External validation of a smartphone app model to predict the need for massive transfusion using five different definitions.

BACKGROUND: Previously, a model to predict massive transfusion protocol (MTP) (activation) was derived using a single-institution data set. The PRospective, Observational, Multicenter, Major Trauma Transfusion database was used to externally validate this model's ability to predict both MTP activation and massive transfusion (MT) administration using multiple MT definitions. METHODS: The app model was used to calculate the predicted probability of MTP activation or MT delivery. The five definitions of MT used were: (1) 10 units packed red blood cells (PRBCs) in 24 hours, (2) Resuscitation Intensity score ≥ 4, (3) critical administration threshold, (4) 4 units PRBCs in 4 hours; and (5) 6 units PRBCs in 6 hours. Receiver operating curves were plotted to compare the predicted probability of MT with observed outcomes. RESULTS: Of 1,245 patients in the data set, 297 (24%) met definition 1, 570 (47%) met definition 2, 364 (33%) met definition 3, 599 met definition 4 (49.1%), and 395 met definition 5 (32.4%). Regardless of the outcome (MTP activation or MT administration), the predictive ability of the app model was consistent: when predicting activation of the MTP, the area under the curve for the model was 0.694 and when predicting MT administration, the area under the curve ranged from 0.695 to 0.711. CONCLUSION: Regardless of the definition of MT used, the app model demonstrates moderate ability to predict the need for MT in an external, homogenous population. Importantly, the app allows the model to be iteratively recalibrated ("machine learning") and thus could improve its predictive capability as additional data are accrued. LEVEL OF EVIDENCE: Diagnostic test study/Prognostic study, level III.

Time is the enemy: Mortality in trauma patients with hemorrhage from torso injury occurs long before the "golden hour".

INTRODUCTION: The concept of the "Golden Hour" has been a time-honored tenet of prehospital trauma care, despite a paucity of data to substantiate its validity. Non-compressible torso hemorrhage has been demonstrated to be a significant cause of mortality in both military and civilian settings. We sought to characterize the impact of prehospital time and torso injury severity on survival. Furthermore, we hypothesized that time would be a significant determinant of mortality in patients with higher Abbreviated Injury Scale (AIS) grades of torso injury (AIS ≥ 4) and field hypotension (prehospital SBP ≤ 110 mmHg) as these injuries are commonly associated with hemorrhage. METHODS: Data for this analysis was generated from a registry of 2,523,394 injured patients entered into the National Trauma Data Bank Research Data Set from 2012 to 2014. Patients with torso injury were identified utilizing Abbreviated Injury Scale (AIS) for body regions 4 (Thorax) and 5 (Abdomen). Specific inclusion criteria for this study included pre-hospital time, prehospital SBP ≤110 mmHg, torso injury qualified by AIS and mortality. Patients with non-survivable torso injury (AIS = 6), severe head injuries (AIS ≥ 3), no signs of life in the field (SBP = 0), interfacility transfers, or those with any missing data elements were excluded. This classification methodology identified a composite cohort of 42,135 adult patients for analysis. RESULTS: The overall mortality rate of the study population was 7.9% (3326/42,135); Torso AIS and prehospital time were noted to be strong independent predictors of patient mortality in all population strata of the analysis (P < 0.05). The data demonstrated a profound incremental increase in mortality in the early time course after injury associated with torso AIS ≥4. CONCLUSION: In patients with high-grade torso injury, AIS grades ≥4, the degree anatomic disruption is associated with significant hemorrhage. In our study, a precipitous rise in patient mortality was exhibited in this high-grade injury group at prehospital times <30 min. Our data highlight the critical nature of prehospital time in patients with non-compressible torso hemorrhage. However, realizing that evacuation times ≤30 min may not be realistic, particularly in rural or austere environments, future efforts should be directed toward the development of therapies to increase the window of survival in the prehospital environment.

Characterization of human, dog and rabbit corpus cavernosum type 5 phosphodiesterases.

