Aptameric hirudins as selective and reversible EXosite-ACTive site (EXACT) inhibitors.

Potent and selective inhibition of the structurally homologous proteases of coagulation poses challenges for drug development. Hematophagous organisms frequently accomplish this by fashioning peptide inhibitors combining exosite and active site binding motifs. Inspired by this biological strategy, we create several EXACT inhibitors targeting thrombin and factor Xa de novo by linking EXosite-binding aptamers with small molecule ACTive site inhibitors. The aptamer component within the EXACT inhibitor (1) synergizes with and enhances the potency of small-molecule active site inhibitors by many hundred-fold (2) can redirect an active site inhibitor's selectivity towards a different protease, and (3) enable efficient reversal of inhibition by an antidote that disrupts bivalent binding. One EXACT inhibitor, HD22-7A-DAB, demonstrates extraordinary anticoagulation activity, exhibiting great potential as a potent, rapid onset anticoagulant to support cardiovascular surgeries. Using this generalizable molecular engineering strategy, selective, potent, and rapidly reversible EXACT inhibitors can be created against many enzymes through simple oligonucleotide conjugation for numerous research and therapeutic applications.

Development and Validation of a Natural Language Processing Model to Identify Low-Risk Pulmonary Embolism in Real Time to Facilitate Safe Outpatient Management.

STUDY OBJECTIVE: This study aimed to (1) develop and validate a natural language processing model to identify the presence of pulmonary embolism (PE) based on real-time radiology reports and (2) identify low-risk PE patients based on previously validated risk stratification scores using variables extracted from the electronic health record at the time of diagnosis. The combination of these approaches yielded an natural language processing-based clinical decision support tool that can identify patients presenting to the emergency department (ED) with low-risk PE as candidates for outpatient management. METHODS: Data were curated from all patients who received a PE-protocol computed tomography pulmonary angiogram (PE-CTPA) imaging study in the ED of a 3-hospital academic health system between June 1, 2018 and December 31, 2020 (n=12,183). The "preliminary" radiology reports from these imaging studies made available to ED clinicians at the time of diagnosis were adjudicated as positive or negative for PE by the clinical team. The reports were then divided into development, internal validation, and temporal validation cohorts in order to train, test, and validate an natural language processing model that could identify the presence of PE based on unstructured text. For risk stratification, patient- and encounter-level data elements were curated from the electronic health record and used to compute a real-time simplified pulmonary embolism severity (sPESI) score at the time of diagnosis. Chart abstraction was performed on all low-risk PE patients admitted for inpatient management. RESULTS: When applied to the internal validation and temporal validation cohorts, the natural language processing model identified the presence of PE from radiology reports with an area under the receiver operating characteristic curve of 0.99, sensitivity of 0.86 to 0.87, and specificity of 0.99. Across cohorts, 10.5% of PE-CTPA studies were positive for PE, of which 22.2% were classified as low-risk by the sPESI score. Of all low-risk PE patients, 74.3% were admitted for inpatient management. CONCLUSION: This study demonstrates that a natural language processing-based model utilizing real-time radiology reports can accurately identify patients with PE. Further, this model, used in combination with a validated risk stratification score (sPESI), provides a clinical decision support tool that accurately identifies patients in the ED with low-risk PE as candidates for outpatient management.

Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis.

ABSTRACT: Cell-surface exposure of phosphatidylserine (PS) is essential for phagocytic clearance and blood clotting. Although a calcium-activated phospholipid scramblase (CaPLSase) has long been proposed to mediate PS exposure in red blood cells (RBCs), its identity, activation mechanism, and role in RBC biology and disease remain elusive. Here, we demonstrate that TMEM16F, the long-sought-after RBC CaPLSase, is activated by calcium influx through the mechanosensitive channel PIEZO1 in RBCs. PIEZO1-TMEM16F functional coupling is enhanced in RBCs from individuals with hereditary xerocytosis (HX), an RBC disorder caused by PIEZO1 gain-of-function channelopathy. Enhanced PIEZO1-TMEM16F coupling leads to an increased propensity to expose PS, which may serve as a key risk factor for HX clinical manifestations including anemia, splenomegaly, and postsplenectomy thrombosis. Spider toxin GsMTx-4 and antigout medication benzbromarone inhibit PIEZO1, preventing force-induced echinocytosis, hemolysis, and PS exposure in HX RBCs. Our study thus reveals an activation mechanism of TMEM16F CaPLSase and its pathophysiological function in HX, providing insights into potential treatment.

