Systemic Circulation Research Articles

Postnatal outcome following fetal aortic valvuloplasty for critical aortic stenosis.

To report our experience of fetal aortic valvuloplasty (FAV) for critical aortic stenosis (AS), with a focus on the postnatal evolution of the patients. This was a retrospective study including all fetuses with critical AS which underwent FAV in a single center between January 2011 and June 2022. FAV was performed under ultrasound guidance. Technical success was based upon balloon inflation across the aortic valve and improvement of the antegrade aortic flow across the aortic valve. At birth, a biventricular circulation (BVC) strategy was decided assuming the left ventricular (LV) systolic and diastolic function would ensure the systemic circulation. Sixty-three FAV procedures were performed in 58 fetuses, at a median (range) gestational age of 26.2 (20.3-32.2) weeks. The procedure was technically successful in 50/58 (86.2%) fetuses. There were 11/58 (19.0%) cases of in-utero demise and 9/58 (15.5%) terminations of pregnancy. No patient was liveborn after an unsuccessful procedure. Thirty-eight (65.5%) infants were liveborn, at a median (range) gestational age of 38.1 (29.0-40.6) weeks, of whom 21 (55.3%) required prostaglandin treatment. Twenty-eight of the 38 (73.7%) liveborn children (48.3% of the study population) entered the BVC pathway at birth. Among them, 20 (71.4%) required an aortic valvuloplasty procedure at birth (11 (55.0%) percutaneous balloon, nine (45.0%) surgical) and eight (28.6%) did not require any treatment at birth, but, of these, five (62.5%) underwent surgical valvuloplasty between day 26 and day 1200 of age. Eleven (39.3%) of the infants with BVC at birth required a second intervention and four (14.3%) of them required a third intervention. Two (7.1%) infants who entered the BVC pathway at birth underwent conversion to univentricular circulation (UVC). None of the surviving children with BVC developed pulmonary hypertension. The overall survival rate in those with BVC at birth was 22/28 (78.6%) at a median (range) follow-up of 23.3 (2.0-112.6) months. Ten of the 58 (17.2%) patients had UVC at birth. Among these, six (60.0%) received compassionate care from birth and four (40.0%) underwent surgery. Three of the 10 patients who had UVC at birth were still alive at the latest follow-up assessment, at a median (range) gestational age of 24.3 (8.3-48.7) months. FAV for critical AS led to increase of antegrade aortic flow in 86.2% of fetuses, with BVC being achieved in 48.3% (73.7% of the liveborn cases). Among patients with BVC at birth, the rate of reintervention was high, but 78.6% of these children were alive at the latest evaluation. © 2024 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Simulation of low energy building thermal energy cycle in IoT smart city planning based on environmental sensors and deep learning

With the intensification of global climate change, the reduction of building energy consumption has become an important goal of smart city development. By optimizing the thermal energy circulation system, low energy buildings can not only reduce energy consumption, but also improve living comfort. In recent years, with the help of environmental sensors and deep learning technology, the intelligent management of building heat energy cycle has become a research hotspot. The research constructs an intelligent thermal energy circulation system that integrates multiple environmental sensors for real-time monitoring of indoor and outdoor temperature, humidity and other key environmental parameters. A deep learning algorithm is used to analyze the collected data to optimize the control strategy of the thermal energy cycle. Through simulation, the energy efficiency performance of the scheme under different climatic conditions and building types was evaluated. The experimental results show that the control strategy based on environmental sensors and deep learning can significantly improve the thermal energy utilization efficiency of low-energy buildings, and the average energy consumption is greatly reduced compared with the traditional management mode. The system shows good adaptability and stability under different climate conditions. Therefore, the application of environmental sensors and deep learning technology in the thermal energy cycle of low-energy buildings can effectively promote the energy efficiency management of smart cities.

Paracellular Delivery of Protein Drugs with Smart EnteroPatho Nanoparticles.

