Magnetic Resonance Imaging and Histological Insights Into Deep Venous Arterialisation.

Introduction: Percutaneous deep venous arterialisation (DVA) is emerging as a promising alternative for limb salvage in chronic limb threatening ischaemia (CLTI) patients without any reasonable anatomical option for conventional revascularisation techniques. However, its mechanism of action remains incompletely understood. This report aimed to find some of the histological alterations occurring in the limb following DVA. Report: This short report presents the case of a 53 year old female who underwent DVA for Rutherford 5 CLTI. Although the intervention was successful and showed evidence of improved blood flow to the foot, the post-operative course was notable due to worsening infection leading to a below knee amputation four weeks later. The blood vessels were harvested for histological analysis, which found features of venous arterialisation such as smooth muscle cell proliferation and neointimal hyperplasia, even in the paired posterior tibial vein that did not undergo DVA. Discussion: This case demonstrated unexpected histological changes occurring in the paired posterior tibial vein that did not undergo DVA. This warrants further investigations to fully understand the mechanisms at play in DVA and to explore the role of the paired vein in sustaining arterialised flow to the foot.

The Impact of Sex on Antiplatelet and Anticoagulant Thromboprophylaxis in Patients with Peripheral Artery Disease Post-revascularization.

OBJECTIVE: The aim of this prospective study was to 1) objectively quantify the impact of sex on platelet function in patients with PAD taking antiplatelet and anticoagulant medications and 2) to develop and test a personalized, iterative algorithm which personalizes thromboprophylaxis that incorporates platelet function testing. SUMMARY BACKGROUND DATA: Women with Peripheral Artery Disease (PAD) have worse outcomes as compared to their male counterparts in spite of having lower risk factors. This health disparity may be mitigated by personalizing thromboprophylaxis regimens. METHODS: Patients undergoing revascularization were enrolled. Serial thromboelastography (TEG) and TEG with Platelet Mapping (TEG-PM) was performed up to 6-months post-operatively to determine objective coagulation profiles. In a subset of patients, the Antiplatelet Coagulation Exactness (ACE) algorithm was implemented where patients were iteratively evaluated with TEG and given antiplatelet medications to maintain platelet inhibition at >29%. Statistical analysis was performed using unpaired t-test, ANOVA and Fisher's exact test. RESULTS: One hundred and eighty-one patients met study criteria. 58(32%) patients were females and 123(68%) were males. In the Aspirin cohort, females showed significantly greater clot strength as Maximum Amplitude - Arachidonic Acid (MAAA) and significantly lower platelet inhibition than males: [37.26 vs.32.38, P<0.01] and [52.95% vs.61.65%, P<0.05], respectively. In the Clopidogrel cohort, females showed higher Maximum Amplitude - Adenosine Diphosphate (MAADP) [42.58 vs.40.35, P=NS] compared to males. Females on dual antiplatelet therapy had higher MAADP [39.74 vs.35.07, P=NS] and lower platelet inhibition [45.25% vs.54.99%, P=NS] than males. The incidence of thrombosis of the revascularized segment, defined as thrombotic event, was objectively identified on an arterial duplex. Women showed significantly higher thrombotic events than men [22.95% vs.10.57%, P<0.05] on the same medication. In our pilot study, implementation of the ACE algorithm led to a significant decrease in the thrombosis rate (3%), including non-thrombotic events for females, vs. the historic thrombotic rate (22%) from our institution. CONCLUSIONS: Women with PAD exhibited higher platelet reactivity, clot strength, and reduced platelet inhibition in response to antiplatelet therapy. The use of the ACE algorithm to tailor antiplatelet medication in patients with PAD post-revascularization, resulted in a significant decrease in thrombotic event rates. This may serve as an opportune way to mitigate outcome sex-specific disparities caused by inadequate thromboprophylaxis in women.

Unsupervised classification of multi-contrast magnetic resonance histology of peripheral arterial disease lesions using a convolutional variational autoencoder with a Gaussian mixture model in latent space: A technical feasibility study.