COVID-Necessitated Online Radiology Elective Improves Student Imaging Appropriateness in Clinical Case Vignettes.

RATIONALE AND OBJECTIVES: The use of imaging in medicine has increased considerably over the previous decades, contributing to significant inefficiency of use. Radiology education varies amongst institutions without standardized learning objectives. Consequently, many physicians and student doctors are unprepared to make appropriate choices regarding imaging. In response to COVID-19-engendered restrictions, we created a fully online, image-intensive radiology curriculum to introduce students to clinical radiology and appropriate imaging usage. MATERIALS AND METHODS: A 2-week radiology elective curriculum was created that adopted accessible, free, online-based learning to foster student education and patient safety while upholding academic standards. Each unit included an emphasis on imaging appropriateness. Students assembled an elective portfolio including self-assessments and prepared a clinical radiology conference to present as a radiologist in training. Two final assessments were required. One consisted of clinical vignettes based on American College of Radiology (ACR) Appropriateness Criteria (AC). The second was an MRI safety quiz. RESULTS: Third and fourth year students at five institutions (N = 97) completed the elective. Examination scores on an assessment adapted from the ACR AC were significantly improved compared to previously published scores of medical students who took ACR AC-based assessments without taking a radiology course. The course was published and shared with medical schools worldwide. CONCLUSION: The elective successfully educated students in radiology through a virtual platform and introduced them to the concept of appropriateness in medical imaging. These goals were accomplished using a free, online, easily accessible curriculum. Incorporation of additional topics within the discipline of radiology should be included in the curriculum in the future.

A new method for sex estimation based on femoral cross-sectional geometry measurements and its validation using recent and ancient populations.

Estimating sex is a fundamental task in biological and forensic anthropology. This study aimed to develop new methods for sex estimation based on femoral cross-sectional geometry (CSG) variables and to test their applicability in recent and ancient assemblages. The sample was divided into a study group (living individuals, N = 124) for creating sex prediction equations and two test groups: living individuals (N = 31) and prehistoric individuals (N = 34). The prehistoric sample was divided into three subgroups according to subsistence strategy (hunter-gatherers, early farmers that also hunted, and farmers and herders). Femoral CSG variables (size, strength, and shape) were measured from CT images using dedicated software. Discriminant functions for sex estimation were calculated for various bone completeness scenarios and validated using the test groups. Size and strength parameters were sexually dimorphic, while shape was not. Discriminant functions for sex estimation produced success rates in the living sample between 83.9 and 93.5%; the distal shaft yielded the highest results. Success rates were lower among the prehistoric test sample, with better results (83.3%) for the mid-Holocene population (farmers and herders) than for earlier groups (e.g., hunter-gatherers; < 60%). These results were compared with those obtained using other methods for sex estimation based on various skeletal elements. This study provides new, reliable, and simple methods with high success rates for sex estimation based on femoral CSG variables obtained automatically from CT images. Discriminant functions were created for various conditions of femoral completeness. However, these functions should be used carefully in past populations from different settings.

Malaria and typhoid fever among patients presenting with febrile illnesses in Ga West Municipality, Ghana.

