Pressure Catheter Research Articles

Clinical, Experimental, and Computational Validation of a New Doppler-Based Index for Coarctation Severity Assessment

Long-term morbidity including hypertension often persists in coarctation patients despite current guidelines. Coarctation severity can be invasively assessed via peak-to-peak catheter pressure gradient (PPCG), which is estimated noninvasively via simplified Bernoulli equation and conventionally reported as peak instantaneous Doppler gradient (PIDG). However, underlying simplifications of the equation limit diagnostic accuracy. We studied the diagnostic performance of a new Doppler-based diastolic index called the continuous flow pressure gradient (CFPG) versus conventional indices in assessing coarctation severity. In a rabbit model mimicking human aortic coarctation, temporal blood pressure waveforms revealed the diastolic instantaneous pressure gradients and spectral Doppler features impacted by coarctation severity. We therefore hypothesized that CFPG provides superior correlation with coarctation gradients measured invasively. PIDG and CFPG were quantified using color flow echocardiography in humans and rabbits with discrete coarctations. Results were compared with PPCG in rabbits (n=34) and arm-leg systolic gradients (n=25) in humans via 1-way analysis of variance, Pearson's correlation, linear regression, and Bland-Altman analysis. A threshold of CFPG ≥ 4.6mm Hg was identified via the Youden index as representative of PPCG ≥ 20mm Hg (the current guideline value for coarctation intervention) in rabbits, while a CFPG ≥1.0mm Hg represented an arm-leg systolic gradient ≥20mm Hg in humans. Accuracy measures revealed superior correlation of CFPG (R2>0.80) and mild receiver operating characteristic improvement (area under the receiver operating characteristic curve, 0.94-0.95) compared with PIDG (R2<0.63; area under the receiver operating characteristic curve, 0.89-0.95). Inter-/intraobserver variability tested by intraclass correlation coefficient revealed measurement reliability with differences ≤8.2% and 10.7%, respectively. Computational simulations of anesthetized versus conscious hemodynamics showed parameters were minimally impacted by isoflurane inherent in the dataused to derive CFPG. These results confirm the potential diagnostic accuracy of CFPG in echocardiography-based coarctation severity assessment. We are optimistic that CFPG will be useful for translation of results from preclinical studies that revisit current guidelines to limit morbidity in humans with aortic coarctation.

Comparison of Stroke Volume Variation-based goal-directed Therapy Versus Standard Fluid Therapy in Patients Undergoing Head and Neck Surgery: A Randomized Controlled Study

Background:Perioperative fluid therapy is used to avoid dehydration and hypovolemia. Optimum perioperative fluid administration may improve postoperative outcomes after major surgery, and the optimal strategy remains controversial and uncertain.Aims:The primary outcome was the total amount of intraoperative fluids given between perioperative goal-directed fluid therapy (GDFT) guided by a hemodynamic monitoring system and standard fluid therapy based on “mean arterial pressure-diuresis” data in patients undergoing head and neck surgery. The secondary outcomes were the hemodynamics and laboratory variables, postoperative complications, length of mechanical ventilation, intensive care unit and hospital stay.Study Design:A randomized controlled study.Methods:Sixty patients were scheduled and randomized into two groups of 30 patients each: in the study group, an arterial pressure catheter was inserted and connected to the FloTrac system, whereas in the control group, an arterial pressure catheter was inserted and integrated into the hemodynamic monitoring system with a special transducer. The control group had fluids administered at the discretion of the anesthesiologist according to the mean arterial pressure >65 mmHg and diuresis >0.5 ml/kg/h. In the study group, fluid management was administered to achieve a target value of ≤13% through the stroke volume variation.Results:The total amounts of fluid in the intraoperative period were different between the groups, with the study group receiving significantly more fluids (P = 0.0455). The length of hospital stay was significantly longer in the study group than in the control group (P = 0.012), but prolonged oxygen demand was significantly more frequent in the control group than in the study group (P = 0.017). No difference was found in hemodynamics, lactate kinetics, and vasoactive agent requirements.Conclusion:The standard fluid therapy guided by conventional circulatory parameters appears sufficient for patients with low-to-moderate risk during head and neck surgery.

In vivo measurement of intradiscal pressure changes related to thrust and non-thrust spinal manipulation in an animal model: a pilot study

