• Cryo-EM structure of the human cardiac myosin filament

  Dutta, Debabrata; Nguyen, Vu; Campbell, Kenneth S; Padrón, Raúl; Craig, Roger (2023-11-01)

  Pumping of the heart is powered by filaments of the motor protein myosin that pull on actin filaments to generate cardiac contraction. In addition to myosin, the filaments contain cardiac myosin-binding protein C (cMyBP-C), which modulates contractility in response to physiological stimuli, and titin, which functions as a scaffold for filament assembly1. Myosin, cMyBP-C and titin are all subject to mutation, which can lead to heart failure. Despite the central importance of cardiac myosin filaments to life, their molecular structure has remained a mystery for 60 years2. Here we solve the structure of the main (cMyBP-C-containing) region of the human cardiac filament using cryo-electron microscopy. The reconstruction reveals the architecture of titin and cMyBP-C and shows how myosin's motor domains (heads) form three different types of motif (providing functional flexibility), which interact with each other and with titin and cMyBP-C to dictate filament architecture and function. The packing of myosin tails in the filament backbone is also resolved. The structure suggests how cMyBP-C helps to generate the cardiac super-relaxed state3; how titin and cMyBP-C may contribute to length-dependent activation4; and how mutations in myosin and cMyBP-C might disturb interactions, causing disease5,6. The reconstruction resolves past uncertainties and integrates previous data on cardiac muscle structure and function. It provides a new paradigm for interpreting structural, physiological and clinical observations, and for the design of potential therapeutic drugs.
• First pass effect as an independent predictor of functional outcomes in medium vessel occlusions: An analysis of an international multicenter study

  Radu, Răzvan Alexandru; Costalat, Vincent; Fahed, Robert; Ghozy, Sherief; Siegler, James E; Shaikh, Hamza; Khalife, Jane; Abdalkader, Mohamad; Klein, Piers; Nguyen, Thanh N; et al. (2023-10-27)

  Introduction: First pass effect (FPE), achievement of complete recanalization (mTICI 2c/3) with a single pass, is a significant predictor of favorable outcomes for endovascular treatment (EVT) in large vessel occlusion stroke (LVO). However, data concerning the impact on functional outcomes and predictors of FPE in medium vessel occlusions (MeVO) are scarce. Patients and methods: We conducted an international retrospective study on MeVO cases. Multivariable logistic modeling was used to establish independent predictors of FPE. Clinical and safety outcomes were compared between the two study groups (FPE vs non-FPE) using logistic regression models. Good outcome was defined as modified Rankin Scale 0-2 at 3 months. Results: Eight hundred thirty-six patients with a final mTICI ⩾ 2b were included in this analysis. FPE was observed in 302 patients (36.1%). In multivariable analysis, hypertension (aOR 1.55, 95% CI 1.10-2.20) and lower baseline NIHSS score (aOR 0.95, 95% CI 0.93-0.97) were independently associated with an FPE. Good outcomes were more common in the FPE versus non-FPE group (72.8% vs 52.8%), and FPE was independently associated with favorable outcome (aOR 2.20, 95% CI 1.59-3.05). 90-day mortality and intracranial hemorrhage (ICH) were significantly lower in the FPE group, 0.43 (95% CI, 0.25-0.72) and 0.55 (95% CI, 0.39-0.77), respectively. Conclusion: Over 2/3 of patients with MeVOs and FPE in our cohort had a favorable outcome at 90 days. FPE is independently associated with favorable outcomes, it may reduce the risk of any intracranial hemorrhage, and 3-month mortality.
• Stent-assisted Woven EndoBridge device for the treatment of intracranial aneurysms: an international multicenter study

  Diestro, Jose Danilo Bengzon; Dibas, Mahmoud; Adeeb, Nimer; Regenhardt, Robert W; Vranic, Justin E; Guenego, Adrien; Lay, Sovann V; Renieri, Leonardo; Balushi, Ali Al; Shotar, Eimad; et al. (2023-10-20)