A general platform for the safe and effective oral delivery of biologics would revolutionize the administration of protein-based drugs, improving access for patients and lowering the financial burden on the health-care industry. Because of their dimensions and physiochemical properties, nanomaterials stand as promising vehicles for navigating the complex and challenging environment in the gastrointestinal (GI) tract. Recent developments have led to materials that protect protein drugs from degradation and enable controlled release in the small intestine, the site of absorption for most proteins. Yet, once present in the small intestine, the protein must transit through the secreted mucus and epithelial cells of the intestinal mucosa into systemic circulation, a process that remains a bottleneck for nanomaterial-based delivery. One attractive pathway through the intestinal mucosa is the paracellular route, which avoids cell trafficking and other degradative processes in the interior of cells. Direct flux between cells is regulated by epithelial tight junctions (TJs) that seal the paracellular space and prevent protein flux. Here, we describe a smart nanoparticle system that directly and transiently disrupts TJs for improved protein delivery, an unrealized goal to-date. We take inspiration from enteropathogenic bacteria that adhere to intestinal epithelia and secrete inhibitors that block TJ interactions in the local environment. To mimic these natural mechanisms, we engineer nanoparticles (EnteroPatho NPs) that attach to the epithelial glycocalyx and release TJ modulators in response to the intestinal pH. We show that EnteroPatho NPs lead to TJ disruption and paracellular protein delivery, giving rise to a general platform for oral delivery.

Microplastic contamination of food: sources, detection methods, and health implications

Microplastic contamination in food has emerged as a significant global concern, with potential implications for human health. Microplastics, defined as plastic particles smaller than 5 mm, originate from various sources, including plastic waste fragmentation, synthetic textiles, and industrial processes. These particles have been detected in multiple food products, particularly seafood, drinking water, salt, honey, and processed foods, posing a risk of chronic exposure through ingestion. The small size of microplastics allows them to penetrate tissues and potentially enter systemic circulation, raising concerns about their bioaccumulation and toxicological effects. This review provides a comprehensive analysis of the pathways through which microplastics enter the food chain, focusing on contamination in aquatic ecosystems and food packaging. We also examine the analytical techniques used for detecting microplastics in food, including spectroscopic methods, and discuss the challenges of standardizing detection protocols. Finally, the potential health risks, including toxicity and chemical leaching, are explored, alongside recommendations for future research and regulatory strategies.

Biochar from paddy field - A solution to reduce PFAS pollution in the environment

Generally, activated carbons demonstrated a notable ability to capture long-chain PFAS, but exhibited relatively lower effectiveness for short-chain PFAS. Thirteen commercially available activated carbons in Japan underwent testing for their adsorption capacity of PFAS in water. The activated carbon derived from rice husk, Triporous™-PFAS, exhibited the highest adsorption capacity (over 95%) for PFAS from ultrashort-chain (perfluorocarbon chain: C1 for perfluorocarboxylic acid (PFCA) and C2 for perfluoroalkane sulfonic acid (PFSA)) to long-chain PFAS (C13 for PFCA and C10 for PFSA). An earlier lysimeter study highlighted Andosol, representative soil in Japan, as a potential medium for removing PFAS from irrigation water. Considering cultivating rice on Andosol fields and producing biochar from rice husks and rice straw, a new rice cultivation system is proposed. This system aims to facilitate continuous removal of PFAS from the environment in Asia. Japanese rice cultivation system produces not only rice but also biochar to remove PFAS from water circulation system. The total fluorine content in the tested activated carbon materials ranged from 0.18 to 38 μg g−1 F. Based on the results from background F blank and adsorption capacity, TriporousTM-PFAS-F was shown to be an option to lower the method detection limit for a proposed international standard method for measuring total PFAS.

Plasma Somatostatin Levels Are Lower in Patients with Coronary Stenosis and Significantly Increase after Stent Implantation.

