Biventricular catheterization combined with pressure-volume loop monitoring provides insight into the dynamic effects of left ventricular assist devices ramp on right ventricular function.

Ramp studies are utilized for speed optimization of continuous flow left ventricular assist devices (CF-LVADs). We here report the utility of combined left and right heart catheterization during a ramp study to ensure a comprehensive understanding of the hemodynamic implications on both ventricles. Pressure-volume loop (PV loop) monitoring uncovered compromised systolic and mildly compromised right ventricular function with increasing LVAD speeds, despite improvement in left ventricular unloading. These findings informed patient management and highlight the potential utility of PV loop monitoring as an adjunct to left and right heart catheterization during ramp studies of next-generation LVADs.

Developing patient-derived organoids to demonstrate JX24120 inhibits SAMe synthesis in endometrial cancer by targeting MAT2B.

Endometrial cancer (EC) is one of the most common gynecologic malignancies, which lacking effective drugs for intractable conditions or patients unsuitable for surgeries. Recently, the patient-derived organoids (PDOs) are found feasible for cancer research and drug discoveries. Here, we have successfully established a panel of PDOs from EC and conducted drug repurposing screening and mechanism analysis for cancer treatment. We confirmed that the regulatory ß subunit of methionine adenosyltransferase (MAT2B) is highly correlated with malignant progression in endometrial cancer. Through drug screening on PDOs, we identify JX24120, chlorpromazine derivative, as a specific inhibitor for MAT2B, which directly binds to MAT2B (Kd = 4.724 µM) and inhibits the viability of EC PDOs and canonical cell lines. Correspondingly, gene editing assessment demonstrates that JX24120 suppresses tumor growth depending on the presence of MAT2B in vivo and in vitro. Mechanistically, JX24120 induces inhibition of S-adenosylmethionine (SAMe) synthesis, leading to suppressed mTORC1 signaling, abnormal energy metabolism and protein synthesis, and eventually apoptosis. Taken together, our study offers a novel approach for drug discovery and efficacy assessment by using the PDOs models. These findings suggest that JX24120 may be a potent MAT2B inhibitor and will hopefully serve as a prospective compound for endometrial cancer therapy.

Silencing of tropomodulin 1 inhibits acute myeloid leukemia cell proliferation and tumor growth by elevating karyopherin alpha 2-mediated autophagy.

Evidence shows that tropomodulin 1 (TMOD1) is a powerful diagnostic marker in the progression of several cancer types. However, the regulatory mechanism of TMOD1 in tumor progression is still unclear. Here, we showed that TMOD1 was highly expressed in acute myeloid leukemia (AML) specimens, and TMOD1-silencing inhibited cell proliferation by inducing autophagy in AML THP-1 and MOLM-13 cells. Mechanistically, the C-terminal region of TMOD1 directly bound to KPNA2, and TMOD1-overexpression promoted KPNA2 ubiquitylation and reduced KPNA2 levels. In contrast, TMOD1-silencing increased KPNA2 levels and facilitated the nuclear transfer of KPNA2, then subsequently induced autophagy and inhibited cell proliferation by increasing the nucleocytoplasmic transport of p53 and AMPK activation. KPNA2/p53 inhibitors attenuated autophagy induced by silencing TMOD1 in AML cells. Silencing TMOD1 also inhibited tumor growth by elevating KPNA2-mediated autophagy in nude mice bearing MOLM-13 xenografts. Collectively, our data demonstrated that TMOD1 could be a novel therapeutic target for AML treatment.

Piracetam reduces oxidative stress and mitochondrial function impairment in an in vitro model of vascular dementia.

