Aortic Valve Calcification Density Measured by MDCT in the Assessment of Aortic Stenosis Severity.

BACKGROUND: Aortic valve calcification (AVC) indexation to the aortic annulus (AA) area measured by Doppler echocardiography (AVCdEcho) provides powerful prognostic information in patients with aortic stenosis (AS). However, the indexation by AA measured by multidetector computed tomography (AVCdCT) has never been evaluated. The aim of this study was to compare AVC, AVCdCT, and AVCdEcho with regard to hemodynamic correlations and clinical outcomes in patients with AS. METHODS: Data from 889 patients, mainly White, with calcific AS who underwent Doppler echocardiography and multidetector computed tomography within the same episode of care were retrospectively analyzed. AA was measured both by Doppler echocardiography and multidetector computed tomography. AVCdCT severity thresholds were established using receiver operating characteristic curve analyses in men and women separately. The primary end point was the occurrence of all-cause mortality. RESULTS: Correlations between gradient/velocity and AVCd were stronger (both P≤0.005) using AVCdCT (r=0.68, P<0.001 and r=0.66, P<0.001) than AVC (r=0.61, P<0.001 and r=0.60, P<0.001) or AVCdEcho (r=0.61, P<0.001 and r=0.59, P<0.001). AVCdCT thresholds for the identification of severe AS were 334 Agatston units (AU)/cm2 for women and 467 AU/cm2 for men. On a median follow-up of 6.62 (6.19-9.69) years, AVCdCT ratio was superior to AVC ratio and AVCdEcho ratio to predict all-cause mortality in multivariate analyses (hazard ratio [HR], 1.59 [95% CI, 1.26-2.00]; P<0.001 versus HR, 1.53 [95% CI, 1.11-1.65]; P=0.003 versus HR, 1.27 [95% CI, 1.11-1.46]; P<0.001; all likelihood test P≤0.004). AVCdCT ratio was superior to AVC ratio and AVCdEcho ratio to predict survival under medical treatment in multivariate analyses (HR, 1.80 [95% CI, 1.27-1.58]; P<0.001 compared with HR, 1.55 [95% CI, 1.13-2.10]; P=0.007; HR, 1.28 [95% CI, 1.03-1.57]; P=0.01; all likelihood test P<0.03). AVCdCT ratio predicts mortality in all subgroups of patients with AS. CONCLUSIONS: AVCdCT appears to be equivalent or superior to AVC and AVCdEcho to assess AS severity and predict all-cause mortality. Thus, it should be used to evaluate AS severity in patients with nonconclusive echocardiographic evaluations with or without low-flow status. AVCdCT thresholds of 300 AU/cm2 for women and 500 AU/cm2 for men seem to be appropriate to identify severe AS. Further studies are needed to validate these thresholds, especially in diverse populations.

Gamma entrainment using audiovisual stimuli alleviates chemobrain pathology and cognitive impairment induced by chemotherapy in mice.

Patients with cancer undergoing chemotherapy frequently experience a neurological condition known as chemotherapy-related cognitive impairment, or "chemobrain," which can persist for the remainder of their lives. Despite the growing prevalence of chemobrain, both its underlying mechanisms and treatment strategies remain poorly understood. Recent findings suggest that chemobrain shares several characteristics with neurodegenerative diseases, including chronic neuroinflammation, DNA damage, and synaptic loss. We investigated whether a noninvasive sensory stimulation treatment we term gamma entrainment using sensory stimuli (GENUS), which has been shown to alleviate aberrant immune and synaptic pathologies in mouse models of neurodegeneration, could also mitigate chemobrain phenotypes in mice administered a chemotherapeutic drug. When administered concurrently with the chemotherapeutic agent cisplatin, GENUS alleviated cisplatin-induced brain pathology, promoted oligodendrocyte survival, and improved cognitive function in a mouse model of chemobrain. These effects persisted for up to 105 days after GENUS treatment, suggesting the potential for long-lasting benefits. However, when administered to mice 90 days after chemotherapy, GENUS treatment only provided limited benefits, indicating that it was most effective when used to prevent the progression of chemobrain pathology. Furthermore, we demonstrated that the effects of GENUS in mice were not limited to cisplatin-induced chemobrain but also extended to methotrexate-induced chemobrain. Collectively, these findings suggest that GENUS may represent a versatile approach for treating chemobrain induced by different chemotherapy agents.

