Descending Thoracic and Thoracoabdominal Aortic Aneurysm Repairs: The Society of Thoracic Surgeons Adult Cardiac Surgery Database Analysis.

BACKGROUND: Contemporary national outcomes of open and endovascular aortic repair for descending thoracic aortic aneurysms (DTAAs) and thoracoabdominal aortic aneurysms (TAAAs) are unclear. This study evaluated this issue by using The Society of Thoracic Surgeons (STS) Adult Cardiac Surgery Database (ACSD). METHODS: From July 1, 2017 to June 30, 2022, study investigators identified 3522 adults who underwent planned DTAA repair (open, 328; endovascular, 1895) or TAAA repair (open, 870; endovascular, 429), after excluding ascending aorta or aortic arch aneurysms (zone 0, 1, or 2), interventions with a proximal extent in zone 0 or zone 1, juxtarenal or infrarenal aortic interventions, hybrid procedures, aortic trauma, and aortic infection. RESULTS: Most DTAA interventions (85.2%) were endovascular repairs, whereas most TAAA interventions were open repairs (66.9%). For DTAA interventions, the operative mortality, permanent stroke rate, and rate of spinal cord injury were 4.2%, 3.8%, and 2.4% for endovascular repairs and 9.2%, 8.5%, and 4.6% for open repairs, respectively (all P < .05). For TAAA interventions, the operative mortality, permanent stroke rate, and rate of spinal cord injury were 6.5%, 2.1%, and 3.0% for endovascular repairs and 11.7%, 6.0%, and 12.2% for open repairs, respectively (all P < .05). Increasing annual open TAAA repair volume was associated with lower odds of experiencing the composite of operative mortality, permanent stroke, or spinal cord injury. CONCLUSIONS: On the basis of STS ACSD data, endovascular repair was the predominant approach for treating DTAA, whereas most patients undergoing TAAA interventions had an open surgical repair. Outcome differences between open and endovascular approaches may be related to patient selection. Increasing center experience with open TAAA repair is associated with improved outcomes.

Cytosolic antibody receptor TRIM21 is required for effective tau immunotherapy in mouse models.

Aggregates of the protein tau are proposed to drive pathogenesis in neurodegenerative diseases. Tau can be targeted by using passively transferred antibodies (Abs), but the mechanisms of Ab protection are incompletely understood. In this work, we used a variety of cell and animal model systems and showed that the cytosolic Ab receptor and E3 ligase TRIM21 (T21) could play a role in Ab protection against tau pathology. Tau-Ab complexes were internalized to the cytosol of neurons, which enabled T21 engagement and protection against seeded aggregation. Ab-mediated protection against tau pathology was lost in mice that lacked T21. Thus, the cytosolic compartment provides a site of immunotherapeutic protection, which may help in the design of Ab-based therapies in neurodegenerative disease.

Five-year outcomes of endovascular repair of complicated acute type B aortic dissections.

OBJECTIVE: Thoracic endovascular aortic repair is the standard of care for acute complicated type B aortic dissections, but long-term single-device outcomes are limited. METHODS: Fifty patients were treated with the Valiant Captivia thoracic stent graft (Medtronic Inc, Santa Rosa, Calif) for acute complicated type B aortic dissections in this prospective, nonrandomized Dissection Trial. All-cause mortality, secondary procedures, and serious adverse events were assessed, and a core lab evaluated images for aortic remodeling. RESULTS: Compliance for both clinical and imaging follow-up was 78% (18 out of 23) for the available patients at 5 years. Notable baseline characteristics were 86% of patients (43 out of 50) had malperfusion, 20% (10 out of 50) had ruptures, and 94% (46 out of 49) had DeBakey class IIIB dissections. The 5-year freedom from dissection-related mortality, secondary procedures related to the dissection, and endoleaks was 83%, 86%, and 85%, respectively. After 5 years, 89% of patients (16 out of 18) had a completely thrombosed false lumen in the stented segment of the aorta and the true lumen diameter over the length of stent graft was stable or increased for 94% of patients (16 out of 17) while the false lumen diameter was stable or decreased in 77% (13 out of 17) after 5 years. CONCLUSIONS: In the Dissection Trial, patients experienced positive and sustained measures of aortic remodeling. Survival outcomes, need for secondary procedures, and adverse event rates were consistent with previous thoracic endovascular aortic repair studies. Although limitations exist with the follow-up compliance, the Valiant Captivia thoracic stent graft system was effective in the long-term management of acute complicated type B aortic dissections in this patient population with a challenging condition.

