A mathematical model of tissue axial and radial diffusion in the microvasculature for intravascular microscopy and phosphorescence quenching data.

This study aims to extend earlier Krogh Cylinder Models of an oxygen profile by considering axial diffusion and analytically solving Fick's Law Partial Differential Equation with novel boundary conditions via the separation of variables. We next prospectively collected a total of 20 animals, which were randomly assigned to receive either fresh or two-week-old stored red blood cell (RBC) transfusions and PQM oxygen data were measured acutely (90 min) or chronically (24 h). Transfusion effects were evaluated in vivo using intravital microscopy of the dorsal skinfold window chamber in Golden Syrian Hamsters. Hamsters were initially hemorrhaged by 50% of total blood volume and resuscitated 1-h post hemorrhage. PQM data were subsequently collected and fit the derived 2D Krogh cylinder model. Systemic hemodynamics (mean arterial pressure, heart rate) were similar in both pre and post-transfusion with either stored or fresh cells. Transfusion with stored cells was found to impair axial and radial oxygen gradients as quantified by our model and consistent with previous studies. Specifically, we observed a statistically significant decrease in the arteriolar tissue radial oxygen gradient after transfusion with stored RBCs at 24 h compared with fresh RBCs (0.33 ± 0.17 mmHg µ m-1 vs, 0.14 ± 0.12 mmHg µ m-1; p = 0.0280). We also observed a deficit in the arteriolar tissue oxygen gradient (0.03 ± 0.01 mmHg µ m-1 fresh vs. 0.018 ± 0.007 mmHg µ m-1 stored; p = 0.0185). We successfully derived and validated an analytical 2D Krogh cylinder model in an animal model of microhemodynamic oxygen diffusion aberration secondary to storage lesions.

Stunting in infancy is associated with atypical activation of working memory and attention networks.

Stunting is associated with poor long-term cognitive, academic and economic outcomes, yet the mechanisms through which stunting impacts cognition in early development remain unknown. In a first-ever neuroimaging study conducted on infants from rural India, we demonstrate that stunting impacts a critical, early-developing cognitive system-visual working memory. Stunted infants showed poor visual working memory performance and were easily distractible. Poor performance was associated with reduced engagement of the left anterior intraparietal sulcus, a region involved in visual working memory maintenance and greater suppression in the right temporoparietal junction, a region involved in attentional shifting. When assessed one year later, stunted infants had lower problem-solving scores, while infants of normal height with greater left anterior intraparietal sulcus activation showed higher problem-solving scores. Finally, short-for-age infants with poor physical growth indices but good visual working memory performance showed more positive outcomes suggesting that intervention efforts should focus on improving working memory and reducing distractibility in infancy.

Changes in oxygen delivery during experimental models of cerebral malaria.

Cerebral malaria (CM) is a severe manifestation of malaria that commonly occurs in children and is hallmarked by neurologic symptoms and significant Plasmodium falciparum parasitemia. It is currently hypothesized that cerebral hypoperfusion from impaired microvascular oxygen transport secondary to parasitic occlusion of the microvasculature is responsible for cerebral ischemia and thus disease severity. Animal models to study CM, are known as experimental cerebral malaria (ECM), and include the C57BL/6J infected with Plasmodium berghei ANKA (PbA), which is ECM-susceptible, and BALB/c infected with PbA, which is ECM-resistant. Here we sought to investigate whether changes in oxygen (O2) delivery, O2 flux, and O2 utilization are altered in both these models of ECM using phosphorescence quenching microscopy (PQM) and direct measurement of microvascular hemodynamics using the cranial window preparation. Animal groups used for investigation consisted of ECM-susceptible C57BL/6 (Infected, n = 14) and ECM-resistant BALB/c (Infected, n = 9) mice. Uninfected C57BL/6 (n = 6) and BALB/c (n = 6) mice were included as uninfected controls. Control animals were manipulated in the exact same way as the infected mice (except for the infection itself). C57BL/6 ECM animals at day 6 of infection were divided into two cohorts: Early-stage ECM, presenting mild to moderate drops in body temperature (>34 < 36 °C) and Late-stage ECM, showing marked drops in body temperature (<33 °C). Data taken from new experiments conducted with these animal models were analyzed using a general linear mixed model. We constructed three general linear mixed models, one for total O2 content, another for total O2 delivery, and the third for total O2 content as a function of convective flow. We found that in both the ECM-susceptible C57BL/6J model and ECM-resistant BALB/c model of CM, convective and diffusive O2 flux along with pial hemodynamics are impaired. We further show that concomitant changes in p50 (oxygen partial pressure for 50% hemoglobin saturation), only 5 mmHg in the case of late-stage CM C57BL/6J mice, and O2 diffusion result in insufficient O2 transport by the pial microcirculation, and that both these changes are required for late-stage disease. In summary, we found impaired O2 transport and O2 affinity in late-stage ECM, but only the former in either early-stage ECM and ECM-resistant strains.