Unique Aspects of Women's Valvular Heart Diseases: Impact for Diagnosis and Treatment.

Valvular heart diseases (VHDs) are a major cause of cardiovascular morbidity and mortality worldwide. As degenerative and functional mechanisms represent the main etiologies in high-income countries are degenerative and functional, while in low income countries etiologie is mostly rheumatic. Although therapeutic options have evolved considerably in recent years, women are consistently diagnosed at later stages of their disease, are delayed in receiving surgical referrals, and exhibit worse postoperative outcomes, compared to men. This difference is a result of the historical underrepresentation of women in studies from which current guidelines were developed. However, in recent years, important research, including more female patients, has been conducted and has highlighted substantial sex-specific differences in the etiology, diagnosis, and treatment of VHDs. Systematic consideration of these sex-specific differences in VHD patients is crucial for providing equitable healthcare and optimizing clinical outcomes in both female and male patients. Hence, this review aims to explore implications of sex-specific particularities for diagnosis, treatment options, and outcomes in women with VHDs.

Les valvulopathies sont une cause majeure de morbidité cardiovasculaire et de mortalité dans le monde. Les mécanismes dégénératifs et fonctionnels représentent maintenant les principales étiologies dans les pays à revenu élevé, mais la maladie valvulaire rhumatismale demeure très prévalente dans les pays à revenu faible. Par ailleurs, même si les options thérapeutiques ont évolué depuis quelques années, les femmes reçoivent systématiquement leur diagnostic à des stades plus avancés de la maladie, sont orientées plus tard en chirurgie et les issues postopératoires sont moins favorables par rapport aux hommes. Cette différence s'explique par une sous-représentation historique des femmes dans les études sur lesquelles reposent les lignes directrices actuelles. Cependant, des études importantes réalisées ces dernières années ont mis au jour des différences substantielles entre les sexes en ce qui a trait à l'étiologie, au diagnostic et au traitement des valvulopathies. Il est essentiel de tenir compte des différences selon le sexe chez les patients atteints d'une valvulopathie pour fournir des soins de santé équitables et optimiser l'issue clinique tant chez les femmes que chez les hommes. Cette analyse vise donc à explorer les implications des particularités selon le sexe en ce qui concerne le diagnostic, les options thérapeutiques et les issues chez les femmes atteintes de valvulopathies.

Multisensory gamma stimulation promotes glymphatic clearance of amyloid.

The glymphatic movement of fluid through the brain removes metabolic waste1-4. Noninvasive 40 Hz stimulation promotes 40 Hz neural activity in multiple brain regions and attenuates pathology in mouse models of Alzheimer's disease5-8. Here we show that multisensory gamma stimulation promotes the influx of cerebrospinal fluid and the efflux of interstitial fluid in the cortex of the 5XFAD mouse model of Alzheimer's disease. Influx of cerebrospinal fluid was associated with increased aquaporin-4 polarization along astrocytic endfeet and dilated meningeal lymphatic vessels. Inhibiting glymphatic clearance abolished the removal of amyloid by multisensory 40 Hz stimulation. Using chemogenetic manipulation and a genetically encoded sensor for neuropeptide signalling, we found that vasoactive intestinal peptide interneurons facilitate glymphatic clearance by regulating arterial pulsatility. Our findings establish novel mechanisms that recruit the glymphatic system to remove brain amyloid.

Electrical stimulation affects the differentiation of transplanted regionally specific human spinal neural progenitor cells (sNPCs) after chronic spinal cord injury.