  Objective: The Woven EndoBridge (WEB) device is an intrasaccular flow disruptor designed for wide-necked bifurcation aneurysms. These aneurysms may require the use of a concomitant stent. The objective of this study was to determine the clinical and radiological outcomes of patients undergoing stent-assisted WEB treatment. In addition, the authors also sought to determine the predictors of a concomitant stent in aneurysms treated with the WEB device. Methods: The data for this study were taken from the WorldWideWEB Consortium, an international multicenter cohort including patients treated with the WEB device. Aneurysms were classified into two groups based on treatment: stent-assisted WEB and WEB device alone. The authors compared clinical and radiological outcomes of both groups. Univariable and multivariable binary logistic regression analyses were performed to determine factors that predispose to stent use. Results: The study included 691 intracranial aneurysms (31 with stents and 660 without stents) treated with the WEB device. The adequate occlusion status did not differ between the two groups at the latest follow-up (83.3% vs 85.6%, p = 0.915). Patients who underwent stenting had more thromboembolic (32.3% vs 6.5%, p < 0.001) and procedural (16.1% vs 3.0%, p < 0.001) complications. Aneurysms treated with a concomitant stent had wider necks, greater heights, and lower dome-to-neck ratios. Increasing neck size was the only significant predictor for stent use. Conclusions: This study demonstrates that there is no difference in the degree of aneurysm occlusion between the two groups; however, complications were more frequent in the stent group. In addition, a wider aneurysm neck predisposes to stent assistance in WEB-treated aneurysms.
• Leveraging Differences in AI and Human "Vision" to Improve Breast Cancer Detection

  Mehta, Tejas S (2023-10-17)

  Screening mammography is the single most effective test to reduce breast cancer mortality. Despite improvements in mammography technology, including digital breast tomosynthesis, it remains an imperfect test, with one in eight cancers missed at time of interpretation. Supplemental imaging with US, contrast-enhanced MRI, or contrast-enhanced mammography has been recommended in women with higher-than-average risk to improve breast cancer detection. However, challenges arise for women who are not identified as being at higher-than-average risk or who may not have access to these tests. Artificial intelligence (AI) models using deep learning technology have the potential to find cancers not identified by humans, improving the efficacy of screening mammography.
• First United States multicenter experience with the new-generation FRED X surface-modified flow diversion stent: feasibility, safety, and short-term efficacy

  Abbas, Rawad; Lan, Matthews; Naamani, Kareem El; Atallah, Elias; Salem, Mohamed; Burkhardt, Jan-Karl; Kühn, Anna Luisa; Puri, Ajit; Monteiro, Andre; Levy, Elad I; et al. (2023-10-06)

  Objective: Flow diversion created a paradigm shift in the treatment of intracranial aneurysms. The new flow redirection endoluminal device with X technology (FRED X) is the latest update of the recent Food and Drug Administration-approved FRED. The FRED X is engineered to reduce material thrombogenicity and enhance vessel healing. In this study, the authors aimed to evaluate the feasibility and early safety and efficacy of the new FRED X. Methods: The authors retrospectively collected and analyzed data from patients who had undergone flow diversion with the new FRED X at four tertiary cerebrovascular centers in the United States from February 2022 through July 2022. Results: Forty-four patients with 45 aneurysms treated using 46 devices comprised the overall study cohort and were divided into two groups: 39 patients with unruptured aneurysms and 5 patients with ruptured aneurysms. The mean patient age was 57.7 ± 9.1 years, and most patients were female (84%). Ninety-one percent of the aneurysms were saccular, with the majority (93%) located in the anterior circulation, specifically the posterior communicating (27%) and carotid ophthalmic (27%) territories. The mean maximum aneurysm diameter was 5.6 ± 4.6 mm, and 20% of the lesions had been previously treated. The mean procedure time was 61.6 minutes, with a mean cumulative fluoroscopy time of 24.6 minutes. Additionally, 7% of the lesions received adjunct treatment. Stent placement was successful in 100% of cases, achieving good wall apposition and complete neck coverage. Further, immediate aneurysm contrast stasis > 90% was observed in 61% of cases. Symptomatic postoperative complications occurred in 3 patients in the unruptured cohort and 1 patient in the ruptured cohort. All patients in the study were discharged on dual antiplatelet regimens with a modified Rankin Scale score of 0. At 6 months after treatment, 89% of cases had adequate occlusion, with < 6% of cases having asymptomatic in-stent stenosis. All patients had excellent functional outcomes. Conclusions: FRED X for the treatment of an intracranial aneurysm is technically feasible alone or in conjunction with intrasaccular embolization. In addition, the study results showed very promising early safety and efficacy. Follow-up studies should establish the long-term safety and efficacy profiles of this new stent.
• Surface modification of neurovascular stents: from bench to patient

  Zoppo, Christopher T; Mocco, J; Manning, Nathan W; Bogdanov, Alexei A. Jr.; Gounis, Matthew J (2023-10-04)