Vascular dementia (VaD) is the most common cause of dementia in older adults. Due to the lack of effective treatment options, there is an urgent need to find an effective pharmaceutical compound to combat VaD. Piracetam has been reported to improve impaired cognitive function in a variety of conditions in both human and animal models. However, the role and mechanism of Piracetam in VaD remain unclear. Therefore this study aimed to elucidate the effect of Piracetam on a cellular model of VaD in vitro. We found that Piracetam enhanced the growth of OGD-stimulated SH-SY5Y cells. In addition, Piracetam inhibited the oxidative stress of OGD-stimulated SH-SY5Y cells. Further, Piracetam improved mitochondrial function of OGD-stimulated SH-SY5Y cells. Mechanistically, Piracetam inhibited the PI3K/Akt/mTOR pathway in OGD-stimulated SH-SY5Y cells. Collectively, Piracetam improved oxidative stress and mitochondrial dysfunction of OGD-stimulated SH-SY5Y cells through PI3K/Akt/mTOR axis. Hence, Piracetam has the potential to serve as a promising drug of VaD.

Long-term kidney outcomes in pediatric continuous-flow ventricular assist device patients.

BACKGROUND: Continuous-flow ventricular assist devices (CF-VADs) are used increasingly in pediatric end-stage heart failure (ESHF) patients. Alongside common risk factors like oxidant injury from hemolysis, non-pulsatile flow constitutes a unique circulatory stress on kidneys. Post-implantation recovery after acute kidney injury (AKI) is commonly reported, but long-term kidney outcomes or factors implicated in the evolution of chronic kidney disease (CKD) with prolonged CF-VAD support are unknown. METHODS: We studied ESHF patients supported > 90 days on CF-VAD from 2008 to 2018. The primary outcome was CKD (per Kidney Disease Improving Global Outcomes (KDIGO) criteria). Secondary outcomes included AKI incidence post-implantation and CKD evolution in the 6-12 months of CF-VAD support. RESULTS: We enrolled 134 patients; 84/134 (63%) were male, median age was 13 [IQR 9.9, 15.9] years, 72/134 (54%) had preexisting CKD at implantation, and 85/134 (63%) had AKI. At 3 months, of the 91/134 (68%) still on a CF-VAD, 34/91 (37%) never had CKD, 13/91 (14%) developed de novo CKD, while CKD persisted or worsened in 49% (44/91). Etiology of heart failure, extracorporeal membrane oxygenation use, duration of CF-VAD, AKI history, and kidney replacement therapy were not associated with different CKD outcomes. Mortality was higher in those with AKI or preexisting CKD. CONCLUSIONS: In the first multicenter study to focus on kidney outcomes for pediatric long-term CF-VAD patients, preimplantation CKD and peri-implantation AKI were common. Both de novo CKD and worsening CKD can happen on prolonged CF-VAD support. Proactive kidney function monitoring and targeted follow-up are important to optimize outcomes.

Gut microbiota, vitamin A deficiency and autism spectrum disorder: an interconnected trio - a systematic review.

Accumulating evidence proves that children with autism have gastrointestinal problems. However, a significant difference in gut microbiota (GM) exists between autistic and non-autistic children. These changes in the GM may stem from several factors. Recently, researchers focused on nutritional factors, especially vitamin deficiency. Thus, our systematic review investigates the connections among autism, GM alterations, and vitamin A deficiency (VAD), by analyzing studies sourced from PubMed and Embase databases spanning from 2010 to 2022. Adhering to PRISMA guidelines, we meticulously selected 19 pertinent studies that established links between autism and GM changes or between autism and VAD. Our findings uniformly point to significant alterations in the GM of individuals with autism, indicating these changes as promising biomarkers for the disorder. Despite the consistent association of GM alterations with autism, our analysis revealed no notable differences in GM composition between individuals with autism and those experiencing VAD. This suggests that VAD, especially when encountered early in life, might play a role in the onset of autism. Furthermore, our review underscores a distinct correlation between reduced levels of retinoic acid in children with autism, a disparity that could relate to the severity of autism symptoms. The implications of our findings are twofold: they not only reinforce the significance of GM alterations as potential diagnostic markers but also spotlight the critical need for further research into nutritional interventions. Specifically, vitamin A supplementation emerges as a promising avenue for alleviating autism symptoms, warranting deeper investigation into its therapeutic potential.

