Shifting the Focus from Dissolution to Permeation: Introducing the Meso-fluidic Chip for Permeability Assessment (MCPA).

In response to the growing ethical and environmental concerns associated with animal testing, numerous in vitro tools of varying complexity and biorelevance have been developed and adopted in pharmaceutical research and development. In this work, we present one of these tools, i.e., the Meso-fluidic Chip for Permeability Assessment (MCPA), for the first time. The MCPA combines an artificial barrier (PermeaPad®) with an organ-on-chip device (MIVO®) and real-time automated concentration measurements, to yield a sustainable, yet effortless method for permeation testing. The system offers three major physiological aspects, i.e., a biomimetic membrane, an optimal membrane interfacial area-to-donor-volume-ratio (A/V) and a physiological flow on the acceptor/basolateral side, which makes the MPCA an ideal candidate for mechanistic studies and excellent in vivo bioavailability predictions. We validated the method with a handful of assorted drug compounds in unstirred and stirred donor conditions, before exploring its applicability as a tool for dissolution/permeation testing on a BCS class III/I drug (pyrazinamide) crystalline adducts and BCS class II/IV (hydrocortisone) amorphous solid dispersions. The results were highly reproducible and clearly displayed the method's potential for evaluating the performance of enabling formulations, and possibly even predicting in vivo performance. We believe that, upon further development, the MCPA will serve as a useful in vitro tool that could push sustainability into pharmaceutics by refining, reducing and replacing animal testing in early-stage drug development.

Interpreting permeability as a function of free drug fraction: The case studies of cyclodextrins and liposomes.

In order to solubilize poorly soluble active pharmaceutical ingredients, various strategies have been implemented over the years, including the use of nanocarriers, such as cyclodextrins and liposomes. However, improving a drug's apparent solubility does not always translate to enhanced bioavailability. This work aimed to investigate to which extent complexation with cyclodextrins and incorporation into liposomes influence drug in vitro permeability and to find a mechanistic description of the permeation process. For this purpose, we investigated hydroxypropyl-ß-cyclodextrin (HP-ß-CD) and phosphatidylcholine liposomes formulations of three chemically diverse compounds (atenolol, ketoprofen and hydrocortisone). We studied drug diffusion of the formulations by UV-localized spectroscopy and advanced data fitting to extract parameters such as diffusivity and bound-/free drug fractions. We then correlated this information with in vitro drug permeability obtained with the novel PermeaPadⓇ barrier. The results showed that increased concentration of HP-ß-CD leads to increased solubilization of the poorly soluble unionized ketoprofen, as well as hydrocortisone. However, this net increment of apparent solubility was not proportional to the increased flux measured. On the other hand, normalising the flux over the empirical free drug concentration, i.e., the free fraction, gave a meaningful absolute permeability coefficient. The results achieved for the liposomal formulation were consistent with the finding on cyclodextrins. In conclusion, we proved the adequacy and usefulness of our method for calculating free drug fractions in the examined enabling formulations, supporting the validity of the established drug diffusion/permeation theory that the unbounded drug fraction is the main driver for drug permeation across a membrane.

Commercially Available Cell-Free Permeability Tests for Industrial Drug Development: Increased Sustainability through Reduction of In Vivo Studies.

Replacing in vivo with in vitro studies can increase sustainability in the development of medicines. This principle has already been applied in the biowaiver approach based on the biopharmaceutical classification system, BCS. A biowaiver is a regulatory process in which a drug is approved based on evidence of in vitro equivalence, i.e., a dissolution test, rather than on in vivo bioequivalence. Currently biowaivers can only be granted for highly water-soluble drugs, i.e., BCS class I/III drugs. When evaluating poorly soluble drugs, i.e., BCS class II/IV drugs, in vitro dissolution testing has proved to be inadequate for predicting in vivo drug performance due to the lack of permeability interpretation. The aim of this review was to provide solid proofs that at least two commercially available cell-free in vitro assays, namely, the parallel artificial membrane permeability assay, PAMPA, and the PermeaPad® assay, PermeaPad, in different formats and set-ups, have the potential to reduce and replace in vivo testing to some extent, thus increasing sustainability in drug development. Based on the literature review presented here, we suggest that these assays should be implemented as alternatives to (1) more energy-intense in vitro methods, e.g., refining/replacing cell-based permeability assays, and (2) in vivo studies, e.g., reducing the number of pharmacokinetic studies conducted on animals and humans. For this to happen, a new and modern legislative framework for drug approval is required.