  Flow-diverting stents (FDs) for the treatment of cerebrovascular aneurysms are revolutionary. However, these devices require systemic dual antiplatelet therapy (DAPT) to reduce thromboembolic complications. Given the risk of ischemic complications as well as morbidity and contraindications associated with DAPT, demonstrating safety and efficacy for FDs either without DAPT or reducing the duration of DAPT is a priority. The former may be achieved by surface modifications that decrease device thrombogenicity, and the latter by using coatings that expedite endothelial growth. Biomimetics, commonly achieved by grafting hydrophilic and non-interacting polymers to surfaces, can mask the device surface with nature-derived coatings from circulating factors that normally activate coagulation and inflammation. One strategy is to mimic the surfaces of innocuous circulatory system components. Phosphorylcholine and glycan coatings are naturally inspired and present on the surface of all eukaryotic cell membranes. Another strategy involves linking synthetic biocompatible polymer brushes to the surface of a device that disrupts normal interaction with circulating proteins and cells. Finally, drug immobilization can also impart antithrombotic effects that counteract normal foreign body reactions in the circulatory system without systemic effects. Heparin coatings have been explored since the 1960s and used on a variety of blood contacting surfaces. This concept is now being explored for neurovascular devices. Coatings that improve endothelialization are not as clinically mature as anti-thrombogenic coatings. Coronary stents have used an anti-CD34 antibody coating to capture circulating endothelial progenitor cells on the surface, potentially accelerating endothelial integration. Similarly, coatings with CD31 analogs are being explored for neurovascular implants.
• Phosphaturic mesenchymal tumor: two cases highlighting differences in clinical and radiologic presentation

  Gu, Joey; Ge, Connie; Joshi, Ganesh; Most, Mathew; Tai, Ryan (2023-10-04)

  Phosphaturic mesenchymal tumors are rare, usually benign neoplasms that occur in the soft tissue or bone and are the cause of nearly all cases of tumor-induced osteomalacia. Tumor-induced osteomalacia due to phosphaturic mesenchymal tumor is a challenging diagnosis to make-patients present with variable clinical and radiologic findings and the culprit neoplasm is often small and can occur anywhere head to toe. We present two cases of phosphaturic mesenchymal tumor in the scapular body and plantar foot. In both cases, the patient endured years of debilitating symptoms before a tissue diagnosis was eventually reached. Descriptions of clinical presentation, laboratory workup, surgical resection, and imaging characteristics, with a focus on CT, MRI, and functional imaging, are provided to assist with the diagnosis and management of this rare entity. A brief review of current literature and discussion of the differential diagnoses of phosphaturic mesenchymal tumor is also provided.
• Dissecting aneurysm of the Posterior Cerebral Artery

  Kuhn, Anna Luisa; Puri, Ajit S; Singh, Jasmeet (2023-09-27)

  Posterior circulation aneurysms are more likely to rupture than those in the anterior circulation but also pose more of a challenge for endovascular treatment or neurosurgical clipping. Aneurysms arising from the posterior cerebral artery are rare; dissecting aneurysms are even rarer. Dissecting posterior cerebral artery aneurysms can be spontaneous or post traumatic. Our case depicts a patient with acute subarachnoid hemorrhage due to a ruptured, dissecting posterior cerebral artery aneurysm who underwent successful endovascular treatment by means of flow diversion.
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  Awake intracerebroventricular delivery and safety assessment of oligonucleotides in a large animal model

  Benatti, Hector Ribeiro; Prestigiacomo, Rachel D; Taghian, Toloo; Miller, Rachael; King, Robert; Gounis, Matthew J; Celik, Ugur; Bertrand, Stephanie; Tuominen, Susan; Bierfeldt, Lindsey; et al. (2023-09-26)

  Oligonucleotide therapeutics offer great promise in the treatment of previously untreatable neurodegenerative disorders; however, there are some challenges to overcome in pre-clinical studies. (1) They carry a well-established dose-related acute neurotoxicity at the time of administration. (2) Repeated administration into the cerebrospinal fluid may be required for long-term therapeutic effect. Modifying oligonucleotide formulation has been postulated to prevent acute toxicity, but a sensitive and quantitative way to track seizure activity in pre-clinical studies is lacking. The use of intracerebroventricular (i.c.v.) catheters offers a solution for repeated dosing; however, fixation techniques in large animal models are not standardized and are not reliable. Here we describe a novel surgical technique in a sheep model for i.c.v. delivery of neurotherapeutics based on the fixation of the i.c.v. catheter with a 3D-printed anchorage system composed of plastic and ceramic parts, compatible with magnetic resonance imaging, computed tomography, and electroencephalography (EEG). Our technique allowed tracking electrical brain activity in awake animals via EEG and video recording during and for the 24-h period after administration of a novel oligonucleotide in sheep. Its anchoring efficiency was demonstrated for at least 2 months and will be tested for up to a year in ongoing studies.
• Transvenous Embolization of Dural Arteriovenous Fistulas Through the Galenic (Deep Venous) System: Multicenter Case Series and Meta-Analysis