Prony Analysis of Left Ventricle Pressure and Volume.

Direct measurement of cardiac pressure-volume (PV) relationships is the gold standard for assessment of ventricular hemodynamics, but few innovations have been made to "multi-beat" PV analysis beyond traditional signal processing. The Prony method solves the signal recovery problem with a series of dampened exponentials or sinusoids. It achieves this by extracting the amplitude, frequency, dampening, and phase of each component. Since its inception, application of the Prony method to biologic and medical signal has demonstrated a relative degree of success, as a series of dampened complex sinusoids easily generalizes to multifaceted physiological processes. In cardiovascular physiology, the Prony analysis has been used to determine fatal arrythmia from electrocardiogram signals. However, application of the Prony method to simple left ventricular function based on pressure and volume analysis is absent. We have developed a new pipeline for analysis of pressure volume signals recorded from the left ventricle. We propose fitting pressure-volume data from cardiac catheterization to the Prony method for pole extraction and quantification of the transfer function. We implemented the Prony algorithm using open-source Python packages and analyzed the pressure and volume signals before and after severe hemorrhagic shock, and after resuscitation with stored blood. Each animal (n = 6 per group) underwent a 50% hemorrhage to induce hypovolemic shock, which was maintained for 30 min, and resuscitated with 3-week-old stored RBCs until 90% baseline blood pressure was achieved. Pressure-volume catheterization data used for Prony analysis were 1 s in length, sampled at 1000 Hz, and acquired at the time of hypovolemic shock, 15 and 30 min after induction of hypovolemic shock, and 10, 30, and 60 min after volume resuscitation. We next assessed the complex poles from both pressure and volume waveforms. To quantify deviation from the unit circle, which represents deviation from a Fourier series, we counted the number of poles at least 0.2 radial units away from it. We found a significant decrease in the number of poles after shock (p = 0.0072 vs. baseline) and after resuscitation (p = 0.0091 vs. baseline). No differences were observed in this metric pre and post volume resuscitation (p = 0.2956). We next found a composite transfer function using the Prony fits between the pressure and volume waveforms and found differences in both the magnitude and phase Bode plots at baseline, during shock, and after resuscitation. In summary, our implementation of the Prony analysis shows meaningful physiologic differences after shock and resuscitation and allows for future applications to broader physiological and pathophysiological conditions.

Poor air quality is associated with impaired visual cognition in the first two years of life: A longitudinal investigation.

Background: Poor air quality has been linked to cognitive deficits in children, but this relationship has not been examined in the first year of life when brain growth is at its peak. Methods: We measured in-home air quality focusing on particulate matter with diameter of <2.5 µm (PM2.5) and infants' cognition longitudinally in a sample of families from rural India. Results: Air quality was poorer in homes that used solid cooking materials. Infants from homes with poorer air quality showed lower visual working memory scores at 6 and 9 months of age and slower visual processing speed from 6 to 21 months when controlling for family socio-economic status. Conclusions: Thus, poor air quality is associated with impaired visual cognition in the first two years of life, consistent with animal studies of early brain development. We demonstrate for the first time an association between air quality and cognition in the first year of life using direct measures of in-home air quality and looking-based measures of cognition. Because indoor air quality was linked to cooking materials in the home, our findings suggest that efforts to reduce cooking emissions should be a key target for intervention. Funding: Bill & Melinda Gates Foundation grant OPP1164153.

