Review of Systemic Mock Circulation Loops for Evaluation of Implantable Cardiovascular Devices and Biological Tissues.

CLINICAL IMPACT: On needs-based ex vivo monitoring of implantable devices or tissues/organs in cardiovascular simulators provides new insights and paves new paths for device prototypes. The insights gained could not only support the needs of patients, but also inform engineers, scientists and clinicians about undiscovered aspects of diseases (during routine monitoring). We analyze seminal and current work and highlight a variety of opportunities for developing preclinical tools that would improve strategies for future implantable devices. Holistically, mock circulation loop studies can bridge the gap between in vivo and in vitro approaches, as well as clinical and laboratory settings, in a mutually beneficial manner.

Development, evaluation, pharmacokinetic and biodistribution estimation of resveratrol-loaded solid lipid nanoparticles for prostate cancer targeting.

BACKGROUND AND AIM: The study was to extend systemic circulation and biological half-life (t1/2) of trans-resveratrol (RSV) using solid lipid nanoparticles (RSV-SLN) to improve its anti-cancer potential. METHODS: RSV-SLN was prepared by solvent emulsification evaporation technique and proceeded for evaluation like particle size, PDI, zeta potential, in vitro release, in vitro cytotoxicity, cellular internalisation, haemolysis and erythrocyte membrane integrity, platelet aggregation and pharmacokinetic studies in rats. Moreover, cancer cells accumulation of RSV-SLN also needs to be evaluated for proving their targeting ability. RESULT: Prepared SLN showed 126.85 ± 12.09 nm particle size, -24.23 ± 3.27 mV Zeta potential and 74.67 ± 4.76%. release at 48 h and haemocompatible. The cellular internalisation image showed the SLN reach in a cytoplasm and nucleus of PC3 prostate cells. RSV-SLN exhibited high t1/2 (8.22 ± 1.36 h) and 7.19 ± 0.69 h MRT (Mean residence time) and lower clearance i.e. 286.42 ± 13.64 mL/min/kg. The bio-distribution of RSV-SLN was found to be extremely high in prostate cells and accumulate 7.56 times greater than that of RSV solution. CONCLUSION: The developed RSV-SLN can be applied as potential carrier for delivery of drug of chemotherapeutics at an extend systemic circulation and targeting efficiency at tumour site.

The cardiovascular system and associated disorders.

The cardiovascular system, consisting of the heart as the 'pump' and the vascular network of blood vessels, is responsible for the distribution of blood around the body. Oxygen molecules attach to haemoglobin in red blood cells and are transported around the body where the oxygen aids cellular metabolism. Any blockage in the blood vessels as a result of build-up of plaques in the endothelium layer would result in an interruption in blood supply and therefore oxygen deprivation (ischaemia). This would lead to necrosis of the distal area of the affected vessel and is known as an infarct. This article aims to describe the normal anatomy and physiology of the cardiovascular system and to explain some of the common associated disorders, with a brief guide to the management of a common heart disorder, myocardial infarction. A case study is included to enhance the knowledge of management of myocardial infarction. An in-depth knowledge and understanding of the cardiovascular system and its associated disorders will enable the nurse to safely assess a patient, recognise a deteriorating patient and seek early intervention.

Circulating extracellular vesicles induce monocyte dysfunction and are associated with sepsis and high mortality in cirrhosis.