  Srinivasan, Visish M; Karahalios, Katherine; Colasurdo, Marco; Rhodenheiser, Emmajane; Scherschinski, Lea; Lazaro, Tyler T; Cortez, Gustavo; Gross, Bradley A; Kuhn, Anna Luisa; Puri, Ajit S; et al. (2023-09-25)

  Background and objectives: Arteriovenous fistulas involving the deep venous system have often been treated with microsurgery or transarterial embolization. Increasing familiarity with transvenous navigation and improved endovascular access systems may facilitate transvenous embolization (TVE) for these rare and challenging lesions. Methods: We performed a retrospective study of neurointerventional databases of 6 high-volume centers. We identified all cases of arteriovenous fistulas with deep transvenous embolizations for arteriovenous fistula. Details regarding demographics, fistula characteristics, treatment considerations, clinical outcomes, and fistula occlusion were obtained and analyzed. The meta-analysis used the same inclusion criteria. Results: Seventeen cases of TVE were identified. The most common reasons for TVE included prior treatment failure with microsurgery (n = 2) or transarterial embolization (n = 3) or inaccessible arterial pedicles (n = 4). For patients with full clinical outcome data (n = 14), 2 patients had worsened modified Rankin Scale, 8 patients had no change, and 4 were improved at a median clinical follow-up of 3.5 months. Angiographic obliteration was achieved in 15/17 cases (88.2%). In 1 case, catheterization around a sharp turn in the basal vein of Rosenthal could not be performed. In another case, despite successful TVE, there was residual lesion which was treated 1 year later by microsurgical clipping and excision. Conclusion: Transvenous approaches for embolization of deep arteriovenous fistulas have become possible with modern endovascular catheter systems and liquid embolics. These lesions can be treated safely and effectively through endovascular approaches, which may spare patients the traversal of deep structures needed for microsurgical approaches to these regions. The outcomes of TVE are comparable with published outcomes of microsurgical interruption.
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  Partial skeletal muscle-specific Drp1 knockout enhances insulin sensitivity in diet-induced obese mice, but not in lean mice

  Kugler, Benjamin A; Lourie, Jared; Berger, Nicolas; Lin, Nana; Nguyen, Paul; DosSantos, Edzana; Ali, Abir; Sesay, Amira; Rosen, H Grace; Kalemba, Baby; et al. (2023-09-09)

  Objective: Dynamin-related protein 1 (Drp1) is the key regulator of mitochondrial fission. We and others have reported a strong correlation between enhanced Drp1 activity and impaired skeletal muscle insulin sensitivity. This study aimed to determine whether Drp1 directly regulates skeletal muscle insulin sensitivity and whole-body glucose homeostasis. Methods: We employed tamoxifen-inducible skeletal muscle-specific heterozygous Drp1 knockout mice (mDrp1+/-). Male mDrp1+/- and wildtype (WT) mice were fed with either a high-fat diet (HFD) or low-fat diet (LFD) for four weeks, followed by tamoxifen injections for five consecutive days, and remained on their respective diet for another four weeks. In addition, we used primary human skeletal muscle cells (HSkMC) from lean, insulin-sensitive, and severely obese, insulin-resistant humans and transfected the cells with either a Drp1 shRNA (shDrp1) or scramble shRNA construct. Skeletal muscle and whole-body insulin sensitivity, skeletal muscle insulin signaling, mitochondrial network morphology, respiration, and H2O2 production were measured. Results: Partial deletion of the Drp1 gene in skeletal muscle led to improved whole-body glucose tolerance and insulin sensitivity (P < 0.05) in diet-induced obese, insulin-resistant mice but not in lean mice. Analyses of mitochondrial structure and function revealed that the partial deletion of the Drp1 gene restored mitochondrial dynamics, improved mitochondrial morphology, and reduced mitochondrial Complex I- and II-derived H2O2 (P < 0.05) under the condition of diet-induced obesity. In addition, partial deletion of Drp1 in skeletal muscle resulted in elevated circulating FGF21 (P < 0.05) and in a trend towards increase of FGF21 expression in skeletal muscle tissue (P = 0.095). In primary myotubes derived from severely obese, insulin-resistant humans, ShRNA-induced-knockdown of Drp1 resulted in enhanced insulin signaling, insulin-stimulated glucose uptake and reduced cellular reactive oxygen species (ROS) content compared to the shScramble-treated myotubes from the same donors (P < 0.05). Conclusion: These data demonstrate that partial loss of skeletal muscle-specific Drp1 expression is sufficient to improve whole-body glucose homeostasis and insulin sensitivity under obese, insulin-resistant conditions, which may be, at least in part, due to reduced mitochondrial H2O2 production. In addition, our findings revealed divergent effects of Drp1 on whole-body metabolism under lean healthy or obese insulin-resistant conditions in mice.
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  Impact of e-ASPECTS software on the performance of physicians compared to a consensus ground truth: a multi-reader, multi-case study

