Attenuation of Nerve Agent Induced Neurodegenerative and Neuroinflammatory Changes in Rats with New Combination Treatment of Galantamine, Atropine and Midazolam.

Acute nerve agent exposure can kill a person within minutes or produce multiple neurotoxic effects and subsequent brain damage with potential long-term adverse outcomes. Recent abuse of nerve-agents on Syrian civilians, during Japan terrorist attacks, and personal assassinations in the UK, and Malaysia indicate their potential threat to world population. Existing nerve agent antidotes offer only incomplete protection especially, if the treatment is delayed. To develop the effective drugs, it is advantageous to elucidate the underlying mechanisms of nerve agent-induced multiple neurological impairments. This study aimed to investigate the molecular basis of neuroinflammation during nerve agent toxicity with focus on inflammasome-associated proteins and neurodegeneration. In rats, NOD-like receptor family pyrin domain containing 3 (NLRP3), and glial fibrillary acidic protein (GFAP) immunoreactivity levels were considerably increased in the hippocampus, piriform cortex, and amygdala areas after single subcutaneous soman exposure (90 µg/kg-1). Western analysis indicated a notable increase in the neuroinflammatory indicator proteins, high mobility group box 1 (HMGB1) and inducible nitric oxide synthase (iNOS) levels. The presence of fluorojade-C-stained degenerating neurons in distinct rat brain areas is indicating the neurodegeneration during nerve agent toxicity. Pre-treatment with galantamine (3 mg/kg, - 30 min) followed by post-treatment of atropine (10 mg/kg, i.m.) and midazolam (5 mg/kg, i.m.), has completely protected animals from death induced by supra-lethal dose of soman (2XLD50) and reduced the neuroinflammatory and neurodegenerative changes. Results highlight that this new prophylactic and therapeutic drug combination might be an effective treatment option for soldiers deployed in conflict areas and first responders dealing with accidental/deliberate release of nerve agents.

An empirical model for world record running speeds with distance, age, and sex: anaerobic and aerobic contributions to performance.

The objective of this study is to derive mathematical equations that closely describe published data on world record running speed as a function of distance, age and sex. Running speed declines with increasing distance and age. Over long distances, where aerobic metabolism is dominant, speed declines in proportion to the logarithm of distance. Over short distances, anaerobic metabolism contributes significantly to performance, and speed is increased relative to the trend of the long-distance data. Equations are derived that explicitly represent these effects. The decline in speed with age is represented by an age-dependent multiplicative factor, which exhibits increasing sensitivity to age as age increases. Using these equations, data are analyzed separately for males and females, and close fits to published data are demonstrated, particularly for younger age groups. These equations provide insight into the contributions of aerobic and anaerobic components of metabolism to athletic performance and a framework for comparisons of performance across wide ranges of distance and age.

Designing an implementation strategy to increase health-related social needs screening: Applying the PRISM framework in a resource-limited clinical setting.

Despite growing acceptability of health-related social needs (HRSN) screening and increasing policy incentives for adoption, clinical implementation of HRSN screening remains low. HRSN screening has been particularly difficult for Community Health Centers (CHCs), which have limited resources to implement and sustain new workflows. While CHCs provide care to patients with disproportionately high levels of unmet social needs, identifying HRSN screening implementation strategies that take CHC-specific contexts into account remains elusive. This study uses the Practical Robust Implementation and Sustainability Model (PRISM) to design an implementation strategy accounting for the unique context of CHCs. We used Rapid Ethnographic Assessment observations and stakeholder focus groups to identify current workflow barriers and facilitators to HRSN screening, and to develop implementation strategies that include multi-level contexts and perspectives. We identified eight themes contributing to low screening implementation: perceived stigma around screening; need for community-based solutions; re-confirming organizational priorities and values; Electronic Medical Record (EMR) limitations; multi-tasking pressures limiting implementation; staff turnover; limited knowledge of regulatory requirements; and community resource availability for referral. Based on the themes, we identified implementation strategies including non-EMR data collection; integration into the workflow for multiple staff members; creation of new training and educational modules; and identification of peer champions for retraining in real time. Administrative requirements are necessary but not sufficient for implementation of HRSN screening in CHCs. Resource-constrained settings benefit from context-specific stakeholder engagement to improve implementation success. The use of PRISM ensured contextual factors were central to the implementation strategy design.