BACKGROUND: Clinicians in areas where malaria and typhoid fever are co-endemic often treat infected patients irrationally, which may lead to the emergence of drug resistance and extra cost to patients. This study determined the proportion of febrile conditions attributable to either malaria and/or typhoid fever and the susceptibility patterns of Salmonella spp. isolates to commonly used antimicrobial agents in Ghana. METHODS: One hundred and fifty-seven (157) febrile patients attending the Ga West Municipal Hospital, Ghana, from February to May 2017 were sampled. Blood samples were collected for cultivation of pathogenic bacteria and the susceptibility of the Salmonella isolates to antimicrobial agents was performed using the Kirby-Bauer disk diffusion method with antibiotic discs on Müller Hinton agar plates. For each sample, conventional Widal test for the detection of Salmonella spp was done as well as blood film preparation for detection of Plasmodium spp. Data on the socio-demographic and clinical characteristics of the study participants were collected using an android technology software kobo-collect by interview. RESULTS: Of the total number of patients aged 2-37 years (median age = 6 years, IQR 3-11), 82 (52.2%) were females. The proportion of febrile patients with falciparum malaria was 57/157 (36.3%), while Salmonella typhi O and H antigens were detected in 23/157 (14.6%) of the samples. The detection rate of Salmonella spp in febrile patients was 10/157 (6.4%). Malaria and typhoid fever coinfection using Widal test and blood culture was 9 (5.7%) and 3 (1.9%), respectively. The isolates were highly susceptible to cefotaxime, ceftriaxone, ciprofloxacin, and amikacin but resistant to ampicillin, tetracycline, co-trimoxazole, gentamicin, cefuroxime, chloramphenicol, and meropenem. CONCLUSION: Plasmodium falciparum and Salmonella spp coinfections were only up to 1.9%, while malaria and typhoid fever, individually, were responsible for 36.3% and 6.4%, respectively. Treatment of febrile conditions must be based on laboratory findings in order not to expose patients to unnecessary side effects of antibiotics and reduce the emergence and spread of drug resistance against antibiotics.

Clot Imaging Using Photostable Nanodiamond.

While thrombosis is the leading cause of morbidity and mortality in the United States, an understanding of its triggers, progression, and response to anticoagulant therapy is lacking. Intravital fluorescence microscopy has advanced the study of thrombus formation by providing targeted, multi-color contrast. However, photodegradation of fluorophores limits the application in longitudinal studies (e.g., clot progression and/or dissolution). Fluorescent nanodiamond (FND) is a fluorophore which utilizes intrinsic fluorescence of chromogenic centers within and protected by the diamond crystalline lattice. Recent developments in diamond processing have allowed for the controlled production of nanodiamonds emitting in green or red. Here, the use of FND to label blood clots and/or clot lysis is demonstrated and compared to commonly used organic fluorophores. Model ex vivo clots were formed with incorporated labeled fibrinogen to allow imaging. FND was shown to match the morphology of organic fluorophore labels absent of photobleaching over time. The addition of tissue plasminogen activator (tPa) allowed visualization of the clot lysis stage, which is vital to studies of both DVT and pulmonary embolism resolution.

Evolutionary roots of the risk of hip fracture in humans.

The transition to bipedal locomotion was a fundamental milestone in human evolution. Consequently, the human skeleton underwent substantial morphological adaptations. These adaptations are responsible for many of today's common physical impairments, including hip fractures. This study aims to reveal the morphological changes in the proximal femur, which increase the risk of intracapsular hip fractures in present-day populations. Our sample includes chimpanzees, early hominins, early Homo Neanderthals, as well as prehistoric and recent humans. Using Geometric Morphometric methods, we demonstrate differences in the proximal femur shape between hominids and populations that practiced different lifestyles. We show that the proximal femur morphology is a risk factor for intracapsular hip fracture independent of osteoporosis. Changes in the proximal femur, such as the shortening of the femoral neck and an increased anterolateral expansion of the greater trochanter, are associated with an increased risk for intracapsular hip fractures. We conclude that intracapsular hip fractures are a trade-off for efficient bipedal walking in humans, and their risk is exacerbated by reduced physical activity.

Synthesis and characterisation of group 8 tris(1-benzyl-1,2,3-triazol-4-yl)-p-anisolylmethane complexes.