Targeted protein degradation using intracellular antibodies and its application to neurodegenerative disease.

Antibodies mediate the majority of their effects in the extracellular domain, or in intracellular compartments isolated from the cytosol. Under a growing list of circumstances, however, antibodies are found to gain access to the cytoplasm. Cytosolic immune complexes are bound by the atypical antibody receptor TRIM21, which mediates the rapid degradation of the immune complexes at the proteasome. These discoveries have informed the development of TRIM-Away, a technique to selectively deplete proteins using delivery of antibodies into cells. A range of related approaches that elicit selective protein degradation using intracellular constructs linking antibody fragments to degradative effector functions have also been developed. These methods hold promise for inducing the degradation of proteins as both research tools and as a novel therapeutic approach. Protein aggregates are a pathophysiological feature of neurodegenerative diseases and are considered to have a causal role in pathology. Immunotherapy is emerging as a promising route towards their selective targeting, and a role of antibodies in the cytosol has been demonstrated in cell-based assays. This review will explore the mechanisms by which therapeutic antibodies engage and eliminate intracellularly aggregated proteins. We will discuss how future developments in intracellular antibody technology may enhance the therapeutic potential of such antibody-derived therapies.

Tau assemblies do not behave like independently acting prion-like particles in mouse neural tissue.

A fundamental property of infectious agents is their particulate nature: infectivity arises from independently-acting particles rather than as a result of collective action. Assemblies of the protein tau can exhibit seeding behaviour, potentially underlying the apparent spread of tau aggregation in many neurodegenerative diseases. Here we ask whether tau assemblies share with classical pathogens the characteristic of particulate behaviour. We used organotypic hippocampal slice cultures from P301S tau transgenic mice in order to precisely control the concentration of extracellular tau assemblies in neural tissue. Whilst untreated slices displayed no overt signs of pathology, exposure to recombinant tau assemblies could result in the formation of intraneuronal, hyperphosphorylated tau structures. However, seeding ability of tau assemblies did not titrate in a one-hit manner in neural tissue. The results suggest that seeding behaviour of tau arises at high concentrations, with implications for the interpretation of high-dose intracranial challenge experiments and the possible contribution of seeded aggregation to human disease.

Target-induced clustering activates Trim-Away of pathogens and proteins.

Trim-Away is a recently developed technology that exploits off-the-shelf antibodies and the RING E3 ligase and cytosolic antibody receptor TRIM21 to carry out rapid protein depletion. How TRIM21 is catalytically activated upon target engagement, either during its normal immune function or when repurposed for targeted protein degradation, is unknown. Here we show that a mechanism of target-induced clustering triggers intermolecular dimerization of the RING domain to switch on the ubiquitination activity of TRIM21 and induce virus neutralization or drive Trim-Away. We harness this mechanism for selective degradation of disease-causing huntingtin protein containing long polyglutamine tracts and expand the Trim-Away toolbox with highly active TRIM21-nanobody chimeras that can also be controlled optogenetically. This work provides a mechanism for cellular activation of TRIM RING ligases and has implications for targeted protein degradation technologies.

Successful Outcomes following Repair of a Type A Aortic Dissection during Pregnancy.

Type A aortic dissections during pregnancy are rare but lethal events, with reported mortalities as high as 60%. Unique changes in hemodynamics, hormone-related alterations in aortic tissue, and preexisting risk factors place patients at an elevated risk for dissection. We report a successful repair of a Type A aortic dissection at 32 weeks of gestation, with excellent outcomes in both mother and child. This report highlights the importance of gestational age and multidisciplinary effort.