Modelling drug diffusion through unstirred water layers allows real-time quantification of free/loaded drug fractions and release kinetics from colloidal-based formulations.

The correlation between in vivo and in vitro data is yet not sufficiently optimized to allow a significant reduction and replacement of animal testing in pharmaceutical development. One of the main reasons for this lies in the poor mechanistic understanding and interpretation of the physical mechanisms enabling formulation rely on for deploying the drug. One mechanism that still lacks a proper interpretation is the kinetics of drug release from nanocarriers. In this work, we investigate two different types of classical enabling formulations - i) cyclodextrin solutions and ii) liposomal dispersions - by a combination of an experimental method (i.e. UV-Vis localized spectroscopy) and mathematical modelling/numerical data fitting. With this approach, we are able to discriminate precisely between the amount of drug bound to nanocarriers or freely dissolved at any time point; in addition, we can precisely estimate the binding and diffusivity constants of all chemical species (free drug/bound drug). The results obtained should serve as the first milestone for the further development of reliable in vitro/in silico models for the prediction of in vivo drug bioavailability when enabling formulations are used.

Quantifying the barrier for the movement of cyclobis(paraquat-p-phenylene) over the dication of monopyrrolotetrathiafulvalene.

A bistable [2]pseudorotaxane 1⊂CBPQT·4PF6 and a bistable [2]rotaxane 2·4PF6 have been synthesised to measure the height of an electrostatic barrier produced by double molecular oxidation (0 to +2). Both systems have monopyrrolotetrathiafulvalene (MPTTF) and oxyphenylene (OP) as stations for cyclobis(paraquat-p-phenylene) (CBPQT4+). They have a large stopper at one end while the second stopper in 24+ is composed of a thioethyl (SEt) group and a thiodiethyleneglycol (TDEG) substituent, whereas in 1⊂CBPQT4+, the SEt group has been replaced with a less bulky thiomethyl (SMe) group. This seemingly small difference in the substituents on the MPTTF unit leads to profound changes when comparing the physical properties of the two systems allowing for the first measurement of the deslipping of the CBPQT4+ ring over an MPTTF2+ unit in the [2]pseudorotaxane. Cyclic voltammetry and 1H NMR spectroscopy were used to investigate the switching mechanism for 1⊂CBPQT·MPTTF4+ and 2·MPTTF4+, and it was found that CBPQT4+ moves first to the OP station producing 1⊂CBPQT·OP6+ and 2·OP6+, respectively, upon oxidation of the MPTTF unit. The kinetics of the complexation/decomplexation process occurring in 1⊂CBPQT·MPTTF4+ and in 1⊂CBPQT·OP6+ were studied, allowing the free energy of the transition state when CBPQT4+ moves across a neutral MPTTF unit (17.0 kcal mol-1) or a di-oxidised MPTTF2+ unit (24.0 kcal mol-1) to be determined. These results demonstrate that oxidation of the MPTTF unit to MPTTF2+ increases the energy barrier that the CBPQT4+ ring must overcome for decomplexation to occur by 7.0 kcal mol-1.

Towards a better mechanistic comprehension of drug permeation and absorption: Introducing the diffusion-partitioning interplay.