Background/Objectives: Stimulated capsaicin-sensitive peptidergic sensory nerves release somatostatin (SST), which has systemic anti-inflammatory and analgesic effects, correlating with the severity of tissue injury. Previous studies suggest that SST release into the systemic circulation is likely to serve as a protective mechanism during thoracic and orthopedic surgeries, scoliosis operations, and septic conditions, all involving significant tissue damage, pain, and inflammation. In a severe systemic inflammation rat model, SST released from sensory nerves into the bloodstream enhanced innate defense, reducing mortality. Inflammation is the key pathophysiological process responsible for the formation, progression, instability, and healing of atherosclerotic plaques. Methods: We measured SST-like immunoreactivity (SST-LI) in the plasma of healthy volunteers in different age groups and also that of stable angina patients with coronary heart disease (CHD) using ELISA and tracked changes during invasive coronary interventions (coronarography) with and without stent implantation. Samples were collected at (1) pre-intervention, (2) after coronarography, (3) 2 h after coronarography initiation and coronary stent placement, and (4) the next morning. Results: There was a strong negative correlation between SST-LI concentrations and age; the plasma SST-LI of older healthy volunteers (47-73 years) was significantly lower than in young ones (24-27 years). Baseline SST-LI in CHD patients who needed stents was significantly reduced compared to those not requiring stents. Plasma SST-LI significantly increased two hours post stent insertion and the next morning compared to pre-intervention levels. Conclusions: Age-related SST decrease might be a consequence of lower gene expression within specific hypo-thalamic nuclei as has been previously demonstrated in rodent animals. Reperfusion of ischemic myocardium post-stent implantation may trigger SST release, potentially offering protective benefits in coronary heart disease. Investigating this SST-mediated mechanism could offer valuable insights for future therapies.

A STEP INTO THE FUTURE (review of the book “Russian economy: who is to blame? What to do?”)

The review provides an overview of the main ideas of the book with the catchy title “Russian Economy: Who is to Blame? What to do?”, prepared by a team of authors under the leadership of Doctor of Economics, Professor S. I. Kretov. The monograph’s breakthrough ideas are noted, including the proposal to form a new contour of the circulation sphere, based on Free Sovereign Development Certificates (USSR rubles with demurrage). The authors’ proposals will make it possible to form a sovereign circulation system, which assumes the priority of the production sector and serves its needs. The ideas expressed deserve their thoughtful critical assessment by the academic and professional community, testing in model industries and, I hope, subsequent implementation. Separately, the relevance of the proposals made back in 2021 is noted, as well as their practical value for solving the problems of developing the Russian economy.

Oral fast dissolving films made with alginate and whey protein for resveratrol delivery

Resveratrol is a natural polyphenol with low bioavailability because of poor hydro-solubility and extensive first-pass effect. The delivery to oral mucosa via oral fast dissolving films (OFDFs) is a useful administration route to bypass the first-pass metabolism through direct adsorption into the systemic circulation. In this study, the OFDFs was fabricated with loading of excessive and soluble resveratrol in various ratios of whey protein isolate (WPI) and alginate. The solubility of resveratrol was improved in the presence of WPI and/or alginate, which was further affected by glycerol. The OFDFs were characterized in term of thickness, disintegration time, intermolecular interaction, structure, mechanical properties and thermal degradation. At a glycerol/biopolymer ratio of 1:2 and the WPI/alginate ratios between 5:1 and 1:1, the OFDFs disintegrated within 30 s and completely dissolved within 60 s, containing 30–50 μg/cm2 dissolved resveratrol in water. The permeation percentage of 89% was the most at the WPI/alginate ratio of 3:1. Oral mucosa permeation of resveratrol in OFDFs was significantly greater than that in the corresponding film solution. The films exhibited fast disintegration and promotion of resveratrol permeation. These results demonstrate that WPI and alginate were effective in the preparation of OFDFs for enhancing the permeability of resveratrol. It is thus suggested that biopolymer-based OFDFs are potential carriers for oral delivery of polyphenols.

A phase Ib/II study of pacritinib, an interleukin 1 receptor associated kinase 1 (IRAK1) inhibitor, in patients (pts) with solid tumors harboring the 1q21.3 copy number amplification (CNA).