PURPOSE: To investigate the feasibility of a deep learning algorithm combining variational autoencoder (VAE) and two-dimensional (2D) convolutional neural networks (CNN) for automatically quantifying hard tissue presence and morphology in multi-contrast magnetic resonance (MR) images of peripheral arterial disease (PAD) occlusive lesions. METHODS: Multi-contrast MR images (T2-weighted and ultrashort echo time) were acquired from lesions harvested from six amputated legs with high isotropic spatial resolution (0.078 mm and 0.156 mm, respectively) at 9.4 T. A total of 4014 pseudo-color combined images were generated, with 75% used to train a VAE employing custom 2D CNN layers. A Gaussian mixture model (GMM) was employed to classify the latent space data into four tissue classes: I) concentric calcified (c), II) eccentric calcified (e), III) occluded with hard tissue (h) and IV) occluded with soft tissue (s). Test image probabilities, encoded by the trained VAE were used to evaluate model performance. RESULTS: GMM component classification probabilities ranged from 0.92 to 0.97 for class (c), 1.00 for class (e), 0.82-0.95 for class (h) and 0.56-0.93 for the remaining class (s). Due to the complexity of soft-tissue lesions reflected in the heterogeneity of the pseudo-color images, more GMM components (n=17) were attributed to class (s), compared to the other three (c, e and h) (n=6). CONCLUSION: Combination of 2D CNN VAE and GMM achieves high classification probabilities for hard tissue-containing lesions. Automatic recognition of these classes may aid therapeutic decision-making and identifying uncrossable lesions prior to endovascular intervention.

Optimizing the fabrication of electrospun nanofibers of prochlorperazine for enhanced dissolution and permeation properties.

Despite being an approved antiemetic for more than five decades, the clinical usefulness of prochlorperazine is limited by its low solubility and inconsistent absorption in the gastrointestinal tract, which presents challenges for nanotherapeutic interventions. Here, we report the preparation of a highly soluble and permeable nanofiber formulation of prochlorperazine using the Quality-by-Design approach. The final nanofiber formulation with drug entrapment of 88.02 ± 1.14 % was obtained at 20.0 kV, with a flow rate of 0.5 ml/h and tip-to-collector distance of 19.9 cm. Physio-mechanical properties, such as thickness (0.42 ± 0.02 mm), pH resistance (7.04 ± 0.08), folding endurance (54 ± 5), and tensile strength (0.244 ± 0.02 N.mm-2), were appropriate for packaging and application to oromucosal surfaces. The content uniformity (93.48-106.63 %) and weight variation (<1.8 mg) of the optimal nanofiber formulation were within the permissible limits prescribed for orodispersible films. Microscopical investigations confirm a randomly deposited and dense network of woven nanofibers with an average diameter of 363 ± 5.66 nm. The drug particles were embedded homogeneously on the fiber in the nanoform (4.27 ± 1.34 nm). The spectral analysis using TEM-EDS shows diffraction peaks of sulfur and chlorine, the elemental constituents of prochlorperazine. The drug was amorphized in the nanofiber formulation, as led by the decline of the crystallinity index from 87.25 % to 7.93 % due to electrostatic destabilization and flash evaporation of the solvent. The enthalpy of fusion values of the drug in the nanofiber mat decreased significantly to 23.6 J/g compared to its pristine form, which exhibits a value of 260.7 J/g. The nanofibers were biocompatible with oral mucosal cells, and there were no signs of mucosal irritation compared to 1 % sodium lauryl sulfate. The fiber mats rapidly disintegrated within <1 s and released ≈91.49 ± 2.1 % of the drug within 2 min, almost 2-fold compared to the commercial Stemetil MD® tablets. Similarly, the cumulative amount of the drug permeated across the unit area of the oromucosal membrane was remarkably high (31.28 ± 1.30 µg) compared to 10.17 ± 1.11 µg and 13.10 ± 1.79 µg from the cast film and drug suspension. Our results revealed these nanofiber formulations have the potential to be fast-dissolving oromucosal delivery systems, which can result in enhanced bioavailability with an early onset of action due to rapid disintegration, dissolution, and permeation.