Successful explantation of children from the Berlin Heart EXCOR® ventricular assist device: A systematic review.

BACKGROUND: The Berlin Heart EXCOR® (BHE) can bridge children with severe heart failure to transplantation, but some are successfully weaned and spared transplantation. This study seeks to identify characteristics of children amenable to successful explantation with BHE support. METHODS: Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 guidelines were used. Five databases were screened for original, English articles measuring BHE support in patients <18 years old based on title and abstract. Exclusion criteria were applied: full-text availability, <10 total pediatric BHE patients, zero successful explantations from BHE, nonprimary literature, adult and pediatric results that could not be separated, and studies with overlapping patient information. Studies were analyzed with descriptive statistics. RESULTS: From 41 857 potential studies, 14 were analyzed with data from 58 hospitals on four continents from 1990 to 2020. There were 984 BHE patients. The most common diagnosis was dilated cardiomyopathy (n = 318, 32.3%), followed by congenital heart disease (n = 249, 25.3%). There were 85 (8.6%) children explanted with favorable outcomes. The underlying diagnosis was known in 44 (51.8%) cases: 14 (8.4%) of 166 cardiomyopathies, 17 (48.6%) of 35 myocarditis, and 12 (16.7%) of 72 with congenital heart disease were explanted. When the type of support was known, the rate of LVAD patients explanted was 21.3% (n = 19/89) and 2.4% (n = 1/42) of BiVAD patients were explanted. CONCLUSION: Explantation from BHE is not uncommon at 8.6%, but significant variation exists in the explantation data reported. Myocarditis and LVAD support may be populations suitable for weaning. Standardization of reporting measures and prospective registries may help identify patients suitable for this alternative to transplant and help develop weaning protocols.

Percutaneous intravascular micro-axial blood pump: current state and perspective from engineering view.

The utilization of a minimally invasively placed catheter-mounted intravascular micro-axial flow blood pump (IMFBP) is increasing in the population with advanced heart failure. The current development of IMFBPs dates back around the 1990s, namely the Hemopump with a wire-drive system and the Valvopump with a direct-drive system. The wire-drive IMFBPs can use a brushless motor in an external console unit to transmit rotational force through the drive wire rotating the impeller inside the body. The direct-drive IMFBPs require an ultra-miniature and high-power brushless motor. Additionally, the direct-drive system necessitates a mechanism to protect against blood immersion into the motor. Therefore, the direct-drive IMFBPs can be categorized into two types of devices: those with seal mechanisms or those with sealless mechanisms using magnetically coupling. The IMFBPs can be classified into two groups depending on their purpose. One group is for cardiogenic shock following a heart attack or for use in high-risk percutaneous coronary intervention (PCI), and the other group serves the purpose of acute decompensated heart failure. Both direct-drive IMFBPs and wire-drive IMFBPs have their own advantages and disadvantages, and efforts are being made to develop and improve, and clinically implement them, leveraging their own strengths. In addition, there is a possibility that innovative new devices may be invented. For researchers in the field of artificial heart development, IMFBPs offer a new area of research and development, providing a novel treatment option for severe heart failure.

