A distinct biomolecular profile identifies monoclonal mast cell disorders in patients with idiopathic anaphylaxis.

BACKGROUND: Clonal mast cell disorders are known to occur in a subset of patients with systemic reactions to Hymenoptera stings. This observation has prompted the question of whether clonal mast cell disorders also occur in patients with idiopathic anaphylaxis (IA). OBJECTIVE: We sought to determine the prevalence of clonal mast cell disorders among patients with IA, criteria to identify those patients who require a bone marrow biopsy, and whether the pathogenesis of IA involves a hyperresponsive mast cell compartment. METHODS: We prospectively enrolled patients with IA (≥3 episodes/y) who then underwent a medical evaluation that included a serum tryptase determination, allele-specific quantitative PCR (ASqPCR) for the KIT D816V mutation, and a bone marrow examination. Mast cells were cultured from peripheral blood CD34+ cells and examined for releasability after FcεRI aggregation. RESULTS: Clonal mast cell disease was diagnosed in 14% of patients referred with IA. ASqPCR for the KIT D816V mutation was a useful adjunct in helping identify those with systemic mastocytosis but not monoclonal mast cell activation syndrome. A modified overall clonal prediction model was developed by using clinical findings, a serum tryptase determination, and ASqPCR. There was no evidence of a hyperresponsive mast cell phenotype in patients with IA. CONCLUSION: Patients with clonal mast cell disease can present as having IA. Distinct clinical and laboratory features can be used to select those patients more likely to have an underlying clonal mast cell disorder (monoclonal mast cell activation syndrome or systemic mastocytosis) and thus candidates for a bone marrow biopsy.

Abnormal bone marrow histopathology in paediatric mastocytosis.

The diagnostic criteria for paediatric mastocytosis are largely based on adult studies and bone marrow findings are not well described in children. We evaluated use of the World Health Organization (WHO) criteria for the diagnosis of systemic disease in paediatric mastocytosis. In addition, we identified unique clinico-histopathological features within the biopsies. One hundred and thirteen children with paediatric mastocytosis were evaluated at the National Institutes of Health between 1986 and 2013. Complete bone marrow evaluations were performed in 50 cases. Seven children had repeat procedures. Bone marrows were analysed by histopathology, flow cytometry and for KIT D816V. Bone marrow biopsies displayed mild atypical haematopoietic maturation, increased haematogones and hypocellularity in a sub-set of patients with urticaria pigmentosa, diffuse cutaneous mastocytosis and indolent systemic mastocytosis. Hypocellularity was most pronounced in those with urticaria pigmentosa. Haematogones were highest, on average, in patients with diffuse cutaneous mastocytosis or mastocytomas. There was no evidence of peripheral blood cytopenias, myelodysplastic syndrome, myeloproliferative neoplasm or leukaemia within this cohort. The WHO criteria are applicable for the diagnosis of systemic mastocytosis in paediatrics. Although unsuspected bone marrow findings typically seen in myeloproliferative disorders are frequent in paediatric mastocytosis, patients within this study remained clinically stable without progression to a more aggressive variant.

Quantification of Hepatocellular Carcinoma Vascular Dynamics With Contrast-Enhanced Ultrasound for LI-RADS Implementation.

OBJECTIVE: The aim of this study is to describe a comprehensive contrast-enhanced ultrasound (CEUS) imaging protocol and analysis method to implement CEUS LI-RADS (Liver Imaging Reporting and Data System) in a quantifiable manner. The methods that are validated with a prospective single-center study aim to simplify CEUS LI-RADS evaluation, remove observer bias, and potentially improve the sensitivity of CEUS LI-RADS. MATERIALS AND METHODS: This prospective single-center study enrolled patients with hepatocellular carcinoma (April 2021-June 2022; N = 31; mean age ± SD, 67 ± 6 years; 24 men/7 women). For each patient, at least 2 CEUS loops spanning over 5 minutes were collected for different lesion scan planes using an articulated arm to hold the transducer. Automatic respiratory gating and motion compensation algorithms removed errors due to breathing motion. The long axis of the lesion was measured in the contrast and fundamental images to capture nodule size. Parametric processing of time-intensity curve analysis on linearized data provided quantifiable information of the wash-in and washout dynamics via rise time ( RT ) and degree of washout ( DW ) parameters extracted from the time-intensity curve, respectively. A Welch t test was performed between lesion and parenchyma RT for each lesion to confirm statistically significant differences. P values for bootstrapped 95% confidence intervals of the relative degree of washout ( rDW ), ratio of DW between the lesion and surrounding parenchyma, were computed to quantify lesion washout. Coefficient of variation (COV) of RT , DW , and rDW was calculated for each patient between injections for both the lesion and surrounding parenchyma to gauge reproducibility of these metrics. Spearman rank correlation tests were performed among size, RT , DW , and rDW values to evaluate statistical dependence between the variables. RESULTS: The mean ± SD lesion diameter was 23 ± 8 mm. The RT for all lesions, capturing arterial phase hyperenhancement, was shorter than that of surrounding liver parenchyma ( P < 0.05). All lesions also demonstrated significant ( P < 0.05) but variable levels of washout at both 2-minute and 5-minute time points, quantified in rDW . The COV of RT for the lesion and surrounding parenchyma were both 11%, and the COV of DW and rDW at 2 and 5 minutes ranged from 22% to 31%. Statistically significant relationships between lesion and parenchyma RT and between lesion RT and lesion DW at the 2- and 5-minute time points were found ( P < 0.05). CONCLUSIONS: The imaging protocol and analysis method presented provide robust, quantitative metrics that describe the dynamic vascular patterns of LI-RADS 5 lesions classified as hepatocellular carcinomas. The RT of the bolus transit quantifies the arterial phase hyperenhancement, and the DW and rDW parameters quantify the washout from linearized CEUS intensity data. This unique methodology is able to implement the CEUS-LIRADS scheme in a quantifiable manner for the first time and remove its existing issues of currently being qualitative and suffering from subjective evaluations.