BACKGROUND: There are currently no effective clinical therapies to ameliorate the loss of function that occurs after spinal cord injury. Electrical stimulation of the rat spinal cord through the rat tail has previously been described by our laboratory. We propose combinatorial treatment with human induced pluripotent stem cell-derived spinal neural progenitor cells (sNPCs) along with tail nerve electrical stimulation (TANES). The purpose of this study was to examine the influence of TANES on the differentiation of sNPCs with the hypothesis that the addition of TANES would affect incorporation of sNPCs into the injured spinal cord, which is our ultimate goal. METHODS: Chronically injured athymic nude rats were allocated to one of three treatment groups: injury only, sNPC only, or sNPC + TANES. Rats were sacrificed at 16 weeks post-transplantation, and tissue was processed and analyzed utilizing standard histological and tissue clearing techniques. Functional testing was performed. All quantitative data were presented as mean ± standard error of the mean. Statistics were conducted using GraphPad Prism. RESULTS: We found that sNPCs were multi-potent and retained the ability to differentiate into mainly neurons or oligodendrocytes after this transplantation paradigm. The addition of TANES resulted in more transplanted cells differentiating into oligodendrocytes compared with no TANES treatment, and more myelin was found. TANES not only promoted significantly higher numbers of sNPCs migrating away from the site of injection but also influenced long-distance axonal/dendritic projections especially in the rostral direction. Further, we observed localization of synaptophysin on SC121-positive cells, suggesting integration with host or surrounding neurons, and this finding was enhanced when TANES was applied. Also, rats that were transplanted with sNPCs in combination with TANES resulted in an increase in serotonergic fibers in the lumbar region. This suggests that TANES contributes to integration of sNPCs, as well as activity-dependent oligodendrocyte and myelin remodeling of the chronically injured spinal cord. CONCLUSIONS: Together, the data suggest that the added electrical stimulation promoted cellular integration and influenced the fate of human induced pluripotent stem cell-derived sNPCs transplanted into the injured spinal cord.

A call for qualitative and mixed-methods research on gambling and cannabis.

Gambling disorder and cannabis use disorder are both considered major public health issues. Despite the well-documented frequency of substance use disorders among people with gambling disorder, little is known about the experiences of those who both engage with gambling and cannabis. A scoping review was undertaken to investigate studies focusing on the experiences of people who gamble and use cannabis. Unexpectedly, no qualitative or mixed-methods studies that included an in-depth qualitative component to study the lived experiences of this population were found. This absence highlights the critical need to diversify research methods and fill the gap in knowledge of the lived experiences of people who both gamble and consume cannabis.

Qualitative Experience of Self-Exclusion Programs: A Scoping Review.

Gambling disorder is a major public health issue in many countries. It has been defined as a persistent, recurrent pattern of gambling and is associated with substantial distress or impairment, lower quality of life, and living with a plurality of psychiatric problems. Many people suffering from gambling disorder seek help in ways other than formal treatment seeking, including self-management strategies. One example of responsible gambling tools that has gained popularity in recent years is self-exclusion programs. Self-exclusion entails individuals barring themselves from a gambling venue or a virtual platform. The aim of this scoping review is to summarize the literature on this topic and to explore participants' perceptions and experiences with self-exclusion. An electronic literature search was conducted on 16th May 2022 in the following databases: Academic Search Complete, CINAHL Plus with Full Text, Education Source, ERIC, MEDLINE with Full Text, APA PsycArticles, Psychology and Behavioral Sciences Collection, APA PsychInfo, Social Work Abstracts, and SocINDEX. The search yielded a total of 236 articles, of which 109 remained after duplicates were removed. After full-text reading, six articles were included in this review. The available literature shows that although there are many barriers and limitations to the current self-exclusion programs, self-exclusion is generally viewed as an effective responsible gambling strategy. There is a clear need to improve the current programs by increasing awareness, publicity, availability, staff training, off-site venue exclusion, and technology-assisted monitoring, as well as by adopting more holistic management approaches to gambling disorders in general.

Emerging Applications of Extracardiac Ultrasound in Critically Ill Cardiac Patients.

Point-of-care ultrasound has evolved as an invaluable diagnostic modality and procedural guidance tool in the care of critically ill cardiac patients. Beyond focused cardiac ultrasound, additional extracardiac ultrasound modalities may provide important information at the bedside. In addition to new uses of existing modalities, such as pulsed-wave Doppler ultrasound, the development of new applications is fostered by the implementation of additional features in mid-range ultrasound machines commonly acquired for intensive care units, such as tissue elastography, speckle tracking, and contrast-enhanced ultrasound quantification software. This review explores several areas in which ultrasound imaging technology may transform care in the future. First, we review how lung ultrasound in mechanically ventilated patients can enable the personalization of ventilator parameters and help to liberate them from mechanical ventilation. Second, we review the role of venous Doppler in the assessment of organ congestion and how tissue elastography may complement this application. Finally, we explore how contrast-enhanced ultrasound could be used to assess changes in organ perfusion.