Transcriptional regulation of suppressors of cytokine signaling during infection with Mycobacterium tuberculosis in human THP-1-derived macrophages and in mice.

Mycobacterium tuberculosis (Mtb) infection leads to upregulation of Suppressors of Cytokine signaling (SOCS) expression in host macrophages (Mϕ). SOCS proteins inhibit cytokine signaling by negatively regulating JAK/STAT. We investigated this host-pathogen dialectic at the level of transcription. We used phorbol-differentiated THP-1 Mϕ infected with Mtb to investigate preferential upregulation of some SOCS isoforms that are known to inhibit signaling by IFN-γ, IL-12, and IL-6. We examined time kinetics of likely transcription factors and signaling molecules upstream of SOCS transcription, and survival of intracellular Mtb following SOCS upregulation. Our results suggest a plausible mechanism that involves PGE2 secretion during infection to induce the PKA/CREB axis, culminating in nuclear translocation of C/EBPß to induce expression of SOCS1. Mtb-infected Mϕ secreted IL-10, suggesting a mechanism of induction of STAT3, which may subsequently induce SOCS3. We provide evidence of temporal variation in SOCS isoform exspression and decay. Small-interfering RNA-mediated knockdown of SOCS1 and SOCS3 restored the pro-inflammatory milieu and reduced Mtb viability. In mice infected with Mtb, SOCS isoforms persisted across Days 28-85 post infection. Our results suggest that differential temporal regulation of SOCS isoforms by Mtb drives the host immune response towards a phenotype that facilitates the pathogen's survival.

Peripheral arterial disease treatment planning using noninvasive and invasive imaging methods.

With the growing prevalence and mortality of peripheral arterial disease, preoperative assessment, risk stratification, and determining the correct indication for endovascular and open surgical procedures are essential for therapeutic decision-making. The effectiveness of interventional procedures is significantly influenced by the plaque composition and calcification pattern. Therefore, the identification of patients for whom endovascular treatment is the most appropriate therapeutic solution often remains a challenge. The most commonly used imaging techniques have their own limitations and do not provide findings detailed enough for specific, personalized treatment planning. Using state-of-the-art noninvasive and invasive imaging modalities, it is now possible to obtain a view, not only of the complex vascular anatomy and plaque burden of the lower extremity arterial system, but also of complex plaque structures and various pathologic calcium distribution patterns. In the future, as these latest advancements in diagnostic methods become more widespread, we will be able to obtain more accurate views of the plaque structure and anatomic complexity to guide optimal treatment planning and device selection. We reviewed the implications of the most recent invasive and noninvasive lower extremity imaging techniques and future directions.

Scoping review of atherectomy and intravascular lithotripsy with or without balloon angioplasty in below-the-knee lesions.