BACKGROUND: Sepsis is common in cirrhosis and is often a result of immune dysregulation. Specific stimuli and pathways of inter-cellular communications between immune cells in cirrhosis and sepsis are incompletely understood. Immune cell-derived extracellular vesicles (EV) were studied to understand mechanisms of sepsis in cirrhosis. METHODS: Immune cell-derived EV were measured in cirrhosis patients [Child-Turcotte-Pugh (Child) score A, n = 15; B n = 16; C n = 43 and Child-C with sepsis (n = 38)], and healthy controls (HC, n = 11). In vitro and in vivo functional relevance of EV in cirrhosis and associated sepsis was investigated. RESULTS: Monocyte, neutrophil and hematopoietic stem cells associated EV progressively increased with higher Child score (P < .001)and correlated with liver disease severity indices (r2  > 0.3, P < .001), which further increased in Child C sepsis than without sepsis(P < .001); monocyte EV showing the highest association with disease stage [P = .013; Odds ratio-4.14(1.34-12.42)]. A threshold level of monocyte EV of 53/µl predicted mortality in patients of Child C with sepsis [Odds ratio-6.2 (2.4-15.9), AUROC = 0.76, P < .01]. In vitro EV from cirrhotic with sepsis compared without sepsis, induced mobilization arrest in healthy monocytes within 4 hours (P = .004), reduced basal oxygen consumption rate (P < .001) and induced pro-inflammatory genes (P < .05). The septic-EV on adoptive transfer to C57/BL6J mice, induced sepsis-like condition within 24 h with leukocytopenia (P = .005), intrahepatic inflammation with increased CD11b + cells (P = .03) and bone marrow hyperplasia (P < .01). CONCLUSION: Extracellular vesicles induce functional impairment in circulating monocytes and contribute to the development and perpetuation of sepsis. High levels of monocyte EV correlate with mortality and can help early stratification of sicker patients.

Remodeling of Arterial Tone Regulation in Postnatal Development: Focus on Smooth Muscle Cell Potassium Channels.

Maturation of the cardiovascular system is associated with crucial structural and functional remodeling. Thickening of the arterial wall, maturation of the sympathetic innervation, and switching of the mechanisms of arterial contraction from calcium-independent to calcium-dependent occur during postnatal development. All these processes promote an almost doubling of blood pressure from the moment of birth to reaching adulthood. This review focuses on the developmental alterations of potassium channels functioning as key smooth muscle membrane potential determinants and, consequently, vascular tone regulators. We present evidence that the pattern of potassium channel contribution to vascular control changes from Kir2, Kv1, Kv7 and TASK-1 channels to BKCa channels with maturation. The differences in the contribution of potassium channels to vasomotor tone at different stages of postnatal life should be considered in treatment strategies of cardiovascular diseases associated with potassium channel malfunction.

Delivery of Orally Administered Digestible Antibodies Using Nanoparticles.

Oral administration of medications is highly preferred in healthcare owing to its simplicity and convenience; however, problems of drug membrane permeability can arise with any administration method in drug discovery and development. In particular, commonly used monoclonal antibody (mAb) drugs are directly injected through intravenous or subcutaneous routes across physical barriers such as the cell membrane, including the epithelium and endothelium. However, intravenous administration has disadvantages such as pain, discomfort, and stress. Oral administration is an ideal route for mAbs. Nonetheless, proteolysis and denaturation, in addition to membrane impermeability, pose serious challenges in delivering peroral mAbs to the systemic circulation, biologically, through enzymatic and acidic blocks and, physically, through the small intestinal epithelium barrier. A number of clinical trials have been performed using oral mAbs for the local treatment of gastrointestinal diseases, some of which have adopted capsules or tablets as formulations. Surprisingly, no oral mAbs have been approved clinically. An enteric nanodelivery system can protect cargos from proteolysis and denaturation. Moreover, mAb cargos released in the small intestine may be delivered to the systemic circulation across the intestinal epithelium through receptor-mediated transcytosis. Oral Abs in milk are transported by neonatal Fc receptors to the systemic circulation in neonates. Thus, well-designed approaches can establish oral mAb delivery. In this review, I will introduce the implementation and possibility of delivering orally administered mAbs with or without nanoparticles not only to the local gastrointestinal tract but also to the systemic circulation.

Can the Computed Tomographic Aspect of Porto-Systemic Circulation in Cirrhotic Patients be Associated with the Presence of Variceal Hemorrhage?