Health care systems are encouraged to screen for health-related social needs (HRSN), such as housing and food insecurity, yet it has been difficult to implement these new screening workflows. This is especially true for Community Health Centers (CHCs) that have limited resources to implement new workflows. Using a framework that accounts for the unique environment of CHCs, we observed current workflows and conducted focus groups to develop an implementation strategy to facilitate HRSN screening. The new strategy used paper-based workflows to facilitate patient participation and identified clinical champions to engage staff. While these findings are useful in CHCs that might not have sufficient resources to develop screening processes in the Electronic Medical Record, they are also applicable to other low-resourced settings that might want to include HRSNs in patient care, but do not have resources or staff to do it.

The dependence of maximum oxygen uptake and utilization (V̇O2 max) on hemoglobin-oxygen affinity and altitude.

Oxygen transport from the lungs to peripheral tissue is dependent on the affinity of hemoglobin for oxygen. Recent experimental data have suggested that the maximum human capacity for oxygen uptake and utilization (V̇O2 max) at sea level and altitude (~3000 m) is sensitive to alterations in hemoglobin-oxygen affinity. However, the effect of such alterations on V̇O2 max at extreme altitudes remains largely unknown due to the rarity of mutations affecting hemoglobin-oxygen affinity. This work uses a mathematical model that couples pulmonary oxygen uptake with systemic oxygen utilization under conditions of high metabolic demand to investigate the effect of hemoglobin-oxygen affinity on V̇O2 max as a function of altitude. The model includes the effects of both diffusive and convective limitations on oxygen transport. Pulmonary oxygen uptake is calculated using a spatially-distributed model that accounts for the effects of hematocrit and hemoglobin-oxygen affinity. Systemic oxygen utilization is calculated assuming Michaelis-Menten kinetics. The pulmonary and systemic model components are solved iteratively to compute predicted arterial and venous oxygen levels. Values of V̇O2 max are predicted for several values of hemoglobin-oxygen affinity and hemoglobin concentration based on data from humans with hemoglobin mutations. The model predicts that increased hemoglobin-oxygen affinity leads to increased V̇O2 max at altitudes above ~4500 m.

Attenuated cardiac autonomic function in humans with high-affinity hemoglobin and compensatory polycythemia.

During hypoxic exposure, humans with high-affinity hemoglobin (and compensatory polycythemia) have blunted increases in heart rate compared with healthy humans with typical oxyhemoglobin dissociation curves. This response may be associated with altered autonomic control of heart rate. Our hypothesis-generating study aimed to investigate cardiac baroreflex sensitivity and heart rate variability among nine humans with high-affinity hemoglobin [6 females, O2 partial pressure at 50% [Formula: see text] (P50) = 16 ± 1 mmHg] compared with 12 humans with typical affinity hemoglobin (6 F, P50 = 26 ± 1 mmHg). Participants breathed normal room air for a 10-min baseline, followed by 20 min of isocapnic hypoxic exposure, designed to lower the arterial partial pressure O2 ([Formula: see text]) to ∼50 mmHg. Beat-by-beat heart rate and arterial blood pressure were recorded. Data were averaged in 5-min periods throughout the hypoxia exposure, beginning with the last 5 min of baseline in normoxia. Spontaneous cardiac baroreflex sensitivity and heart rate variability were determined using the sequence method and the time and frequency domain analyses, respectively. Cardiac baroreflex sensitivity was lower in humans with high-affinity hemoglobin than controls at baseline and during isocapnic hypoxic exposure (normoxia: 7 ± 4 vs. 16 ± 10 ms/mmHg, hypoxia minutes 15-20: 4 ± 3 vs. 14 ± 11 ms/mmHg; group effect: P = 0.02, high-affinity hemoglobin vs. control, respectively). Heart rate variability calculated in both the time (standard deviation of the N-N interval) and frequency (low frequency) domains was lower in humans with high-affinity hemoglobin than in controls (all P < 0.05). Our data suggest that humans with high-affinity hemoglobin may have attenuated cardiac autonomic function.

Full waveform inversion for arterial viscoelasticity.