  Kobeissi, Hassan; Kallmes, David F; Benson, John; Nagelschneider, Alex; Madhavan, Ajay; Messina, Steven A; Schwartz, Kara; Campeau, Norbert; Carr, Carrie M; Nasr, Deena M; et al. (2023-09-07)

  Background: The Alberta Stroke Program Early CT Score (ASPECTS) is used to quantify the extent of injury to the brain following acute ischemic stroke (AIS) and to inform treatment decisions. The e-ASPECTS software uses artificial intelligence methods to automatically process non-contrast CT (NCCT) brain scans from patients with AIS affecting the middle cerebral artery (MCA) territory and generate an ASPECTS. This study aimed to evaluate the impact of e-ASPECTS (Brainomix, Oxford, UK) on the performance of US physicians compared to a consensus ground truth. Methods: The study used a multi-reader, multi-case design. A total of 10 US board-certified physicians (neurologists and neuroradiologists) scored 54 NCCT brain scans of patients with AIS affecting the MCA territory. Each reader scored each scan on two occasions: once with and once without reference to the e-ASPECTS software, in random order. Agreement with a reference standard (expert consensus read with reference to follow-up imaging) was evaluated with and without software support. Results: A comparison of the area under the curve (AUC) for each reader showed a significant improvement from 0.81 to 0.83 (p = 0.028) with the support of the e-ASPECTS tool. The agreement of reader ASPECTS scoring with the reference standard was improved with e-ASPECTS compared to unassisted reading of scans: Cohen's kappa improved from 0.60 to 0.65, and the case-based weighted Kappa improved from 0.70 to 0.81. Conclusion: Decision support with the e-ASPECTS software significantly improves the accuracy of ASPECTS scoring, even by expert US neurologists and neuroradiologists.
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  Vascular leiomyoma of the thigh: Classic presentation of a rare tumor with imaging and pathology correlation

  Kulkarni, Ashwini; Tai, Ryan; Bledsoe, Jacob; Joshi, Ganesh (2023-09-06)

  We report a case of a vascular leiomyoma arising from the superficial femoral artery presenting as a non-painful thigh mass in a 55-year-old woman. Leiomyomas typically arise from the uterus and gastrointestinal tract, and rarely arise from vessels. We present this case to emphasize that although extremity leiomyomas are rare, they should be considered if there is a soft tissue mass abutting a vessel. Radiologists should be familiar with the imaging features associated with vascular leiomyomas.
• Molecular Magnetic Resonance Imaging of Aneurysmal Inflammation Using a Redox Active Iron Complex

  King, Robert M; Gounis, Matthew J; Schmidt, Eric J; Leporati, Anita; Gale, Eric M; Bogdanov, Alexei A. Jr. (2023-09-01)