Background and objectives: Variceal bleeding is a serious complication caused by portal hypertension, frequently encountered among cirrhotic patients. The purpose of this study was to determine whether the aspect of the collateral, porto-systemic circulation, as detected by CT are associated with the presence variceal hemorrhage (VH). Materials and Methods: 81 cirrhotic patients who underwent a contrast-enhanced CT examination were retrospectively included in the study. Patients were divided into two groups: Cirrhotic patients with variceal hemorrhage during the hospital admission concomitant, with the CT examination (n = 33) and group 2-cirrhotic patients, without any variceal hemorrhage in their medical history (n = 48). The diameter of the left gastric vein, the presence or absence and dimensions of oesophageal and gastric varices, paraumbilical veins and splenorenal shunts were the indicators assessed on CT. Results: The univariate analysis showed a significant association between the presence of upper GI bleeding and the diameters of paraoesophageal veins, paragastric veins and left gastric vein respectively, all of these CT parameters being higher in patients with variceal bleeding. In the multivariate logistic regression analysis, only the diameter of the left gastric vein was independently associated with the presence of variceal hemorrhage (OR = 1.6 (95% CI: 1.17-2.19), p = 0.003). We found an optimal cut-off value of 3 mm for the diameter of the left gastric vein useful to discriminate among patients with variceal hemorrhage from the ones without it, with a good diagnostic performance (AUC = 0.78, Se = 97%, Sp = 45.8%, PPV = 55.2%, NPV = 95.7%).Conclusions: Our observations point out that an objective CT quantification of porto-systemic circulation can be correlated with the presence of variceal hemorrhage and the diameter of the left gastric vein can be a reliable parameter associated with this condition.

Vasopressors induce passive pulmonary hypertension by blood redistribution from systemic to pulmonary circulation.

Vasopressors are widely used in resuscitation, ventricular failure, and sepsis, and often induce pulmonary hypertension with undefined mechanisms. We hypothesize that vasopressor-induced pulmonary hypertension is caused by increased pulmonary blood volume and tested this hypothesis in dogs under general anesthesia. In normal hearts (model 1), phenylephrine (2.5 µg/kg/min) transiently increased right but decreased left cardiac output, associated with increased pulmonary blood volume (63% ± 11.8, P = 0.007) and pressures in the left atrium, pulmonary capillary, and pulmonary artery. However, the trans-pulmonary gradient and pulmonary vascular resistance remained stable. These changes were absent after decreasing blood volume or during right cardiac dysfunction to reduce pulmonary blood volume (model 2). During double-ventricle bypass (model 3), phenylephrine (1, 2.5 and 10 µg/kg/min) only slightly induced pulmonary vasoconstriction. Vasopressin (1U and 2U) dose-dependently increased pulmonary artery pressure (52 ± 8.4 and 71 ± 10.3%), but did not cause pulmonary vasoconstriction in normally beating hearts (model 1). Pulmonary artery and left atrial pressures increased during left ventricle dysfunction (model 4), and further increased after phenylephrine injection by 31 ± 5.6 and 43 ± 7.5%, respectively. In conclusion, vasopressors increased blood volume in the lung with minimal pulmonary vasoconstriction. Thus, this pulmonary hypertension is similar to the hemodynamic pattern observed in left heart diseases and is passive, due to redistribution of blood from systemic to pulmonary circulation. Understanding the underlying mechanisms may improve clinical management of patients who are taking vasopressors, especially those with coexisting heart disease.

Effect of intravitreal ranibizumab on the ocular circulation of the untreated fellow eye.