Thoracic Endovascular Aortic Repair in Octogenarians and Nonagenarians.

BACKGROUND: The oldest segments of the population are expanding rapidly, and the number of thoracic endovascular aortic repairs (TEVARs) performed in the elderly parallels this trend. We describe our institutional TEVAR experience in octogenarians and nonagenarians. METHODS: All patients 80 years and older undergoing TEVAR at a single institution were reviewed using a prospectively maintained database. Baselines demographics, operative details, and outcomes were retrospectively analyzed. RESULTS: Twenty-five octogenarians and nonagenarians (age, 84.8 ± 3.7 years; 64% male) underwent TEVAR between January 2014 and January 2019. The most common preoperative comorbidities were hypertension (n = 24; 96%) and tobacco use (n = 18; 72%), and the mean modified frailty index was 0.32 ± 0.17. Degenerative aneurysms constituted the majority of aortic pathologies (60%), and most patients were symptomatic (64%), with a mean maximal aortic diameter of 62.7 ± 15.6 mm. Endoleaks were noted in 3 (12%) patients. Intensive care unit length of stay was 2.0 (1.5, 3.0) days, and the total length of stay was 5.0 (3.0, 7.0) days. In-hospital mortality was 12% (n = 3), while the overall 30-day mortality was 16% (n = 4). The median follow-up was 469.0 (76.0, 586.0) days. On univariate analysis, the presence of a postoperative complication was associated with a significantly increased risk of 30-day mortality (P < 0.01). CONCLUSIONS: Despite the inherently elevated operative risk among the elderly, this study demonstrates reasonable success rates for TEVAR in octogenarian and nonagenarian patients. In properly selected patients, advanced age alone should not be a prohibitive factor for TEVAR.

Make Sure You Have a Safety Net: Updates in the Prevention and Management of Infectious Complications in Stem Cell Transplant Recipients.

Hematopoietic stem cell transplant recipients are at increased risk of infection and immune dysregulation due to reception of cytotoxic chemotherapy; development of graft versus host disease, which necessitates treatment with immunosuppressive medications; and placement of invasive catheters. The prevention and management of infections in these vulnerable hosts is of utmost importance and a key "safety net" in stem cell transplantation. In this review, we provide updates on the prevention and management of CMV infection; invasive fungal infections; bacterial infections; Clostridium difficile infection; and EBV, HHV-6, adenovirus and BK infections. We discuss novel drugs, such as letermovir, isavuconazole, meropenem-vaborbactam and bezlotoxumab; weigh the pros and cons of using fluoroquinolone prophylaxis during neutropenia after stem cell transplantation; and provide updates on important viral infections after hematopoietic stem cell transplant (HSCT). Optimizing the prevention and management of infectious diseases by using the best available evidence will contribute to better outcomes for stem cell transplant recipients, and provide the best possible "safety net" for these immunocompromised hosts.

Use of a Dual-Filter Cerebral Embolic Protection Device in Thoracic Endovascular Aortic Repair.