Objective. Arterial viscosity is emerging as an important biomarker, in addition to the widely used arterial elasticity. This paper presents an approach to estimate arterial viscoelasticity using shear wave elastography (SWE).Approach. While dispersion characteristics are often used to estimate elasticity from SWE data, they are not sufficiently sensitive to viscosity. Driven by this, we develop a full waveform inversion (FWI) methodology, based on directly matching predicted and measured wall velocity in space and time, to simultaneously estimate both elasticity and viscosity. Specifically, we propose to minimize an objective function capturing the correlation between measured and predicted responses of the anterior wall of the artery.Results. The objective function is shown to be well-behaving (generally convex), leading us to effectively use gradient optimization to invert for both elasticity and viscosity. The resulting methodology is verified with synthetic data polluted with noise, leading to the conclusion that the proposed FWI is effective in estimating arterial viscoelasticity.Significance. Accurate estimation of arterial viscoelasticity, not just elasticity, provides a more precise characterization of arterial mechanical properties, potentially leading to a better indicator of arterial health.

Sociocultural Costs of the Long-term COVID-19 Outbreak in Bangladesh: A Systematic Review.

Beyond the physical transmission of COVID-19, the pandemic has had far-reaching consequences in Bangladesh, including social and cultural implications. This review paper aimed at identifying and synthesizing the costs of COVID-19 on sociocultural issues in Bangladesh. For this purpose, we conducted a systematic search in MEDLINE, PubMed, ProQuest, Web of Science, Scopus and Google Scholar up to August 2021. Studies related to the costs of COVID-19 were identified, tabulated, analyzed, and synthesized by using a thematic approach. Our final synthesis of 19 studies resulted in five analytical themes: (i) disruption in education, (ii) loss of everyday social interaction, (iii) increase of "new poor" and suicide, (iv) rise of violence against women, and (v) worsening the life of refugees. Our findings showed that the costs of disruption in education, loss of everyday social interaction, and increase of "new poor" and suicide were more evident. Finally, we recommend the government and the community to adopt some integrated actions and policies to combat the problems in improving Bangladeshi sociocultural situations.

Evaluating the Teaching Health Center Graduate Medical Education Model at 10 Years: Practice-Based Outcomes and Opportunities.

Background: Since 2011, the Teaching Health Center Graduate Medical Education (THC GME) program has sought to expand access to care by training residents in safety net settings. Objective: To examine impact on physician scope, location, and patient population served using a unique data set. Methods: Using 2017-2020 data from the American Board of Family Medicine National Graduate Survey, we compared demographics, practice location, populations served, and scope of practice between graduates of THC GME programs and graduates of other family medicine programs. Results: Our sample comprised 8608 (out of 13 465) eligible family medicine graduates 3 years after completion of residency training, for a response rate of 63.9%. THC graduates were significantly more likely than other graduates to practice in a rural location (17.9% to 11.8%), within 5 miles of their residency program (18.9% to 12.9%), and to care for medically underserved populations (35.2% to 18.6%). Their scope of practice was wider than other graduates and more likely to comprise services like buprenorphine prescribing, behavioral health care, and outpatient gynecological procedures. Regression results suggest that THC training is independently correlated with a broader scope of practice. Conclusions: Graduates of THC programs were significantly more likely than graduates of other programs to practice close to their training sites and in rural areas, and to care for underserved patients while maintaining a broader scope of practice than other graduates.

Measurement of wave propagation through a tube using dual transducers for elastography in arteries.

Objective.Measuring waves induced with acoustic radiation force (ARF) in arteries has been studied over the last decade. To date, it remains a challenge to quantitatively assess the local arterial biomechanical properties. The cylindrical shape and waveguide behavior of waves propagating in the arterial wall pose complexities to determining the mechanical properties of the artery.Approach. In this paper, an artery-mimicking tube in water is examined utilizing three-dimensional measurements. The cross-section of the tube is measured while a transducer is translated over 41 different positions along the length of the tube. Motion in the radial direction is calculated using two components of motion which are measured from the two orthogonal views of the cross-section. This enables more accurate estimation of motion along the circumference of tube.Main results. The results provide more information to categorize the motion in tube wall into two types of responses: a transient response and a steady state response. The transient response is caused by ARF application and the waves travel along the length of the tube for a relatively short period of time. This corresponds to the axial and circumferential propagating waves. The two circumferential waves travel along the circumference of tube in CW (clockwise) and CCW (counter-clockwise) direction and result in a standing wave. By using a directional filter, the two waves were successfully separated, and their propagation was more clearly visualized. As a steady state response, a circumferential mode is generated showing a symmetric motion (i.e. the proximal and distal walls move in the opposite direction) following the transient response.Significance.This study provides a more comprehensive understanding of the waves produced in an artery-mimicking tube with ARF application, which will provide opportunities for improving measurement of arterial mechanical properties.