Tetrandrine synergizes with MAPK inhibitors in treating KRAS-mutant pancreatic ductal adenocarcinoma via collaboratively modulating the TRAIL-death receptor axis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies lacking effective therapies. KRAS mutations that occur in over 90% of PDAC are major oncogenic drivers of PDAC. The MAPK signaling pathway plays a central role in KRAS-driven oncogenic signaling. However, pharmacological inhibitors of the MAPK pathway are poorly responded in KRAS-mutant PDAC, raising a compelling need to understand the mechanism behind and to seek new therapeutic solutions. Herein, we perform a screen utilizing a library composed of 800 naturally-derived bioactive compounds to identify natural products that are able to sensitize KRAS-mutant PDAC cells to the MAPK inhibition. We discover that tetrandrine, a natural bisbenzylisoquinoline alkaloid, shows a synergistic effect with MAPK inhibitors in PDAC cells and xenograft models. Mechanistically, pharmacological inhibition of the MAPK pathway exhibits a double-edged impact on the TRAIL-death receptor axis, transcriptionally upregulating TRAIL yet downregulating its agonistic receptors DR4 and DR5, which may explain the limited therapeutic outcomes of MAPK inhibitors in KRAS-mutant PDAC. Of great interest, tetrandrine stabilizes DR4/DR5 protein via impairing ubiquitination-mediated protein degradation, thereby allowing a synergy with MAPK inhibition in inducing apoptosis in KRAS-mutant PDAC. Our findings identify a new combinatorial approach for treating KRAS-mutant PDAC and highlight the role of TRAIL-DR4/DR5 axis in dictating the therapeutic outcome in KRAS-mutant PDAC.

ALOX5 inhibition protects against dopaminergic neurons undergoing ferroptosis.

Oxidative disruption of dopaminergic neurons is regarded as a crucial pathogenesis in Parkinson's disease (PD), eventually causing neurodegenerative progression. (-)-Clausenamide (Clau) is an alkaloid isolated from plant Clausena lansium (Lour.), which is well-known as a scavenger of lipid peroxide products and exhibiting neuroprotective activities both in vivo and in vitro, yet with the in-depth molecular mechanism unrevealed. In this study, we evaluated the protective effects and mechanisms of Clau on dopaminergic neuron. Our results showed that Clau directly interacted with the Ser663 of ALOX5, the PKCα-phosphorylation site, and thus prevented the nuclear translocation of ALOX5, which was essential for catalyzing the production of toxic lipids 5-HETE. LC-MS/MS-based phospholipidomics analysis demonstrated that the oxidized membrane lipids were involved in triggering ferroptotic death in dopaminergic neurons. Furthermore, the inhibition of ALOX5 was found to significantly improving behavioral defects in PD mouse model, which was confirmed associated with the effects of attenuating the accumulation of lipid peroxides and neuronal damages. Collectively, our findings provide an attractive strategy for PD therapy by targeting ALOX5 and preventing ferroptosis in dopaminergic neurons.

Impact of 2016 UNOS pediatric heart allocation policy changes on VAD utilization, waitlist, and post-transplant survival outcomes in children with CHD versus Non-CHD.

AIMS: We analyzed the impact of the revised pediatric heart allocation policy on types of ventricular assist device (VAD) utilization, and waitlist (WL) and post-heart transplant (HT) survival outcomes in congenital heart disease (CHD) versus non-CHD patients before (Era-1) and after (Era-2) pediatric heart allocation policy implementation. METHODS: We retrospectively reviewed the UNOS database from December 16, 2011, through March 31, 2021, for patients < 18 years old and listed for primary HT. We compared the differences observed between Era-1 and Era-2. RESULTS: 5551 patients were listed for HT, of whom 2447(44%) were in Era-1 and 3104(56%) were in Era-2. CHD patients were listed as status 1A unchanged, but the number of patients listed as status 1B decreased in Era-2, whereas the number of non-CHD patients listed as status 1A decreased, but status 1B increased. In Era-2 compared to Era-1, both temporary (1% to 4%, p < .001) and durable VAD (13.6% to 17.8%, p < .001) utilization increased, and the transplantation rate per 100-patient years increased in both groups. The median WL period for CHD patients increased marginally from 70 to 71 days (p = .06), whereas for non-CHD patients it decreased from 61 to 54 days (p < .001). Adjusted 90-day WL survival increased from 84% to 88%, p = .016 in CHD, but there was no significant change in non-CHD patients (p = .57). There was no significant difference in 1-year post-HT survival in CHD and non-CHD patients between Era-1 and Era-2. CONCLUSIONS: In summary, after the revised heart allocation policy implementation, temporary and durable VAD support increased, HT rate increased, waitlist duration marginally increased in the CHD cohort and decreased in the non-CHD cohort, and 90-day WL survival probability improved in children with CHD without significant change in 1-year post-HT outcomes. Future studies are needed to identify changes to the policy that may further improve the listing criteria to improve WL duration and post-HT survival.