Coral reef-associated brachyuran fauna (Crustacea: Decapoda: Brachyura) from Angria Bank off the west coast of India.

Underwater sampling via SCUBA and grab at the Angria Bank coral reefs off the central west coast of India in January 2014 revealed 11 species of Brachyura. Seven species, namely, Thusaenys irami (Laurie, 1906), Tanaocheles bidentata (Nobili, 1901), Portunus convexus De Haan, 1835, Xiphonectes macrophthalmus (Rathbun, 1906), Thalamita gatavakensis Nobili, 1906, Serenius ceylonicus (Laurie, 1906), and Soliella flava (Rathbun, 1894) are reported for the first time from Indian waters. Furthermore, the geographical distribution of T. irami and S. ceylonicus is extended westwards of hitherto known ranges.

Rectification-based Knowledge Retention for Task Incremental Learning.

In the task incremental learning problem, deep learning models suffer from catastrophic forgetting of previously seen classes/tasks as they are trained on new classes/tasks. This problem becomes even harder when some of the test classes do not belong to the training class set, i.e., the task incremental generalized zero-shot learning problem. We propose a novel approach to address the task incremental learning problem for both the non zero-shot and zero-shot settings. Our proposed approach, called Rectification-based Knowledge Retention (RKR), applies weight rectifications and affine transformations for adapting the model to any task. During testing, our approach can use the task label information (task-aware) to quickly adapt the network to that task. We also extend our approach to make it task-agnostic so that it can work even when the task label information is not available during testing. Specifically, given a continuum of test data, our approach predicts the task and quickly adapts the network to the predicted task. We experimentally show that our proposed approach achieves state-of-the-art results on several benchmark datasets for both non zero-shot and zero-shot task incremental learning.

Omalizumab for treatment of idiopathic angioedema.

BACKGROUND: Omalizumab has been found to improve outcomes in patients with chronic spontaneous urticaria (CSU). Idiopathic angioedema (IAE) is increasingly being recognized as a condition with similar underlying mechanisms as CSU and a form of CSU. We hypothesized that add-on therapy with omalizumab would benefit patients with uncontrolled IAE. OBJECTIVE: To study the safety and efficacy of omalizumab for the treatment of IAE in adults. METHODS: We conducted a randomized, placebo-controlled trial to study the efficacy of omalizumab in adults with 2 or more episodes of angioedema (AE) in the past 6 months for which no clinical or laboratory cause of AE could be found. A total of 10 patients were randomized on a 1:1 basis to receive omalizumab 300 mg subcutaneously or placebo every 4 weeks for 24 weeks with a 12-week follow-up period. The primary endpoint was the change in the Angioedema Activity Score. Secondary endpoints included the Angioedema Quality of Life Questionnaire, the Visual Analogue Scale, and the number of angioedema episodes per month. RESULTS: We observed improvement in the Angioedema Activity Score (-2.93 ln odds; 95% confidence interval [CI], -4.84 to -1.02; P = .003), Visual Analogue Scale (-3.49 ln odds; 95% CI, -6.58 to -0.40; P = .03), Angioedema Quality of Life Questionnaire (-9.43 score; 95% CI, -17.63 to -1.24; P = .03), and number of angioedema episodes per month (-1.93 ln count; 95% CI, -3.23 to -0.63; P = .005) in patients who received omalizumab vs placebo. CONCLUSION: This study provides preliminary prospective evidence that omalizumab improves outcomes in patients with IAE. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02966314. CLINICALTRIALS: gov URL:https://clinicaltrials.gov/ct2/show/NCT02966314?term=omalizumab&cond=Angioedema&draw=2&rank=1.

Implications of microvascular dysfunction and nitric oxide mediated inflammation in severe COVID-19 infection.

Infection with COVID-19 has resulted in over 276,000 deaths in the United States and over 1.5 million deaths globally, with upwards of 15% of patients requiring hospitalization. Severe COVID-19 infection is, in essence, a microvascular disease. This contention has been emphasized throughout the course of the pandemic, particularly due to the clinical manifestation of severe infection. In fact, it has been hypothesized and shown in particular instances that microvascular function is a significant prognosticator for morbidity and mortality. Initially thought to be isolated to the pulmonary system and resulting in ARDS, patients with COVID-19 have been observed to have acute cardiac, renal, and thrombolytic complications. Therefore, severe COVID-19 is a vascular disease that has systemic implications. The objective of this review is to provide a mechanistic background for the microvascular nature of severe COVID-19 infection, with a particular emphasis on dysfunction of the endothelial glycocalyx and nitric oxide mediated pathogenesis.