Microbubble-Enhanced Heating: Exploring the Effect of Microbubble Concentration and Pressure Amplitude on High-Intensity Focused Ultrasound Treatments.

High-intensity focused ultrasound (HIFU) is a non-invasive tool that can be used for targeted thermal ablation treatments. Currently, HIFU is clinically approved for treatment of uterine fibroids, various cancers, and certain brain applications. However, for brain applications such as essential tremors, HIFU can only be used to treat limited areas confined to the center of the brain because of geometrical limitations (shape of the transducer and skull). A major obstacle to advancing this technology is the inability to treat non-central brain locations without causing damage to the skin and/or skull. Previous research has indicated that cavitation-induced bubbles or microbubble contrast agents can be used to enhance HIFU treatments by increasing ablation regions and shortening acoustic exposures at lower acoustic pressures. However, little research has been done to explore the interplay between microbubble concentration and pressure amplitude on HIFU treatments. We developed an in vitro experimental setup to study lesion formation at three different acoustic pressures and three microbubble concentrations. Real-time ultrasound imaging was integrated to monitor initial microbubble concentration and subsequent behavior during the HIFU treatments. Depending on the pressure used for the HIFU treatment, there was an optimal concentration of microbubbles that led to enhanced heating in the focal area. If the concentration of microbubbles was too high, the treatment was detrimentally affected because of non-linear attenuation by the pre-focal microbubbles. Additionally, the real-time ultrasound imaging provided a reliable method to monitor microbubble activity during the HIFU treatments, which is important for translation to in vivo HIFU applications with microbubbles.

Association of TIMI myocardial perfusion grade and ST-segment resolution with cardiovascular magnetic resonance measures of microvascular obstruction and infarct size following ST-segment elevation myocardial infarction.

BACKGROUND: Impairment of coronary microvascular perfusion is common among patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI). Cardiovascular magnetic resonance imaging (CMR) can identify microvascular obstruction (MO) following reperfusion of STEMI. We hypothesized that myocardial perfusion, as assessed by the Thrombolysis in Myocardial Infarction (TIMI) Myocardial Perfusion Grade (TMPG), would be associated with a CMR metric of MO in this population. METHODS: Twenty-one STEMI patients who underwent successful primary PCI were evaluated. Contrast-enhanced CMR was performed within 7 days of presentation and repeated at three months. TIMI Flow Grade (TFG), corrected TIMI Frame Count (cTFC), TMPG, MO, infarct size, and left ventricular ejection fraction (EF) were assessed. RESULTS: The median peak creatine phosphokinase (CPK) was 1,775 IU/l (interquartile range 838-3,321). TFG 3 was present following PCI in 19 (90%) patients. CMR evidence of MO was present in 52% following PCI. Abnormal post-PCI TMPG (0/1/2) was present in 48% of subjects and was associated with MO on CMR (90% MO with TMPG 0/1/2 vs. 18% MO with TMPG 3, P < 0.01). Abnormal post-PCI TMPG was also associated with a greater peak CK (median 3,623 IU/l vs. 838 IU/l, P < 0.001) and greater relative infarct size (17.3% vs. 5.2%, P < 0.01). CONCLUSION: Among STEMI patients undergoing primary PCI, post-PCI TMPG correlates with CMR measures of MO and infarct size. The combined use of both metrics in a comprehensive assessment of microvascular integrity and infarct size following STEMI may aid in the evaluation of future therapeutic strategies.

Reconstructing patient-specific cerebral aneurysm vasculature for in vitro investigations and treatment efficacy assessments.