Use of implantable cardioverter-defibrillator in children supported with ventricular assist device: An analysis of data from the EUROMACS registry.

BACKGROUND: Data on the use and outcome of children on ventricular assist device (VAD) support provided with an implantable cardioverter-defibrillator (ICD) remains poor. METHODS: A retrospective analysis of the EUROMACS database on children supported with VAD < 19 years of age from January 1, 2009 to April 1, 2020. Patients with missing data on status of ICD, missing baseline and/or follow up information were excluded. The primary independent variable of interest was the concomitant presence or absence of an ICD at the time of VAD placement. Kaplan-Meier survival analysis was performed to evaluate survival differences between children on VAD with and without an ICD. RESULTS: Out of 303 patients provided with a VAD, 7% (7♀, 15♂) had an ICD implanted and formed the study group. Median age was 14 years, median weight was 43.5 kg, and median BSA was 1.39. Median Intermacs stage was 2 (range: 1-7). Seventeen patients (77%) were transplanted, 4 (18%) died while on support, and 1 (5%) was weaned from device after myocardial recovery. Median time on support was 68 days compared to 361 days in the control group (p: 0.01). Three patients underwent device exchange due to thrombus formation in the pump. There was no difference in survival between groups (p = 0.342). CONCLUSION: The presence of ICD in pediatric patients supported with a VAD is low (7%). Children on VAD support provided with an ICD do not have a survival benefit compared to children without an ICD.

Insights into the daily life of ventricular assist device coordinators: Outcome of an international questionnaire.

BACKGROUND: As the incidence of heart failure in developed countries is on the rise, mechanical circulatory support (MCS) often remains the only treatment option for patients with end-stage heart failure and is well established worldwide. Even though VAD coordinators play a key role in VAD programs, their responsibilities and daily duties are not clearly defined and characterized. Recently published data from the first 5-year multicenter clinical trial assessing experience with the HeartMate 3 left ventricular system (Abbott, Abbott Park, IL) show an overall survival of 61% at 5 years. When it comes to possible improvements to these systems, it is necessary for developers not only to know the status quo but also to determine and consider the visions and wishes of those individuals who take care of patients, provide education and deal with possible complications. This would be helpful a meaningful effort towards implementing a standard of care. METHODS: To fill this knowledge gap, we conducted an online survey using the SurveyMonkey tool, addressing representatives of programs implanting VADs worldwide. Representatives answered a standardized block of 14 questions and were asked to provide responses within 3 months. RESULTS: A total of 91 VAD coordinators from centers of various regions of the world completed the survey. The majority came from European countries. The numbers of patients followed up by the centers ranged from <20 to 390 patients. The majority of VAD coordinators had a nursing background (68%). Seventy-seven percent of the centers operate a 24-h hotline and 3-monthly visits to the outpatient department are most common. Fifty-nine percent of the centers do not use an infection scoring system for driveline wound care. The majority of the centers indicated that an optimized follow-up concept including wound care, medication, and social care is crucial and the key issue for an improved outcome. Smaller components and intensified psychosocial support ranked highest in questions about how to improve quality of life. Surprisingly, the future prospects of telemetric monitoring were not rated high in significance. CONCLUSIONS: There is a wide variability in the composition and tasks of VAD programs worldwide. Implementing a standard of care and improving psychosocial care as well as equipment is regarded most important to improve outcomes and quality of life. From the point of view of those responsible, the significance of telemetric monitoring seemed overrated.