Paralomis White, 1856 (Crustacea: Decapoda: Anomura) from India, with morphological variability in Paralomis indica Alcock amp; Anderson, 1899.

Deep-water king crabs of the genus Paralomis White, 1856 collected during three cruises of the Fishery Oceanographic Research Vessel Sagar Sampada in the western Bay of Bengal (528777 m depths), one cruise in the eastern Bay of Bengal off Great Nicobar Island (337 m depth), and four cruises in the southeastern Arabian Sea (3151245 m) were identified. They are referred to Paralomis ceres Macpherson, 1989, recorded for the first time from Indian waters and P. indica Alcock Anderson, 1899, reported for the first time from the Bay of Bengal and the Andaman Sea. In addition, this study reports the morphological variability among the P. indica populations in the shape of the carapace and dorsal rostral spines, nature of the branchial and cardiac regions and abdominal marginal spines, and the relative lengths of pereopods 24. Mitochondrial Cytochrome oxidase I (594 base pairs) and 16S rRNA (503 bp) gene sequences of P. ceres and P. indica (602 and 497 bp, respectively) revealed that they formed distinct lineages. A key to the Indian Ocean species of Paralomis is provided.

Two axiidean ghost shrimps (Crustacea: Decapoda) from India, Guyanacaris keralam sp. nov. (Axiidae) and Paragourretia galathea (K. Sakai, 2017) (Ctenochelidae).

Ghost shrimps collected from the Indian Exclusive Economic Zone by the Fishery Oceanographic Research Vessel Sagar Sampada during two cruises in the eastern (105 metres depth) and southeastern Arabian Sea (101 and 326 metres depth) were studied. One male, identified as Guyanacaris keralam sp. nov. of the Axiidae, differs from its congeners in the unique armature of the rostrum, gastric region of carapace, pleonal pleural margins, dorsal margins of cheliped fingers, ventral margin of second pereopod merus, and lateral margins of telson; the presence of corneous spines on the propodi and dactyli of third and fourth pereopods, and the relative sizes of the ocular peduncles, antennular peduncle, scaphocerite and cheliped fingers. Guyanacaris K. Sakai, 2011 is re-diagnosed based on the presence of short supraocular spine and post-cervical carina on carapace, dentate margins of first two pleonal pleura, third to fifth pleura with angular to straight posterior margins, antennal scaphocerite with mesial spine at base, and presence of male first pleopod 1. Bruceaxius thailandensis K. Sakai, 2015 is tentatively retained in Bruceaxius K. Sakai, 2011, owing to absence of mesial spine at the base of scaphocerite, tuberculate upper margins of carpus, propodus and dactylus of major cheliped, and tri-segmented appendix masculina on male second pleopod. In addition, two males, diagnosed herein as Paragourretia galathea (K. Sakai, 2017) of the Ctenochelidae, differ from the holotype female only in the relative length of the terminal antennular article and the presence of a distomedian spinule on the telson, of all the features.

Estimating maternity ward birth attendant time use in India: a microcosting study.