The process of passive drug absorption from the gastrointestinal tract is still poorly understood and modelled. Additionally, the rapidly evolving field of pharmaceutics demands efficient, affordable and reliable in vitro tools for predicting in vivo performance. In this work, we combined established methods for quantifying drug diffusivity (localized UV-spectroscopy) and permeability (Permeapad® plate) in order to gain a better understanding of the role of unstirred water layers (UWLs) in drug absorption. The effect of diffusion/permeability media composition and viscosity on the apparent permeation resistance (Rapp) of model drugs caffeine (CAF) and hydrocortisone (HC) were tested and evaluated by varying the type and concentration of viscosity-enhancing agent - glycerol or a poly(ethylene glycol) (PEG) with different average molecular weights. For all types of media, increased viscosity lead to reduction in diffusivity but could not alone explain the observed effect, which was attributed to intermolecular polymer-drug interactions. Additionally, for both drugs, smaller hydrophilic viscosity-enhancing agents (glycerol and PEG 400) had larger influence than larger ones (PEG 3350 and 6000). The results highlighted the role of UWL as an additive barrier to permeation and indicated that diffusion through UWL is the rate-limiting step to CAF's permeation, whilst HC permeability is a partition-driven process.

Mortality in Pulmonary Embolism According to Risk Category at Presentation in Emergency Department: Impact of Cardiac Arrest.

In this investigation we explore whether assessment of the risk of mortality can be refined by stratifying high-risk patients with pulmonary embolism (PE) according to whether they had cardiac arrest. We stratified high-risk patients according to whether they had shock but no cardiac arrest, or cardiac arrest diagnosed in the emergency department (ED). This was a retrospective cohort study based on administrative data from the Nationwide Emergency Department Sample (NEDS), 2016. Included patients were 274,227 who were admitted to the same hospital as the ED or died in the ED. This was 77% of 354,616 patients with pulmonary embolism seen in the ED in 2016. Patients were identified based on International Classification of Diseases, 10th Edition, Clinical Modification (ICD-10-CM) Codes. High-risk with no cardiac arrest were 4,317 of 274,227 (1.6%) and high-risk with cardiac arrest were 1,027 of 274,227 (0.4%). Mortality of high-risk patients who did not have cardiac arrest was 1,753 of 4,317 (41%). Mortality of high-risk patients who had cardiac arrest was 754 of 1027 (74%). Mortality increased with age in high-risk patients who did not have cardiac arrest, but mortality was not age-related in high-risk patients with cardiac arrest. In conclusion, high-risk patients with PE are a heterogeneous group and stratification according to whether they had cardiac arrest refines risk assessment.

Site of Deep Venous Thrombosis and Age in the Selection of Patients in the Emergency Department for Hospitalization Versus Home Treatment.

Despite apparent advantages of home treatment of deep venous thrombosis (DVT) based upon results of randomized controlled trials, physicians maintain a conservative approach, and a large proportion of patients with DVT are hospitalized. In the present investigation we assess whether selection of patients for hospitalization for acute DVT was related to the site of the DVT or to age. This was a retrospective cohort study based on administrative data from the Nationwide Emergency Department Sample, 2016. Patients were identified by International Classification of Diseases-10-Clinical Modification codes. Most, 87,436 of 133,414 (66%), had proximal DVT. A minority of patients with isolated distal DVT were hospitalized, 10,621 of 37,592 (28%). However, hospitalization was selected for 47,459 of 87,436 (54%) with proximal DVT; 4,867 of 7,599 (64%) with pelvic vein DVT; and 611 of 788 (78%) with DVT involving the inferior vena cava. Hospitalization for patients with distal DVT, proximal DVT, and pelvic vein DVT was age-dependent. In conclusion, both the site of acute DVT and age were factors affecting the clinical decision of emergency department physicians to select patients for hospital treatment.

Nineteen-Year Trends in Mortality of Patients Hospitalized in the United States with High-Risk Pulmonary Embolism.