Perianeurysmal hemodynamics play a vital role in the initiation, growth and rupture of intracranial aneurysms. In vitro investigations of aneurysmal hemodynamics are helpful to visualize and measure blood flow, and aiding surgical planning approaches. Improving in vitro model creation can improve the feasibility and accuracy of hemodynamic investigations and surgical planning, improving clinical value. In this study, in vitro models were created from three-dimensional rotational angiography (3DRA) of six patients harboring intracranial aneurysms using a multi-step process involving 3D printing, index of refraction matching and silicone casting that renders the models transparent for flow visualization. Each model was treated with the same commercially-available, patient-specific, endovascular devices (coils and/or stents). All models were scanned by synchrotron X-ray microtomography to obtain high-resolution imaging of the vessel lumen, aneurysmal sac and endovascular devices. Dimensional accuracy was compared by quantifying the differences between the microtomographic reconstructions of the fabricated phantoms and the original 3DRA obtained during patient treatment. True-scale in vitro flow phantoms were successfully created for all six patients. Optical transparency was verified by using an index of refraction matched working fluid that replicated the mechanical behavior of blood. Synchrotron imaging of vessel lumen, aneurysmal sac and endovascular devices was successfully obtained, and dimensional errors were found to be O(100 µm). The creation of dimensionally-accurate, optically-transparent flow phantoms of patient-specific intracranial aneurysms is feasible using 3D printing technology. Such models may enable in vitro investigations of aneurysmal hemodynamics to aid in treatment planning and outcome prediction to devise optimal patient-specific neurointerventional strategies.

Surface acoustic wave nebulization device with dual interdigitated transducers improves SAWN-MS performance.

We compared mass spectrometric (MS) performance of surface acoustic wave nebulization (SAWN) generated by a single interdigitated transducer (IDT) designed to produce a progressive wave (PW) to one with a dual IDT that can in theory generate standing waves (SW). Given that devices using dual IDTs had been shown to produce fewer large size droplets on average, we hypothesized they would improve MS performance by improving the efficiency of desolvation. Indeed, the SW-SAWN chip provided an improved limit of detection of 1 femtomole of peptide placed on chip making it 100× more sensitive than the PW design. However, as measured by high-speed image recording and phase Doppler particle analyzer measurements, there was only a 26% increase in the small diameter (1-10 µm) droplets produced from the new device, precluding a conclusion that the decrease in droplet size was solely responsible for the improvement in MS signal/noise. Given that the dual IDT design produced a more instantaneous plume than the PW design, the more likely contributor to improved MS signal/noise was concluded to be a higher ion flux entering the mass spectrometer for the dual IDT designs. Notably, the dual IDT device allowed production of much higher quality protein mass spectra up to about 20 kDa, compared with the single IDT device. Copyright © 2016 John Wiley & Sons, Ltd.

Convective Leakage Makes Heparin Locking of Central Venous Catheters Ineffective Within Seconds: Experimental Measurements in a Model Superior Vena Cava.

Central venous catheters (CVCs), placed in the superior vena cava (SVC) for hemodialysis or chemotherapy, are routinely filled while not in use with heparin, an anticoagulant, to maintain patency and prevent thrombus formation at the catheter tip. The heparin-locking procedure, however, places the patient at risk for systemic bleeding, as heparin is known to leak from the catheter into the blood stream. We provide evidence from detailed in vitro experiments that shows the driving mechanism behind heparin leakage to be convective-diffusive transport due to the pulsatile flow surrounding the catheter. This novel mechanism is supported by experimental planar laser-induced fluorescence (PLIF) and particle image velocimetry (PIV) measurements of flow velocity and heparin transport from a CVC placed inside a model SVC inside a pulsatile flow loop. The results predict an initial, fast (<10 s), convection-dominated phase that rapidly depletes the concentration of heparin in the near-tip region, the region of the catheter with side holes. This is followed by a slow, diffusion-limited phase inside the catheter lumen, where the concentration is still high, that is insufficient at replenishing the lost heparin concentration in the near-tip region. The results presented here, which are consistent with previous in vivo estimates of 24 hour leakage rates, predict that the concentration of heparin in the near-tip region is essentially zero for the majority of the interdialytic phase, rendering the heparin locking procedure ineffective.

Speed of blood withdrawal and accurate measurement of oxygen content in mixed venous blood.