BackgroundThe intervertebral disc is a known back pain generator and is frequently the focus of spinal manipulative therapy evaluation and treatment. The majority of our current knowledge regarding intradiscal pressure (IDP) changes related to spinal manual therapy involves cadaveric studies with their inherent limitations. Additional in vivo animal models are needed to investigate intervertebral disc physiological and molecular mechanisms related to spinal manipulation and spinal mobilization treatment for low back disorders.MethodsMiniature pressure catheters (Millar SPR-1000) were inserted into either the L4-L5 or L5-L6 intervertebral disc of 3 deeply anesthetized adult cats (Oct 2012-May 2013). Changes in IDP were recorded during delivery of instrument-assisted spinal manipulation (Activator V® and Pulstar®) and motorized spinal flexion with/without manual spinous process contact.ResultsMotorized flexion of 30° without spinous contact decreased IDP of the L4-L5 disc by ~ 2.9 kPa, while physical contact of the L4 spinous process decreased IDP an additional ~ 1.4 kPa. Motorized flexion of 25° with L5 physical contact in a separate animal decreased IDP of the L5-L6 disc by ~ 1.0 kPa. Pulstar® impulses (setting 1–3) increased IDP of L4-L5 and L5-L6 intervertebral discs by ~ 2.5 to 3.0 kPa. Activator V® (setting 1–4) impulses increased L4-L5 IDP to a similar degree. Net changes in IDP amplitudes remained fairly consistent across settings on both devices regardless of device setting suggesting that viscoelastic properties of in vivo spinal tissues greatly dampen superficially applied manipulative forces prior to reaching deep back structures such as the intervertebral disc.ConclusionsThis study marks the first time that feline in vivo changes in IDP have been reported using clinically available instrument-assisted spinal manipulation devices and/or spinal mobilization procedures. The results of this pilot study indicate that a feline model can be used to investigate IDP changes related to spinal manual therapy mechanisms as well as the diminution of these spinal manipulative forces due to viscoelastic properties of the surrounding spinal tissues. Additional investigation of IDP changes is warranted in this and/or other in vivo animal models to provide better insights into the physiological effects and mechanisms of spinal manual therapy at the intervertebral disc level.

Characterization of the mesenteric circulatory physiology during hemorrhagic shock in a swine model

This study aimed to characterize blood flow through the mesenteric circulation during hemorrhage and resuscitation in a large animal model. Five male swine (50-70 kg) underwent anesthesia and placement of flow probes and pressure catheters around and within the superior mesenteric artery, portal vein, and inferior vena cava. A laser doppler flow probe was placed on the intestine to measure end-organ perfusion. Animals were then exsanguinated to a systolic blood pressure of <50mmHg with 60-minutes of shock followed by resuscitation for 120-minutes. Animals were placed into hemorrhagic shock (lactate peak 5.9 ± 2.1 mmol/L vs baseline: 3.4 ± 0.7 mmol/L) with lower pressures and flows during shock and restoration to baseline following resuscitation: SMA (70 vs 36 vs 75 mmHg, p<0.001; 856 vs 371 vs 762 mL/min, p<0.001), portal vein (9 vs 8 vs 10mmHg, p<0.001; 200 vs 52 vs 141 mL/min, p<0.001), IVC (12 vs 7 vs 10 mmHg, p<0.001; 209 vs 27 vs 163 mL/min, p<0.001), and mean arterial pressure (MAP) (67 vs 36 vs 69 mmHg, p<0.001). LDF fell during hemorrhage (1.38 vs 0.38 blood perfusion units (BPU), p<0.001) and did not return to baseline during resuscitation (0.70 BPU, p<0.001). The intestine achieved only 51% of baseline LDF perfusion after resuscitation despite return of mesenteric hemodynamics. Despite macrovascular physiologic restoration after hemorrhagic shock, end organ perfusion did not adequately recover following resuscitation to baseline MAP. Continuous physiologic insult to the mesentery is likely ongoing after systemic hemodynamic restoration.

Abstract P3023: The Regulatory Role Of Mir-21 In Heart Failure With Preserved Ejection Fraction (hfpef)

Introduction: Coronary microvascular dysfunction (CMD) is characterized by impaired endothelial-dependent vasodilation. These impairments are seen in diabetic cardiomyopathy, ischemia with no obstructive coronary artery disease, and heart failure with preserved ejection fraction (HFpEF), but detailed mechanisms have yet to be elucidated. Moreover, how microRNA (miR-21) regulates CMD in HFpEF is not entirely understood. Methods: miR-21 knockout and wild-type (WT) mice were fed a diet high in fat and sugar (HFHS) for 6 months and blood lipid and glucose were measured. Echocardiography and treadmill exercise exertion tests were performed to assess cardiac function. Myocardial blood flow (MBF) under stress was measured by contrast echocardiography or doppler after the treatment with different dosages of norepinephrine and mean arterial blood pressure was measured simultaneously by femoral pressure catheter. Cardiac fibrosis was detected using trichrome staining and molecular pathways were elucidated via gene and protein analysis. Results: Our preliminary data show decreased MBF during stress in WT mice fed a HFHS diet. While ejection fraction was not changed, cardiac index, stroke volume, and running distance were decreased. Furthermore, E/E’ ratio was increased in WT mice fed HFHS diet compared to the WT mice fed a chow diet, suggesting heart failure and impaired diastolic function with normal systolic function. Moreover, perivascular fibrosis was increased in the WT mice fed a HFHS diet compared to WT mice fed a chow diet. However, the ablation of miR-21 reversed all these changes in the mice fed a HFHS diet. Conclusions: miR-21 regulates CMD and ameliorated HFpEF. Further investigation will elucidate the pathways and mechanisms converging with miR-21 to regulate HFpEF.