Enhanced SHP-1 Expression in Podocyturia Is Associated with Kidney Dysfunction in Patients with Diabetes.

Background: Diabetic kidney disease (DKD) remains the leading cause of end stage kidney disease worldwide. Despite significant advances in kidney care, there is a need to improve noninvasive techniques to predict the progression of kidney disease better for patients with diabetes. After injury, podocytes are shed in urine and may be used as a biologic tool. We previously reported that SHP-1 is upregulated in the kidney of diabetic mice, leading to podocyte dysfunction and loss. Our objective was to evaluate the expression levels of SHP-1 in urinary podocytes and kidney tissues of patients with diabetes. Methods: In this prospective study, patients with and without diabetes were recruited for the quantification of SHP-1 in kidney tissues, urinary podocytes, and peripheral blood monocytes. Immunochemistry and mass spectrometry techniques were applied for kidney tissues. Urinary podocytes were counted, and expression of SHP-1 and podocyte markers were measured by quantitative PCR. Results: A total of 66 participants (diabetic n=48, nondiabetic n=18) were included in the analyses. Diabetes was associated with increased SHP-1 expression in kidney tissues (P=0.03). Nephrin and podocin mRNA was not significantly increased in urinary podocytes from patients with diabetes compared with those without diabetes, whereas levels of SHP-1 mRNA expression significantly correlated with HbA1c and estimated glomerular filtration rate (eGFR). Additionally, follow-up (up to 2 years post recruitment) evaluation indicated that SHP-1 mRNA expression continued to increase with eGFR decline. Conclusions: Levels of SHP-1 in urinary podocytes may serve as an additional marker of glomerular disease progression in this population.

APOE4 impairs myelination via cholesterol dysregulation in oligodendrocytes.

APOE4 is the strongest genetic risk factor for Alzheimer's disease1-3. However, the effects of APOE4 on the human brain are not fully understood, limiting opportunities to develop targeted therapeutics for individuals carrying APOE4 and other risk factors for Alzheimer's disease4-8. Here, to gain more comprehensive insights into the impact of APOE4 on the human brain, we performed single-cell transcriptomics profiling of post-mortem human brains from APOE4 carriers compared with non-carriers. This revealed that APOE4 is associated with widespread gene expression changes across all cell types of the human brain. Consistent with the biological function of APOE2-6, APOE4 significantly altered signalling pathways associated with cholesterol homeostasis and transport. Confirming these findings with histological and lipidomic analysis of the post-mortem human brain, induced pluripotent stem-cell-derived cells and targeted-replacement mice, we show that cholesterol is aberrantly deposited in oligodendrocytes-myelinating cells that are responsible for insulating and promoting the electrical activity of neurons. We show that altered cholesterol localization in the APOE4 brain coincides with reduced myelination. Pharmacologically facilitating cholesterol transport increases axonal myelination and improves learning and memory in APOE4 mice. We provide a single-cell atlas describing the transcriptional effects of APOE4 on the aging human brain and establish a functional link between APOE4, cholesterol, myelination and memory, offering therapeutic opportunities for Alzheimer's disease.

Human induced pluripotent stem cells integrate, create synapses and extend long axons after spinal cord injury.

Numerous interventions have been explored in animal models using cells differentiated from human induced pluripotent stem cells (iPSCs) in the context of neural injury with some success. Our work seeks to transplant cells that are generated from hiPSCs into regionally specific spinal neural progenitor cells (sNPCs) utilizing a novel accelerated differentiation protocol designed for clinical translation. We chose a xenotransplantation model because our laboratory is focused on the behaviour of human cells in order to bring this potential therapy to translation. Cells were transplanted into adult immunodeficient rats after moderate contusion spinal cord injury (SCI). Twelve weeks later, cells derived from the transplanted sNPCs survived and differentiated into neurons and glia that filled the lesion cavity and produced a thoracic spinal cord transcriptional program in vivo. Furthermore, neurogenesis and ionic channel expression were promoted within the adjacent host spinal cord tissue. Transplanted cells displayed robust integration properties including synapse formation and myelination by host oligodendrocytes. Axons from transplanted hiPSC sNPC-derived cells extended both rostrally and caudally from the SCI transplant site, rostrally approximately 6 cm into supraspinal structures. Thus, iPSC-derived sNPCs may provide a patient-specific cell source for patients with SCI that could provide a relay system across the site of injury.