Objective: We evaluated how contemporary data on infrapopliteal vessel preparation have been reported to identify knowledge gaps and opportunities for future research. Methods: A literature search was performed on Web of Science, PubMed, and Google Scholar to identify clinical research studies reporting on the outcomes of vessel preparation in below-the-knee lesions between 2006 and 2021. Studies were excluded if they were case reports or case series with a sample size of <10. Results: A total of 15 studies comprising 5450 patients were included in this review, with vessel preparation performed in 2179 cases (40%). Of the 15 studies, 2 were randomized controlled trials, 6 were prospective cohort studies, and 7 were retrospective studies. Only 2 of the 15 studies evaluated intravascular lithotripsy devices, and 6 were noncomparative studies. The mean diameter stenosis treated was 86.7% ± 12.6%, and the lesion length was 71.7 ± 55.3 mm. Large heterogeneity was found in the choice and definitions of end points and lesion characterization. Procedural success ranged between 84% and 90%, and bailout stenting was performed in 0.8% to 15% of cases. Of the five studies comparing procedural success of atherectomy with or without balloon angioplasty to balloon angioplasty alone, only one was in favor of the former (99% vs 90%; P < .001). The remaining studies did not show any statistically significant differences. Similarly, atherectomy had a significantly superior limb salvage rate in only one of seven studies (91% vs 73%; P = .036). In contrast, the seven studies evaluating target lesion revascularization reported conflicting outcomes, with two in favor of atherectomy, two against atherectomy, and three reporting similar outcomes between atherectomy and balloon angioplasty alone. None of the studies evaluating intravascular lithotripsy was comparative. Conclusions: The current body of evidence on vessel preparation in tibial arteries is largely based on observational studies with a large amount of heterogeneity and a number of inconsistencies. Further clinical and experimental studies with more robust study designs are warranted to investigate the comparative efficacy and safety of vessel preparation in calcified tibial arteries.

Automatic Classification of Magnetic Resonance Histology of Peripheral Arterial Chronic Total Occlusions Using a Variational Autoencoder: A Feasibility Study.

The novel approach of our study consists in adapting and in evaluating a custom-made variational autoencoder (VAE) using two-dimensional (2D) convolutional neural networks (CNNs) on magnetic resonance imaging (MRI) images for differentiate soft vs. hard plaque components in peripheral arterial disease (PAD). Five amputated lower extremities were imaged at a clinical ultra-high field 7 Tesla MRI. Ultrashort echo time (UTE), T1-weighted (T1w) and T2-weighted (T2w) datasets were acquired. Multiplanar reconstruction (MPR) images were obtained from one lesion per limb. Images were aligned to each other and pseudo-color red-green-blue images were created. Four areas in latent space were defined corresponding to the sorted images reconstructed by the VAE. Images were classified from their position in latent space and scored using tissue score (TS) as following: (1) lumen patent, TS:0; (2) partially patent, TS:1; (3) mostly occluded with soft tissue, TS:3; (4) mostly occluded with hard tissue, TS:5. Average and relative percentage of TS was calculated per lesion defined as the sum of the tissue score for each image divided by the total number of images. In total, 2390 MPR reconstructed images were included in the analysis. Relative percentage of average tissue score varied from only patent (lesion #1) to presence of all four classes. Lesions #2, #3 and #5 were classified to contain tissues except mostly occluded with hard tissue while lesion #4 contained all (ranges (I): 0.2-100%, (II): 46.3-75.9%, (III): 18-33.5%, (IV): 20%). Training the VAE was successful as images with soft/hard tissues in PAD lesions were satisfactory separated in latent space. Using VAE may assist in rapid classification of MRI histology images acquired in a clinical setup for facilitating endovascular procedures.

Inhaled Adjunct Therapy with Second-Line Drug Candidates for Dose Reduction in Chemotherapeutic Regimens for Multi-drug-Resistant Tuberculosis.

Chemotherapy of multi-drug-resistant tuberculosis (TB) requires prolonged administration of multiple drugs. We investigated whether pulmonary delivery of minute doses of drugs, along with reduced oral doses of the same agents, would affect preclinical efficacy. We prepared dry powder inhalation (DPI) formulations comprising sutezolid (SUT), the second-generation pretomanid analog TBA-354 (TBA), or a fluorinated derivative of TBA-354 (32,625) in a matrix of the biodegradable polymer poly(L-lactide). We established formulation characteristics, doses inhaled by healthy mice, and preclinical efficacy in a mouse model of TB. Oral doses of 100 mg/kg/day or DPI doses of 0.25-0.5 mg/kg/day of drugs SUT, TBA-354, or 32,625 administered over 28 days were sub-optimally effective in reducing lung and spleen burden of Mycobacterium tuberculosis (Mtb) in infected mice. The addition of 0.25-0.5 mg/kg/day of SUT, TBA-354, or 32,625 as DPI to oral doses of 50 mg/kg/day was non-inferior in clearing Mtb from the lungs of infected mice. We concluded that adjunct therapy with inhaled second-line agents has the potential to reduce the efficacious oral dose.