Stress Effects on Pharyngeal Air Pressure and Upper Esophageal Sphincter Pressure During Phonation: The Influence of Vocal Tract Semi-Occlusion

The objective of this study was to determine whether vocal tract semi-occlusion (SOVT) influenced stress effects on pharyngeal air pressure and upper esophageal sphincter (UES) pressure during phonation. Relationships between dysphonia and stress are well recognized but poorly understood. Stress effects act globally on the body, and may be observed beyond intrinsic laryngeal muscles to include pharyngeal muscles and the UES, which contribute to voice modulation. Phonation with SOVT may provide resistance to stress effects on the vocal tract. We hypothesized that stress effects on pharyngeal air pressure and UES pressure would be measurable with a high-resolution, 360° pressure catheter, and that stress effects would be impacted differently by occlusal and non-occlusal phonatory tasks. Ten healthy adults performed sustained vowel tasks (comfortable /a/, and loud /a/), and SOVT tasks (bilabial fricative and straw phonation). Each task was performed during a baseline condition, and during stress induced through a cold pressor task. Pharyngeal air pressure and UES pressure were measured via high-resolution manometry. Changes in pressure between baseline and stress were compared among phonatory tasks. Stress-induced changes to UES pressure differed by phonatory task (P < 0.01). Stress increased UES pressures during vowels, but had no effect during bilabial fricative, and decreased UES pressures during straw phonation. Change in UES pressure with stress was greater for comfortable /a/ and loud /a/ than straw phonation (P=0.048 and P=0.019, respectively), and was not significantly different between comfortable /a/ or loud /a/ and bilabial fricative. Stress-induced changes in pharyngeal air pressure were not significantly different among tasks. These findings help identify possible mechanisms underlying the relationship between stress and voice, and point to the utility of SOVT tasks for training vocal tract resistance to stress. This methodology provides a foundation for measuring changes to extra-laryngeal components of the vocal tract during phonation.

Measurement of Hemodynamic Parameters and Antidepressant Activity in Hypertensive Rats Following Two Weeks Consumption of Acacia Tortilis Leaves Extract

Background: Depression is common in hypertensive patients, and monotherapy may contribute to controlling depression in hypertensive patients and improving socioeconomic outcomes. Previous studies have shown that Acacia tortilis possesses hypotensive activity. Objectives: The present study was planned to evaluate the hemodynamic activity and antidepressant effects of an ethanolic extract of Acacia tortilis leaves (ATEL) in salt-induced hypertensive rats. Methods: Sprague-Dawley rats were divided into 5 groups for experiments. The rats received respective treatment for 15 days: G1: Control (C); G2: hypertensive control (HC: high dietary salt, 4% 10ml/kg); G3-5: HC+ ATEL (50, 100, 150mg/kg respectively). Cardiac hemodynamics (mean arterial blood pressure: MAP and heart rate: HR) were measured in the anaesthetized rats by an invasive method. For this method, one carotid artery was catheterized, a pressure catheter (pressure- volume Millar microtip catheter connected to the Mikro-Tip Pressure-Volume System from Ultra Foundation Systems, PowerLab) was inserted, and the blood pressure (MAP in mm Hg) and HR (beats/min) were monitored continuously during the experiment. For the neuropharmacological studies, antidepressant activity was assessed by a forced swim test on the 15th day. Results: A dose-dependent significant increase in mobility time was observed in rats (G3-5) treated with HC + different doses of ATEL (p &lt; 0.05). However, the mobility time was significantly reduced by HC (G2) treatment compared to the control (p&lt; 0.05). The hypertensive control (high dietary salt: HC) group showed a significant increase in systolic blood pressure (SP), diastolic blood pressure (DP), MAP and HR (p&lt;0.05) compared to the control (G1) group. At all doses (50, 100, and 150 mg/kg), MAP and HR were found to decrease significantly (p&lt;0.05) compared to the values in the HC (G2) group. Further analysis revealed an improvement in heart rate variability (HRV) in ATEL-treated hypertensive rats. Conclusion: The present research suggests that increased dietary salt intake not only increases blood pressure significantly but also increases depression. ATEL contains some efficacious constituents, such as N, N-dimethyltryptamine (DMT: a 5-HT1A agonist), with predominant antidepressant and antihypertensive activity. Hence, ATEL appears to be a valuable plant extract that can be useful, at least as an adjunct, for therapy in patients who suffer from both depression and hypertension.

Use of a Pressure Wire for Automatically Correcting Artifacts in Phasic Pressure Tracings From a Fluid-Filled Catheter

Background/purposeMatching phasic pressure tracings between a fluid-filled catheter and high-fidelity pressure wire has received limited attention, although each part contributes half of the information to clinical decisions. We aimed to study the impact of a novel and automated method for improving the phasic calibration of a fluid-filled catheter by accounting for its oscillatory behavior. Methods/materialsRetrospective analysis of drift check tracings was performed using our algorithm that corrects for mean difference (offset), temporal delays (timing), differential sensitivity of the manifold transducer and pressure wire sensor (gain), and the oscillatory behavior of the fluid-filled catheter described by its resonant frequency and damping factor (how quickly oscillations disappear after a change in pressure). ResultsAmong 2886 cases, correcting for oscillations showed a large improvement in 28 % and a medium improvement in 41 % (decrease in root mean square error >0.5 mmHg to <1 or 1-2 mmHg, respectively). 96 % of oscillators were underdamped with median damping factor 0.27 and frequency 10.6 Hz. Fractional flow reserve or baseline Pd/Pa demonstrated no clinically important bias when ignoring oscillations. However, uncorrected subcycle non-hyperemic pressure ratios (NHPR) displayed both bias and scatter. ConclusionsBy automatically accounting for the oscillatory behavior of a fluid-filled catheter system, phasic matching against a high-fidelity pressure wire can be improved compared to standard equalization methods. The majority of tracings contain artifacts, mainly due to underdamped oscillations, and neglecting them leads to biased estimates of equalization parameters. No clinically important bias exists for whole-cycle metrics, in contrast to significant effects on subcycle NHPR.