BACKGROUND: The risk of periprocedural stroke after thoracic endovascular aortic repair (TEVAR) ranges from 3% to 8%. Although cerebral embolic protection devices (CEPD) are widely utilized in transcatheter aortic valve replacement, there are currently no Food and Drug Administration approved CEPDs for use in TEVAR. We report our initial experience with the off-label use of a dual-filter CEPD in patients undergoing TEVAR. METHODS: Two patients at high risk for embolic stroke underwent TEVAR for descending thoracic aortic aneurysms (DTAAs) at a single institution. A dual-filter CEPD (Sentinel; Boston Scientific, Marlborough, MA) was used in an off-label fashion in both cases. Patient 1 was a 62-year-old woman with a 6.2-cm DTAA, extending from the left subclavian artery (LSCA) to the diaphragm (Zones 3-5) and associated with extensive atherosclerotic disease of the aortic arch. Patient 2 was a 78-year-old woman with a 6.3-cm DTAA, extending from the LSCA (Zone 2) to the sixth intercostal space (Zone 4) with associated mural thrombus. Given the proximity of the aneurysm to the LSCA, a left carotid-subclavian bypass was performed for planned LSCA coverage. RESULTS: Through a percutaneous right radial artery approach using a 6F sheath, the Sentinel dual-filter CEPD was delivered over a 0.014″ guidewire into the thoracic aorta. Under fluoroscopic guidance, the 2 filters were sequentially deployed in the innominate and left common carotid arteries, respectively. Appropriately sized devices were successfully delivered and deployed in the proximal and distal landing zones, respectively. Two devices were used for each patient. Completion angiograms showed successful exclusion of the DTAAs in both cases, without evidence of endoleak. The CEPD filters were retrieved in standard fashion without difficulty. Pathology demonstrated successful capture of embolic debris and fibrin clot in both patients. Neither patient exhibited neurological deficits or device-related complications. Both patients remained neurologically intact at 1- and 2-month follow-up, respectively. Surveillance angiograms revealed successful exclusion of the aneurysm without any evidence of endoleak. CONCLUSIONS: We report the novel off-label use of a dual-filter CEPD in 2 patients undergoing TEVAR. Pathological confirmation of embolic debris in the filters makes this a potential tool for stroke prevention during TEVAR in high-risk patients.

Possible Mechanisms for Maintenance and Regression of Corpus Luteum Through the Ubiquitin-Proteasome and Autophagy System Regulated by Transcriptional Factors.

The corpus luteum (CL) is an important tissue of the female reproductive process which is established through ovulation of the mature follicle. Pulsatile release of prostaglandin F2α from the uterus leads to the regression of luteal cells and restarts the estrous cycle in most non-primate species. The rapid functional regression of the CL, which coincides with decrease of progesterone production, is followed by its structural regression. Although we now have a better understanding of how the CL is triggered to undergo programmed cell death, the precise mechanisms governing CL protein degradation in a very short period of luteolysis remains unknown. In this context, activation of ubiquitin-proteasome pathway (UPP), unfolded protein response (UPR) and autophagy are potential subcellular mechanisms involved. The ubiquitin-proteasome pathway (UPP) maintains tissue homeostasis in the face of both internal and external stressors. The UPP also controls physiological processes in many gonadal cells. Emerging evidence suggests that UPP dysfunction is involved in male and female reproductive tract dysfunction. Autophagy is activated when cells are exposed to different types of stressors such as hypoxia, starvation, and oxidative stress. While emerging evidence points to an important role for the UPP and autophagy in the CL, the key underlying transcriptional mechanisms have not been well-documented. In this review, we propose how CL regression may be governed by the ubiquitin-proteasome and autophagy pathways. We will further consider potential transcription factors which may regulate these events in the CL.

The Role of Antibodies and Their Receptors in Protection Against Ordered Protein Assembly in Neurodegeneration.

Ordered assemblies of proteins are found in the postmortem brains of sufferers of several neurodegenerative diseases. The cytoplasmic microtubule associated protein tau and alpha-synuclein (αS) are found in an assembled state in Alzheimer's disease and Parkinson's disease, respectively. An accumulating body of evidence suggests a "prion-like" mechanism of spread of these assemblies through the diseased brain. Under this hypothesis, assembled variants of these proteins promote the conversion of native proteins to the assembled state. This likely inflicts pathology on cells of the brain through a toxic gain-of-function mechanism. Experiments in animal models of tau and αS pathology have demonstrated that the passive transfer of anti-tau or anti-αS antibodies induces a reduction in the levels of assembled proteins. This is further accompanied by improvements in neurological function and preservation of brain volume. Immunotherapy is therefore considered one of the brightest hopes as a therapeutic avenue in an area currently without disease-modifying therapy. Following a series of disappointing clinical trials targeting beta-amyloid, a peptide that accumulates in the extracellular spaces of the AD brain, attention is turning to active and passive immunotherapies that target tau and αS. However, there are several remaining uncertainties concerning the mechanism by which antibodies afford protection against self-propagating protein conformations. This review will discuss current understanding of how antibodies and their receptors can be brought to bear on proteins involved in neurodegeneration. Parallels will be made to antibody-mediated protection against classical viral infections. Common mechanisms that may contribute to protection against self-propagating protein conformations include blocking the entry of protein "seeds" to cells, clearance of immune complexes by microglia, and the intracellular protein degradation pathway initiated by cytoplasmic antibodies via the Fc receptor TRIM21. As with anti-viral immunity, protective mechanisms may be accompanied by the activation of immune signaling pathways and we will discuss the suitability of such activation in the neurological setting.