Outcomes of systemic bivalirudin and sodium bicarbonate purge solution for Impella 5.5.

BACKGROUND: Impella 5.5 (Abiomed; Danvers, MA) (IMP5) is a commonly used, surgically implanted, tMCS device that requires systemic anticoagulation and purge solution to avoid pump failure. To avoid heparin-induced thrombocytopenia (HIT) from unfractionated heparin (UFH) use, our program has explored the utility of bivalirudin (BIV) for systemic anticoagulation and sodium bicarbonate-dextrose purge solution (SBPS) in IMP5.5. METHODS: This single center, retrospective study included 34 patients supported on IMP5.5 with BIV based AC and SBPS between December 1st 2020 to December 1st 2021.The efficacy and safety end points were incidence of development of HIT, Tissue Plasminogen Activator (tPA) use for suspected pump thrombosis, stroke, and device failure as well as clinically significant bleeding. RESULTS: The median duration of IMP5.5 support was 9.8 days (IQR: 6-15). Most patients were bridged to HTX (58%) followed by recovery (27%) and LVAD implantation (15%). Patients were therapeutic on bivalirudin for 64% of their IMP5.5 support. One patient (2.9%) suffered from ischemic stroke and 26.5% (9) patients developed clinically significant bleeding. tPA was administered to 7(21%) patients. One patient in the entire cohort developed HIT. CONCLUSIONS: Our experience supports the use of systemic BIV and SBPS as a method to avoid heparin exposure in a patient population predisposed to the development of HIT.

Support with Single Ventricle-Ventricular Assist Device (sVAD) in Patients with Functionally Univentricular Circulation Prior to Fontan Operation.

Some patients with functionally univentricular circulation develop cardiac failure refractory to maximal management and are supported with a ventricular assist device (VAD). The purpose of this manuscript is to summarize our previous publications related to single ventricle-ventricular assist device (sVAD) support in patients with functionally univentricular circulation and to describe our current institutional approach at University of Florida to sVAD support in neonates, infants, and children prior to Fontan. Our programmatic philosophy at University of Florida is to strive to identify the minority of neonates with functionally univentricular circulation who are extremely high-risk prior to initiating staged palliation and to stabilize these neonates with primary preemptive sVAD in preparation for cardiac transplantation; our rationale for this approach is related to the challenges associated with failed staged palliation and subsequent bail-out sVAD support and transplantation. A subset of extremely high-risk neonates and infants with functionally univentricular ductal-dependent circulation undergo primary preemptive sVAD insertion and subsequent cardiac transplantation. Support with VAD clearly facilitates survival on the waiting list during prolonged wait times and optimizes outcomes after Norwood (Stage 1) by providing an alternative pathway for extremely high-risk patients. Therefore, the selective utilization of sVAD in extremely high-risk neonates facilitates improved outcomes for all patients with functionally univentricular ductal-dependent circulation. At University of Florida, our programmatic approach to utilizing sVAD support as a bridge to transplantation in the minority of neonates with functionally univentricular circulation who are extremely high-risk for staged palliation is associated with Operative Mortality after Norwood (Stage 1) Operation of 2.9% (2/68) and a one-year survival of 91.1% (82/90) for all neonates presenting with hypoplastic left heart syndrome (HLHS) or HLHS-related malformation with functionally univentricular ductal-dependent systemic circulation. Meanwhile, at University of Florida, for all 82 consecutive neonates, infants, and children supported with pulsatile paracorporeal VAD: Kaplan-Meier survival estimated one year after VAD insertion = 73.3% (95% confidence interval [CI] = 64.1-83.8%), and Kaplan-Meier survival estimated five years after VAD insertion = 68.3% (95% CI = 58.4-79.8%). For all 48 consecutive neonates, infants, and children at University of Florida with biventricular circulation supported with pulsatile paracorporeal VAD: Kaplan-Meier survival estimated one year after VAD insertion = 82.7% (95% CI = 72.4-94.4%), and Kaplan-Meier survival estimated five years after VAD insertion = 79.7% (95% CI = 68.6-92.6%). For all 34 consecutive neonates, infants, and children at University of Florida with functionally univentricular circulation supported with pulsatile paracorporeal sVAD: Kaplan-Meier survival estimated one year after VAD insertion = 59.7% (95% CI = 44.9-79.5%), and Kaplan-Meier survival estimated five years after VAD insertion = 50.5% (95% CI = 35.0-73.0%). These Kaplan-Meier survival estimates for patients supported with pulsatile paracorporeal VAD are better in patients with biventricular circulation in comparison to patients with functionally univentricular circulation both one year after VAD insertion (P=0.026) and five years after VAD insertion (P=0.010). Although outcomes after VAD support in functionally univentricular patients are worse than in patients with biventricular circulation, sVAD provides a reasonable chance for survival. Ongoing research is necessary to improve the outcomes of these challenging patients, with the goal of developing strategies where outcomes after sVAD support in functionally univentricular patients are equivalent to the outcomes achieved after VAD support in patients with biventricular circulation.