OBJECTIVES: Despite global concern over the quality of maternal care, little is known about the time requirements to complete the essential birth practices. Using three microcosting data collection methods within the BetterBirth trial, we aimed to assess time use and the specific time requirements to incorporate the WHO Safe Childbirth Checklist into clinical practice. SETTING: We collected detailed survey data on birth attendant time use within the BetterBirth trial in Uttar Pradesh, India. The BetterBirth trial tested whether the peer-coaching-based implementation of the WHO Checklist was effective in improving the quality of facility-based childbirth care. PARTICIPANTS: We collected measurements of time to completion for 18 essential birth practices from July 2016 through October 2016 across 10 facilities in five districts (1559 total timed observations). An anonymous survey asked about the impact of the WHO Checklist on birth attendants at every intervention facility (15 facilities, 83 respondents) in the Lucknow hub. Additionally, data collectors visited facilities to conduct a census of patients and birth attendants across 20 facilities in seven districts between June 2016 and November 2016 (six hundred and ten 2-hour facility observations). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome measure of this study is the per cent of staff time required to complete the essential birth practices included in the WHO Checklist. RESULTS: When birth attendants were timed, we found practices were completed rapidly (18 s to 2 min). As the patient load increased, time dedicated to clinical care increased but remained low relative to administrative and downtime. On average, WHO Checklist clinical care accounted for less than 7% of birth attendant time use per hour. CONCLUSIONS: We did not find that a coaching-based implementation of the WHO Checklist was a burden on birth attendant's time use. However, questions remain regarding the performance quality of practices and how to accurately capture and interpret idle and break time. TRIAL REGISTRATION NUMBER: NCT02148952.

Nitric oxide releasing nanoparticles reduce inflammation in a small animal model of ARDS.

Acute respiratory distress syndrome (ARDS) is a condition hallmarked by high permeability pulmonary edema and hypoxemic respiratory failure and is associated with high mortality. Current treatment protocols rely on improving O2 delivery, decreasing O2 consumption, and treating the underlying cause of the initial insult. In this study, we used a small rodent model of ARDS, where we induced lung injury with inhalation of lipopolysaccharide (LPS). We investigated three different treatments, namely inhaled NO at 70 ppm, inhaled NO at 140 ppm, and NO-np (10 mg/mL), compared with untreated rodents 72 h after initial insult. Concurrent with treatment, the fraction of inspired O2 was increased after 30 min from 21% to 40% and finally to 60%. At an FiO2 of 60% and 72 h post induction of ARDS, NO-np treated mice had an arterial PO2 (PaO2) of 142 ± 9 mmHg, higher than mice treated with inhaled NO at 70 ppm (87 ± 5 mmHg, p = 8.4 × 10-8) and inhaled NO at 140 ppm (107 ± 6 mmHg, p = 6.1 × 10-6). Neutrophils in both the periphery (1.6 × 105 ± 0.4 × 105 cells) and bronchoalveolar lavage fluid (BALF; 2.7 × 105 ± 0.8 × 105 cells) were reduced in NO-np treated mice compared to mice treated with inhaled NO at 70 ppm (p = 0.0097, 2.4 × 105 ± 0.5 × 105 cells for periphery, p = 0.0075, 3.8 × 105 ± 0.8 × 105 cells for BALF). In summary, we found that treatment with NO-np improved arterial PO2 at a high FiO2 compared to inhaled NO alone and NO-np reduced both circulating and pulmonary interstitial neutrophil count, while inhaled NO did not. Future studies should aim to elucidate the precise mechanisms behind how NO-np mediate neutrophilic inflammation in ARDS.

The Disconnect Between Extracorporeal Circulation and the Microcirculation: A Review.

Extracorporeal circulation (ECC) procedures, such as cardiopulmonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO), take over the function of one or more organs, providing clinicians time to treat underlying pathophysiological conditions. ECMO and CPB carry significant mortality rates for patients, despite prior decades of research focused on the resulting failure of critical organs. Since the focus of these procedures is to support blood flow and provide oxygen-rich blood to tissues, a shift in research toward the effects of ECMO and CPB on the microcirculation is warranted. Along with provoking systemic responses, both procedures disrupt the integrity of red blood cells, causing release of hemoglobin (Hb) from excessive foreign surface contact and mechanical stresses. The effects of hemolysis are especially pronounced in the microcirculation, where plasma Hb leads to nitric oxide scavenging, oxidization, formation of reactive oxygen species, and inflammatory responses. A limited number of studies have investigated the implications of ECMO in the microcirculation, but more work is needed to minimize ECMO-induced reduction of microcirculatory perfusion and consequently oxygenation. The following review presents existing information on the implications of ECMO and CPB on microvascular function and proposes future studies to understand and leverage key mechanisms to improve patient outcomes.

A Comparison of the Mydriatic Efficacy of Tropicamide and Phenylephrine Eye Drops Administered as a Vaporized Spray in One Eye and Conventional Drop Instillation in the Other Eye in an Indian Pediatric Cohort.