The tris(1,2,3-triazol-4-yl)methane framework offers a highly versatile architecture for ligand design, yet the coordination chemistry of this class of ligand remains largely unexplored. We report here the synthesis and characterisation of the homoleptic complexes [M(ttzm)2](PF6)2 (ttzm = tris(1-benzyl-1,2,3-triazol-4-yl)-p-anisolylmethane; M = Fe (Fe), Ru (Ru), Os (Os)). Initial attempts to prepare Ru by reaction of [Ru(p-cymene)Cl2]2 and ttzm also led to the isolation of the heteroleptic complex [Ru(p-cymene)(ttzm)](PF6)2. The structures of [Ru(p-cymene)(ttzm)](PF6)2, [Fe(ttzm)2]2+ (as its BPh4- salt) and Os were solved by X-ray diffraction. The homoleptic Fe(II) and Os(II) containing cations adopt distorted octahedral geometries due to the steric interactions between the ansiole and triazole rings of the ttzm ligands. The homoleptic complexes all adopt a low-spin d6 configuration and exhibit reversible M(II)/M(III) processes (+0.35 to +0.72 V vs. Fc/Fc+). These oxidation processes are cathodically shifted relative to those of related hexatriazole donor based complexes with density functional theory (DFT) calculations showing the metal d-orbitals are destabilised through a π-donor contribution from the triazole rings. The complexes all show prominent UV-visible absorption bands between 350 and 450 nm assigned to transitions of 1MLCT character. Whilst none of the homoleptic complexes are emissive in room temperature fluid solutions, Os is emissive at 77 K in an EtOH/MeOH glass (λmax 472 nm).

Minimal role for the alternative pathway in complement activation by HIT immune complexes.

BACKGROUND: Anti-platelet factor 4 (PF4)/heparin immune complexes that cause heparin-induced thrombocytopenia (HIT) activate complement via the classical pathway. Previous studies have shown that the alternative pathway of complement substantially amplifies the classical pathway of complement activation through the C3b feedback cycle. OBJECTIVES: These studies sought to examine the contributions of the alternative pathway to complement activation by HIT antibodies. METHODS: Using IgG monoclonal (KKO) and/or patient-derived HIT antibodies, we compared the effects of classical pathway (BBK32 and C1-esterase inhibitor [C1-INH]), alternative pathway (anti-factor B [fB] or factor D [fD] inhibitor) or combined classical and alternative pathway inhibition (soluble complement receptor 1 [sCR1]) in whole blood or plasma. RESULTS: Classical pathway inhibitors BBK32 and C1-INH and the combined classical/alternative pathway inhibitor sCR1 prevented KKO/HIT immune complex-induced complement activation, including release of C3 and C5 activation products, binding of immune complexes to B cells, and neutrophil activation. The alternative pathway inhibitors fB and fD, however, did not affect complement activation by KKO/HIT immune complexes. Similarly, alternative pathway inhibition had no effect on complement activation by unrelated immune complexes consisting of anti-dinitrophenyl (DNP) antibody and the multivalent DNP--keyhole limpet hemocyanin antigen. CONCLUSIONS: Collectively, these findings suggest the alternative pathway contributes little in support of complement activation by HIT immune complexes. Additional in vitro and in vivo studies are required to examine if this property is shared by most IgG-containing immune complexes or if predominance of the classic pathway is limited to immune complexes composed of multivalent antigens.

Sex-related differences in D-dimer levels for venous thromboembolism screening.

BACKGROUND: D-dimer is generally considered positive above 0.5 mg/L irrespective of sex. However, women have been shown to be more likely to have a positive D-dimer after controlling for other factors. Thus, differences may exist between males and females for using D-dimer as a marker of venous thromboembolic (VTE) disease. We hypothesized that the accuracy of D-dimer tests may be enhanced by using appropriate cutoff values that reflect sex-related differences in D-dimer levels. METHODS: This research is a secondary analysis of a multicenter, international, prospective, observational study of adult (18+ years) patients suspected of VTE, with low-to-intermediate pretest probability based on Wells criteria ≤ 6 for pulmonary embolism (PE) and ≤ 2 for deep vein thrombosis (DVT). VTE diagnoses were based on computed tomography, ventilation perfusion scanning, or venous ultrasound. D-dimer levels were tested for statistical difference across groups stratified by sex and diagnosis. Multivariable regression was used to investigate sex as a predictor of diagnosis. Sex-specific optimal D-dimer thresholds for PE and DVT were calculated from receiver operating characteristic analyses. A Youden threshold (D-dimer level coinciding with the maximum of sensitivity plus specificity) and a cutoff corresponding to 95% sensitivity were calculated. Statistical difference for cutoffs was tested via 95% confidence intervals from 2,000 bootstrapped samples. RESULTS: We included 3,586 subjects for analysis, of whom 61% were female. Race demographics were 63% White, 27% Black/African American, and 6% Hispanic. In the suspected PE cohort, 6% were diagnosed with PE, while in the suspected DVT cohort, 11% were diagnosed with DVT. D-dimer levels were significantly higher in males than females for the PE-positive group and the DVT-negative group, but males had significantly lower D-dimer levels than females in the PE-negative group. Regression models showed male sex as a significant positive predictor of DVT diagnosis, controlling for D-dimer levels. The Youden thresholds for PE patients were 0.97 (95% CI = 0.64 to 1.79) mg/L and 1.45 (95% CI = 1.36 to 1.95) mg/L for females and males, respectively; 95% sensitivity cutoffs for this group were 0.64 (95% CI = 0.20 to 0.89) and 0.55 (95% CI = 0.29 to 1.61). For DVT, the Youden thresholds were 0.98 (95% CI = 0.84 to 1.56) mg/L for females and 1.25 (95% CI = 0.65 to 3.33) mg/L for males with 95% sensitivity cutoffs of 0.33 (95% CI = 0.2 to 0.61) and 0.32 (95% CI = 0.18 to 0.7), respectively. CONCLUSION: Differences in D-dimer levels between males and females are diagnosis specific; however, there was no significant difference in optimal cutoff values for excluding PE and DVT between the sexes.