Human, dog and rabbit corpus cavernosum type 5 phosphodiesterases (PDE5) were isolated and their characteristics were compared. The three enzymes showed Km values of 0.8, 2.1 and 2.3 uM, respectively. They exhibited similar pH-dependence with optimal pH being 7.5. They required Mg++ for activity and the activity was suppressed by high concentrations of Zn++ (0.1-1 mM). Sildenafil potently inhibited the three enzymes with IC50 values of 3.6, 1.7 and 3.0 nM, respectively. Dipyridamole and IBMX (3-isobutyl-1-methylxanthine) each also inhibited the three enzymes with similar, albeit lower, potencies (IC50 about 1.1 and 5.7 uM, respectively). However, zaprinast exhibited a significantly higher potency against the rabbit enzyme (IC50 53 nM) than against the human and dog PDE5s (IC5s 332 and 217 nM, respectively). Thus, the corpus cavernosum PDE5s are very similar among the various species with the only significant difference being their sensitivity to zaprinast. Human platelet PDE5 was also characterized by comparison with the corpus cavernosum enzyme. The platelet enzyme exhibited a Km, pH-, Mg++- and Zn++-dependence, and sensitivity to sildenafil and zaprinast very similar to those of the corpus cavernosum PDE5. However, compared with corpus cavernosum PDE5, the platelet enzyme exhibited higher sensitivity to dipyridamole and IBMX (IC50 0.46 and 1.8 uM, respectively). This study shows that despite similar kinetics and enzymatic properties, corpus cavernosum PDE5s from different species, and corpus cavernosum and platelet PDE5s, can have differential sensitivity to pharmacological inhibitors.

Sources of error in maximum velocity estimation using linear phased-array Doppler systems with steady flow.

Using linear-array Doppler ultrasound (US) transducers, the measured maximum velocity may be in error and lead to incorrect clinical diagnosis. This study investigates the existence and cause of maximum velocity estimation errors for steady flow of a blood-mimicking fluid in a tissue-mimicking phantom. A specially designed system was used that enabled fine control of flow rate, transducer positioning and transducer angle relative to the flow phantom. Doppler machine settings (transducer aperture size, focal depth, beam-steering, gain) were varied to investigate a wide range of clinical applications. To estimate the maximum velocity, a new signal-to-noise ratio (SNR) independent method was developed to calculate the maximum frequency from an ensemble averaged Doppler power spectrum. This enabled the impact of each factor on the total Doppler error to be determined. When using the new maximum frequency estimator, it was found that the effect of transducer focal depth, intratransducer, intramachine, intermachine (that was tested) and beam-steering did not significantly contribute to maximum velocity estimation errors. Instead, it was the dependence of the maximum velocity on the Doppler angle that made, by far, the greatest contribution to the estimation error. Because our maximum frequency estimator took into account the effect of intrinsic spectral broadening, the degree of overestimation error was not as great as that previously published. Thus, the effects of Doppler angle and intrinsic spectral broadening are the chief sources of Doppler US error and should be the focus of future efforts to improve the accuracy.

Factors influencing blood flow patterns in the human right coronary artery.

Evidence suggests that atherogenesis is linked to local hemodynamic factors such as wall shear stress. We investigated the velocity and wall shear stress patterns within a human right coronary artery (RCA), an important site of atherosclerotic lesion development. Emphasis was placed on evaluating the effect of flow waveform and inlet flow velocity profile on the hemodynamics in the proximal, medial, and distal arterial regions. Using the finite-element method, velocity and wall shear stress patterns in a rigid, anatomically realistic model of a human RCA were computed. Steady flow simulations (ReD=500) were performed with three different inlet velocity profiles; pulsatile flow simulations utilized two different flow waveforms (both with Womersley parameter=1.82, mean ReD=233), as well as two of the three inlet profiles. Velocity profiles showed Dean-like secondary flow features that were remarkably sensitive to the local curvature of the RCA model. Particularly noteworthy was the "rotation" of these Dean-like profiles, which produced large local variations in wall shear stress along the sidewalls of the RCA model. Changes in the inlet velocity profiles did not produce significant changes in the arterial velocity and wall shear stress patterns. Pulsatile flow simulations exhibited remarkably similar cycle-average wall shear stress distributions regardless of waveform and inlet velocity profile. The oscillatory shear index was very small and was attributed to flow reversal in the waveform, rather than separation. Cumulatively, these results illustrate that geometric effects (particularly local three-dimensional curvature) dominate RCA hemodynamics, implying that studies attempting to link hemodynamics with atherogenesis should replicate the patient-specific RCA geometry.