Neurogenesis Using P19 Embryonal Carcinoma Cells.

The P19 cell line derived from a mouse embryo-derived teratocarcinoma has the ability to differentiate into the three germ layers. In the presence of retinoic acid (RA), the suspension cultured P19 cell line is induced to differentiate into neurons. This phenomenon is extensively investigated as a neurogenesis model in vitro. Therefore, the P19 cell line is very useful for molecular and cellular studies associated with neurogenesis. However, protocols for neuronal differentiation of P19 cell line described in the literature are very complex. The method developed in this study are simple and will play a part in elucidating the molecular mechanisms in neurodevelopmental abnormalities and neurodegenerative diseases.

Inhibition of TBC1D5 activates Rab7a and can enhance the function of the retromer cargo-selective complex.

The retromer complex is a vital component of the endosomal protein sorting machinery necessary for sorting into both the endosome-to-Golgi retrieval pathway and also the endosome-to-cell-surface recycling pathway. Retromer mediates cargo selection through a trimeric complex comprising VPS35, VPS29 and VPS26, which is recruited to endosomes by binding to Rab7a and Snx3. Retromer function is linked to two distinct neurodegenerative diseases, Parkinson's disease and Alzheimer's disease and modulating retromer function has been proposed as an avenue to explore for a putative therapy in these conditions. We hypothesised that activating Rab7a to promote the recruitment of retromer to endosomes could positively modulate its activity. Here, we show that inhibition of the GTPase activating protein TBC1D5 can enhance Rab7a activation and lead to a gain of function for retromer.

Analysis of novel endosome-to-Golgi retrieval genes reveals a role for PLD3 in regulating endosomal protein sorting and amyloid precursor protein processing.

The processing of amyloid precursor protein (APP) to the neurotoxic pro-aggregatory Aß peptide is controlled by the mechanisms that govern the trafficking and localisation of APP. We hypothesised that genes involved in endosomal protein sorting could play an important role in regulating APP processing and, therefore, analysed ~ 40 novel endosome-to-Golgi retrieval genes previously identified in a genome-wide siRNA screen. We report that phospholipase D3 (PLD3), a type II membrane protein, functions in endosomal protein sorting and plays an important role in regulating APP processing. PLD3 co-localises with APP in endosomes and loss of PLD3 function results in reduced endosomal tubules, impaired trafficking of several membrane proteins and reduced association of sortilin-like 1 with APP.

The Influences of Emotion on Learning and Memory.

Emotion has a substantial influence on the cognitive processes in humans, including perception, attention, learning, memory, reasoning, and problem solving. Emotion has a particularly strong influence on attention, especially modulating the selectivity of attention as well as motivating action and behavior. This attentional and executive control is intimately linked to learning processes, as intrinsically limited attentional capacities are better focused on relevant information. Emotion also facilitates encoding and helps retrieval of information efficiently. However, the effects of emotion on learning and memory are not always univalent, as studies have reported that emotion either enhances or impairs learning and long-term memory (LTM) retention, depending on a range of factors. Recent neuroimaging findings have indicated that the amygdala and prefrontal cortex cooperate with the medial temporal lobe in an integrated manner that affords (i) the amygdala modulating memory consolidation; (ii) the prefrontal cortex mediating memory encoding and formation; and (iii) the hippocampus for successful learning and LTM retention. We also review the nested hierarchies of circular emotional control and cognitive regulation (bottom-up and top-down influences) within the brain to achieve optimal integration of emotional and cognitive processing. This review highlights a basic evolutionary approach to emotion to understand the effects of emotion on learning and memory and the functional roles played by various brain regions and their mutual interactions in relation to emotional processing. We also summarize the current state of knowledge on the impact of emotion on memory and map implications for educational settings. In addition to elucidating the memory-enhancing effects of emotion, neuroimaging findings extend our understanding of emotional influences on learning and memory processes; this knowledge may be useful for the design of effective educational curricula to provide a conducive learning environment for both traditional "live" learning in classrooms and "virtual" learning through online-based educational technologies.

