection processes.

Amyand Hernia: As Seen on Point-of-Care Emergency Ultrasound.

ABSTRACT: Amyand hernia is a rare type of inguinal hernia defined by the presence of the appendix in the inguinal hernia sac. Clinical diagnosis of Amyand hernia can be challenging because this diagnosis is typically made intraoperatively, often as an incidental finding. Preoperative diagnosis by computed tomography and radiology ultrasound has previously been reported; however, there exists no reports of the diagnosis being made by point-of-care ultrasound. We present a case of Amyand hernia visible on point-of-care ultrasound performed by a pediatric emergency medicine physician.

Sedation and analgesia needs in methamphetamine intoxicated patients: much ado about nothing.

BACKGROUND: Methamphetamine (M) is a widely used, powerful sympathomimetic drug that produces significant CNS stimulation. Its use is associated with psychiatric disorders, abnormal brain chemistry, and cardiovascular disease. Pre-hospital M use is associated with increased intubation, intensive care unit admission, and hospital length of stay. The purpose of this study was to determine the influence of acute M use on analgesia and sedation requirements in mechanically ventilated trauma patients. METHODS: This single center retrospective cohort study included injured adult patients (≥16 years) admitted to the trauma intensive care unit (TICU) between 2016 and 2018 who were mechanically ventilated and had a urine drug screen (UDS) completed. The primary outcome was the median sedation and total analgesia administered during the first 48 hours of TICU admission, expressed as propofol, dexmedetomidine, lorazepam, and morphine equivalents. Secondary endpoints included the median Richmond Agitation Sedation Scale (RASS) score, median Critical Pain Observation Tool (CPOT) score, ventilator days, length of stay, in-hospital mortality, and discharge disposition. RESULTS: A total of 245 patients were included in the final analysis (53 M+ and 192 M-). The patients were mostly men (78%) and sustained blunt trauma (89%) with a median age of 35 (IQR 26-52) years and median ISS of 11 (IQR 4-24). A M+ UDS was associated with increased morphine requirements, defined as greater than the cohort median of 1.91 mg/kg, during the first 12 hours of admission on the univariable analysis (OR 2.03; 95% CI, 1.07-3.82). There was no difference in median propofol (M+ 30 mcg/kg/min vs. M- 30 mcg/kg/min, p=0.58) or total morphine equivalents (M+ 5.42 mg/kg s. M- 3.89 mg/kg, p=0.30) over 48 hours between M+ and M- groups to achieve similar RASS and CPOT scores. CONCLUSION: To achieve the same level of pain control and depth of sedation, intubated TICU patients with a M+ UDS do not require more analgesia and sedation than patients with a M- UDS during the first 48 hours of admission.

Rapid quantification of fecal indicator bacteria in water using the most probable number - loop-mediated isothermal amplification (MPN-LAMP) approach on a polymethyl methacrylate (PMMA) microchip.

Fecal contamination of water and its associated pathogens are a major public health concern in both developing and industrialized areas. Fecal indicator bacteria (FIB) are commonly used to assess microbial water quality, but they require a relatively long period of incubation time. Currently, molecular techniques have been applied to rapidly detect FIB. However, these molecular techniques require expensive and sophisticated equipment. In this study, we developed a rapid on-chip gene quantification method based on loop-mediated isothermal amplification (LAMP) PCR. The LAMP assays can measure the target genes of the fecal indicator bacteria (FIB), including E. coli and Enterococcus spp, using the most probable number (MPN) approach. The colorimetric LAMP assay allows for naked-eye observation of the PCR reaction as few as 4 gene copies / well. When the reaction ends, MPN measurement of positive outcomes on the white-based PMMA (polymethacrylic acid) microchips provides the concentrations of the target genes of FIB with a confidence interval. We validated the feasibility of the MPN-LAMP approach by obtaining a strong correlation between the results of the MPN estimations and the qPCR analysis. Moreover, the MPN-LAMP approach was used to quantify the FIB in different environmental water collected from the freshwater reservoirs, beach, agriculture farm, and sewage. Our research demonstrates that the MPN- LAMP method enables us to easily and quickly quantifying FIB genes isolated from the environment without expensive qPCR instruments.

Bevacizumab-associated thrombotic microangiopathy treated with eculizumab: A case series and systematic review of the literature.

BACKGROUND: Bevacizumab is a recombinant monoclonal antibody against the vascular endothelial growth factor A (VEGF-A) ligand that is used in the management of various solid malignancies. The adverse effect profiles of angiogenesis inhibitors, such as bevacizumab, have become increasingly well characterized and include renal manifestations such as hypertension, proteinuria, and thrombotic microangiopathy. Eculizumab inhibits terminal-complement activation and is used to treat atypical hemolytic uremic syndrome. There has been growing usage of eculizumab to treat bevacizumab-associated thrombotic microangiopathy. MATERIALS AND METHODS: We performed a systematic review of the literature to identify full-text articles that describe the use of eculizumab for bevacizumab-associated thrombotic microangiopathy. RESULTS: Our systematic review identified 522 unique articles of which 5 were included in the final review. 9 cases, including 2 new cases presented in this review, were identified in which eculizumab was used in the management of bevacizumab-associated thrombotic microangiopathy. Hematologic parameters and kidney function stabilized or improved in all cases, and the 2 patients who required renal replacement therapy were able to discontinue dialysis. CONCLUSIONS: Given the findings of this systematic review, the use of eculizumab in the treatment of bevacizumab-associated thrombotic microangiopathy warrants further study, particularly in severe cases.