43 Background: The role of IRAK1 pathway in inflammatory and immune response is established in autoimmune diseases but less well-understood in cancer. Chromosome 1q21.3 CNA detected in plasma cell-free DNA was observed in pts with advanced solid tumors, and associated with IRAK1 upregulation. In preclinical animal models, IRAK1 upregulation promoted tumorigenesis, while its inhibition led to decreased tumor growth. Pacritinib is a JAK2/FLT3 inhibitor that is FDA approved for treatment in myelofibrosis, but also have known activity against IRAK1. We hypothesize that pacritinib may be effective in disease control of pts with plasma 1q21.3 CNA. Methods: A phase Ib/II clinical trial was designed to investigate the efficacy of pacritinib in pts with treatment (rx) refractory solid tumors harboring 1q21.3 CNA. Serial pt tumor and blood samples were collected and analyzed to elucidate the effect of IRAK1 inhibition on tumor microenvironment and systemic immune modulation. Results: 330 patients were screened, 1q21.3 CNA was detected in 30.1% of pts. Highest incidence of 1q21.3 CNA positivity was detected in breast cancer (39.8%), colorectal cancer (39.7%) and lung cancer (36.1%). 12 pts were commenced on rx over 3 dose levels (DL) (DL1: n=6, DL2: n=3, DL3: n=3). At DL1 (200mg BID), no DLTs were observed, but 2 pts had G3 transaminitis attributed to drug/disease, and 1 pt had intolerable G2 rash; decision was made for dose reduction. At DL2 (200mg OM, 100mg ON), no DLTs were observed. Reescalation to 200mg BID (DL3) was carried out with no DLT observed. Pacritinib at 200mg BD was declared the recommended phase II dose in pts with solid tumors. In the dose expansion cohort, 8 pts (4 colorectal cancer, 3 hepatobiliary [HPB] cancer, 1 lung cancer) have been enrolled thus far. No objective responses were observed. Within pts with HPB tumors, 1 pt with pancreatic cancer had a progression-free survival (PFS) of 25.0 weeks, and 1 pt with cholangiocarcinoma had a PFS of 15.9 weeks. Preliminary analysis of serial tumor biopsy samples suggest an expansion of CD8+ T cell population with pacritinib rx. Serial peripheral blood mononuclear cells analysis showed no significant trend in change in CD8+ T cell population, but a predominance of PD-1+ T cells with rx, and also an increase in CD4+ T cell population. In the myeloid cell population, there appears to be decrease in dendritic cell population, but no significant change in trend of macrophage was observed. Conclusions: Pacritinib at 200mg BID is safe and tolerable in pts with solid tumors. IRAK1 inhibition appears to modulate immune cell populations both in the tumor microenvironment and systemic circulation. Dose expansion is underway, with potential signal of disease control in HPB tumors. Clinical trial information: NCT04520269 .

Illuminating the fight against breast cancer: Preparation and visualized photothermal therapy of hyaluronic acid coated ZIF-8 loading with indocyanine green and cryptotanshinone for triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by higher recurrence rate and mortality. Thermally-mediated ablation via photothermal therapy (PTT) demonstrates considerable promise for the eradication of breast cancer. Nonetheless, the efficacy of PTT is impeded by the thermal tolerance of tumor cells, which is attributed to the augmented expression of heat shock proteins (HSPs). These proteins, which function as ATP-dependent molecular chaperones, confer protection to cancer cells against the cytotoxic heat generated during PTT. Glycolysis is an important way for breast cancer cells to produce ATP, which can promote the occurrence and development of lung metastasis of breast cancer. Therefore, inhibiting glycolysis may diminish the expression of HSPs, curtail the growth of breast cancer, and prevent its metastasis. Glycolytic metabolism plays a pivotal role in the ATP biosynthesis within breast cancer cells, facilitating the progression and dissemination of pulmonary metastases. Consequently, targeting glycolysis presents a strategic approach to HSP expression, the proliferation of breast cancer, and impede its metastatic spread. Herein, we designed an indocyanine green (ICG) and cryptotanshinone (CTS) loaded hyaluronic acid (HA) coated Zeolitic Imidazolate Framework-8 (ZIF-8) drug delivery system. The drug delivery system had excellent photothermal properties, which could reach temperature sufficient for photothermal ablation of tumor cells. (ICG + CTS)@HA-ZIF-8 also showed pH-responsive drug release, enhancing the sustained release of ICG and CTS to extend their systemic circulation duration. Moreover, the HA modification of ZIF-8 served to augment its targeting capabilities both in vitro and in vivo, leveraging the enhanced permeation and retention (EPR) effect, as well as active tumor targeting via the CD44 receptor pathway, resulting in a higher drug concentration and a better therapeutic effect in tumor. (ICG + CTS)@HA-ZIF-8 could downregulate the expression of glycolysis-related protein pyruvate kinase-M2 (PKM2), thereby inhibiting the glycolysis process, further suppressing tumor cell energy metabolism, downregulating the expression of HSPs, overcoming tumor cell heat resistance, and improving PTT effect. It exhibited a notable suppressive impact on both the proliferation and migration of breast cancer cells, potentially offering innovative insights for the visualized PTT in breast cancer treatment.