The CathPilot: Performance Validation and Preclinical Safety and Feasibility Assessment.

OBJECTIVES: Peripheral endovascular revascularization procedures often fail due to technical limitations of guidewire support, steering, and visualization. The novel CathPilot catheter aims to address these challenges. This study assesses the safety and feasibility of the CathPilot and compares its performance to conventional catheters for peripheral vascular interventions. METHODS: The study compared the CathPilot to non-steerable and steerable catheters. The success rates and access times for a relevant target inside a tortuous vessel phantom model were assessed. The reachable workspace within the vessel and the guidewire's force delivery capabilities were also evaluated. To validate the technology, chronic total occlusion tissue samples were used ex vivo to compare crossing success rates with conventional catheters. Finally, in vivo experiments in a porcine aorta were conducted to evaluate safety and feasibility. RESULTS: The success rates for reaching the set targets were 31%, 69%, and 100% with the non-steerable catheter, the steerable catheter, and the CathPilot, respectively. CathPilot had a significantly larger reachable workspace, and allowed for up to four times higher force delivery and pushability. In crossing of chronic total occlusion samples, the CathPilot achieved a success rate of 83% and 100%, for fresh and fixed lesions respectively, which was also significantly higher than conventional catheters. The device was fully functional in the in vivo study, and there were no signs of coagulation or damage to the vessel wall. CONCLUSION: This study shows the safety and feasibility of the CathPilot system and its potential to reduce failure and complication rates in peripheral vascular interventions. The novel catheter outperformed conventional catheters in all defined metrics. This technology can potentially improve the success rate and outcome of peripheral endovascular revascularization procedures.

Experimental Protocol and Phantom Design and Development for Performance Characterization of Conventional Devices for Peripheral Vascular Interventions.

Conventional catheter-based interventions for treating peripheral artery disease suffer high failure and complication rates. The mechanical interactions with the anatomy constrain catheter controllability, while their length and flexibility limit their pushability. Also, the 2D X-ray fluoroscopy guiding these procedures fails to provide sufficient feedback about the device location relative to the anatomy. Our study aims to quantify the performance of conventional non-steerable (NS) and steerable (S) catheters in phantom and ex vivo experiments. In a 10 mm diameter, 30 cm long artery phantom model, with four operators, we evaluated the success rate and crossing time in accessing 1.25 mm target channels, the accessible workspace, and the force delivered through each catheter. For clinical relevance, we evaluated the success rate and crossing time in crossing ex vivo chronic total occlusions. For the S and NS catheters, respectively, users successfully accessed 69 and 31% of the targets, 68 and 45% of the cross-sectional area, and could deliver 14.2 and 10.2 g of mean force. Using a NS catheter, users crossed 0.0 and 9.5% of the fixed and fresh lesions, respectively. Overall, we quantified the limitations of conventional catheters (navigation, reachable workspace, and pushability) for peripheral interventions; this can serve as a basis for comparison with other devices.

To Cross or Not to Cross: Using MRI-Histology to Characterize Dense Collagenous Plaque in Critical Limb Ischemia.

Peripheral artery disease (PAD) is caused by atherosclerotic buildup in the lower extremities, leading to obstruction and inadequate perfusion to the peripheral vasculature. Impenetrable plaques initially treated with percutaneous vascular intervention (PVI) have led to worse secondary bypass outcomes and amputation in patients. In this case report, we discuss the importance of using magnetic resonance imaging (MRI) histology in PVI planning in a patient with critical limb ischemia. PVI attempts to recanalize the limb failed because of an impenetrable occlusion in the popliteal artery that was not identified on routine preoperative imaging. Subsequent bypass occluded multiple times eventually requiring an above-knee amputation. An MRI-histology protocol-using ultrashort echo time (UTE) and T2-weighted (T2W) sequences-that was performed prior to the index PVI identified the occlusion as a dense collagen plaque. Histology analysis of the amputated specimen confirmed the MRI finding. This imaging modality offers a novel approach to characterize plaque composition and morphology, thereby identifying lesions at greatest risk of PVI failure and potentially playing an important role in selecting the right candidates for an endovascular-first approach.