Full wave simulation of arterial response under acoustic radiation force.

With the ultimate goal of estimating arterial viscoelasticity using shear wave elastography, this paper presents a practical methodology to simulate the response of a human carotid artery under acoustic radiation force (ARF). The artery is idealized as a nearly incompressible viscoelastic hollow cylinder submerged in incompressible, inviscid fluid. For this idealization, we develop a multi-step methodology for efficient computation of three-dimensional response under complex ARF excitation, while capturing the fluid-structure interaction between the arterial wall and the surrounding fluid. The specific steps include (a) performing dimensional reduction through semi-analytical finite element formulation, (b) efficient finite element discretization using traditional and recent techniques. The computational efficiency is further enhanced by utilizing (c) modal superposition, followed by, where appropriate, (d) impulse response function. In addition to developing the methodology, convergence analysis is performed for a typical arterial geometry, leading to recommendations on various discretization parameters. At the end, the computational effort is shown to be several orders of magnitude less than the traditional, fully three-dimensional analysis using finite element methods, leading to a practical yet accurate simulation of arterial response under ARF excitations.

The influence of acoustic radiation force beam shape and location on wave spectral content for arterial dispersion ultrasound vibrometry.

Objective. Arterial dispersion ultrasound vibrometry (ADUV) relies on the use of guided waves in arterial geometries for shear wave elastography measurements. Both the generation of waves through the use of acoustic radiation force (ARF) and the techniques employed to infer the speed of the resulting wave motion affect the spectral content and accuracy of the measurement. In particular, the effects of the shape and location of the ARF beam in ADUV have not been widely studied. In this work, we investigated how such variations of the ARF beam affect the induced motion and the measurements in the dispersive modes that are excited.Approach.The study includes an experimental evaluation on an arterial phantom and anin vivovalidation of the observed trends, observing the two walls of the waveguide, simultaneously, when subjected to variations in the ARF beam extension (F/N) and focus location.Main results.Relying on the theory of guided waves in cylindrical shells, the shape of the beam controls the selection and nature of the induced modes, while the location affects the measured dispersion curves (i.e. variation of phase velocity with frequency or wavenumber, multiple modes) across the waveguide walls.Significance.This investigation is important to understand the spectral content variations in ADUV measurements and to maximize inversion accuracy by tuning the ARF beam settings in clinical applications.

Functional implications of microvascular heterogeneity for oxygen uptake and utilization.

In the vascular system, an extensive network structure provides convective and diffusive transport of oxygen to tissue. In the microcirculation, parameters describing network structure, blood flow, and oxygen transport are highly heterogeneous. This heterogeneity can strongly affect oxygen supply and organ function, including reduced oxygen uptake in the lung and decreased oxygen delivery to tissue. The causes of heterogeneity can be classified as extrinsic or intrinsic. Extrinsic heterogeneity refers to variations in oxygen demand in the systemic circulation or oxygen supply in the lungs. Intrinsic heterogeneity refers to structural heterogeneity due to stochastic growth of blood vessels and variability in flow pathways due to geometric constraints, and resulting variations in blood flow and hematocrit. Mechanisms have evolved to compensate for heterogeneity and thereby improve oxygen uptake in the lung and delivery to tissue. These mechanisms, which involve long-term structural adaptation and short-term flow regulation, depend on upstream responses conducted along vessel walls, and work to redistribute flow and maintain blood and tissue oxygenation. Mathematically, the variance of a functional quantity such as oxygen delivery that depends on two or more heterogeneous variables can be reduced if one of the underlying variables is controlled by an appropriate compensatory mechanism. Ineffective regulatory mechanisms can result in poor oxygen delivery even in the presence of adequate overall tissue perfusion. Restoration of endothelial function, and specifically conducted responses, should be considered when addressing tissue hypoxemia and organ failure in clinical settings.