Extreme weather event causes the death of White-collared Swift Streptoprocne zonaris (Shaw, 1796) (Aves, Apodidae) individuals in sinkholes in the State of Goiás, Brazil

The use of caves and rocky walls is common for some birds, like swifts, to shelter, sleep, nest, feed, and protect themselves from predators, wind, and rain. Several environmental and ecological factors associated with the habits and adaptations of certain species allow birds to use cave environments. The White-collared Swift Streptoprocne zonaris (Shaw, 1796) is distributed from Mexico and the Antilles south to northern Argentina, Paraguay, and southern Brazill, being frequent in areas with waterfalls and river rapids with rocky beds and crystal-clear water. Individuals live in flocks and have the habit of roosting and nesting in damp, dark caves or behind waterfalls. Herein, we aim to report the case and identify the cause of death of S. zonaris individuals found dead in a sinkhole in the State of Goiás, Brazil, in 2020. Global warming resulting from anthropogenic emissions of greenhouse gases can alter the natural fluctuations of atmospheric circulation systems, responsible for rainfall distribution, substantially affecting rainfall and increasing the frequency of heavy rainfall events in some locations. Due to climate change and the increasing frequency of flooding records, we have raised the hypothesis and drawn attention to our record may have been originated due to these climatic events. However, we do not dismiss the hypothesis that the flooding may be due to an extreme event. The fact that S. zonaris spends the night and nests close to water bodies makes the species more susceptible to the effects of a flash flood. Further studies will be able to show the real effects of global warming on the species.

Navigating Central Oxytocin Transport: Known Realms and Uncharted Territories.

Complex mechanisms govern the transport and action of oxytocin (Oxt), a neuropeptide and hormone that mediates diverse physiologic processes. While Oxt exerts site-specific and rapid effects in the brain via axonal and somatodendritic release, volume transmission via CSF and the neurovascular interface can act as an additional mechanism to distribute Oxt signals across distant brain regions on a slower timescale. This review focuses on modes of Oxt transport and action in the CNS, with particular emphasis on the roles of perivascular spaces, the blood-brain barrier (BBB), and circumventricular organs in coordinating the triadic interaction among circulating blood, CSF, and parenchyma. Perivascular spaces, critical conduits for CSF flow, play a pivotal role in Oxt diffusion and distribution within the CNS and reciprocally undergo Oxt-mediated structural and functional reconstruction. While the BBB modulates the movement of Oxt between systemic and cerebral circulation in a majority of brain regions, circumventricular organs without a functional BBB can allow for diffusion, monitoring, and feedback regulation of bloodborne peripheral signals such as Oxt. Recognition of these additional transport mechanisms provides enhanced insight into the systemic propagation and regulation of Oxt activity.