Effect of inotropic agents on oxygenation and cerebral perfusion in acute brain injury.

IntroductionTissue hypoxia and insufficient energy delivery is one of the mechanisms behind the occurrence of several complications in acute brain injured patients. Several interventions can improve cerebral oxygenation; however, the effects of inotropic agents remain poorly characterized.MethodsRetrospective analysis including patients suffering from acute brain injury and monitored with brain oxygen pressure (PbtO2) catheter, in whom inotropic agents were administered according to the decision of the treating physician's decision; PbtO2 values were collected before, 1 and 2 h after the initiation of therapy from the patient data monitoring system. PbtO2 “responders” were patients with a relative increase in PbtO2 from baseline values of at least 20%.ResultsA total of 35 patients were included in this study. Most of them (31/35, 89%) suffered from non-traumatic subarachnoid hemorrhage (SAH). Compared with baseline values [20 (14–24) mmHg], PbtO2 did not significantly increase over time [19 (15–25) mmHg at 1 h and 19 (17–25) mmHg at 2 h, respectively; p = 0.052]. A total of 12/35 (34%) patients were PbtO2 “responders,” in particular if low PbtO2 was observed at baseline. A PbtO2 of 17 mmHg at baseline had a sensibility of 84% and a specificity of 91% to predict a PbtO2 responder. A significant direct correlation between changes in PbtO2 and cardiac output [r = 0.496 (95% CI 0.122 to 0.746), p = 0.01; n = 25] and a significant negative correlation between changes in PbtO2 and cerebral perfusion pressure [r = −0.389 (95% CI −0.681 to −0.010), p = 0.05] were observed.ConclusionsIn this study, inotropic administration significantly increased brain oxygenation in one third of brain injured patients, especially when tissue hypoxia was present at baseline. Future studies should highlight the role of inotropic agents in the management of tissue hypoxia in this setting.

A Novel, Cardiac-Derived Algorithm for Uterine Activity Monitoring in a Wearable Remote Device.

Background: Uterine activity (UA) monitoring is an essential element of pregnancy management. The gold-standard intrauterine pressure catheter (IUPC) is invasive and requires ruptured membranes, while the standard-of-care, external tocodynamometry (TOCO)’s accuracy is hampered by obesity, maternal movements, and belt positioning. There is an urgent need to develop telehealth tools enabling patients to remotely access care. Here, we describe and demonstrate a novel algorithm enabling remote, non-invasive detection and monitoring of UA by analyzing the modulation of the maternal electrocardiographic and phonocardiographic signals. The algorithm was designed and implemented as part of a wireless, FDA-cleared device designed for remote pregnancy monitoring. Two separate prospective, comparative, open-label, multi-center studies were conducted to test this algorithm. Methods: In the intrapartum study, 41 laboring women were simultaneously monitored with IUPC and the remote pregnancy monitoring device. Ten patients were also monitored with TOCO. In the antepartum study, 147 pregnant women were simultaneously monitored with TOCO and the remote pregnancy monitoring device. Results: In the intrapartum study, the remote pregnancy monitoring device and TOCO had sensitivities of 89.8 and 38.5%, respectively, and false discovery rates (FDRs) of 8.6 and 1.9%, respectively. In the antepartum study, a direct comparison of the remote pregnancy monitoring device to TOCO yielded a sensitivity of 94% and FDR of 31.1%. This high FDR is likely related to the low sensitivity of TOCO. Conclusion: UA monitoring via the new algorithm embedded in the remote pregnancy monitoring device is accurate and reliable and more precise than TOCO standard of care. Together with the previously reported remote fetal heart rate monitoring capabilities, this novel method for UA detection expands the remote pregnancy monitoring device’s capabilities to include surveillance, such as non-stress tests, greatly benefiting women and providers seeking telehealth solutions for pregnancy care.

Development of a Pleural Pressure Catheter via Continuous Fiberoptic Esophageal Pressure Measurements.

There is growing research showing the importance of measuring esophageal pressure as a surrogate for pleural pressure for patients on mechanical ventilators. The most common measurement method uses a balloon catheter, whose accuracy can vary based on patient anatomy, balloon position, balloon inflation, and the presence of other tubes in the esophagus. The authors present the development and initial testing results of a new combination catheter, utilizing fiberoptic pressure sensing to provide more accurate esophageal pressure measurements and allowing for the incorporation of a feeding tube and temperature sensor.