PURPOSE: To evaluate the effects of unilateral intravitreal ranibizumab (IVR) on the ocular circulation of the fellow eyes. METHODS: Fifteen eyes of 15 patients with macular edema (average age 69.6 ± 11.8 years) were studied. Eleven eyes had diabetic macular edema (DME) and four eyes had macular edema associated with a branch retinal vein occlusion. Each eye received 0.5 mg of IVR. The blood circulation on the optic nerve head of the treated and untreated eyes were determined by laser speckle flowgraphy (LSFG, Softcare Co., Ltd) before, 1 day, and 1 week after the IVR. The mean blur rate (MBR) and the relative changes of the MBRs determined as dMBR(%) = 100-(MBR before/MB after) × 100) were evaluated. The central macular thickness (CMT) and the rate of reduction in the thickness (dCMT = 100-(CMT before/CMT after) × 100) were also evaluated. RESULTS: The mean dMBR was significantly higher in the treated eyes than the untreated eyes at 1 day (-16.4 ± 17.0% vs 2.31 ± 19.3%) and at 1 week (-12.0 ± 14.6% vs 4.50 ± 25.9%) after the IVR (P = 0.02, paired t tests). CONCLUSION: These findings indicate that if ranibizumab enters the systemic circulation, the concentration is not high enough to affect the ocular circulation of the fellow eyes.

Hybrid Palliation for Ductal-Dependent Systemic Circulation.

We reviewed our hybrid palliation experience for 91 neonates, with ductal-dependent systemic circulation, born between August 2007 and October 2015. For analysis, we stratified the 91 patients by a risk factor (RF) score and divided them into three groups: (1) high-risk two-functional ventricles (2V) median RF score of 3 (N = 20); (2) low-risk one-functional ventricle (1V) RF score 0-1 (N = 32); and (3) high-risk 1V RF score ≥2 (N = 39). Midterm survival (median 4 years) by group was: (1) 95 %, (2) 91 %, and (3) 15 %, (p = 0.001). In conclusion, hybrid palliation was associated with excellent midterm results for high-risk 2V and low-risk 1V patients with ductal-dependent systemic circulation. In contrast, high-risk 1V patients had significantly worse outcomes.

Preparation and evaluation of a buflomedil hydrochloride niosomal patch for transdermal delivery.

CONTEXT: Niosomes are the non-ionic surfactant vesicles obtained on hydration of synthetic non-ionic surfactants. These are the promising vehicles for effective transdermal drug delivery. OBJECTIVE: The present research work was aimed to develop niosomal-based transdermal buflomedil hydrochloride patch containing a stable formulation with improved drug permeation. MATERIALS AND METHODS: Niosomes were prepared by solvent evaporation method using 32 factorial design. All the formulations were evaluated for vesicle size, zeta potential and percent entrapment efficiency. Optimized niosomal and liposomal formulation were loaded into a patch system. All the patches were then characterized for drug-excipient interaction study, scanning electron microscopy, pharmacotechnical properties and in vitro permeation studies. RESULT: F9 formulation having optimum vesicle size (10.09 ± 1.2 µm), highest zeta potential (-85.4 ± 0.56 mV) and maximum percent entrapment efficiency (97.09 ± 0.11%) was selected as optimized formulation. In case of liposomes, formulation F12 was selected. Patches loaded with niosomes showed 95.12 ± 1.19% cumulative amount of drug permeated as compared to liposomal vesicle-loaded patches which showed 82.21 ± 1.24% and control patches 70.10 ± 1.33%. DISCUSSION: Flux, permeation rate and permeability coefficient were found to be higher in case of niosomal patches as compared to liposomal patches and control patches. Surfactant present in niosomes act as a penetration enhancer which contribute in the permeation enhancement of buflomedil hydrochloride from niosomes. CONCLUSION: Thus, it was concluded that niosomal vesicles represented to be an efficient and stable vesicular carrier for transdermal delivery of buflomedil hydrochloride.

Exercise training mode effects on myokine expression in healthy adults: A systematic review with meta-analysis.