BACKGROUND: Measurement of mixed venous oxygen saturation helps determine whether cardiac output and oxygen delivery are sufficient for metabolic needs. As recommended by the American Association of Critical-Care Nurses guideline, blood samples for determining mixed venous oxygen saturation are obtained by slowly, in 1 to 2 minutes, withdrawing 1.5 mL of blood from the distal port of the pulmonary artery catheter. In theory, the negative force of rapid withdrawal could pull oxygenated blood from the pulmonary capillary bed, causing falsely elevated saturation values. OBJECTIVE: To determine if the speed of withdrawal affects oxygen content in blood samples used to measure mixed venous oxygen saturation. METHODS: The sample consisted of heart failure patients with pulmonary artery catheters admitted to a cardiac intensive care unit. A prospective, randomized, 2 × 2 crossover design was used to compare mixed venous oxygen saturation in blood samples obtained quickly or slowly. A total of 50 sets of saturation values were analyzed. Each set included 1 blood sample obtained slowly, in 1 to 2 minutes, and 1 obtained rapidly, in 5 seconds. RESULTS: The mean difference in saturation values between the fast and the slow groups was -0.3 (CI, -1.5 to 0.8; P = .55), indicating that no meaningful systematic bias is attributable to fast withdrawal of blood. CONCLUSIONS: Rapid blood sampling does not falsely elevate measurements of mixed venous oxygen saturation.

Accuracy of residents' retrospective perceptions of 16-hour call admitting shift compliance and characteristics.

BACKGROUND: The Accreditation Council for Graduate Medical Education Resident-Fellow Survey measurement of compliance with duty hours uses remote retrospective resident report, the accuracy of which has not been studied. We investigated residents' remote recall of 16-hour call-shift compliance and workload characteristics at 1 institution. METHODS: We sent daily surveys to second- and third-year internal medicine residents immediately after call shifts from July 2011 to June 2012 to assess compliance with 16-hour shift length and workload characteristics. In June 2012, we sent a survey with identical items to assess residents' retrospective perceptions of their call-shift compliance and workload characteristics over the preceding year. We used linear models to compare on-call data to residents' retrospective data. RESULTS: We received a survey response from residents after 497 of 648 call-shifts (77% response). The end-of-year perceptions survey was completed by 87 of 95 residents (92%). Compared with on-call data, the recollections of 5 (6%) residents were accurate; however, 48 (56%) underestimated and 33 (38%) overestimated compliance with the 16-hour shift length requirement. The average magnitude of under- and overestimation was 18% (95% confidence interval  =  13-23). Using a greater than 10% absolute difference to define under- and overestimation, 39 (45%) respondents were found to be accurate, 27 (31%) underestimated compliance, and 20 (23%) overestimated compliance. Residents overestimated census size, long call admissions, and admissions after 5 pm. CONCLUSIONS: Internal medicine residents' remote retrospective reporting of compliance with the 16-hour limit on continuous duty and workload characteristics was inaccurate compared with their immediate recall and included errors of underestimation and overestimation.

Laparoscopic clam shell partial fundoplication achieves effective reflux control with reduced postoperative dysphagia and gas bloating.

BACKGROUND: We describe a novel laparoscopic "clam shell" partial fundoplication, incorporating a modified Toupet with an anterior fundic flap for the management of medically recalcitrant gastroesophageal reflux disease. We hypothesize that this clam-shell-like mechanism allows a dynamic rather than rigid circumferential antireflux barrier allowing effective reflux control (compared with partial fundoplication) with reduced occurrence of postoperative dysphagia, gas bloating and vagal nerve injury (compared with Nissen fundoplication). METHODS: Between November 2002 and May 2006, 140 patients (82 female; mean age, 53 years) underwent this laparoscopic clam shell fundoplication procedure for medically recalcitrant gastroesophageal reflux disease (n = 94) or large paraesophageal hernias (n = 46). Preoperative invasive studies (endoscopy, manometry, pH monitoring) and noninvasive studies (barium swallow and radionuclide gastroesophageal motility) revealed esophageal dysmotility in 26 patients. Routine barium swallow and radionuclide studies were performed 6 months postoperatively and then at yearly intervals. RESULTS: There was no mortality or conversions to open procedures. Mean operative time was 45 minutes; median hospital stay was 1 day (range, 1 to 4). Overall control of reflux symptoms was seen in 95% of patients. Postoperative gas bloating and significant dysphagia occurred in only 11% and 6% of patients, respectively. Three patients (2%) experienced postoperative complications (pneumonia, 2; pleural effusion requiring drainage, 1). Postoperative studies demonstrated reflux in 8 patients (5%) and the presence of small hiatal hernias in 5 patients (4%) during a mean follow-up 19 months (range, 7 to 42). Twenty five patients (17%) underwent postoperative esophageal dilation (median dilations, 1; range, 1 to 3) for dysphagia (11 of these patients had preoperative esophageal dysmotility). Five patients underwent repeat fundoplication (recurrent reflux, 2; gas bloating, 1; dysphagia, 2). CONCLUSIONS: Clam shell near-circumferential fundoplication may be considered as an attractive alternative antireflux approach to Nissen fundoplication, particularly among patients at risk for postoperative dysphagia or gas bloating.