P-076 Standard IV cannula aspiration of testicular sperm: A novel, efficient and minimally invasive aspiration technique

Abstract Study question Can we aspirate enough testicular tissue for sperm retrieval in non-obstructive azoospermia (NOA), using a wide bore 14-G Standard IV cannula in comparison to micro-TESE? Summary answer Standard IV cannula Aspiration (SIVCA) can yield an ample amount of testicular tissue sufficient for sperm retrieval through a single puncture site on the scrotum. What is known already The current conventional method of testicular sperm aspiration is fine needle aspiration (FNA). FNA has the advantage of being a cost-effective and minimally invasive procedure compared to open testicular sperm extraction (TESE). But FNA with its conventional 23-G needle may not always yield enough testicular tissue for sperm retrieval. Furthermore, FNA may require multiple punctures on the scrotum to retrieve enough tissues from different areas of the testis. Study design, size, duration A 24 months prospective cohort study conducted at a specialized IVF center. A total of 130 men aged from 22 to 53 years old (35.03 +/- 9.04) with NOA and normal testicular volume (≥ 12ml) were enrolled in the study. The men had testicular biopsies taken at the day of their partners’ ovum pick-up. On each patient, the testes were randomized to undergo SIVCA on one testis followed by micro-TESE on the contralateral testis. Participants/materials, setting, methods After local anesthesia, a wide bore 14-G standard IV cannula was introduced near the lower pole of the testis. The needle was withdrawn and the catheter introduced into the testicular tissue. A 20-ml syringe was secured to the catheter and constant negative pressure applied and secured with a clamp. Back and forth motions were performed covering as many areas of the testis as possible. Micro-TESE was then performed on the contralateral testis. Main results and the role of chance Sperm retrieval rates (SRR) were compared between the two techniques using McNemar χ2 test. A P-value of less than 0.05 was considered to be statistically significant. Out of a total of 130 cases, an adequate tissue sample could successfully be aspirated using SIVCA in 122 cases, showing a 0.93 probability of success. In those 8 cases where SIVCA had not yielded sufficient tissue and were reverted to micro-TESE, 2 cases were positive for sperm retrieval. Whenever tissue aspiration was successful with both methods, both SIVCA and micro-TESE showed similar success rate with respect to SRR (56.2 vs 57.3%; McNemar P = 1.000). Limitations, reasons for caution Both FNA and SIVCA are not easy to perform on small sized testes. Moreover if testicular tissue is fibrotic or sclerotic, it may be difficult to aspirate and micro-TESE would be the ideal choice to yield enough testicular tissue. Further blinded randomized control studies with larger datasets are recommended. Wider implications of the findings The use of a peripheral IV wide bore cannula is suitable for the aspiration of adequate amounts of testicular tissue for sperm searching whilst requiring only a single puncture on the scrotum. We recommend routinely starting off with SIVCA to search for sperm before reverting to micro-TESE. Trial registration number Unique Protocol ID: SIVCA Protocol registration Records number will be made available to the public through the ClinicalTrials.gov web site within 2 to 5 days of today 31/1/2022

Constant Pressure Convection-Enhanced Delivery Increases Volume Dispersed With Catheter Movement in Agarose.

Convection-enhanced delivery (CED) has been extensively studied for drug delivery to the brain due to its inherent ability to bypass the blood-brain barrier. Unfortunately, CED has also been shown to inadequately distribute therapeutic agents over a large enough targeted tissue volume to be clinically beneficial. In this study, we explore the use of constant pressure infusions in addition to controlled catheter movement as a means to increase volume dispersed (Vd) in an agarose gel brain tissue phantom. Constant flow rate and constant pressure infusions were conducted with a stationary catheter, a catheter retracting at a rate of 0.25 mm/min, and a catheter retracting at a rate of 0.5 mm/min. The 0.25 mm/min and 0.5 mm/min retracting constant pressure catheters resulted in significantly larger Vd compared to any other group, with a 105% increase and a 155% increase compared to the stationary constant flow rate catheter, respectively. These same constant pressure retracting infusions resulted in a 42% and 45% increase in Vd compared to their constant flow rate counterparts. Using constant pressure infusions coupled with controlled catheter movement appears to have a beneficial effect on Vd in agarose gel. Furthermore, constant pressure infusions reveal the fundamental limitation of flow-driven infusions in both controlled catheter movement protocols as well as in stationary protocols where maximum infusion volume can never be reliably obtained.

Abstract 1042: Fc3TSR improves intratumoral treatment delivery by normalizing tumor vasculature and reducing interstitial fluid pressure in an orthotopic, syngeneic mouse model of epithelial ovarian cancer