Numerical simulation of the leakage flow of the hydrodynamically levitated centrifugal blood pump for extracorporeal mechanical circulatory support systems.

Extracorporeal centrifugal pumps are widely used in various forms of mechanical circulatory support, including extracorporeal membrane oxygenation and ventricular assist device. A durable centrifugal pump was developed by implementing a new hydrodynamic bearing design that prevents the impeller from touching to the casing wall and provides sufficient washout through the pump to prevent thrombus formation in the pump. The hydrodynamic bearings of the pump are composed of dual annular paths located on both sides of the impeller. Computational fluid dynamics analyses were performed on the flow field inside the pump to estimate the leakage flow through the gap and its impact on the pump efficiency and biocompatibility. The calculations were performed for motor speeds from 3000 to 5000 rpm and flow rates from 1.0 to 9.0 L/min. The leakage flow increased linearly with increasing pressure head of the pump, and the total leakage flow ranged from 2.0 to 27.3% of the total flow. The average wall shear stresses in the casing bottom ranged from 10.6 to 40.9 Pa. The leakage flow of the centrifugal pump with the hydrodynamically levitated impeller had a measurable impact on hydraulic energy losses while enhancing the washout flow to achieve good anti-thrombogenicity.

Japan should initiate the discussion on voluntary assisted dying legislation now.

BACKGROUND: No laws or official guidelines govern voluntary assisted dying (VAD) in Japan. A legislative bill on the termination of life-sustaining measures has yet to be sent to deliberations for legislation, due to strong opposition that has prevented it from being submitted to the Diet. However, Japan has recently witnessed several cases involving VAD. MAIN TEXT: Against this backdrop, we argue that Japan should begin discussion on VAD legislation, referring to the Voluntary Assisted Dying Act 2017 (VADA2017), which was established in 2017 in Victoria, Australia. VADA2017 puts in place a wide range of stringent safeguards and is considered worldwide to be the safest and most conservative policy on a physician offering assisted dying based on the patient's premeditated request. We consider what opposing opinions from society would arise in response to the VADA2017. Among these will include arguments against VAD itself, those against the validation of this act, and opinions that oppose even the initiation of the dialogue on VAD. CONCLUSIONS: We conclude that to protect the right to life among those placed in vulnerable positions and, at the same time, to respect decision-making of those who wish for immediate death due to unbearable suffering, the dialogue must immediately begin with that on introducing a policy more conservative than that of the VADA2017, which solidly considers arguments against VAD.

A multipurpose Extracorporeal Life Support Circuit: a concept for multiorgan transplant and circulatory support service Healthcare provider.