BACKGROUND: Several advanced treatments of high-risk patients with pulmonary embolism have been used in recent decades. We assessed the 19-year national trend in mortality of high-risk patients with pulmonary embolism to determine what impact, if any, advanced therapy might have had on mortality. METHODS: Mortality (case fatality rate) was assessed in patients with a primary (first-listed) diagnosis of high-risk pulmonary embolism who were hospitalized during the period from 1999 to 2014 and in 2016 and 2017. High-risk was defined as patients with pulmonary embolism who were in shock or suffered cardiac arrest. International Classification of Diseases, 9th revision, Clinical Modification codes were used for data on the period from 1999 to 2014, and version 10 codes were used for data on the years 2016 and 2017. Trends in mortality were assessed according to treatment. RESULTS: From 1999 to 2017 (excluding 2015), 58,784 patients were hospitalized in United States with a primary diagnosis of pulmonary embolism that was high risk. Mortality in all high-risk patients decreased from 72.7% in 1999 to 49.8% in 2017 (P < .0001). Most high-risk patients (60.3%) were treated with anticoagulants alone and did not receive an inferior vena cava filter. Mortality in these patients decreased from 79.0% in 1999 to 55.7% in 2017 (P < .0001). Thrombolytic therapy was administered to 16.1% of high-risk patients, open pulmonary embolectomy alone was used in 4.3%, and extracorporeal membrane oxygenation was used in 0.4%. CONCLUSIONS: Mortality of high-risk patients with pulmonary embolism has decreased. This decrease can be attributed to improved treatment of patients with shock and with cardiac arrest, and does not reflect advances in therapy for pulmonary embolism.

In-Hospital Risks and Management of Deep Venous Thrombosis According to Location of the Thrombus.

BACKGROUND: Whether deep venous thrombosis involving the pelvic veins or inferior vena cava is associated with higher in-hospital mortality or higher prevalence of in-hospital pulmonary embolism than proximal or distal lower extremity deep venous thrombosis is not known. METHODS: This was a retrospective cohort study based on administrative data from the Nationwide Inpatient Sample, 2016, 2017. Patients hospitalized with a primary diagnosis of deep venous thrombosis at known locations were identified by International Classification of Diseases-10-Clinical Modification codes. RESULTS: In-hospital all-cause mortality with deep venous thrombosis involving the inferior vena cava in patients treated only with anticoagulants was 2.2% versus 0.8% with pelvic vein deep venous thrombosis (p<0.0001), 0.7% with proximal deep venous thrombosis (p<0.0001) and 0.2% with distal deep venous thrombosis (p<0.0001).  Mortality with anticoagulants was similar with pelvic vein deep venous thrombosis compared with proximal lower extremity deep venous thrombosis, 0.8% versus 0.7% (p=0.39). Lower mortality was shown with pelvic vein deep venous thrombosis treated with thrombolytics than with anticoagulants, 0% versus 0.8% (p<0.0001). In-hospital pulmonary embolism occurred in 11% to 23%, irrespective of the site of deep venous thrombosis. CONCLUSION: Patients with deep venous thrombosis involving the inferior vena cava had higher in-hospital mortality than patients with deep venous thrombosis at other locations. Pelvic vein deep venous thrombosis did not result in higher mortality or more in-hospital pulmonary embolism than proximal lower extremity deep venous thrombosis.  The incidence of in-hospital pulmonary embolism was considerable with deep venous thrombosis at all sites.

Effects of Thrombolytic Therapy in Low-Risk Patients With Pulmonary Embolism.