Appendicitis: why so complicated? Analysis of 5755 consecutive appendectomies.

A perceived high rate of complicated (gangrenous or perforated) appendicitis, despite advances in laboratory and radiographic diagnostic modalities, prompted a review of our experience with appendicitis followed by a prospective analysis that examined the time course from presentation to definitive treatment in 218 consecutive patients. In 5755 appendectomies, our overall rate of complicated appendicitis was 32 per cent; higher in males, in the young, and in the elderly; and relatively stable over each year reviewed. Prospectively, we determined that of the various time intervals, the time from the onset of symptoms to first seeking medical attention is the only significant predictor of complicated appendicitis (39.8 vs 16.5 hours for acute appendicitis). On the other hand, the time from surgical evaluation to operative intervention was significantly shorter for complicated appendicitis (3.8 vs 4.7 hours for acute appendicitis). The high rate of complicated appendicitis with its subsequent sequelae of increased morbidity and resource expenditure is primarily the direct result of patient delay in seeking medical attention and not the result of diagnostic dilemma or surgical delay. Public education, specifically targeting those groups at risk, may provide a substantial and significant solution to the complicated appendix.

Primary aortoduodenal fistula and Q fever: an underrecognized association?

We report a rare case of primary aortoduodenal fistula (ADF) secondary to a Coxiella burnetii (Q fever) infection in a patient with an abdominal aortic aneurysm. A review of the available literature on the vascular complications of Q fever is presented. Q fever should be suspected in vascular patients with close animal contact when a standard infectious work-up is unrevealing. Diagnostic steps and management strategies for primary ADF are also briefly reviewed.

Blunt splenic injuries: dedicated trauma surgeons can achieve a high rate of nonoperative success in patients of all ages.

BACKGROUND: Selective nonoperative management (NOM) of blunt splenic injuries is becoming a more prevalent practice. Inclusion criteria for NOM, which have been a source of controversy, continue to evolve. Age > or = 55 years has been proposed as a predictor for failure of and even a contraindication to NOM of blunt splenic trauma. Additionally, the high rate of NOM in children (up to 79%) has been attributed to their management by pediatric surgeons. We evaluated our experience with NOM of blunt splenic injury with special attention to these age groups. METHODS: By using our trauma registry, all patients with blunt splenic injuries (documented by computed tomography, operative findings, or both) cared for over a 36-month period, at a single American College of Surgeons verified Level I trauma center were reviewed. Detailed chart reviews were performed to examine admission demographics, laboratory data, radiologic findings, outcome measures, and patient management strategy. All patients were managed by nonpediatric trauma surgeons. We then compared our adult data with that in the recent literature and our pediatric data with that of the National Pediatric Trauma Registry over the same time period. RESULTS: We identified 251 consecutive patients with blunt splenic injuries. Eighteen patients who expired in the immediate postinjury period were excluded from statistical evaluation. No deaths occurred as a result of splenic injury. Of the remaining 233 patients, 73 patients (31%) required early celiotomy, 160 patients (69%) were selected for NOM, with 151 patients (94%) being successfully managed without operation. Blunt splenic injury occurred in 23 patients age 55 years or older. Eighteen patients (78%) were selected for NOM and 17 patients (94%) were successfully treated without operation. Blunt splenic injury occurred in 35 patients less than 16 years of age. Thirty-two patients (91%) were selected for NOM. Thirty-one patients (89% of all pediatric patients) were successfully treated without operation. CONCLUSION: Age > or = 55 years is not a contraindication to nonoperative management of blunt splenic injuries. Children with blunt splenic injuries can be successfully managed nonoperatively by nonpediatric trauma surgeons.

Color Doppler velocity accuracy proximal to regurgitant orifices: influence of orifice aspect ratio.