Bacterial drug-resistance patterns and genetic diversity of bacteria-associated bacteriuria in diabetic patients in Ghana.

Objectives: Our study aimed to determine the etiology of urinary tract infections (UTIs), resistance profiles of isolated bacteria, and virulence factors of Escherichia coli associated with bacteriuria in diabetic patients in Ghana. Methods: Midstream urine samples from 982 diabetic patients were tested for uropathogens at the National Diabetes Management and Research Centre in Ghana, using standard bacteriological methods, with antibiogram testing of the isolates using the Kirby-Bauer disk diffusion, as per CLSI guidelines. Polymerase chain reaction (PCR) was used to investigate the phylogenetic groupings and virulence factor (VF) genes of isolated E. coli. Results: The overall prevalence of UTIs was 9.2%, and the main uropathogens were Klebsiella spp. (55.6%) and Escherichia coli (31.3%). Age, duration of diabetes, and a previous history of UTIs were risk factors associated with UTI (p-value < 0.05). High levels of antibacterial resistance to cefuroxime (84%), ampicillin (80%), and gentamicin (70.7%) were observed. The distribution of VFs in each phylogenetic group revealed that sfa-iutA-KpsTMII-KpsTMIII genes were associated with group B2, and iutA-ibe were associated with group D. Conclusions: The isolated uropathogens were highly resistant, and the E. coli isolates possessed varying VFs. Continuous monitoring of bacteria associated with UTI in diabetics is highly recommended.

Metallo-Beta-Lactamase-Producing Acinetobacter spp. from Clinical Isolates at a Tertiary Care Hospital in Ghana.

Metallo-beta-lactamase-producing Acinetobacter spp. is a major challenge for therapeutic treatment of nosocomial infections. This study is aimed at determining the prevalence of MBL-producing Acinetobacter spp. among 87 clinical isolates of Acinetobacter spp. from the Korle-Bu Teaching Hospital, Accra, between August 2014 and July 2015. Acinetobacter spp. was identified by standard bacteriological method, and resistance to different antibiotics was assessed with the Kirby-Bauer disc diffusion method. Meropenem-resistant Acinetobacter isolates were screened for enzyme activity using the modified Hodge test (MHT) and combined disc test (CDT). Additionally, multiplex PCR was used to determine MBL genes presence (blaVIM, blaIMP, and blaNDM). All Acinetobacter isolates showed high resistance to cefotaxime (90.8%), ceftazidime (75.9%), cotrimoxazole (70.1%), ciprofloxacin (64.4%), gentamicin (72.4%), levofloxacin (67.8%), and meropenem (59.8%). A total of 54 (62.1%) of Acinetobacter isolates were multidrug-resistant. Out of 52 (59.8%) meropenem-resistant Acinetobacter, 3 (5.8%) were carbapenemase producers by MHT, whilst, 23 (44.2%) were CDT positive. There was no significant difference between the resistance pattern of amikacin, ceftazidime, cotrimoxazole, ciprofloxacin, and meropenem amongst CDT-positive and CDT-negative isolates (p > 0.05). A total of 7/87 (8.1%) CDT-positive Acinetobacter isolates harboured blaNDM; of these, 4 (57.1%) were from wound swabs, urine (n = 2) (28.6%), and ear swab (n = 1) (14.3%). The study revealed that less than 9% of Acinetobacter spp. contained blaNDM encoding genes. Strict antibiotics usage plan and infection control measures are required to prevent the spread of these resistance genes.