Effects of phospholipid type and particle size on lipid nanoparticle distribution in vivo and in pancreatic islets

Lipid nanoparticles (LNPs) have recently been used as nanocarriers in drug delivery systems for nucleic acid drugs. Their practical applications are currently primarily limited to the liver and specific organs. However, altering the type and composition ratio of phospholipids improves their distribution in organs other than the liver, such as the spleen and lungs. This study aimed to elucidate the effects of LNP components and particle size on in vivo distribution through systemic circulation to pancreatic islets to achieve better targeting of islets, which are a fundamental therapeutic target for diabetes. Fluorescence-labeled LNPs were prepared using three phospholipids: 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), and 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), with particle sizes of 30–160 nm (diameter) using a microfluidic device. Baffled-structured iLiNP devices with adjusted flow-rate ratios and total flow rates were used. After the intravenous administration of LNPs to C57BL/6 J mice, the distribution of each LNP type to the major organs, including the pancreas and pancreatic islets, was compared using ex vivo fluorescence imaging and observation of pancreatic tissue sections. DSPC-LNPs- and DOPE-LNPs showed the highest distribution in the spleen and liver, respectively. In contrast, the DOPC-LNPs showed the highest distribution in the pancreas and the lowest distribution in the liver and spleen. In addition, smaller particles showed better distribution throughout the pancreas. The most significant LNP distribution in the islets was observed for DOPC-LNPs with a particle size of 160 nm. Furthermore, larger LNPs tended to be distributed in the islets, whereas smaller LNPs tended to be distributed in the exocrine glands. DOPC-LNPs were distributed in the islets at all cholesterol concentrations, with a high distribution observed at >40% cholesterol and > 3% PEG and the distribution was higher at 24 h than at 4 h. Thus, LNP composition and particle size significantly affected islet distribution characteristics, indicating that DOPC-LNPs may be a drug delivery system for effectively targeting the pancreas and islets.

Enhancement of terahertz emission from aqueous NaCl solutions

Exploration of terahertz sources with high electric fields and broad bandwidth is of great importance for terahertz application. In this work, the enhancement of terahertz emission from aqueous NaCl solutions induced by femtosecond laser pulses has been demonstrated by experiments. The power of the terahertz wave emission from the NaCl solution with a concentration of 30% is 1.86 times stronger than that from liquid water under equivalent excitation conditions. By means of a liquid circulation system with accurate pressure and temperature control, the influence of parameters such as solution concentration, liquid temperature, and medium size on the terahertz emission has been investigated. According to the experiment results, strong terahertz pulses are radiated from NaCl solutions with higher concentration, higher temperature, and smaller diameter. In addition, the physical mechanisms responsible for strong terahertz radiation have been analyzed by actual measurements and numerical simulations.

Design of hospitals for the post-pandemic era: an international survey of design professionals on infection control design strategies

ABSTRACT The COVID-19 pandemic placed unpreceded stress on healthcare systems, highlighting their deficiencies and vulnerabilities. The risk of cross-infection among patients and healthcare workers increased significantly, hindering the overall healthcare process. Hospital design should meet the challenges that will be posed by future pandemics, especially infection control. This paper reports on the results of an online survey for healthcare design professionals and academics from across the globe. The questionnaire addressed how hospital design can contribute to the infection control during future pandemic situations. Respondents agreed that the benefits of designing hospitals to meet the needs of pandemic/emergency situations outweigh the additional cost, and that infection control should play a more pronounced role when designing hospitals for the coming era. Results indicate that the overall organization of hospitals should allow for the compartmentation of critical/isolation departments/units and the creation of separate circulation routes to suit this compartmentation during pandemic times. The circulation system of the emergency departments and Intensive Care Units (ICU) should allow for the separation of infectious patients from others during pandemic times. 20–30% of the ICU beds of tertiary level care hospitals should be designed as single patient rooms. 53% of these rooms should be easily convertible to Air-Borne-Infection Isolation (AII) rooms, 44% should have an additional space for adding anterooms during pandemics, and 55% of these rooms should have permanent storage spaces for Personal Protective Equipment. The inpatient units should also be designed to support infection control. AII rooms should be grouped in designated inpatient units.