Many noninvasive methodologies used for the accurate evaluation of valvular regurgitation require precise velocity measurements from ultrasound instruments. Previous studies have indicated that velocity measurements from color Doppler (CD) instruments are susceptible to errors due to the interaction of the ultrasound beam and the proximal orifice flow field. This study examined the influence of high aspect ratio (AR) orifices on the CD velocity error. Center line velocity error distributions for orifices ranging from 7.07 to 78.5 mm2, varying in shape from circular to an AR = 8 ellipse, were evaluated using a numerical model of the ultrasound beam and the simulated regurgitant flow field. An in vitro study was also performed and confirmed the findings of the numerical model. The study showed that increasing AR does not significantly change the error characteristics. The study confirmed that orifice size is the dominant factor in the error distribution, and that corrections speculated for circular orifices can be extended to elliptical orifices without significant errors.

Effects of chronic anti-interleukin-5 monoclonal antibody treatment in a murine model of pulmonary inflammation.

The maturation of eosinophils in bone marrow, their migration to pulmonary tissue, and their subsequent degranulation and release of toxic granule proteins contributes to the pathophysiology observed in asthma. Interleukin-5 (IL-5) is essential for these processes to occur. Therefore, much emphasis has been placed on attempts to inhibit the production or activity of IL-5 in order to attenuate the inflammatory aspect of asthma. In this report, the immunological consequences of long-term exposure to an antibody recognizing IL-5 (TRFK-5) were studied in a murine pulmonary inflammation model. A single dose of TRFK-5 (1 mg/ kg, intraperitoneally) reversibly inhibited antigen-dependent lung eosinophilia in mice for at least 12 wk and inhibited the release of eosinophils from bone marrow for at least 8 wk. Normal responses to aerosol challenge were attained after 24 wk. In mice treated acutely with antibody (2 h before challenge), 50% inhibition of pulmonary eosinophilia occurred when 0. 06 mg/kg TRFK-5 was administered (intraperitoneally; ED50), resulting in 230 ng/ml (IC50) in serum. In mice treated with one dose of TRFK-5 (1 mg/kg) and rested before challenge, the antibody exhibited a half-life of 2.4 wk. After 18 to 19 wk, antigen challenge-induced eosinophilia was inhibited by 50% and serum levels of TRFK-5 were 25 ng/ml. TRFK-5 remaining in mice 8 wk after a single injection of TRFK-5 was sufficient to inhibit at least 50% of the eosinophilia induced in blood 3 h after injection of recombinant murine IL-5 (10 microg/kg, intravenously). To assess the biologic effect of long-term exposure of mice to antibody, several parameters of immune-cell function were measured. Throughout the extended period of activity of TRFK-5 (>/= 12 wk) there were no gross effects on antigen-dependent increases in T-cell recruitment into bronchoalveolar fluid (BALF), in IL-4 and IL-5 steady-state mRNA levels in lung tissue, or in immunoglobulin E (IgE) and IgG levels in serum. There was a small increase in IL-5 steady-state mRNA production in TRFK-5-treated mice after 2 h or 2 wk, but this was not observed at other times examined. In untreated mice, IL-5 steady-state mRNA production in response to antigen challenge decreased > 6-fold with age, although at all time points there was an increase in mRNA levels following challenge. Therefore, at later times, 25 ng/ml rather than 230 ng/ml of TRFK-5 inhibited BALF eosinophilia, probably because of reduced IL-5 levels. Twenty-four weeks after treatment with TRFK-5, when challenge-induced eosinophilia was restored, there was an excess of CD4(+) T cells in BALF from challenged mice. However, these T cells had no measurable effects on other responses to challenge, including cytokine production, B-cell accumulation, and immunoglobulin production in serum. Thus, the biologic duration of TRFK-5 was several months, and its activity was due to the presence of antibody above a therapeutic threshold rather than to any profound effect on the immune system.

Selective inhibition of IL-5 receptor alpha-chain gene transcription by IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor in human blood eosinophils.