Abstract A hallmark of solid tumors is the need for vascularization to supply oxygen and nutrients. Aggressive pro-angiogenic signals induced by tumors lead to malformation of vessels characterized by reduced pericyte coverage and low perfusion. As a result of this vascular dysfunction, tumors have elevated hypoxia and high interstitial fluid pressure (IFP), yielding an aggressive phenotype, and reducing efficacy and trafficking of intravenous therapies to the tumor core. Anti-angiogenic therapies aim to reduce angiogenic stimuli and normalize tumor vessels. The three type-1-repeat (3TSR) region of thrombospondin-1 contains the majority of its anti-angiogenic properties in a small bioactive peptide. These functions are mediated through the membrane protein, CD36. We have previously shown that administration of native 3TSR leads to improved tumor perfusion, and enhancing delivery of chemotherapy drugs and oncolytic viruses. We have developed a novel compound, Fc3TSR, that has two 3TSR peptides linked with a Fc to increase in vitro and in vivo efficacy. In an orthotopic, mouse model of ovarian cancer, we examined the effect of Fc3TSR treatment on tumor IFP using a 1.2Fr pressure catheter guided into the tumor core of anesthetized mice. Compared to untreated controls, mice treated with Fc3TSR had significantly lower IFP, even after considering differences in heart rate among animals. Immunofluorescence on fixed sentinel lymph nodes revealed enhanced presence of immune cells, a positive predictor of lymphatic patency. To determine impact on chemotherapy delivery, mice were injected with 40mCi paclitaxel and tumor uptake of the isotope was measured. At 12, 24 and 48h post injection, Fc3TSR treated tumors had significantly increased uptake of paclitaxel compared to untreated or 3TSR treated mice. In vitro cell viability assays and western blot analysis of cleaved-caspase-3 revealed that Fc3TSR enhances direct apoptosis in human ovarian cell lines (OVCAR-2 and 36M2) compared to untreated cells or those treated with native 3TSR at equimolar concentrations. In a human subcutaneous xenograft model using 36M2 cells in SCID mice, Fc3TSR significantly reduced tumor volume as a single agent compared to PBS controls.Fc3TSR causes direct ovarian tumor cell apoptosis in vitro and significant anti-tumor effects in vivo. In vivo, Fc3TSR causes potent vascular normalization, decreases tumor hypoxia and IFP in the tumor core. As such, Fc3TSR has the potential to remodel multiple aspects of the tumor microenvironment which would otherwise obstruct treatment delivery and efficacy in solid tumors. The multi-modal aspects of Fc3TSR makes this therapeutic approach attractive for the treatment of advanced ovarian cancer and other malignancies that typically overcome single-agent therapy. Citation Format: Kathy Matuszewska, Madison Pereira, Leslie Ogilvie, Duncan Petrik, Allison Gartung, Dipak Panigrahy, Kin-Ming Lo, Jack Lawler, Jeremy Simpson, Jim Petrik. Fc3TSR improves intratumoral treatment delivery by normalizing tumor vasculature and reducing interstitial fluid pressure in an orthotopic, syngeneic mouse model of epithelial ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1042.

An EHG-based Preterm Delivery Prediction Algorithm via Convolution Neural Network

Premature delivery is one of the direct factors that affect the early development and safety of infants. Its direct clinical manifestation is the change of uterine contraction intensity and frequency. Uterine Electrohysterography(EHG) signal collected from the abdomen of pregnant women can accurately and effectively reflect the uterine contraction, which has higher clinical application value than invasive monitoring technology such as intrauterine pressure catheter. Therefore, the research of fetal preterm birth recognition algorithm based on EHG is particularly important for perinatal fetal monitoring. We proposed a convolution neural network(CNN) based on EHG fetal preterm birth recognition algorithm, and a deep CNN model was constructed by combining the Gramian angular difference field(GADF) with the transfer learning technology. The structure of the model was optimized using the clinical measured term-preterm EHG database. The classification accuracy of 94.38% and F1 value of 97.11% were achieved. The experimental results showed that the model constructed in this paper has a certain auxiliary diagnostic value for clinical prediction of premature delivery.

Diaphragm muscle function in a mouse model of early-onset spasticity.

Spasticity is a common symptom in many developmental motor disorders, including spastic cerebral palsy (sCP). In sCP, respiratory dysfunction is a major contributor to morbidity and mortality, yet it is unknown how spasticity influences respiratory physiology or diaphragm muscle (DIAm) function. To investigate the influence of spasticity on DIAm function, we assessed in vivo transdiaphragmatic pressure (Pdi - measured using intraesophageal and intragastric pressure catheters under conditions of eupnea, hypoxia/hypercapnia and occlusion) including maximum Pdi (Pdimax via bilateral phrenic nerve stimulation), ex vivo DIAm-specific force and fatigue (using muscle strips stimulated with platinum plate electrodes), and type-specific characteristics of DIAm fiber cross sections (using immunoreactivity against myosin heavy chain slow and 2A) in spa and wildtype mice. Spa mice show reduced Pdimax, reduced DIAm specific force, and altered fatigability and atrophy of type IIx/IIb fibers. These findings suggest marked DIAm dysfunction may underlie the respiratory phenotype of sCP.NEW & NOTEWORTHY Developmental motor control dysfunctions, including spastic cerebral palsy (sCP) often have respiratory components. Spa mutant mice exhibit a spastic phenotype closely resembling sCP symptoms. Using the spa mouse model of spastic cerebral palsy (sCP), we quantified transdiaphragmatic pressure deficits, diaphragm muscle weakness, and fiber type-specific atrophy, improving our understanding of respiratory dysfunctions in sCP.

Soft silicone‐based neural interface to modulate bladder function: chronic studies in awake behaving cats