We performed this investigation to determine the effects on mortality of thrombolytic therapy in low-risk patients with pulmonary embolism (PE). This was a retrospective cohort study based on administrative data from the Nationwide Inpatient Sample, 2016 and 2017. Patients with a primary (first-listed) diagnosis of acute PE who were not in shock and not on a ventilator who did not have acute cor pulmonale were defined as low-risk. Patients were identified by International Classification of Diseases-10-Clinical Modification Codes. Mortality was assessed according to treatment with catheter-directed thrombolysis, intravenous thrombolytic therapy, or anticoagulants alone. Mortality with inferior vena cava (IVC) filters was also assessed. Mortality was lowest in low-risk patients treated with anticoagulants alone, 6,765 of 331,430 (2.0%). Mortality was somewhat higher with catheter-directed thrombolysis, 195 of 6915 (2.8%; p <0.0001), and highest with intravenous thrombolysis 510 of 5,200 (9.8%; p <0.0001). Matched patients showed similar results. IVC filters did not reduce mortality in patients treated with anticoagulants alone. Mortality was only 0.5% higher in patients treated with anticoagulants who had saddle PE than in patients with nonsaddle PE, 450 of 17,935 (2.5%) versus 6,315 of 313,495 (2.0%; p <0.0001). However, a larger proportion of low-risk patients with saddle PE received catheter-directed thrombolysis than patients who had nonsaddle PE, 2,330 of 21,760 (11%) versus 4,585 of 321,785 (1.4%; p <0.0001). Similarly, a larger proportion of patients with saddle PE received intravenous thrombolytic therapy than patients with nonsaddle PE, 1,495 of 21,760 (6.9%) versus 3,705 of 321,785 (1.2%; p <0.0001). In conclusion, low-risk patients with PE did not have lower mortality with catheter-directed thrombolysis or intravenous thrombolytic therapy than with anticoagulants alone, and IVC filters did not reduce mortality with anticoagulants alone.

Hospitalizations for High-Risk Pulmonary Embolism.

BACKGROUND: The incidence of pulmonary embolism has been increasing. It has been suggested that this may reflect overdiagnosis due to widespread use of computed tomographic pulmonary angiography. The purpose of the present investigation is to further evaluate whether the increasing incidence of pulmonary embolism represents overdiagnosis. METHODS: This was a retrospective cohort study based on administrative data from the National (Nationwide) Inpatient Sample 1999-2014. International Classification of Diseases, Ninth Revision, Clinical Modification codes were used. The population of the United States according to year was determined from the Centers for Disease Control and Prevention. RESULTS: The incidence of pulmonary embolism increased from 65/100,000 population in 1999 to 137/100,000 population in 2014 (P < .0001). High-risk pulmonary embolism increased from 2.2/100,000 population to 9.9/100,000 population (P < .0001). The incidence of primary pulmonary embolism increased from 40/100,000 population in 1999 to 73/100,000 population in 2014 (P < .0001). High-risk pulmonary embolism in patients with a primary diagnosis of pulmonary embolism increased from 0.8/100,000 population in 1999 to 2.3/100,000 population in 2014 (P < .0001). Among patients with pulmonary embolism, the incidence of high-risk pulmonary embolism increased from 1999-2014 (P = .0025). In-hospital all-cause mortality in high-risk patients was 102,402 of 195,909 (52.2%). CONCLUSIONS: The incidence of high-risk pulmonary embolism has increased concordantly with the increasing incidence of all pulmonary embolism. Increasing proportions of patients with potentially lethal pulmonary embolism are being diagnosed.

Civilian Forensic Technician and Sworn Police Officer Job-Related Stress.

Forensic Technicians provide crime scene investigation services and are exposed to stressful violent crimes, motor vehicle accidents, biological or chemical hazards, and other appalling imagery. Forensic Technicians would likely experience physical and psychological stress after exposure to trauma, and security vulnerabilities similar to Sworn Police Officers. The perceived availability of mental health resources, job-related physical, psychological stress, and traumatic experiences of both Forensic Technicians and Sworn Police Officers from California law enforcement agencies were investigated using a self-reported survey. Responses were evaluated for any significant differences in the perceived stress, job-related physical stress, and resulting psychological impact affecting the participants. The survey contained a mix of True/False, Circle/Check the Appropriate Box, or Likert Scale (1-5) responses. The results were evaluated statistically and discussed. Results indicated Sworn Police Officers and Forensic Technicians have different on-duty stress levels, but similar off-duty stress levels. Nearly two-thirds of 54 job-related stressors were not significantly different between the two occupations. However, Forensic Technicians reported more adverse effects in 17 physical and psychological job-related activities compared with Sworn Police Officers. Forensic Technicians reported lower awareness levels and availability of agency mental health support services than were reported by Sworn Police Officers. This study reports for the first time an unexpected outcome that perceived and job-related psychological stress is greater for Forensic Technicians than Sworn Police Officers. Possible reasons for this disparity will be discussed as well as stress management tools that should be implemented to reduce health risk factors for both career professionals as well as increase public safety.