BACKGROUND: The benefits of exercise are well known; however, many of the underlying molecular mechanisms are not fully understood. Skeletal muscle secretes myokines, which mediate muscle-organ crosstalk. Myokines regulate satellite-cell proliferation and migration, inflammatory cascade, insulin secretion, angiogenesis, fatty oxidation, and cancer suppression. To date, the effects of different exercise modes (namely, aerobic and resistance exercise) on myokine response remain to be elucidated. This is crucial considering the clinical implementation of exercise to enhance general health and wellbeing and as a medical treatment. METHODS: A systematic search was undertaken in PubMed, Medline, CINAHL, Embase, SPORTDiscus, and Web of Science in April 2023. Eligible studies examining the effects of a single bout of exercise on interleukin15 (IL-15), irisin, secreted protein acidic and rich in cysteine (SPARC), oncostatin M (OSM), and decorin were included. A random-effects meta-analysis was also undertaken to quantify the magnitude of change. RESULTS: Sixty-two studies were included (n = 1193). Overall, exercise appeared to induce small to large increases in myokine expression, with effects observed immediately after to 60 min post-exercise, although these were mostly not statistically significant. Both aerobic and resistance exercise resulted in changes in myokine levels, without any significant difference between training modes, and with the magnitude of change differing across myokines. Myokine levels returned to baseline levels within 180 min to 24 h post-exercise. However, owing to potential sources of heterogeneity, most changes were not statistically significant, indicating that precise conclusions cannot be drawn. CONCLUSION: Knowledge is limited but expanding with respect to the impact of overall and specific effects of exercise on myokine expression at different time points in the systemic circulation. Further research is required to investigate the effects of different exercise modes at multiple time points on myokine response.

Association between endotoxemia and blood no in the portal circulation of cirrhotic patients: results of a pilot study.

Pathophysiology of portal vein thrombosis (PVT) in cirrhosis is still not entirely understood. Elevated levels of lipopolysaccharides (LPS) in portal circulation are significantly associated with hypercoagulation, increased platelet activation and endothelial dysfunction. The aim of the study was to investigate if LPS was associated with reduced portal venous flow, the third component of Virchow's triad, and the underlying mechanism. Serum nitrite/nitrate, as a marker of nitric oxide (NO) generation, and LPS were measured in the portal and systemic circulation of 20 patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedure; portal venous flow velocity (PVV) was also measured in each patient and correlated with NO and LPS levels. Serum nitrite/nitrate and LPS were significantly higher in the portal compared to systemic circulation; a significant correlation was found between LPS and serum nitrite/nitrate (R = 0.421; p < 0.01). Median PVV before and after TIPS was 15 cm/s (6-40) and 31 cm/s (14-79), respectively. Correlation analysis of PVV with NO and LPS showed a statistically significant negative correlation of PVV with portal venous NO concentration (R = - 0.576; p = 0.020), but not with LPS. In vitro study with endothelial cells showed that LPS enhanced endothelial NO biosynthesis, which was inhibited by L-NAME, an inhibitor of NO synthase, or TAK-242, an inhibitor of TLR4, the LPS receptor; this effect was accomplished by up-regulation of eNOS and iNOS. The study shows that in cirrhosis, endotoxemia may be responsible for reduced portal venous flow via overgeneration of NO and, therefore, contribute to the development of PVT.

No Measurable Transfer of Oxytocin-Receptor Agonist Merotocin Detected in Human Breast Milk.

Objective: The study aimed to assess the transfer of merotocin from systemic circulation to breast milk in early postpartum women and women with established lactation. Methods: This was a two-part, multicenter, open-label, parallel-group study. Merotocin was administered as a single 90-minute intravenous (iv) infusion mimicking the intranasal pharmacokinetic profile. In Part A, 12 early postpartum women received doses of either 4 µg (n = 6) or 16 µg (n = 6) of merotocin within 4 days of delivery. In Part B, six women with established lactation received 20 µg of merotocin. The total concentration of merotocin in plasma and breast milk and its metabolites excreted in breast milk were measured at various time points. Adverse events (AEs) were also assessed for both parts of the study. Results: In both early postpartum and established lactation groups (mean age, 26.3 years; 83.3% Caucasian), merotocin and its metabolites in breast milk were below the limit of quantification (25.0 pg/mL) at all time points. Sixteen treatment-emergent AEs occurred in early postpartum women only, including seven events of uterine spasm and three of breast engorgement. There was one moderate event, whereas all the other events were considered mild. Conclusion: Merotocin was undetectable in breast milk after single iv administration of up to 20 µg in early postpartum women and women with established lactation.