Direct bladder wall stimulation has been attempted for decades to restore bladder function in people with spinal cord injury and other voiding dysfunctions. However, these efforts were limited by co‐activation of the urethra, legs and other pelvic organs at stimulus intensities that evoked bladder contractions. Neural interfaces for the detrusor muscle itself face several challenges due to its structure and the volume changes it undergoes in normal function. We designed a stretchable silicone net that can be placed around the bladder body to anchor a soft electrode array that interfaces directly with the base of bladder to generate bladder contractions.We created implantable versions of the electrode nets and tested them in chronic experiments. We implanted 5 healthy cats (4 females, 1 male) and tested them with and without anesthesia for 2‐3 months. A pressure catheter was implanted into the bladder to control volume and measure pressure.Bladder wall stimulation through various electrode configurations (monopolar, bipolar), temporal patterns (single electrode, sequential stimulation of multiple electrodes) and stimulus intensities were able to generate complete bladder emptying. In behaving cats, bladder wall stimulation at many different stimulus intensities elicited efficient voiding at physiological bladder pressures (med: 41, IQR: 27‐60 cmH2O). However, there was little relationship (r&lt;0.28) between stimulation amplitude and bladder pressure itself. Rather, stimulation amplitude had an effect on the time between stimulation onset and bladder contraction onset. At low stimulation amplitudes, there was a longer time between stimulation onset and voiding (med: 35s, IQR: 13.5‐68.2s) than occurred at higher amplitudes, which evoked more rapid voiding (med: 23s, IQR: 10‐45s). This contrasts with anesthetized tests, where stimulation at 3 ± 2 mA evoked increases in bladder pressure up to 35 cmH2O. These results suggest that stimulation of the bladder wall recruits sensory pathways leading to an urge to void, but that can be suppressed by the animals. For most of the duration of the implants, stimulation evoked functional voiding with consistent electrical stimulation thresholds. However, after several months there was a failure of an implanted bond that limited the overall duration of the implants.Chronic experiments demonstrate that these electrode nets can be used as a neural interface to generate or initiate comfortable, complete bladder emptying in awake behaving cats. Future efforts include understanding the effects of evoked sensations on voiding and improving the integrity of the bonding between the flexible conductors and the lead wire.

Continuous Ultrasonic Transit‐Time Blood Flow and Arterial Blood Pressure Monitoring in Freely Moving Sprague‐Dawley Rats via Implantable Telemetry

BACKGROUNDSimultaneous blood flow and pressure measurements provide a more comprehensive hemodynamic assessment in cardiovascular studies. However, current cardiac output (CO) measurements, by flow probes or imaging, require either anesthesia or a tethered setup, which result in limitations due to anesthesia effects and/or monitoring time.OBJECTIVEThe objective of this study was to use an implantable telemetry device (EndoGear (EG), Transonic Systems Inc., Ithaca, NY) to measure continuous CO (real‐time ascending aortic blood flow), and mean arterial pressure (MAP) in conscious, freely moving rats and to verify the ability of the system to capture well‐known circadian oscillations in major cardiovascular parameters.METHODSAll procedures were approved by the Institutional Animal Care and Use Committee of Wayne State University and complied with the NIH Guide for the Care and Use of Laboratory Animals. Male Sprague‐Dawley rats were implanted with EG transmitters to continuously monitor CO, MAP, temperature, and activity for 5 weeks. An ultrasonic transit‐time flow probe was placed around the ascending aorta via a right lateral thoracotomy (4th intercostal space). The pressure catheter was inserted into the iliac artery and advanced (approximately 2.5 cm) into the abdominal aorta, while the transmitter was implanted intraperitoneally via a midline laparotomy approach. The inductive power receiver associated with the implant was positioned in an abdominal subcutaneous pocket. After surgery, rats received thermal support, prophylactic analgesics, and antibiotics, as well as fluid supplementation. Body weight, food and fluid intake were monitored daily for the first 10 days and then bi‐weekly until the end of the study. Animal checks and necessary handling were conducted at specific times to minimize circadian disturbances.RESULTSChanges in MAP, heart rate (HR, captured from pressure and flow traces), CO, stoke volume (SV, calculated as CO/HR), and temperature revealed, as expected, a clear circadian pattern characterized by lower values during the light phase. MAP decreased by ~5%, from 96.9 ± 0.15 to 92.1 ± 0.19 mmHg (p&lt;0.05). HR decreased by ~10%, from 369 ± 3 to 329 ± 6 bpm (p&lt;0.05). CO decreased by ~14%, from 91.6 ± 1.79 to 78.4 ± 1.89 ml/min (p&lt;0.05). SV decreased by ~7%, from 245 ± 3.5 to 238 ± 1.4 μl (p&lt;0.05). The decreases in temperature and activity during the light phase were subtle yet significant.CONCLUSIONSThe telemetry device was able to effectively measure continuous changes in CO and MAP. Preservation of the circadian rhythm indicates favorable post‐operative outcome after extensive surgery and complex chronic implantation in rats.

Disease Associated Microglia Is Identified As A Major Contributor To Neuroinflammation Associated To Chronic Hypoxia Induced‐Pulmonary Hypertension