High affinity receptor for IL-5 (IL-5R), a predominant eosinophil maturation factor, is composed of an IL-5-binding alpha-chain (IL-5R alpha) and a signal-transducing beta-chain that is shared by IL-3 and granulocyte-macrophage CSF (GM-CSF) receptors (IL-3R and GM-CSFR). By Northern blot analysis of mRNAs obtained from normal human blood eosinophils, we show in this report that the hematopoietic cytokines IL-5, IL-3, and GM-CSF down-regulate IL-5R alpha mRNA while up-regulating alpha-chain mRNAs for both IL-3R and GM-CSFR as well as the beta-chain mRNA. More detailed characterization reveals that the down-regulation of IL-5R alpha mRNA is specific to IL-3, IL-5, and GM-CSF; occurs very rapidly (reaching maximum inhibition within 2 h); is cytokine dose dependent; and does not require protein synthesis. Nuclear run-on and mRNA stability experiments demonstrate that cytokine-induced inhibition of IL-5R alpha mRNA accumulation occurs at the level of IL-5R alpha gene transcription, whereas enhanced accumulation of mRNAs for IL-3R alpha and the beta-chain results from reduced mRNA degradation. We suggest from these experiments that in human blood eosinophils, IL-5R alpha gene transcription and IL-5R alpha mRNA metabolism can be regulated by mechanisms that are distinct from those used for IL-3R alpha and GM-CSFR alpha.

Evaluation of the proximal flow field to circular and noncircular orifices of different aspect ratios.

Investigations of valvular regurgitation attempt to specify flow field characteristics and apply them to the proximal isovelocity surface area (PISA) method for quantifying regurgitant flow. Most investigators assume a hemispherical shape to these equivelocity shells proximal to an axisymmetric (circular) orifice. However, in vivo flow fields are viscous and regurgitant openings vary in shape and size. By using centerline profiles and isovelocity surfaces, this investigation describes the flow field proximal to circular and elliptical orifices. Steady, proximal flow fields are obtained with two- and three-dimensional computational fluid dynamic (CFD) simulations. These simulations are verified by in vitro, laser-Doppler velocimetry (LDV) experiments. The data show that a unique, normalized proximal flow field results for each orifice shape independent of orifice flow or size. The distinct differences in flow field characteristics with orifice shape may provide a mechanism for evaluating orifice characteristics and regurgitant flows. Instead of the hemispherical approximation technique, this study attempts to show the potential to define a universal flow evaluation method based on the details of the flowfield according to orifice shape. Preliminary results indicate that Magnetic Resonance (MR) and Color Doppler (CD) may reproduce these flow details and allow such a procedure in vivo.

Expression, purification, and characterization of human cAMP-specific phosphodiesterase (PDE4) subtypes A, B, C, and D.

Although four members (A, B, C, and D) of the cAMP-specific phosphodiesterase (PDE4) family have been cloned by different groups, no study comparing the characteristics of purified human PDE4 subtypes has been published. In this study, we have expressed human PDE4 A, B, C, and D in insect (SF9) cells by using the baculovirus expression system, purified the expressed proteins, and compared their characteristics. The recombinant PDE4 subtypes all showed catalytic activity for cAMP with a K(m) of 1-5 microM. V(max) values differed significantly among these subtypes with the following order: C > B > A > D. PDE4 A, B, C, and D showed a very similar Mg2+ dependence profile. PDE4 B and C showed similar pH profiles with the optimal pH being 8.0. The pH profiles of PDE4 A and D were very different from each other and from those of B and C, with the optimal pH being 6.5 and 7.5, respectively. Furthermore, although PDE4 A, B, C, and D were all inhibited by the standard PDE4 inhibitors rolipram, Ro20-1724, and etazolate, the inhibitory potency varied. Thus, by several criteria including kinetics, pH dependency, and inhibitor sensitivity, various PDE4 subtypes differ significantly from one another.

Accuracy of color doppler velocity in the flow field proximal to a regurgitant orifice: implications for color doppler quantitation of valvular incompetence.