The effect of inclination on flow and heat transfer in a 3×3 rod bundle channel in a natural circulation system

Unlike ordinary nuclear power reactors, the floating nuclear power plants are constantly affected by sea waves and are often under inclined condition. The flow and heat transfer characteristics in the rod bundle channel for inclined condition is crucial for the design and operation of floating nuclear power plants. This paper experimentally investigates the flow resistance and heat transfer in an inclined 3 × 3 rod bundle channel at 10∼15 MPa in a natural circulation system and the inclination angle is 10°–30°. The mass flux becomes smaller as the experimental loop is inclined due to the decrease of the natural circulation driving force. As the system inclination angle becomes larger, the mass flux decreases more. Re and the outlet mass quality also affect the mass flux decreasing amplitude for inclined condition. For single phase flow, the friction coefficient correlation in a rod bundle channel is developed and the MAE (mean absolute error) is 2.82 %. The friction coefficients when the channel is inclined are larger than the friction coefficients when the channel is vertical. Correlations for Nu in the static vertical rod bundle channel are also developed and the MAE is less than 2 %. The heat transfer coefficient is enhanced for inclined condition if the effect of mass flux change is eliminated. For flow boiling, inclination has little effect on the number and size of the bubbles for highly subcooled boiling, while inclination has large influence on the flow pattern for saturated boiling. When the inclination angle becomes larger, the two phase multiplier increases. As the outlet mass quality increases, the increasing amplitude of two phase multiplier will become even larger when the inclination angle is larger. The heat transfer coefficient of flow boiling increases when the channel is inclined, and the enhancement is larger when the mass flux is smaller. When the inclination angle is 30°, the boiling heat transfer coefficient could increase by 25.7 % at a low mass flux. The paper reveals the quantitive influence of inclination on both single phase flow and flow boiling in the rod bundle channel. The working pressure and temperature have reached the operating conditions of the floating nuclear power plants, and the results can be applied to the design of nuclear power floating plants and pressurized water reactor using rod bundle fuel assembly.

Peripheral immune biomarkers for immune checkpoint inhibition of solid tumours.

With the rapid adoption of immunotherapy for the treatment of cancer comes the pressing need for readily accessible biomarkers to guide immunotherapeutic strategies and offer insights into outcomes with specific treatments. Regular sampling of solid tumour tissues outside of melanoma for immune monitoring is not often feasible; conversely, routine, frequent interrogation of circulating immune biomarkers is entirely possible. As immunotherapies and immune checkpoint inhibitors, in particular, are more widely used in first-line, neoadjuvant, and metastatic settings, the discovery and validation of peripheral immune biomarkers are urgently needed across solid tumour types for improved prediction and prognostication of clinical outcomes in response to immunotherapy, as well as elucidation of mechanistic underpinnings of the intervention. Careful experimental design, encompassing both retrospective and prospective studies, is required in such biomarker identification studies, and concerted efforts are essential for their advancement into clinical settings. In this review, we summarize shared immune features between the tumour microenvironment and systemic circulation, evaluate exploratory peripheral immune biomarker studies, and discuss associations between candidate biomarkers with clinical outcomes. We also consider integration of multiple peripheral immune parameters for better prediction and prognostication and discuss considerations in study design to further evaluate the clinical utility of candidate peripheral immune biomarkers for immunotherapy of solid tumours. Peripheral immune biomarkers are critical for improved prediction and prognostication of clinical outcomes for patients with solid tumours treated with immune checkpoint inhibition. Candidate peripheral biomarkers, such as cytokines, soluble factors, and immune cells, have potential as biomarkers to guide immunotherapy of solid tumours. Multiple peripheral immune parameters may be integrated to improve prediction and prognostication. The potential of peripheral immune biomarkers to guide immunotherapy of solid tumours requires critical work in biomarker discovery, validation, and standardization.