Purpose: To determine by serial measurements and compare the pupillary mydriasis effect of tropicamide and phenylephrine drops administered as a vaporized spray over closed lids in one eye and through conventional instillation of eye drops in the other eye in a pediatric cohort. Methods: This prospective study was conducted on healthy children aged 6-15 years. After visual assessment, investigator 1 examined the child for initial pupillary size. Investigator 2 instilled the drops in one eye and applied the spray to the other eye randomly, and the response of the child was noted using the Wong-Baker pain rating scale. The eyes receiving the spray and the eyes receiving drop instillation were considered as Groups 1 and 2, respectively. Subsequently, serial pupillary measurements were carried out every 10 min for up to 40 min by investigator 1. The patient compliance for the two methods of drug instillation was also compared. Results: The study comprised 80 eyes. At 40 min, both the groups showed no statistical difference in the mydriasis effect, with Group 1 showing 7.23 mm mydriasis and Group 2 showing 7.58 mm (P = 0.058). The analysis of the pain rating scale showed better compliance with the spray method of drug instillation, which was statistically significant (P = 0.044). Conclusions: Our study shows that spray application is a less invasive method for pupillary dilatation, which has better compliance and provides equally good dilatation as conventional methods. This study proves the efficacy of spray application in an Indian pediatric cohort.

Two new species of the genus Galathea Fabricius, 1793 (Crustacea: Decapoda: Anomura: Galatheidae) from the Andaman Sea, India.

Two new species of the galatheid squat lobster genus Galathea Fabricius, 1793 are described from the Andaman Sea, India. Galathea nicobarica sp. nov. closely resembles G. rubromaculata Miyake & Baba, 1967a, but differs in the armature of the branchial carapace margin and shape of the dactylus of the third maxilliped. Galathea tirmiziae sp. nov. is allied to G. consobrina De Man, 1902 and G. tagaro Macpherson & Robainas-Barcia, 2015, but is distinguished by the merus of the third maxilliped lacking a disto-extensor spine and the proportionally more slender merus of the second pereopod.

First records of two species of reef-associated mantis shrimps (Crustacea: Stomatopoda) from India.

The coastal marine environments in the Indian Exclusive Economic Zone harbour a rich diversity of mantis shrimps. However, several regions have not been adequately surveyed for their stomatopod faunal composition. In this paper, we report the first records of two species, Gonodactylopsis drepanophora (de Man, 1902) and Cloridina malaccensis (Manning, 1968) from Indian waters. Samples were collected using a chain dredge deployed by the Fishery Oceanographic Research Vessel Sagar Sampada on the shallow reefs (5356 m depths) of the Andaman Sea and Bay of Bengal during AugustNovember 2019. Gonodactylopsis drepanophora was previously known only from Indonesia, and Cloridina malaccensis from Southeast Asia, New Caledonia and Madagascar.

RRx-001 Increases Erythrocyte Preferential Adhesion to the Tumor Vasculature.