IntroductionPulmonary hypertension (PH) is a progressive disease that leads to right heart failure and death. Increased sympathetic activity in PH patients is associated with a worse prognosis due to a series of well‐established downstream sequelae. However, the mechanism behind chronic elevation in sympathetic activity in PH is poorly understood. Our fundamental hypothesis is that neuroinflammation in the hypothalamic paraventricular nucleus (PVN) is essential for elevated sympathetic activity in PH. This hypothesis is supported by our published data demonstrating: 1) increased number of microglia in the PVN is observed in multiple animal models of PH; 2) Microglia inhibition attenuates sympathetic activity and PH cardiopulmonary effects. However, microglia are, a heterogeneous with respect to gene expression and function. Indicating that characterization of the specific microglia subtypes involved in PH pathophysiology would be the key to identify possible targets to improve PH therapy.Methods3‐months‐old SD rats were subjected to monocrotaline induced PH model. After 28 days, CD45+CD11b+ cells were isolated from the PVN followed by single‐cell RNA Sequencing (scRNA Seq) analysis. The disease associated microglia (DAM), which highly express Trem2, displayed the most significant phenotypic changes in PH. 3‐months‐old WT mice (n=12/group) were exposed to chronic hypoxia induced‐PH (CH‐PH) (10%O2) or Normoxia for 4 weeks in a ventilated chamber. CD45+CD11b+ cells were isolated from the PVN to evaluate TREM2 expression by flow cytometry in the same population. Then, TREM2 global knock‐out mice (TREM2‐KO) and WT (n=10/group) were exposed to CH‐PH model and pulmonary hemodynamics were evaluated using a Millar pressure catheter in a terminal procedure.ResultsWe identified 10 clusters as microglia/macrophage. Following evaluation of several cluster markers used to identify microglia subtypes, we found the cluster with the most significant differences in gene profile and biological processes by comparing control and PH samples. This cluster was identified as the disease‐associated microglia (DAM), characterized by high expression of TREM2. Data was also confirmed in chronic hypoxia induced PH (CH‐PH) model by flow cytometry. CH induced a two‐fold increase of TREM2+microglia (CD11+, CD45+, TMEM119+) expression compared to normoxia controls. Fascinatingly, TREM2 deficient mice demonstrated a significant attenuation in the pulmonary pressure, represented by its surrogate the right ventricular systolic pressure (RVSP), and remarkably, reduction in overall lung inflammation induced by hypoxia.ConclusionsWhile TREM2 contribution has been extensively studied in neurodegenerative diseases and cancer therapy, these experiments are the first to demonstrate the potential of Trem2 targeted therapy in context of PH. Moreover, we believe that data generated from these studies may lead to translational studies evaluating the potential of TREM2 as a therapeutic target for PH.

Hypertensive Dahl Salt‐Sensitive Rats Demonstrate a Reduction in Central Blood Pressure Following the Short‐Term Treatment with Ivabradine and Spironolactone

IntroductionA proper management of central blood pressure (cBP) has been recently recognized as a novel therapeutic target to reduce cardiovascular risks among hypertensive (HT) patients. Considering that the hypotensive action of most antihypertensive drugs does not persist after treatment interruption, the search for compounds which would permanently reduce the level of cBP remains vital. It has been previously reported that a mineralocorticoid receptor antagonist spironolactone (SL) as well as a “pure” heart rate lowering drug ivabradine (IVA) can both affect the level of cBP and cardiac structure in hypertension.HypothesisIt was hypothesized that combined treatment with SL and IVA could permanently reduce cBP in chronically HT animals via alterations in myocardial properties.MethodsSelf‐sustaining hypertension was induced in 20 male (seven‐week‐old) Dahl salt‐sensitive rats by feeding them a high‐salt (HS) diet (8% NaCl) for 7 weeks. Then all HT rats were switched back to a normal‐salt (NS) diet (0.3% NaCl) and randomized in two experimental groups to receive ether a combined treatment (HT‐T) with IVA (10 mg/kg/day) and SL (20 mg/kg/day) or the vehicle alone (HT‐V) for 8 weeks via intraperitoneal ALZET osmotic pumps. The ten age‐matched male rats fed a NS diet only were used as normotensive controls (NT‐C). Heart rate and peripheral blood pressure were evaluated every week in conscious rats using a CODA tail‐cuff plethysmography system. One week following treatment termination, the central (aortic) and cardiac hemodynamic parameters were assessed in anesthetized rats using an intravascular/intracardiac Millar micro‐tip pressure catheter and a PowerLab data acquisition system. Subsequently, rats were euthanized, and their hearts were excised, weighed and processed to paraffin for histology and quantitative morphology.ResultsAfter 7 weeks on a HS diet, all experimental rats had markedly elevated mean arterial pressure (MAP) and heart rate. Subsequent replacement of a HS diet with a NS diet did reduce the level of MAP by ~12%, but in both HT groups it remained significantly higher than in NT‐C rats throughout the rest of the study on average by ~27% (P≤0.001). On the other hand, during eight weeks of treatment, heart rate was persistently reduced only in HT‐T rats on average by ~38% and ~27% (P≤0.001) compared to HT‐V and NT‐C groups, respectively. At the end of the study, the invasive hemodynamic measurements showed that although cBP remained markedly elevated in all HT rats compared to a NT‐C group, the level of cBP in HT‐T rats was significantly lower than that in HT‐V group (149.4±4.3 vs. 167.5±3.3 mmHg in MAP, P≤0.01). Moreover, a reduction in cBP among HT‐T rats was associated with decreased left ventricular (LV) contractility and delayed active relaxation as compared to HT‐V rats. At the same time, histological examination of the hearts has confirmed that sustained hypertension caused significant LV hypertrophy (P≤0.001) and myocardial fibrosis (P≤0.01) in both HT groups. Most important, compared to a HT‐V group, the HT‐T rats had thicker LV free wall (3.20±0.06 vs. 2.94±0.11 mm, P≤0.05) and a markedly higher myocardial density of monocytes/macrophages (228.8±12.5 vs 62.4±7.1 CD68‐positive cells/mm2, P≤0.0001).ConclusionOur findings demonstrated that concurrent treatment of chronically HT rats with IVA and SL led to a sustained reduction in cBP and that such hypotensive effect was associated with ongoing myocardial remodeling in treated animals.