Muscle oxygenation during normoxic and hypoxic cycling exercise in humans with high-affinity haemoglobin.

NEW FINDINGS: What is the central question of this study? Do humans with high-affinity haemoglobin (HAH) demonstrate attenuated skeletal muscle deoxygenation during normoxic and hypoxic exercise? What is the main finding and its importance? Examination of near-infrared spectroscopy-derived muscle oxygenation profiles suggests that fractional oxygen extraction is blunted during hypoxic exercise in humans with HAH compared with control subjects. However, muscle tissue oxygen saturation levels were higher in humans with HAH during exercise in normoxia compared with control subjects. These alterations in fractional oxygen extraction in humans with HAH might influence blood flow regulation and exercise capacity during hypoxia. ABSTRACT: Recently, researchers in our laboratory have shown that humans with genetic mutations resulting in high-affinity haemoglobin (HAH) demonstrate better maintained aerobic capacity and peak power output during hypoxic exercise versus normoxic exercise in comparison to humans with normal-affinity haemoglobin. However, the influence of HAH on tissue oxygenation within exercising muscle during normoxia and hypoxia is unknown. Therefore, we examined near-infrared spectroscopy-derived oxygenation profiles of the vastus lateralis during graded cycling exercise in normoxia and hypoxia among humans with HAH (n = 5) and control subjects with normal-affinity haemoglobin (n = 12). The HAH group elicited a blunted increase of deoxygenated haemoglobin + myoglobin during hypoxic exercise compared with the control group (P = 0.03), suggesting reduced fractional oxygen extraction in the HAH group. In addition, the HAH group maintained a higher level of muscle tissue oxygen saturation during normoxic exercise (HAH, 75 ± 4% vs. controls, 65 ± 3%, P = 0.049) and there were no differences between groups in muscle tissue oxygen saturation during hypoxic exercise (HAH, 68 ± 3% vs. controls, 68 ± 2%, P = 0.943). Overall, our results suggest that humans with HAH might demonstrate divergent patterns of fractional oxygen extraction during hypoxic exercise and elevated muscle tissue oxygenation during normoxic exercise compared with control subjects.

Predictors of loss to follow-up from HIV antiretroviral therapy in Namibia.

Despite progress on population-level HIV viral suppression, unknown outcomes amongst people who have initiated antiretroviral therapy (ART) in low- and middle-income countries, commonly referred to as loss to follow-up (LTFU), remains a barrier. The mean global estimate of LTFU is 20%, exceeding the World Health Organization target of <15%. Pervasive predictors associated with LTFU include younger age, low body mass index, low CD4 count, advanced HIV clinical stage and certain ART regimens. In Namibia, ART use by eligible individuals exceeds 85%, surpassing the global average. Nonetheless, LTFU remains a barrier to achieving viral suppression and requires research to elucidate context-specific factors. An observational cohort study was conducted in Namibia in 2012 by administering surveys to individuals who presented for HIV care and initiated ART for the first time. Additional data were collected from routine medical data monitoring systems. Participants classified as LTFU at 12 months were traced to confirm their status. Predictors of LTFU were analyzed using multivariable logistic regression. Of those who presented consecutively to initiate ART, 524 were identified as eligible to enroll in the study, 497 enrolled, and 474 completed the baseline questionnaire. The cohort had mean age 36 years, 39% were male, mean CD4 cell count 222 cells/mm3, 17% were WHO HIV clinical stage III-IV, and 14% started efavirenz-based regimens. Tracing participants classified as LTFU yielded a re-categorization from 27.8% (n = 132) to 14.3% (n = 68) LTFU. In the final multivariable model, factors associated with confirmed LTFU status were: younger age (OR 0.97, 95% CI 1.00-1.06, p = 0.02); male sex (OR 2.34, CI 1.34-4.06, p = 0.003); difficulty leaving work or home to attend clinic (OR 2.55, CI 1.40-4.65, p = 0.002); and baseline efavirenz-based regimen (OR 2.35, CI 1.22-4.51, p = 0.01). Interventions to reduce LTFU should therefore target young men, particularly those who report difficulty leaving work or home to attend clinic and are on an efavirenz-based regimen.