Red blood cells (RBCs) serve a variety of functions beyond mere oxygen transport both in health and pathology. Notably, RRx-001, a minimally toxic pleiotropic anticancer agent with macrophage activating and vascular normalization properties currently in Phase III trials, induces modification to RBCs which could promote vascular adhesion similar to sickle cells. This study assessed whether RBCs exposed to RRx-001 adhere to the tumor microvasculature and whether this adhesion alters tumor viability. We next investigated the biomechanics of RBC adhesion in the context of local inflammatory cytokines after treatment with RRx-001 as a potential mechanism for preferential tumor aggregation. Human HEP-G2 and HT-29 tumor cells were subcutaneously implanted into nu/nu mice and were infused with RRx-001-treated and Technetium-99m (99mTc)-labeled blood. RBC adhesion was quantified in an in vitro human umbilical vein endothelial cell (HUVEC) assay under both normoxic and hypoxic conditions with administration of either lipopolysaccharide (LPS) or Tumor necrosis alpha (TNFα) to mimic the known inflammation in the tumor microenvironment. One hour following administration of 99mTc labeled RBCs treated with 10 mg/kg RRx-001, we observed an approximate 2.0-fold and 1.5-fold increase in 99mTc-labeled RBCs compared to vehicle control in HEPG2 and HT-29 tumor models, respectively. Furthermore, we observed an approximate 40% and 36% decrease in HEP-G2 and HT-29 tumor weight, respectively, following treatment with RRx-001. To quantify RBC adhesive potential, we determined τ50, or the shear stress required for 50% disassociation of RBCs from HUVECs. After administration of TNF-α under normoxia, τ50 was determined to be 4.5 dynes/cm2 (95% CI: 4.3-4.7 dynes/cm2) for RBCs treated with 10 µM RRx-001, which was significantly different (p < 0.05) from τ50 in the absence of treatment. Under hypoxic conditions, the difference of τ50 with (4.8 dynes/cm2; 95% CI: 4.6-5.1 dynes/cm2) and without (2.6 dynes/cm2; 95% CI: 2.4-2.8 dynes/cm2) 10 µM RRx-001 treatment was exacerbated (p = 0.05). In conclusion, we demonstrated that RBCs treated with RRx-001 preferentially aggregate in HEP-G2 and HT-29 tumors, likely due to interactions between RRx-001 and cysteine residues within RBCs. Furthermore, RRx-001 treated RBCs demonstrated increased adhesive potential to endothelial cells upon introduction of TNF-α and hypoxia suggesting that RRx-001 may induce preferential adhesion in the tumor but not in other tissues with endothelial dysfunction due to conditions prevalent in older cancer patients such as heart disease or diabetic vasculopathy.

Application of negative tissue interstitial pressure improves functional capillary density after hemorrhagic shock in the absence of volume resuscitation.

Microvascular fluid exchange is primarily dependent on Starling forces and both the active and passive myogenic response of arterioles and post-capillary venules. Arterioles are classically considered resistance vessels, while venules are considered capacitance vessels with high distensibility and low tonic sympathetic stimulation at rest. However, few studies have investigated the effects of modulating interstitial hydrostatic pressure, particularly in the context of hemorrhagic shock. The objective of this study was to investigate the mechanics of arterioles and functional capillary density (FCD) during application of negative tissue interstitial pressure after 40% total blood volume hemorrhagic shock. In this study, we characterized systemic and microcirculatory hemodynamic parameters, including FCD, in hamsters instrumented with a dorsal window chamber and a custom-designed negative pressure application device via intravital microscopy. In large arterioles, application of negative pressure after hemorrhagic shock resulted in a 13 ± 11% decrease in flow compared with only a 7 ± 9% decrease in flow after hemorrhagic shock alone after 90 minutes. In post-capillary venules, however, application of negative pressure after hemorrhagic shock resulted in a 31 ± 4% decrease in flow compared with only an 8 ± 5% decrease in flow after hemorrhagic shock alone after 90 minutes. Normalized FCD was observed to significantly improve after application of negative pressure after hemorrhagic shock (0.66 ± 0.02) compared to hemorrhagic shock without application of negative pressure (0.50 ± 0.04). Our study demonstrates that application of negative pressure acutely improves FCD during hemorrhagic shock, though it does not normalize FCD. These results suggest that by increasing the hydrostatic pressure gradient between the microvasculature and interstitium, microvascular perfusion can be transiently restored in the absence of volume resuscitation. This study has significant clinical implications, particularly in negative pressure wound therapy, and offers an alternative mechanism to improve microvascular perfusion during hypovolemic shock.

Uncertainty Class Activation Map (U-CAM) Using Gradient Certainty Method.

Understanding and explaining deep learning models is an imperative task. Towards this, we propose a method that obtains gradient-based certainty estimates that also provide visual attention maps. Particularly, we solve for visual question answering task. We incorporate modern probabilistic deep learning methods that we further improve by using the gradients for these estimates. These have two-fold benefits: a) improvement in obtaining the certainty estimates that correlate better with misclassified samples and b) improved attention maps that provide state-of-the-art results in terms of correlation with human attention regions. The improved attention maps result in consistent improvement for various methods for visual question answering. Therefore, the proposed technique can be thought of as a tool for obtaining improved certainty estimates and explanations for deep learning models. We provide detailed empirical analysis for the visual question answering task on all standard benchmarks and comparison with state of the art methods.