Lung Point-of-Care Ultrasound in Pediatric COVID-19: A Case Series.

Lung point-of-care ultrasound (POCUS) has been shown to be useful for identifying pulmonary pathology in adult patients with coronavirus disease 2019 (COVID-19). However, pediatric literature for POCUS in COVID-19 is limited. The objective of this case series was to describe lung POCUS findings in pediatric patients with COVID-19. Three patients with COVID-19 who had lung POCUS performed in a pediatric emergency department were included. Point-of-care ultrasound revealed bilateral abnormalities in all patients, including pleural line irregularities, scattered and coalescing B-lines, consolidations, and pleural effusions. Additional pediatric studies are necessary to gain a broader understanding of COVID-19's sonographic appearance in this age group and to determine whether POCUS may be helpful to facilitate diagnosis and expedite management decisions.

Inpatient use of racemic epinephrine for children admitted with croup.

BACKGROUND: Pediatric patients with croup are frequently admitted if they require two doses of racemic epinephrine (RE) in the emergency department (ED). We aimed to identify factors associated with the need for additional therapy (> 2 RE doses) among pediatric patients with croup. METHODS: We performed a single-center retrospective study of consecutive patients admitted from the ED with a diagnosis of croup between January 1, 2011 and December 31, 2015. Primary outcome was need for > 2 doses of RE. Secondary outcomes included time to third RE and 72-hour return visits. We performed logistic regression to identify factors associated with use of > 2 RE doses during hospitalization, and survival analysis to identify time to dosing of 3rd RE from 2nd RE. RESULTS: Of 353 included admissions [250 (70.8%) males, median age 1.48, interquartile range 0.97-2.51 years], 106/353 (30.0%) required > 2 RE. In univariate logistic regression, only recent use of steroids within 1 day prior to presentation (4.18, 1.48-11.83; P = 0.007) was associated with need for > 2 RE. Survival from third RE was 0.74 (95% CI 0.69-0.78), which was similar to the survival at 12 hours (0.70, 95% CI 0.65-0.75). Return visits occurred in 19 (5.4%) patients, of whom 12/19 (63.2%) were given RE. CONCLUSIONS: Patients hospitalized for croup with recent use of steroids prior to ED presentation have a greater need for > 2 RE during hospitalization. The majority who require inpatient RE will do so within 8-12 hours. These data provide information for risk stratification and duration of monitoring for patients hospitalized with croup.

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A.

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.

No effect of single-dose intranasal insulin treatment on verbal memory and sustained attention in patients with schizophrenia.

BACKGROUND: Impairments in verbal memory and attention are among the most severe and disabling cognitive deficits in patients with schizophrenia. Whereas efficacy for cognition has not yet been established for any pharmacologic strategy in schizophrenia, an accumulating body of evidence suggests a possible beneficial role of insulin. METHODS: We conducted a double-blind, placebo-controlled trial to examine the effect of single-dose intranasal insulin treatment on cognition in nondiabetic patients with schizophrenia. After fasting for 12 hours, subjects received either 40 IU regular human insulin or placebo administered by intranasal pump. The Hopkins Verbal Learning Test and the Continuous Performance Test-Identical Pairs were administered before and 30 minutes after intranasal treatment. RESULTS: Thirty patients were enrolled and completed the study. The 2 treatment groups (insulin vs placebo, n = 15 in each group) did not differ on any demographic or general clinical variable (P > 0.40). There was no significant difference between the 2 treatment groups in change on Hopkins Verbal Learning Test immediate recall total score and delayed recall score, or on CPT d', hits rate, reaction time of hits, or false-alarm rate (P > 0.1). CONCLUSIONS: Results of the present study suggest that single-dose intranasal insulin treatment does not have a large-enough effect on verbal memory or sustained attention to be detected by a sample of this size in patients with schizophrenia but was safe and well tolerated. Longitudinal studies to explore cognitive benefits of repeated dosing of intranasal insulin treatment are needed.

Safety of the thrombopoiesis-stimulating agents for the treatment of immune thrombocytopenia.

The thrombopoiesis-stimulating agents (TSAs) are a novel class of drugs for the treatment of chronic immune thrombocytopenia (ITP). Roimplostim and eltrombopag, the first two TSAs to enter clinical use, received regulatory approval in 2008 and stand poised to change the treatment paradigm in ITP. However, important questions regarding the safety of these agents, particularly with long-term use, remain partially unanswered. The primary objective of this article is to review the reported toxicities associated with the TSAs including rebound thrombocytopenia, thrombosis, hepatotoxicity, formation of neutralizing antibodies, bone marrow fibrosis, hematologic malignancy, cataract formation, and common adverse events. The incidence and severity of these toxicities as well as strategies for monitoring patient safety and pharmacovigilance are discussed.

Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury.

Selectins and their ligands mediate leukocyte rolling, allowing interactions with chemokines that lead to integrin activation and arrest. Here we show that E-selectin is crucial for generating a secondary wave of activating signals, transduced specifically by E-selectin ligand-1, that induces polarized, activated alpha(M)beta(2) integrin clusters at the leading edge of crawling neutrophils, allowing capture of circulating erythrocytes or platelets. In a humanized mouse model of sickle cell disease, the capture of erythrocytes by alpha(M)beta(2) microdomains leads to acute lethal vascular occlusions. In a model of transfusion-related acute lung injury, polarized neutrophils capture circulating platelets, resulting in the generation of oxidative species that produce vascular damage and lung injury. Inactivation of E-selectin or alpha(M)beta(2) prevents tissue injury in both inflammatory models, suggesting broad implications of this paradigm in thromboinflammatory diseases. These results indicate that endothelial selectins can influence neutrophil behavior beyond its canonical rolling step through delayed, organ-damaging, polarized activation.

Intravenous immunoglobulins reverse acute vaso-occlusive crises in sickle cell mice through rapid inhibition of neutrophil adhesion.

Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model suggest that adherent white blood cells (WBCs) play a key role in vaso-occlusion by capturing circulating red blood cells (RBCs) in venules. Commercial intravenous immunoglobulin (IVIG) given before the inflammatory stimuli increased microcirculatory blood flow and survival. To mimic the clinical situation in which SCD patients seek medical attention after the onset of symptoms, we developed an in vivo model in which the therapeutic intervention (eg, IVIG) was administered after in the inflammatory challenge. In this setting, IVIG rapidly (<10 minutes) reduced adherent leukocyte numbers and dramatically inhibited interactions between RBCs and WBCs, resulting in improved microcirculatory blood flow and survival of sickle cell "Berkeley" mice. Longer survival correlated positively with blood flow (P=.001) and negatively with the number of adherent leukocytes (P=.001) and RBC-WBC interactions (P=.002). Using multichannel digital fluorescence videomicroscopy, we found that IVIG affected specifically the recruitment of neutrophils. Moreover, further analyses of leukocyte behavior revealed that IVIG significantly increased rolling velocities, indicating that it alters adhesion pathways involved in slow rolling. These data suggest that the potential therapeutic benefits of IVIG in SCD crises should be evaluated in a clinical trial.

Sexual functioning, psychopathology and quality of life in patients with schizophrenia.

OBJECTIVE: The present study was to characterize relationships among sexual functioning, schizophrenia symptoms and quality of life measures. In addition, sexual functioning was compared among patients treated with different antipsychotic agents. METHODS: Outpatient subjects were assessed using the Positive and Negative Symptom Scale (PANSS), the Changes in Sexual Functioning Questionnaire (CSFQ) and the Hamilton Rating Scale for Depression (HAMD). Quality of life was assessed using two different instruments: observer-rated Heinrich's Quality of Life Scale (QLS) and self-rated The Behavior and Symptom Identification Scale (BASIS). RESULTS: One hundred twenty-four patients with schizophrenia or schizoaffective disorder were enrolled in the study. Eight-six patients (69%) completed at least part of the CSFQ assessment, which generated at least one valid subscale score. High rates of sexual impairment were found in both male and female patients (65%-94% across different subscales). For males, higher scores on the PANSS-positive subscale were associated with a lower frequency of sexual activity (p=0.04). For females, higher scores on the PANSS-positive subscale and PANSS-general psychopathology subscale were significantly associated with more difficulty in both sexual arousal and orgasm (p's<0.05). For both males and females, there were no significant relationships between any CSFQ subscale measures and the quality of life measures (p's>0.05). No significant differences were found among three antipsychotic treatment groups (clozapine, olanzapine or typical agents) on any CSFQ subscale measures or quality of life measures after controlling for PANSS total scores (p's>0.05). CONCLUSIONS: Effective treatment strategies still need to be developed to address sexual dysfunction and quality of life in patients with schizophrenia.

Imaging receptor microdomains on leukocyte subsets in live mice.

We present a simple method to identify the recruitment of leukocyte subsets and determine concurrent surface-receptor clustering in live mice. We show that CD45+ F4/80- Gr-1+ neutrophils are robustly recruited in surgery-activated cremasteric venules, whereas adherent CD45+ B220+ B lymphocytes were dominant in bone marrow venules. Most adherent Gr-1+ leukocytes are not firmly stationary but actively migrate on TNF-alpha-activated cremasteric venular endothelium and exhibit marked polarization of surface PSGL-1, but not LFA-1, to the trailing edge.