The demand for efficient and adaptable life support systems in the field of Extracorporeal Life Support (ECLS) is steadily increasing. To meet this growing need, there is a requirement for a versatile extracorporeal life support circuit that can be effectively applied in various medical scenarios, especially in tertiary hospitals where multiple ECLS services are utilized. These services include Extracorporeal Membrane Oxygenation (ECMO) for addressing respiratory or cardiac problems, Ventricular Assist Device (VAD) as a bridge to recovery or heart transplant, and Venovenous Bypass (VVB) for assisting liver transplantation. In light of this, we propose the creation of a multipurpose circuit that integrates multiple extracorporeal life support (ECLS) functions to cater to diverse medical needs. This innovative circuit not only offers cost-effectiveness and enhanced safety but also ensures optimal utilization, thereby revolutionizing the realm of life support technologies.

Exploratory Transcriptomic Profiling Reveals the Role of Gut Microbiota in Vascular Dementia.

Stroke is the second most common cause of cognitive impairment and dementia. Vascular dementia (VaD), a cognitive impairment following a stroke, is common and significantly impacts the quality of life. We recently demonstrated via gut microbe transplant studies that the gut microbe-dependent trimethylamine-N-oxide (TMAO) pathway impacts stroke severity, both infarct size and long-term cognitive outcomes. However, the molecular mechanisms that underly the role of the microbiome in VaD have not been explored in depth. To address this issue, we performed a comprehensive RNA-sequencing analysis to identify differentially expressed (DE) genes in the ischemic cerebral cortex of mouse brains at pre-stroke and post-stroke day 1 and day 3. A total of 4016, 3752 and 7861 DE genes were identified at pre-stroke and post-stroke day 1 and day 3, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated pathways of neurodegeneration in multiple diseases, chemokine signaling, calcium signaling, and IL-17 signaling as the key enriched pathways. Inflammatory response genes interleukin-1 beta (Il-1ß), chemokines (C-X-C motif chemokine ligand 10 (Cxcl10), chemokine ligand 2 (Ccl2)), and immune system genes (S100 calcium binding protein 8 (S100a8), lipocalin-2 (Lcn2)) were among the most significantly upregulated genes. Hypocretin neuropeptide precursor (Hcrt), a neuropeptide, and transcription factors such as neuronal PAS domain protein 4 (Npas4), GATA binding protein 3 (Gata3), and paired box 7 (Pax7) were among the most significantly downregulated genes. In conclusion, our results indicate that higher plasma TMAO levels induce differential mRNA expression profiles in the ischemic brain tissue in our pre-clinical stroke model, and the predicted pathways provide the molecular basis for regulating the TMAO-enhanced neuroinflammatory response in the brain.

Endothelial Dysfunction in Neurodegenerative Diseases.

The cerebral vascular system stringently regulates cerebral blood flow (CBF). The components of the blood-brain barrier (BBB) protect the brain from pathogenic infections and harmful substances, efflux waste, and exchange substances; however, diseases develop in cases of blood vessel injuries and BBB dysregulation. Vascular pathology is concurrent with the mechanisms underlying aging, Alzheimer's disease (AD), and vascular dementia (VaD), which suggests its involvement in these mechanisms. Therefore, in the present study, we reviewed the role of vascular dysfunction in aging and neurodegenerative diseases, particularly AD and VaD. During the development of the aforementioned diseases, changes occur in the cerebral blood vessel morphology and local cells, which, in turn, alter CBF, fluid dynamics, and vascular integrity. Chronic vascular inflammation and blood vessel dysregulation further exacerbate vascular dysfunction. Multitudinous pathogenic processes affect the cerebrovascular system, whose dysfunction causes cognitive impairment. Knowledge regarding the pathophysiology of vascular dysfunction in neurodegenerative diseases and the underlying molecular mechanisms may lead to the discovery of clinically relevant vascular biomarkers, which may facilitate vascular imaging for disease prevention and treatment.