Catheter-Directed Thrombolysis in Submassive Pulmonary Embolism and Acute Cor Pulmonale.

Treatment of submassive (intermediate-risk) pulmonary embolism (PE), defined as hemodynamically stable with right ventricular (RV) dysfunction, showed lower in-hospital all-cause mortality with intravenous thrombolytic therapy than with anticoagulants, but at an increased risk of major bleeding. The present investigation was performed to test whether catheter-directed thrombolysis reduces mortality without increasing bleeding in submassive PE. This was a retrospective cohort study based on administrative data from the Nationwide Inpatient Sample. In 2016, 13,130 patients were hospitalized with PE and acute cor pulmonale, were stable, and treated with catheter-directed thrombolysis in 1,500 (11%) or anticoagulants alone in 11,630 (89%). Mortality was lower with catheter-directed thrombolysis than with anticoagulants in unmatched patients, 35 of 1,500 (2.3%) compared with 755 of 11,630 (6.5%; p <0.0001) and in matched patients, 30 of 1,260 (2.4%) compared with 440 of 6,910 (6.4%; p <0.0001). Time-dependent analysis showed catheter-directed thrombolysis reduced mortality if administered within the first 3 days. Patients with saddle PE treated with anticoagulants had lower mortality than non-saddle PE, 75 of 1,730 (4.3%) compared with 680 of 9,900 (6.9%; p < 0.0001) in unmatched patients and 45 of 1,305 (3.4%) compared with 395 of 5,605 (7.0%; p < 0.0001) in matched patients. Mortality was not lower with inferior vena cava filters either in those who received catheter-directed thrombolysis or those treated with anticoagulants. There were no fatal or nonfatal adverse events associated with catheter-directed thrombolysis. In conclusion, patients with submassive PE appear to have lower in-hospital all-cause mortality with catheter-directed thrombolysis administered within 3 days than with anticoagulants, and risks are low.

Adjunctive Therapy and Mortality in Patients With Unstable Pulmonary Embolism.

Mortality with adjunctive therapy in patients with unstable pulmonary embolism, defined as those in shock or on ventilator support, is sparsely studied and requires further investigation. This was a retrospective cohort study based on administrative data from the Nationwide Inpatient Sample, 2016. In-hospital all-cause mortality in unstable patients with acute pulmonary embolism was assessed according to treatment. Patients were identified by International Classification of Diseases-10-Clinical Modification Codes. Most unstable patients, 85%, received only anticoagulants. Their mortality was 3,080 of 6,635 (46%) without an inferior vena cava (IVC) filter, and mortality was much less with an IVC filter, 285 of 1,185 (24%) (p <0.0001). Mortality with catheter-directed thrombolysis alone, 70 of 235 (30%), did not differ significantly from mortality with anticoagulants plus an IVC filter, p = 0.07, although a trend favored the latter. Intravenous thrombolytic therapy without an IVC filter showed a mortality of 295 of 695 (42%) which tended to be lower than mortality with anticoagulants alone (p = 0.06). The addition of an IVC filter to intravenous thrombolytic therapy resulted in a mortality of 20 of 165 (12%), which was the lowest mortality with any combination of adjunctive treatments. Intravenous thrombolytic therapy, however, was associated with more adverse effects of therapy than catheter-directed thrombolysis or anticoagulants.