Human Cadaveric Model for Vessel Preparation Device Testing in Calcified Tibial Arteries.

To describe an ex vivo model for vessel preparation device testing in tibial arteries. We performed orbital atherectomy (OA), intravascular lithotripsy (IVL), and plain balloon angioplasty (POBA) on human amputated limbs with evidence of concentric tibial artery calcification. The arterial segments were then harvested for ex vivo processing which included imaging with microCT, decalcification, and histology. The model was tested out in 15 limbs and was successful in 14 but had to be aborted in 1/15 case due to inability to achieve wire access. A total of 22 lesions were treated with OA on 3/22 lesions, IVL on 8/22, and POBA without vessel preparation on the remaining 11/22. Luminal gain was assessed with intravascular ultrasound and histology was able to demonstrate plaque disruption, dissections, and cracks within the calcified lesions. A human cadaveric model using amputated limbs is a feasible, high-fidelity option for evaluating the performance of vessel preparation devices in calcified tibial arteries.

Catheter-Directed Interventions for the Treatment of Lower Extremity Deep Vein Thrombosis.

Lower extremity deep vein thrombosis (DVT) leads to significant morbidity including pain, swelling, and difficulty walking in the affected limb. If left untreated, DVT increases the risk of pulmonary embolism (PE), recurrent venous thromboembolism (VTE), and post thrombotic syndrome (PTS). The objective of this review was to identify catheter-directed interventions and their success rates for the treatment of lower extremity DVT. A comprehensive search of current and emerging catheter-directed interventions for lower extremity DVT treatment was conducted in PubMed and Google Scholar. Clinical trials, retrospective and prospective observational studies, and case reports were identified to classify percutaneous mechanical thrombectomy (PMT), catheter-directed thrombolysis (CDT), and pharmacomechanical CDT (PCDT) devices based on their mechanism of action and indication of use. Catheter-directed interventions such as PMT, CDT, and PCDT offer an alternative therapeutic strategy for DVT management, particularly in patients with limb-threatening conditions and absolute contraindications to anticoagulants. Currently, there are limited guidelines for the use of mechanical and pharmacomechanical devices because of the lack of clinical evidence available for their use in treatment. Future studies are required to determine the short and long-term effects of using catheter-directed interventions as well as their effectiveness in treating acute versus subacute and chronic DVT.

From bench to bedside: A narrative review and institutional experience with experimental models for vascular device design and translation.

The past 2 decades have seen a rise in vascular innovations and a rapid evolution in endovascular device technology, with the emergence of atherectomy, intravascular lithotripsy, drug elution technology, thrombectomy devices, and many more. Like all other medical devices, vascular devices undergo a life cycle composed of a concept phase, a planning and design phase, a regulatory process, a launch phase, and a post-market stage. Experimental and preclinical models are required at various stages of the life cycle to aid in the designing, refining, and feasibility testing of novel devices before they are transferred to clinical practice. The experimental testing of these devices relies heavily on the ability to simulate human anatomy and physiology, and to mimic or induce specific disease processes. Computational and benchtop models play very important roles at the early stages of the manufacturing process, and animal and cadaveric models are indispensable for testing the mechanistic performance, safety, and efficacy of novel devices before they are used in clinical trials and regulatory approval is obtained for public use.

Association between isolated abnormal coagulation profile on transfusion following major surgery: A NSQIP analysis of individuals without bleeding disorders.