Regionally Specific Human Pre-Oligodendrocyte Progenitor Cells Produce Both Oligodendrocytes and Neurons after Transplantation in a Chronically Injured Spinal Cord Rat Model after Glial Scar Ablation.

Chronic spinal cord injury (SCI) is a devastating medical condition. In the acute phase after injury, there is cell loss resulting in chronic axonal damage and loss of sensory and motor function including loss of oligodendrocytes that results in demyelination of axons and further dysfunction. In the chronic phase, the inhibitory environment within the lesion including the glial scar can arrest axonal growth and regeneration and can also potentially affect transplanted cells. We hypothesized that glial scar ablation (GSA) along with cell transplantation may be required as a combinatorial therapy to achieve functional recovery, and therefore we proposed to examine the survival and fate of human induced pluripotent stem cell (iPSC) derived pre-oligodendrocyte progenitor cells (pre-OPCs) transplanted in a model of chronic SCI, whether this was affected by GSA, and whether this combination of treatments would result in functional recovery. In this study, chronically injured athymic nude (ATN) rats were allocated to one of three treatment groups: GSA only, pre-OPCs only, or GSA+pre-OPCs. We found that human iPSC derived pre-OPCs were multi-potent and retained the ability to differentiate into mainly oligodendrocytes or neurons when transplanted into the chronically injured spinal cords of rats. Twelve weeks after cell transplantation, we observed that more of the transplanted cells differentiated into oligodendrocytes when the glial scar was ablated compared with no GSA. Further, we also observed that a higher percentage of transplanted cells differentiated into V2a interneurons and motor neurons in the pre-OPCs only group when compared with GSA+pre-OPCs. This suggests that the local environment created by ablation of the glial scar may have a significant effect on the fate of cells transplanted into the injury site.

3D Printed Neural Regeneration Devices.

Neural regeneration devices interface with the nervous system and can provide flexibility in material choice, implantation without the need for additional surgeries, and the ability to serve as guides augmented with physical, biological (e.g., cellular), and biochemical functionalities. Given the complexity and challenges associated with neural regeneration, a 3D printing approach to the design and manufacturing of neural devices could provide next-generation opportunities for advanced neural regeneration via the production of anatomically accurate geometries, spatial distributions of cellular components, and incorporation of therapeutic biomolecules. A 3D printing-based approach offers compatibility with 3D scanning, computer modeling, choice of input material, and increasing control over hierarchical integration. Therefore, a 3D printed implantable platform could ultimately be used to prepare novel biomimetic scaffolds and model complex tissue architectures for clinical implants in order to treat neurological diseases and injuries. Further, the flexibility and specificity offered by 3D printed in vitro platforms have the potential to be a significant foundational breakthrough with broad research implications in cell signaling and drug screening for personalized healthcare. This progress report examines recent advances in 3D printing strategies for neural regeneration as well as insight into how these approaches can be improved in future studies.

Safety and Efficacy of Rose Bengal Derivatives for Glial Scar Ablation in Chronic Spinal Cord Injury.

There are no effective therapies available currently to ameliorate loss of function for patients with spinal cord injuries (SCIs). In addition, proposed treatments that demonstrated functional recovery in animal models of acute SCI have failed almost invariably when applied to chronic injury models. Glial scar formation in chronic injury is a likely contributor to limitation on regeneration. We have removed existing scar tissue in chronically contused rat spinal cord using a rose Bengal-based photo ablation approach. In this study, we compared two chemically modified rose bengal derivatives to unmodified rose bengal, both confirming and expanding on our previously published report. Rats were treated with unmodified rose bengal (RB1) or rose bengal modified with hydrocarbon (RB2) or polyethylene glycol (RB3), to determine the effects on scar components and spared tissue post-treatment. Our results showed that RB1 was more efficacious than RB2, while still maintaining minimal collateral effects on spared tissue. RB3 was not taken up by the cells, likely because of its size, and therefore had no effect. Treatment with RB1 also resulted in an increase in serotonin eight days post-treatment in chronically injured spinal cords. Thus, we suggest that unmodified rose Bengal is a potent candidate agent for the development of a therapeutic strategy for scar ablation in chronic SCI.