  Objectives: Inflammation plays a key role in driving brain aneurysmal instability and rupture, but clinical tools to noninvasively differentiate between inflamed and stable aneurysms are lacking. We hypothesize that imaging oxidative changes in the aneurysmal microenvironment driven by myeloid inflammatory cells may represent a noninvasive biomarker to evaluate rupture risk. In this study, we performed initial evaluation of the oxidatively activated probe Fe-PyC3A as a tool for magnetic resonance imaging (MRI) of inflammation in a rabbit model of saccular aneurysm. Materials and methods: The difference in longitudinal relaxivity ( r1 ) in reduced and oxidized states of Fe-PyC3A was measured in water and blood plasma phantoms at 3 T. A rabbit saccular aneurysm model was created by endovascular intervention/elastinolysis with subsequent decellularization in situ. Rabbits were imaged at 4 weeks (n = 4) or 12 weeks (n = 4) after aneurysmal induction, when luminal levels of inflammation reflected by the presence of myeloperoxidase positive cells are relatively high and low, respectively, using a 3 T clinical scanner. Both groups were imaged dynamically using a 2-dimensional T1-weighted fast field echo pulse MRI sequence before and up to 4 minutes postinjection of Fe-PyC3A. Dynamic imaging was then repeated after an injection of gadobutrol (0.1 mmol/kg) as negative control probe. Rabbits from the 12-week aneurysm group were also imaged before and 20 minutes and 3 hours after injection of Fe-PyC3A using an axial respiratory gated turbo-spin echo (TSE) pulse sequence with motion-sensitized driven equilibrium (MSDE) preparation. The MSDE/TSE imaging was repeated before, immediately after dynamic acquisition (20 minutes postinjection), and 3 hours after injection of gadobutrol. Aneurysmal enhancement ratios (ERs) were calculated by dividing the postinjection aneurysm versus skeletal muscle contrast ratio by the preinjection contrast ratio. After imaging, the aneurysms were excised and inflammatory infiltrate was characterized by fluorometric detection of myeloperoxidase activity and calprotectin immunostaining, respectively. Results: In vitro relaxometry showed that oxidation of Fe-PyC3A by hydrogen peroxide resulted in a 15-fold increase of r1 at 3 T. Relaxometry in the presence of blood plasma showed no more than a 10% increase of r1 , indicating the absence of strong interaction of Fe-PyC3A with plasma proteins. Dynamic imaging with Fe-PyC3A generated little signal enhancement within the blood pool or adjacent muscle but did generate a transient increase in aneurysmal ER that was significantly greater 4 weeks versus 12 weeks after aneurysm induction (1.6 ± 0.30 vs 1.2 ± 0.03, P < 0.05). Dynamic imaging with gadobutrol generated strong aneurysmal enhancement, but also strong enhancement of the blood and muscle resulting in smaller relative ER change. In the 12-week group of rabbits, MSDE/TSE imaging showed that ER values measured immediately after dynamic MRI (20 minutes postinjection) were significantly higher ( P < 0.05) in the case of Fe-PyC3A (1.25 ± 0.06) than for gadobutrol injection (1.03 ± 0.03). Immunohistochemical corroboration using anticalprotectin antibody showed that leukocyte infiltration into the vessel walls and luminal thrombi was significantly higher in the 4-week group versus 12-week aneurysms (123 ± 37 vs 18 ± 7 cells/mm 2 , P < 0.05). Conclusions: Magnetic resonance imaging using Fe-PyC3A injection in dynamic or delayed acquisition modes was shown to generate a higher magnetic resonance signal enhancement in aneurysms that exhibit higher degree of inflammation. The results of our pilot experiments support further evaluation of MRI using Fe-PyC3A as a noninvasive marker of aneurysmal inflammation.
• The balloon occlusion sheath for stroke (BOSS) balloon guide catheter for stroke intervention: Safety and technical success

  Cuoco, Joshua A; Entwistle, John J; Siddiq, Farhan; Puri, Ajit S; Woodward, Keith; Hanel, Ricardo A; Ansari, Sameer A; Frei, Donald; Patel, Biraj M (2023-08-30)

  Background: We describe the first-in-human experience using the Balloon Occlusion Stroke Sheath (BOSSTM) balloon-guide catheter to perform stroke thrombectomy in 50 consecutive patients enrolled in the Flow Arrest Safety and Technical success with balloon-guide catheters trial. This aspiration system includes a novel 9.4F balloon-guide catheter conduit for the insertion and guidance of catheters with a balloon providing temporary flow arrest. Methods: The Flow Arrest Safety and Technical success with balloon-guide catheter trial is a single-arm, prospective, multi-center, non-randomized, observational registry evaluating the use of the market-released BOSSTM balloon-guide catheter in adult patients diagnosed with an acute ischemic stroke attributable to large vessel occlusion. The purpose of the current trial was to assess the safety and technical success associated with the use of the BOSSTM balloon-guide catheter. Results: Fifty patients met inclusion criteria with a mean baseline National Institutes of Health Stroke Scale (NIHSS) of 16. Treatment devices, including aspiration and stent retriever devices, were used in a total of 88 passes. The BOSSTM balloon-guide catheter was compatible with all stroke thrombectomy treatment devices used in 98% (49/50) of procedures. Balloon inflation and flow arrest were achieved in 100% (50/50) and 98% (49/50) of cases, respectively. Balloon deflation and retraction were observed in 100% (50/50) of cases. Successful reperfusion (modified thrombolysis in cerebral infarction score > 2b) was achieved in 100% of cases with single-pass reperfusion achieved in 62% (31/50) of cases. Conclusions: The BOSSTM balloon-guide catheter is a safe and technically effective adjunctive device for mechanical thrombectomy of acute ischemic stroke due to large vessel occlusion.
• Levels of Synaptic Proteins in Brain and Neurofilament Light Chain in Cerebrospinal Fluid and Plasma of OVT73 Huntington's Disease Sheep Support a Prodromal Disease State