INTRODUCTION: Preoperative coagulation screening for patients without bleeding disorders remains controversial. The combinatorial risk of INR, aPTT, and platelet count (PLT) abnormalities leading to bleeding requiring transfusion is not known in these patients. We examined the association between abnormal coagulation profile and the risk of transfusion following common elective surgery in patients without bleeding disorders. STUDY DESIGN AND METHODS: We utilized the National Surgical Quality Improvement Program (NSQIP) database from 2004 to 2018 to identify patients without a history of bleeding disorders undergoing common 23 major elective procedures across 10 specialties. Multivariable logistic regression was used to assess the association between coagulation profile and bleeding requiring packed red blood cell transfusion intra-/post-operatively. RESULTS: Of the 672,075 patients meeting inclusion criteria, 53.7% presented with normal coagulation profile preoperatively. Overall, 12.2% (n = 82,368) received transfusion. In the setting of normal aPTT/PLT, both Equivocal INR of 1.1-1.5 (aOR 1.41, 95% CI 1.38-1.44) and Abnormal INR of >1.5 (aOR 1.81, 95% CI 1.71-1.93) were significantly associated with an increased risk of transfusion. Equivocal (60-70) and Abnormal (>70) aPTT with normal INR/PLT did not demonstrate a comparable risk of transfusion. We observed a synergistic effect of combinatorial lab abnormalities on the risk of transfusion when both Abnormal INR/aPTT and Low PLT of <100,000 were present (aOR 5.18, 95% CI 3.04-8.84), compared to the effect of Abnormal INR/aPTT and normal/elevated PLT (aOR 1.90, 95% CI 1.48-2.45). DISCUSSION: The preoperative presence of abnormal findings in INR or PLT was significantly associated with the risk of bleeding requiring transfusion during intraoperative and postoperative periods.

Preparation and Evaluation of Low-Dose Calcitriol Dry Powder Inhalation as Host-Directed Adjunct Therapy for Tuberculosis.

BACKGROUND: It is unclear whether Vitamin D is efficacious as a host-directed therapy (HDT) for patients of tuberculosis (TB). We investigated pulmonary delivery of the active metabolite of Vitamin D3, i.e., 1, 25-dihydroxy vitamin D3 (calcitriol) in a mouse model of infection with Mycobacterium tuberculosis (Mtb). METHODS: We optimized a spray drying process to prepare a dry powder inhalation (DPI) of calcitriol using a Quality by Design (QbD) approach. We then compared outcomes when Mtb-infected mice were treated with inhaled calcitriol at 5 ng/kg as a stand-alone intervention versus DPI as adjunct to standard oral anti-tuberculosis therapy (ATT). RESULTS: The DPI with or without concomitant ATT markedly improved the morphology of the lungs and mitigated histopathology in both the lungs and the spleens. The number of nodular lesions on the lung surface decreased from 43.7 ± 3.1 to 22.5 ± 3.9 with the DPI alone and to 9.8 ± 2.5 with DPI + ATT. However, no statistically significant induction of host antimicrobial peptide cathelicidin or reduction in bacterial burden was seen with the DPI alone. DPI + ATT did not significantly reduce the bacterial burden in the lungs compared to ATT alone. CONCLUSIONS: We concluded that HDT using the low dose calcitriol DPI contributed markedly to mitigation of pathology, but higher dose may be required to evoke significant induction of bactericidal host response and bactericidal activity in the lung.

Imaging: New Frontiers in Vascular Training.

Advances in medical imaging have redefined the practice of vascular surgery. Current training programs for vascular surgery do not incorporate formal training in vascular imaging other than in duplex ultrasound when a physician is undergoing the vascular interpretation certification process. Yet imaging modalities and techniques have grown exponentially in the adjacent fields of interventional radiology, interventional and diagnostic cardiology, and neuroradiology, so much so that advanced imaging fellowships have been established in these fields. This article reviews the current state of vascular imaging training, identifies gaps in the current training regimen, and proposes an advanced vascular imaging fellowship for the future.