The association of cumulative vasoactive drugs and neurodevelopmental outcomes in preterm Infants <29 weeks gestation.

OBJECTIVE: To assess the effect of cardiovascular medications on the neurodevelopment of preterm infants, as measured by calculated cumulative time of vasoactive-inotropic score (VISct). METHODS: A retrospective study was conducted on preterm infants who developed significant hypotension defined as a mean BP more than 2SDs below the mean for GA and received treatment with duration > 6 hours for each hypotensive episode, we calculated the vasoactive inotropic score (VIS) and cumulative exposure to cardiovascular medications over time (VISct). The composite Bayley III was reported from the high-risk follow-up clinic for the surviving infants between 18 to 21 months corrected age. RESULTS: VISct was significantly higher in infants with abnormal neurodevelopment. Cognitive Bayley was the most affected component with median (IQR) VISct 882.5(249,2047) versus 309(143,471) (p-value 0.012), followed by language function with VISct 786(261,1563.5), versus 343(106.75,473.75) (p-value 0.016) when those with Bayley III <85 were compared with those with normal Bayley IIIs. CONCLUSION: High VISct scores may have negative effect on cognitive and language neurodevelopmental outcomes.

Reactive oxygen species augment contractile responses of saphenous artery in 10-15-day-old but not adult rats: Substantial role of NADPH oxidases.

Reactive oxygen species (ROS) produced by NADPH oxidases (NOX, a key source of ROS in vascular cells) are involved in the regulation of vascular tone, but this has been explored mainly for adult organisms. Importantly, the mechanisms of vascular tone regulation differ significantly in early postnatal ontogenesis and adulthood, while the vasomotor role of ROS in immature systemic arteries is poorly understood. We tested the hypothesis that the functional contribution of NADPH oxidase-derived ROS to the regulation of peripheral arterial tone is higher in the early postnatal period than in adulthood. We studied saphenous arteries from 10- to 15-day-old ("young") and 3- to 4-month-old ("adult") male rats using lucigenin-enhanced chemiluminescence, quantitative PCR, Western blotting, and isometric myography. We demonstrated that both basal and NADPH-stimulated superoxide anion radical (O2•-) production was significantly higher in the arteries from young in comparison to adult rats. Importantly, pan-inhibitor of NADPH oxidase VAS2870 (10 µM) reduced NADPH-induced O2•- production in arteries of young rats. Saphenous arteries of both young and adult rats demonstrated high levels of Nox2 and Nox4 mRNAs, while Nox1 and Nox3 mRNAs were not detected. The protein contents of NOX2 and NOX4 were significantly higher in arterial tissue of young compared to adult animals. Moreover, VAS2870 (10 µM) had no effect on methoxamine-induced contractile responses of adult arteries but decreased them significantly in young arteries; such effect of VAS2870 persisted after removal of the endothelium. Finally, NOX2 inhibitor GSK2795039 (10 µM), but not NOX1/4 inhibitor GKT137831 (10 µM) weakened methoxamine-induced contractile responses of arteries from young rats. Thus, ROS produced by NOX2 have a pronounced contractile influence in saphenous artery smooth muscle cells of young, but not adult rats, which is associated with the increased vascular content of NOX2 protein at this age.

Choroidal Thickness Increases During Parasympathetic Dominance After Immersion of the Foot in Warm Water.