Color Doppler is routinely used in estimates of valvular regurgitation. Velocity and subsequently flow measurements are made at about 7-10 cm from the ultrasonic transducer. Error in velocity measurement may occur due to spatial broadening of the color Doppler beam in the axial, azimuthal and lateral directions. Error in velocity may also occur due to wall filters since the filtering process is not uniform throughout the velocity range indicated by the color bar. An attempt to estimate this error was made using an in vitro orifice model, a numerical finite element model (FEM), and information from the manufacturer. We found that the acoustic beam spatial expansion, wall filter sensitivity and Nyquist limit (NYL) have to be considered simultaneously to account for errors. The combined spatial expansion and wall filter effect on velocity was estimated as a weighted average over the sample volume. The error distributions are not universal but depend on orifice size and flow. For a 3-mm orifice and 100 cm s NYL the overall effect was overestimation of low velocities and significant underestimation of high velocities due to the high velocity gradients inside the sample volume. For the 5- and the 10-mm orifice the effect was less accentuated. Based on this overall error distribution, a correction was incorporated on color Doppler obtained data. The incorporated correction yielded better agreement with numerical velocity data. This correction is important in the application of the proximal isovelocity surface area (PISA) technique and the evaluation of regurgitant flowrates.

Complications of needle catheter jejunostomy in 2,022 consecutive applications.

BACKGROUND: We commonly use needle catheter jejunostomy (NCJ) for early enteral feeding in selected patients. Review of our approach was prompted by the suggestion that enteral feeding represents a "stress test" for the bowel and may be associated with a high complication rate. MATERIALS AND METHODS: We reviewed patients with NCJ inserted over the past 16 years by prospective database, chart review, and conference minutes, with emphasis on complications. RESULTS: During the conduct of 28,121 laparotomies, 2,022 NCJs inserted in 1,938 patients (7.2%) resulted in 34 NCJ-related complications in 29 patients (1.5%) The most common complication was premature loss of the catheter from occlusion or dislodgment (n = 15; 0.74%), and the most serious was bowel necrosis (n = 3; 0.15%). CONCLUSIONS: Needle catheter jejunostomy may be inserted and used with a low complication rate. Most complications were preventable through greater attention to detail and better monitoring of physical examination of patients with marginal gut function.

A numerical and experimental investigation of the flow acceleration region proximal to an orifice.

Attempts to quantify valvular regurgitation have recently been focused on the proximal orifice flow field. A complete description of the proximal orifice flow field is provided in this investigation. A steady state in vitro model accessible by both color Doppler ultrasound (CDU) and laser Doppler velocimetry (LDV) was utilized. Velocities for varying flow rates and orifices were calculated by finite element modeling (FEM), by LDV and by CDU. The steady flow model was composed of circular orifices of 3, 5 and 10 mm diameters at flow rates from 0.7 to 10 L/min. Regurgitant flow rates were calculated from the proximal CDU data by two separate methods. The first approach utilized angle corrected velocities while the second approach utilized only velocities which did not require angle correction (centerline velocities). Both methods correlated well with known flow rates (y = 0.97x -0.09, r = 0.98, SEE = 0.45, p < 0.0001; and y = 1.0x + 0.07, r = 0.99, SEE = 0.27, p < 0.0001, respectively) and were superior to results obtained by assuming a hemispherical geometry as is done in the aliasing technique. The methodology provides a complete analysis of the proximal flow field and involves fewer geometric assumptions than the aliasing approach. This may prove to be an advantage when analyzing in vivo flow fields with complex, uncertain geometry.

AIDS and hemophilia: implications for interventions with families.

Informational needs of hemophiliacs must first be assessed to develop effective educational and prevention programs. A survey of 132 hemophilia patients and family members was conducted to determine the information needs, the preferred source of information and the patients' knowledge of AIDS. Results indicated that the major source of information for the patients was the media; the preferred source was the hemophilia treatment center. Most patients wanted more information about the treatment of AIDS and how to cope with the stresses of AIDS. Although patients indicated that they had received sufficient information about the sexual transmission of AIDS, answers to knowledge questions indicated important misconceptions. Results are discussed with respect to the development of educational and prevention programs for hemophiliacs and their families.