Toward improved accuracy in shear wave elastography of arteries through controlling the arterial response to ultrasound perturbation in-silico and in phantoms.

Dispersion-based inversion has been proposed as a viable direction for materials characterization of arteries, allowing clinicians to better study cardiovascular conditions using shear wave elastography. However, these methods rely ona prioriknowledge of the vibrational modes dominating the propagating waves induced by acoustic radiation force excitation: differences between anticipated and real modal content are known to yield errors in the inversion. We seek to improve the accuracy of this process by modeling the artery as a fluid-immersed cylindrical waveguide and building an analytical framework to prescribe radiation force excitations that will selectively excite certain waveguide modes using ultrasound acoustic radiation force. We show that all even-numbered waveguide modes can be eliminated from the arterial response to perturbation, and confirm the efficacy of this approach within silicotests that show that odd modes are preferentially excited. Finally, by analyzing data from phantom tests, we find a set of ultrasound focal parameters that demonstrate the viability of inducing the desired odd-mode response in experiments.

Information transmission in a two-step cascade: interplay of activation and repression.

We present an information-theoretic formalism to study signal transduction in four architectural variants of a model two-step cascade with increasing input population. Our results categorize these four types into two classes depending upon the effect of activation and repression on mutual information, net synergy, and signal-to-noise ratio. Using the Gaussian framework and linear noise approximation, we derive the analytic expressions for these metrics to establish their underlying relationships in terms of the biochemical parameters. We also verify our approximations through stochastic simulations.

Analysis of flow resistance in the pulmonary arterial circulation: implications for hypoxic pulmonary vasoconstriction.

Hypoxic pulmonary vasoconstriction (HPV) plays an essential role in distributing blood in the lung to enhance ventilation-perfusion matching and blood oxygenation. In this study, a theoretical model of the pulmonary vasculature is used to predict the effects of vasoconstriction over specified ranges of vessel diameters on pulmonary vascular resistance (PVR). The model is used to evaluate the ability of hypothesized mechanisms of HPV to account for observed levels of PVR elevation during hypoxia. The vascular structure from pulmonary arteries to capillaries is represented using scaling laws. Vessel segments are modeled as resistive elements and blood flow rates are computed from physical principles. Direct vascular responses to intravascular oxygen levels have been proposed as a mechanism of HPV. In the lung, significant changes in oxygen level occur only in vessels less than 60 µm in diameter. The model shows that observed levels of hypoxic vasoconstriction in these vessels alone cannot account for the elevation of PVR associated with HPV. However, the elevation in PVR associated with HPV can be accounted for if larger upstream vessels also constrict. These results imply that upstream signaling by conducted responses to engage constriction of arterioles plays an essential role in the elevation of PVR during HPV.NEW & NOTEWORTHY A theoretical model of the pulmonary vasculature is used to predict the effects of vasoconstriction over specified ranges of vessel diameters on pulmonary vascular resistance (PVR). The model shows that observed levels of hypoxic vasoconstriction in terminal vessels cannot account for the elevation of PVR associated with hypoxic pulmonary vasoconstriction (HPV). Upstream signaling by conducted responses to engage constriction of arterioles, therefore, plays an essential role in the elevation of PVR during HPV.

Multimodal guided wave inversion for arterial stiffness: methodology and validation in phantoms.

Arterial stiffness is an important biomarker for many cardiovascular diseases. Shear wave elastography is a recent technique aimed at estimating local arterial stiffness using guided wave inversion (GWI), i.e. matching the computed and measured wave dispersion. This paper develops and validates a new GWI approach by synthesizing various recent observations and algorithms: (a) refinements to signal processing to obtain more accurate experimental dispersion curves; (b) an efficient forward model to compute theoretical dispersion curves for immersed, incompressible cylindrical waveguides; (c) an optimization framework based on the recent observation that the measured dispersion curve is multimodal, i.e. it matches for not one but two different wave modes in two different frequency ranges. The resulting inversion approach is validated using extensive experimental data from rubber tube phantoms, not only for modulus estimation but also to simultaneously estimate modulus and wall thickness. The observations indicate that the modulus estimates are best performed with the information on wall thickness. The approach, which takes less than half a minute to run, is shown to be accurate, with the modulus estimated with less than 4% error for 70% of the experiments.