PURPOSE: This study aimed to assess the course of changes in choroidal morphology after immersion of the foot in warm water at 40°C using enhanced depth imaging optical coherence tomography (EDI-OCT). METHODS: Forty-three right eyes of 43 healthy participants were included. Changes in choroidal morphology were determined using EDI-OCT to evaluate subfoveal choroidal thickness (SCT). Systolic, diastolic, and mean blood pressures (SBP, DBP, and MBP, respectively) were also measured to determine systemic circulatory dynamics at baseline, immediately after immersion (0 min), and 10, 20, and 30 min after immersion. RESULTS: Immediately after immersion, SBP, DBP, and MBP were significantly declined versus baseline. In contrast, the SCT was significantly increased after warm water immersion. However, all these parameters did not change significantly compared to the baseline within 30 min. CONCLUSION: In the normal eye, parasympathetic nerve activity induced by warming stimuli increases choroidal morphology in response to a decrease in systemic circulatory activity, which normalizes within 30 min. The findings of this study may provide basic data for the prevention and treatment of various choroidal diseases in which sympathetic hyperactivity is involved in the pathogenesis.

Assessment of systemic circulation using ultrasound Doppler in late onset neonatal sepsis and its clinical correlation: an observational study.

OBJECTIVES: To measure the Doppler velocimetry parameters in the anterior cerebral artery (ACA), superior mesenteric artery (SMA), and main renal artery (RA) in neonates with late-onset sepsis and correlate it with associated clinical morbidities. METHODOLOGY: Prospective observational study carried out at a tertiary-level neonatal intensive care unit in India in 2022, enrolling 20 neonates with late-onset neonatal sepsis (LONS). Baseline characteristics and sepsis parameters obtained. Serial ultrasound performed on days 1, 3, and 7 from the day of clinical sepsis in the ACA, SMA, and RA and velocimetry measurements obtained. The findings were compared with 20 gestational age (GA) matched neonates in the control arm. RESULTS: The mean GA of neonates with LONS was 31.03 ± 2.79 weeks and their mean birthweight was 1474 ± 509.99 g. The peak systolic velocity, resistive and pulsatility indices were significantly higher in ACA, SMA, and RA and the end-diastolic velocity was significantly lower in ACA and RA (P < 0.05) in LONS. The incidences of intraventricular hemorrhage (IVH), necrotising enterocolitis (NEC), and acute kidney injury (AKI) in neonates with LONS were 45%, 50%, and 10% respectively. A subgroup analysis of the Doppler velocimetry parameters in the neonates with LONS and for neonates with and without clinical outcomes did not suggest a significant difference. CONCLUSION: LONS is associated with alterations in cerebral, splanchnic, and renal perfusion seen as abnormal blood flow velocimetry and vascular resistance which may predispose to IVH, NEC, and AKI.

Potential targeting of the tumor microenvironment to improve cancer virotherapy.

In 2015, oncolytic virotherapy was approved for clinical use, and in 2017, recombinant adeno-associated virus (AAV) delivery was also approved. However, systemic administration remains challenging due to the limited number of viruses that successfully reach the target site. Although the US Food and Drug Administration (FDA) permits the use of higher doses of AAV to achieve greater rates of transduction, most AAV still accumulates in the liver, potentially leading to toxicity there and elsewhere. Targeting the tumor microenvironment is a promising strategy for cancer treatment due to the critical role of the tumor microenvironment in controlling tumor progression and influencing the response to therapies. Newly discovered evidence indicates that administration routes focusing on the tumor microenvironment can promote delivery specificity and transduction efficacy within the tumor. Here, we review approaches that involve modifying viral surface features, modulating the immune system, and targeting the physicochemical characteristics in tumor microenvironment to regulate therapeutic delivery. Targeting tumor acidosis presents advantages that can be leveraged to enhance virotherapy outcomes and to develop new therapeutic approaches that can be integrated with standard treatments.