Current Controversies in Caring for the Critically Ill Pulmonary Embolism Patient.

Emergency physicians must be prepared to rapidly diagnose and resuscitate patients with pulmonary embolism (PE). Certain aspects of PE resuscitation run counter to typical approaches. A specific understanding of the pathophysiology of PE is required to avoid cardiovascular collapse potentially associated with excessive intravenous fluids and positive pressure ventilation. Once PE is diagnosed, rapid risk stratification should be performed and treatment guided by patient risk class. Although anticoagulation remains the mainstay of PE treatment, emergency physicians also must understand the indications and contraindications for thrombolysis and should be aware of new therapies and models of care that may improve outcomes.

Crosstalk reduction for multi-channel optical phase metrology.

Digitally enhanced heterodyne interferometry (DEHI) combines the sub-wavelength displacement measurements of conventional laser interferometry with the multiplexing capabilities of spread-spectrum modulation techniques to discriminate between multiple electric fields at a single photodetector. Technologies that benefit from DEHI include optical phased arrays, which require the simultaneous phase measurement of a large number of electric fields. A consequence of measuring the phase of multiple electric fields is the introduction of crosstalk, which can degrade measurement precision. This work analytically and experimentally investigates the crosstalk when using DEHI to measure the phase of an arbitrarily large number of electric fields at a single photodetector. Also considered is the practical limit the dynamic range of the photodetector and shot noise imposes on the number of electric fields that can be discriminated. We describe how to minimize crosstalk by design. Experimental results demonstrate up to 55 dB suppression of crosstalk between two electric fields with a phase measurement bandwidth of 20 kHz and 1-10 pm/Hz displacement sensitivity for audio frequencies. Additionally, we demonstrate scaling of crosstalk proportional to the square-root of the number of electric fields when using an M-sequence modulation. Based on this analysis, we estimate that digitally enhanced heterodyne interferometry should be capable of measuring the phase of several hundreds of electric fields at a single photodetector while maintaining the same measurement bandwidth.

In-Orbit Performance of the GRACE Follow-on Laser Ranging Interferometer.

The Laser Ranging Interferometer (LRI) instrument on the Gravity Recovery and Climate Experiment (GRACE) Follow-On mission has provided the first laser interferometric range measurements between remote spacecraft, separated by approximately 220 km. Autonomous controls that lock the laser frequency to a cavity reference and establish the 5 degrees of freedom two-way laser link between remote spacecraft succeeded on the first attempt. Active beam pointing based on differential wave front sensing compensates spacecraft attitude fluctuations. The LRI has operated continuously without breaks in phase tracking for more than 50 days, and has shown biased range measurements similar to the primary ranging instrument based on microwaves, but with much less noise at a level of 1 nm/sqrt[Hz] at Fourier frequencies above 100 mHz.

Highly Elevated Quantitative D-Dimer Assay Values Increase the Likelihood of Venous Thromboembolism.

Objectives In patients with suspected venous thromboembolism (VTE), the D-dimer assay is commonly utilized as part of the workup. The assay is primarily used to determine whether to proceed with radiographic imaging. We compared D-dimer levels in patients suspected of having VTE. We hypothesized that higher D-dimer values predict a higher likelihood of subsequent VTE diagnosis. Methods We conducted a secondary analysis of a multinational, prospective observational study of low- to intermediate-risk adult patients presenting to the emergency department with suspicion of VTE. Demographic and clinical data were collected in a structured manner. Advanced imaging including ultrasound, computed tomography (CT) pulmonary angiography, and ventilation/perfusion scanning was obtained at the discretion of the treating physicians. Imaging was evaluated by board-certified radiologists in real time. D-dimer values' bins were evaluated using a logistic regression model. Results We evaluated 1,752 patients for suspected deep vein thrombosis (DVT), with 191 (10.4%) DVT positive. We evaluated 1,834 patients for suspected pulmonary embolism (PE), with 108 (5.9%) PE positive. Higher D-dimer values in both groups were associated with higher likelihood of subsequent VTE diagnosis, with D-dimer values > 3,999 ng/mL in both groups having the highest incidence of VTE. More than 50% of those patients were VTE positive. Conclusions Increasing D-dimer values predict increased likelihood of being found VTE positive in this patient population. Among those in the highest D-dimer category, > 3,999 ng/mL, over half of patients were VTE positive. Further research could determine additional nuance in D-dimer as a tool to work up suspected VTE.