  Sapp, Ellen; Boudi, Adel; Reid, Suzanne J; Trombetta, Bianca A; Kivisäkk, Pia; Taghian, Toloo; Arnold, Steven E; Howland, David; Gray-Edwards, Heather L; Kegel-Gleason, Kimberly B; et al. (2023-08-29)

  Background: Synaptic changes occur early in patients with Huntington's disease (HD) and in mouse models of HD. An analysis of synaptic changes in HD transgenic sheep (OVT73) is fitting since they have been shown to have some phenotypes. They also have larger brains, longer lifespan, and greater motor and cognitive capacity more aligned with humans and can provide abundant biofluids for in vivo monitoring of therapeutic interventions. Objective: The objective of this study was to determine if there were differences between 5- and 10-year-old OVT73 and wild-type (WT) sheep in levels of synaptic proteins in brain and in neurofilament light chain (NfL) in cerebrospinal fluid (CSF) and plasma. Methods: Mutant huntingtin (mHTT) and other proteins were measured by western blot assay in synaptosomes prepared from caudate, motor, and piriform cortex in 5-year-old and caudate, putamen, motor, and piriform cortex in 10-year-old WT and OVT73 sheep. Levels of NfL, a biomarker for neuronal damage increased in many neurological disorders including HD, were examined in CSF and plasma samples from 10-year-old WT and OVT73 sheep using the Simoa NfL Advantage kit. Results: Western blot analysis showed mHTT protein expression in synaptosomes from OVT73 sheep was 23% of endogenous sheep HTT levels at both ages. Significant changes were detected in brain levels of PDE10A, SCN4B, DARPP32, calmodulin, SNAP25, PSD95, VGLUT 1, VAMP1, and Na+/K+-ATPase, which depended on age and brain region. There was no difference in NfL levels in CSF and plasma in OVT73 sheep compared to age-matched WT sheep. Conclusions: These results show that synaptic changes occur in brain of 5- and 10-year-old OVT73 sheep, but levels of NfL in biofluids are unaffected. Altogether, the data support a prodromal disease state in OVT73 sheep that involves the caudate, putamen and cortex.
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  Heterozygous FOXJ1 Mutations Cause Incomplete Ependymal Cell Differentiation and Communicating Hydrocephalus

  Hou, Connie C; Li, Danielle; Berry, Bethany C; Zheng, Shaokuan; Carroll, Rona S; Johnson, Mark D; Yang, Hong Wei (2023-08-24)

  Heterozygous mutations affecting FOXJ1, a transcription factor governing multiciliated cell development, have been associated with obstructive hydrocephalus in humans. However, factors that disrupt multiciliated ependymal cell function often cause communicating hydrocephalus, raising questions about whether FOXJ1 mutations cause hydrocephalus primarily by blocking cerebrospinal fluid (CSF) flow or by different mechanisms. Here, we show that heterozygous FOXJ1 mutations are also associated with communicating hydrocephalus in humans and cause communicating hydrocephalus in mice. Disruption of one Foxj1 allele in mice leads to incomplete ependymal cell differentiation and communicating hydrocephalus. Mature ependymal cell number and motile cilia number are decreased, and 12% of motile cilia display abnormal axonemes. We observed decreased microtubule attachment to basal bodies, random localization and orientation of basal body patches, loss of planar cell polarity, and a disruption of unidirectional CSF flow. Thus, heterozygous FOXJ1 mutations impair ventricular multiciliated cell differentiation, thereby causing communicating hydrocephalus. CSF flow obstruction may develop secondarily in some patients harboring FOXJ1 mutations. Heterozygous FOXJ1 mutations impair motile cilia structure and basal body alignment, thereby disrupting CSF flow dynamics and causing communicating hydrocephalus.
• Radiology program director's perspective on a novel hands-on advanced elective