Relevance of distinctions and parallels between the US and EU guidelines for determination of comparative effectiveness and safety of the orally inhaled drug products

Approval of drug products for market registration warrants, among other data, evidence to support their safety and effectiveness in the target populations. The extent of investigations to provide the supporting evidence varies between the new innovator products and their follow-on versions generally referred to as Generic Drugs Products in the United States and Hybrids in the Europe. The new drug applications entail large data sets encompassing both nonclinical and clinical product developments. Safety and effectiveness in man is studied in sequentially phased clinical trials, including post marketing evaluations (Where applicable). However, for the generic/hybrid products the safety and effectiveness are established through determination of bioequivalence in head-to-head comparison between the originator and the follow-ons. Methods for documentation of bioequivalence for drug products that reach target site(s) through systemic circulation are aligned worldwide. However, establishing bioequivalence of orally inhaled drug products is complex as drug delivery to the local site(s) of action is independent of the systemic circulation. Documentation of bioequivalence gets further complicated due to the Drug-Device combination nature of these products. The guidelines for establishment of BE of locally acting orally inhaled drugs products vary among certain geographies. This article examines the scientific underpinning of distinctions and similarities between the US and EU guidelines.

Novel Vesicular Bilosomal Delivery Systems for Dermal/Transdermal Applications.

The application of therapeutically active molecules through the dermal/transdermal route into the skin has evolved as an attractive formulation strategy in comparison to oral delivery systems for the treatment of various disease conditions. However, the delivery of drugs across the skin is limited due to poor permeability. Dermal/transdermal delivery is associated with ease of accessibility, enhanced safety, better patient compliance, and reduced variability in plasma drug concentrations. It has the ability to bypass the first-pass metabolism, which ultimately results in steady and sustained drug levels in the systemic circulation. Vesicular drug delivery systems, including bilosomes, have gained significant interest due to their colloidal nature, improved drug solubility, absorption, and bioavailability with prolonged circulation time for a large number of new drug molecules. Bilosomes are novel lipid vesicular nanocarriers comprising bile salts, such as deoxycholic acid, sodium cholate, deoxycholate, taurocholate, glycocholate or sorbitan tristearate. These bilosomes are associated with high flexibility, deformability, and elasticity attributed to their bile acid component. These carriers are advantageous in terms of improved skin permeation, increased dermal and epidermal drug concentration, and enhanced local action with reduced systemic absorption of the drug, resulting in reduced side effects. The present article provides a comprehensive overview of the biopharmaceutical aspects of dermal/transdermal bilosome delivery systems, their composition, formulation techniques, characterization methods, and applications.

Insulin-like growth factor binding protein-3 (igfbp-3) and igfbp-5 in yellowtail kingfish (Seriola lalandi): molecular characterization and expression levels under different nutritional status and stocking density.

Insulin-like growth factor-binding proteins (IGFBPs) play important roles in regulating growth and development by binding to IGF, where IGFBP-3 and IGFBP-5 are the main binding carriers of IGF in the circulation system. In the present study, the gene sequences of igfbp-3, igfbp-5a, and igfbp-5b were cloned from the liver of yellowtail kingfish (Seriola lalandi). The ORF sequences of igfbp-3, igfbp-5a, and igfbp-5b were 888, 801, and 804bp in length, which encoded 295, 266, and 267 amino acids, respectively. The above three genes were widely expressed in yellowtail kingfish tissues, with igfbp-3 being the most highly expressed in the heart, brain, and gonads, while igfbp-5a and igfbp-5b were both most highly expressed in the liver and kidney. The expression levels of igfbp-3, igfbp-5a, and igfbp-5b were detected throughout the embryonic and larval stages, suggesting their roles in early development and growth regulation of yellowtail kingfish. Besides, igfbp-3 and igfbp-5a were significantly up-regulated in the liver under food deprivation and high-density rearing conditions, which was exactly opposite to the growth performance of yellowtail kingfish, implying that they may serve as biomarkers of adverse culture conditions. Overall, the above results initially identified the molecular characteristics of igfbp-3/-5a/-5b in yellowtail kingfish and implied that they might play important roles in the growth and development, providing a basis for further research on underlying regulatory mechanisms.