D-dimer levels in VTE patients with distal and proximal clots.

OBJECTIVES: There is growing evidence that venous thromboembolism (VTE) patients with distal clots (distal calf deep vein thrombosis [DVT] and sub-segmental pulmonary embolism [PE]) may not routinely benefit from anticoagulation. We compared the D-dimer levels in VTE patients with distal and proximal clots. METHODS: We conducted a multinational, prospective observational study of low-to-intermediate risk adult patients presenting to the emergency department (ED) with suspected VTE. Patients were classified as distal (calf DVT or sub-segmental PE) or proximal (proximal DVT or non-sub-segmental PE) clot groups and compared with univariate and multivariate analyses. RESULTS: Of 1752 patients with suspected DVT, 1561 (89.1%) had no DVT, 78 (4.4%) had a distal calf DVT, and 113 (6.4%) had a proximal DVT. DVT patients with proximal clots had higher D-dimer levels (3760 vs. 1670 mg/dL) than with distal clots. Sensitivity and negative predictive value (NPV) for proximal DVT at an optimal D-dimer cutoff of 5770 mg/dL were 40.7% and 52.1% respectively. Of 1834 patients with suspected PE, 1726 (94.1%) had no PE, 7 (0.4%) had isolated sub-segmental PE, and 101 (5.5%) had non-sub-segmental PE. PE patients with proximal clots had higher D-dimer levels (4170 vs. 2520 mg/dL) than those with distal clots. Sensitivity and NPV for proximal PE at an optimal D-dimer cutoff of 3499 mg/dL were 57.4% and 10.4% respectively. CONCLUSIONS: VTE patients with proximal clots had higher D-dimer levels than patients with distal clots. However, D-dimer levels cannot be used alone to discriminate between VTE patients with distal or proximal clots.

Emergency Department Discharge of Pulmonary Embolus Patients.

BACKGROUND: Hospitalization for low-risk pulmonary embolism (PE) is common, expensive, and of questionable benefit. OBJECTIVE: The objective was to determine if low-risk PE patients discharged from the emergency department (ED) on rivaroxaban require fewer hospital days compared to standard of care (SOC). METHODS: Multicenter, open-label randomized trial in low-risk PE defined by Hestia criteria. Adult subjects were randomized to early ED discharge on rivaroxaban or SOC. Primary outcome was total number of initial hospital hours, plus hours of hospitalization for bleeding or venous thromboembolism (VTE), 30 days after randomization. A 90-day composite safety endpoint was defined as major bleeding, clinically relevant nonmajor bleeding, and mortality. RESULTS: Of 114 randomized subjects, 51 were early discharge and 63 were SOC. Of 112 (98.2%) receiving at least one dose of study drug, 99 (86.8%) completed the study. Initial hospital LOS was 4.8 hours versus 33.6 hours, with a mean difference of -28.8 hours (95% confidence interval [CI] = -42.55 to -15.12 hours) for early discharge versus SOC, respectively. At 90 days, mean total hospital days (for any reason) were less for early discharge than SOC, 19.2 hours versus 43.2 hours, with a mean difference of 26.4 hours (95% CI = -46.97 to -3.34 hours). At 90 days, there were no bleeding events, recurrent VTE, or deaths. The composite safety endpoint was similar in both groups, with a difference in proportions of 0.005 (95% CI = -0.18 to 0.19). Total costs were $1,496 for early discharge and $4,234 for SOC, with a median difference of $2,496 (95% CI = -$2,999 to -$2,151). CONCLUSIONS: Low-risk ED PE patients receiving early discharge on rivaroxaban have similar outcomes to SOC, but fewer total hospital days and lower costs over 30 days.