  Newbury, Alex; Cerniglia, Christopher A; DeBenedectis, Carolynn M; Harman, Aaron; Lo, Hao S (2023-08-18)

  With the advent of the USMLE Step 1 exam moving to a pass/fail status, Radiology Program Directors (PDs) and Associate Program Directors (APDs) need alternative methods of identifying interested and engaged medical students who are applying to their program. Additionally, undergraduate radiology medical education in the United States varies widely from institution to institution with no universal mandatory radiology component. To address these problems, we implemented an advanced fourth year hands-on radiology elective where the students were treated as first year radiology residents (R1s), giving them resident-level access to the Picture Archive and Communication System (PACS) and dictation software, and allowing them to perform entry-level procedures with appropriate supervision. After implementation of the elective, a 5-question online survey was sent to two hundred and ninety-eight PDs and APDs via the Association of Program Directors in Radiology (APDR) listserv, of which seventy-two responses were compiled, yielding a response rate of 24%. The survey focused on how a hands-on medical student elective would help in assessing prospective candidates and predicting R1 performance. Most respondents felt interest in radiology, motivation, and interpersonal skills would be better assessed after such an elective and the vast majority felt hands-on Advanced Elective would be at least slightly predictive of first year resident performance. Based on this information, we believe implementing a hands-on advanced radiology elective would significantly help address the passive nature of traditional radiology electives, providing valuable information to PDs and APDs and giving the best possible radiology experience to our medical students.
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  Precision medicine using whole genome sequencing in a cat identifies a novel COL5A1 variant for classical Ehlers-Danlos syndrome

  McElroy, Abigail; Gray-Edwards, Heather L; Coghill, Lyndon M; Lyons, Leslie A (2023-08-18)

  Background: Ehlers-Danlos syndromes (EDS) are a heterogeneous group of heritable connective tissue disorders occurring in both human and veterinary patients. The genetics of these disorders are poorly described in small animal patients. Hypothesis/objectives: Define the clinical manifestations and genetic cause of a suspected form of EDS in a cat. Animals: A 14-week-old male domestic medium hair cat was presented with skin hyperextensibility and fragility. The classic tragic facial expression was observed as well as chronic pruritus and mild hyperesthesia. Methods: Blood samples and a skin biopsy sample were collected from the affected cat. Clinical examinations, histology, electron microscopy and whole genome sequencing were conducted to characterize the clinical presentation and identify possible pathogenic DNA variants to support a diagnosis. Criteria defining variant pathogenicity were examined including human disease variant databases. Results: Histology showed sparse, disorganized collagen and an increase in cutaneous mast cells. Electron microscopy identified ultrastructural defects commonly seen in collagen type V alpha 1 chain (COL5A1) variants including flower-like collagen fibrils in cross-section. Whole genome sequencing and comparison with 413 cats in the 99 Lives Cat Genome Sequencing Consortium database identified a novel splice acceptor site variant at exon 4 in COL5A1 (c.501-2A>C). Conclusions and clinical importance: Our report broadens the current understanding of EDS in veterinary patients and supports the use of precision medicine techniques in clinical veterinary practice. The classification of variants for pathogenicity should be considered in companion animals.
• Relative Loss of Small Pulmonary Vessels on Imaging and Risk of Recurrence of Resected Lung Adenocarcinoma

  Synn, Andrew J; Litchman, Tess D; de Margerie-Mellon, Constance; Bankier, Alexander A; Rahaghi, Farbod N; Washko, George R; San José Estépar, Raúl; VanderLaan, Paul A; Rice, Mary B (2023-08-17)

  Adenocarcinoma is the most common lung cancer subtype, and represents an increasing proportion of all lung cancers. While the prognosis of resectable, early-stage non-small cell lung cancer (NSCLC) is overall highly favorable, patients with recurrent disease suffer markedly worse outcomes than those without recurrence, including a strikingly higher risk of death. Pulmonary vascular pathology, including pulmonary hypertension (PH), may contribute to high mortality in patients with lung cancer. Image analysis-based quantification of the relative loss (or “pruning”) of small pulmonary vessels is a promising non-invasive biomarker of vasculopathy that is linked to more severe lung disease and PH5–7. The objective of this study is to determine if vascular pruning, quantified by computed tomography (CT) imaging, is associated with risk of cancer recurrence and/or death in patients with early-stage lung adenocarcinoma.

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