Technique profile: mesenteric reconstructions for occlusive disease.

Visceral ischemic syndromes are rare but catastrophic disorders. In acute presentations, treatment modalities include thrombolytic therapy, open surgical revascularization and percutaneous endovascular therapy. Endovascular therapy has become the most commonly utilized treatment option for chronic mesenteric ischemia and should be considered the first line of therapy for patients with anatomically suitable lesions or excessive open surgical risk. Open surgical revascularization has been associated with outstanding long-term outcomes. The various surgical and endovascular techniques and their associated outcomes for the treatment of mesenteric ischemic syndromes are reviewed in detail.

Retromer-mediated endosomal protein sorting: The role of unstructured domains.

The retromer complex is a key element of the endosomal protein sorting machinery that is conserved through evolution and has been shown to play a role in diseases such as Alzheimer's disease and Parkinson's disease. Through sorting various membrane proteins (cargo), the function of retromer complex has been linked to physiological processes such as lysosome biogenesis, autophagy, down regulation of signalling receptors and cell spreading. The cargo-selective trimer of retromer recognises membrane proteins and sorts them into two distinct pathways; endosome-to-Golgi retrieval and endosome-to-cell surface recycling and additionally the cargo-selective trimer functions as a hub to recruit accessory proteins to endosomes where they may regulate and/or facilitate retromer-mediated endosomal proteins sorting. Unstructured domains present in cargo proteins or accessory factors play key roles in both these aspects of retromer function and will be discussed in this review.

Subspace-based technique for speckle noise reduction in ultrasound images.

BACKGROUND AND PURPOSE: Ultrasound imaging is a very essential technique in medical diagnosis due to its being safe, economical and non-invasive nature. Despite its popularity, the US images, however, are corrupted with speckle noise, which reduces US images qualities, hampering image interpretation and processing stage. Hence, there are many efforts made by researches to formulate various despeckling methods for speckle reduction in US images. METHODS: In this paper, a subspace-based speckle reduction technique in ultrasound images is proposed. The fundamental principle of subspace-based despeckling technique is to convert multiplicative speckle noise into additive via logarithmic transformation, then to decompose the vector space of the noisy image into signal and noise subspaces. Image enhancement is achieved by nulling the noise subspace and estimating the clean image from the remaining signal subspace. Linear estimation of the clean image is derived by minimizing image distortion while maintaining the residual noise energy below some given threshold. The real US data for validation purposes were acquired under the IRB protocol (200210851-7) at the University of California Davis, which is also consistent with NIH requirements. RESULTS: Experiments are carried out using a synthetically generated B-mode ultrasound image, a computer generated cyst image and real ultrasound images. The performance of the proposed technique is compared with Lee, homomorphic wavelet and squeeze box filter (SBF) in terms of noise variance reduction, mean preservation, texture preservation and ultrasound despeckling assessment index (USDSAI). The results indicate better noise reduction capability with the simulated images by the SDC than Lee, Wavelet and SBF in addition to less blurry effect. With the real case scenario, the SDC, Lee, Wavelet and SBF are tested with images obtained from raw radio frequency (RF) data. Results generated using real US data indicate that, in addition to good contrast enhancement, the autocorrelation results shows better preservation of image texture by SDC than Lee, Wavelet and SBF. CONCLUSION: In general, the performance of the SDC filter is better than Lee, Wavelet and SBF in terms of noise reduction, improvement in image contrast and preservation of the autocorrelation profiles. Furthermore, the filter required less computational time compared to Lee, Wavelet and SBF, which indicates its suitability for real time application.