Impact of Mucin on Drug Diffusion: Development of a Straightforward in Vitro Method for the Determination of Drug Diffusivity in the Presence of Mucin.

Mucosal drug delivery accounts for various administration routes (i.e., oral, vaginal, ocular, pulmonary, etc.) and offers a vast surface for the permeation of drugs. However, the mucus layer which shields and lubricates all mucosal tissues can compromise drugs from reaching the epithelial site, thus affecting their absorption and therapeutic effect. Therefore, the effect of the mucus layer on drug absorption has to be evaluated early in the drug-development phase, prior to in vivo studies. For this reason, we developed a simple, cost-effective and reproducible method employing UV-visible localized spectroscopy for the assessment of the interaction between mucin and drugs with different physicochemical characteristics. The mucin-drug interaction was investigated by measuring the drug relative diffusivity (Drel) in the presence of mucin, and the method was validated by fitting experimental and mathematical data. In vitro permeability studies were also performed using the mucus-covered artificial permeation barrier (mucus-PVPA, Phospholipid Vesicle-based Permeation Assay) for comparison. The obtained results showed that the diffusion of drugs was hampered by the presence of mucin, especially at higher concentrations. This novel method proved to be suitable for the investigation on the extent of mucin-drug interaction and can be successfully used to assess the impact that the mucus layer has on drug absorption.

Effect on Mortality With Inferior Vena Cava Filters in Patients Undergoing Pulmonary Embolectomy.

In the absence of a randomized controlled trial, it is important to obtain as much evidence as possible by other methods on whether inferior vena cava (IVC) filters reduce mortality in patients who undergo pulmonary embolectomy. Therefore, this retrospective cohort study based data from the National Inpatient Sample 2009 to 2014 was undertaken. We assessed in-hospital all-cause mortality in stable and unstable (in shock or on ventilator support) patients with acute pulmonary embolism who underwent pulmonary embolectomy. International Classification of Diseases-9-Clinical Modification (ICD-9-CM) codes were used to identify patients. Co-morbidities were assessed by the updated Charlson co-morbidity index. A time-dependent analysis was performed to control for immortal time bias. In stable patients who underwent pulmonary embolectomy, mortality with an IVC filter was 50 of 1,212 (4.1%) compared with 202 of 755 (27%) with no IVC filter (p <0.0001). In unstable patients, mortality with an IVC filter was 108 of 598 (18%) compared with 179 of 358 (50%) with no IVC filter (p <0.0001). Mortality was reduced with IVC filters only if the filters were inserted in the first 4 or 5 days. Co-morbid conditions and immortal time bias could not explain these results. We conclude that both stable and unstable patients who underwent pulmonary embolectomy had a lower mortality with IVC filters if inserted in the first 4 or 5 days.

Development of a biodosimeter for radiation triage using novel blood protein biomarker panels in humans and non-human primates.

Purpose: In a significant nuclear event, hundreds of thousands of individuals will require rapid triage for absorbed radiation to ensure effective medical treatment and efficient use of medical resources. We are developing a rapid screening method to assess whether an individual received an absorbed dose of ≥2 Gy based on the analysis of a specific panel of blood proteins in a fingerstick blood sample.Materials and methods: We studied a data set of 1051 human blood samples obtained from radiotherapy patients, normal healthy individuals, and several special population groups. We compared the findings in humans with those from irradiation studies in non-human primates (NHPs).Results: We identified a panel of three protein biomarkers, salivary alpha amylase (AMY1), Flt3 ligand (FLT3L), and monocyte chemotactic protein 1 (MCP1), which are upregulated in human patients receiving fractionated doses of total body irradiation (TBI) therapy as a treatment for cancer. These proteins exhibited a similar radiation response in NHPs after single acute or fractionated doses of ionizing radiation.Conclusion: Our work provides confidence in this biomarker panel for biodosimetry triage using fingerstick blood samples and in the use of NHPs as a model for irradiated humans.