Computer Aided Intracranial Aneurysm Treatment Based on 2D/3D Mapping, Virtual Deployment and Online Distal Marker Detection.

PURPOSE: To introduce a computational tool for peri-interventional intracranial aneurysm treatment guidance that maps preoperative planning information from simulation onto real-time X-Ray imaging. METHODS: Preoperatively, multiple flow diverter (FD) devices are simulated based on the 3D mesh of the vessel to treat, to choose the optimal size and location. In the peri-operative stage, this 3D information is aligned and mapped to the continuous 2D-X-Ray scan feed from the operating room. The current flow diverter position in the 3D model is estimated by automatically detecting the distal FD marker locations and mapping them to the treated vessel. This allows to visually assess the possible outcome of releasing the device at the current position, and compare it with the one chosen pre-operatively. RESULTS: The full pipeline was validated using retrospectively collected biplane images from four different patients (5 3D-DSA datasets in total). The distal FD marker detector obtained an average F1-score of 0.67 ( ± 0.224 ) in 412 2D-X-Ray scans. After aligning 3D-DSA + 2D-X-Ray datasets, the average difference between simulated and deployed positions was 0.832 mm ( ± 0.521 mm). Finally, we qualitatively show that the proposed approach is able to display the current location of the FD compared to their pre-operatively planned position. CONCLUSIONS: The proposed method allows to support the FD deployment procedure by merging and presenting preoperative simulation information to the interventionists, aiding them to make more accurate and less risky decisions.

Collaterals at angiography guide clinical outcomes after endovascular stroke therapy in HERMES.

BACKGROUND: Robust collateral circulation has been linked with better reperfusion and clinical outcomes. It remains unclear how individual assessments of collateral circulation may be translated into clinical practice. METHODS: The pooled Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke Trials (HERMES) angiography dataset was analyzed by a centralized, independent imaging core blinded to other clinical data. Conventional angiography was acquired immediately prior to endovascular therapy. Collaterals were graded with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN) system and associated with baseline patient characteristics, reperfusion, and day 90 modified Rankin Score (mRS). Both 90-day all-cause mortality and day 90 mRS were modeled via multivariable logistic regression. RESULTS: Angiography was available in 376/605 (62%) patients. Baseline ASPECTS (Alberta Stroke Program Early CT Score) (p=0.043), history of diabetes mellitus (p=0.048), site of occlusion (p<0.001), and degree of subsequent Thrombolysis in Cerebral Infarction (TICI) reperfusion (p<0.001) were associated with collateral grades. ASITN collateral grade was strongly associated with ordinal mRS from baseline to 90 days in an unadjusted analysis (p<0.001). Multivariable regression demonstrated that collateral status is a strong determinant of mRS outcome in the presence of other predictors (OR=1.37 per grade, 95% CI [1.05 to 1.74], p=0.018). By comparing ORs, 1 unit of ASITN was determined to be approximately equivalent to 4.5 points of NIHSS, 11 years of age, 1.5 points of ASPECTS, or 100 min less delay from onset to puncture, in terms of impact on mRS. CONCLUSIONS: Individual collateral physiology may contribute significantly to reperfusion success and clinical outcomes after acute ischemic stroke. Building a consensus for the role of angiographic collateral assessment in the allocation of adjuvant reperfusion therapies may help galvanize a precision medicine approach in stroke.

Pathology of acute sub-lethal or near-lethal irradiation of nonhuman primates prophylaxed with the nutraceutical, gamma tocotrienol.

Exposure to high, marginally lethal doses or higher of ionizing radiation, either intentional or accidental, results in injury to various organs. Currently, there is only a limited number of safe and effective radiation countermeasures approved by US Food and Drug Administration for such injuries. These approved agents are effective for only the hematopoietic component of the acute radiation syndrome and must be administered only after the exposure event: currently, there is no FDA-approved agent that can be used prophylactically. The nutraceutical, gamma-tocotrienol (GT3) has been found to be a promising radioprotector of such exposure-related injuries, especially those of a hematopoietic nature, when tested in either rodents or nonhuman primates. We investigated the nature of injuries and the possible protective effects of GT3 within select organ systems/tissues caused by both non-lethal level (4.0 Gy), as well as potentially lethal level (5.8 Gy) of ionizing radiation, delivered as total-body or partial-body exposure. Results indicated that the most severe, dose-dependent injuries occurred within those organ systems with strong self-renewing capacities (e.g., the lymphohematopoietic and gastrointestinal systems), while in other tissues (e.g., liver, kidney, lung) endowed with less self-renewal, the pathologies noted tended to be less pronounced and less dependent on the level of exposure dose or on the applied exposure regimen. The prophylactic use of the test nutraceutical, GT3, appeared to limit the extent of irradiation-associated pathology within blood forming tissues and, to some extent, within the small intestine of the gastrointestinal tract. No distinct, global pattern of bodily protection was noted with the agent's use, although a hint of a possible radioprotective benefit was suggested not only by a lessening of apparent injury within select organ systems, but also by way of noting the lack of early onset of moribundity within select GT3-treated animals.

Safety, pharmacokinetics, and potential neurological interactions of ivermectin, tafenoquine, and chloroquine in Rhesus macaques.

Ivermectin (IVM) could be used for malaria control as treated individuals are lethal to blood-feeding Anopheles, resulting in reduced transmission. Tafenoquine (TQ) is used to clear the liver reservoir of Plasmodium vivax and as a prophylactic treatment in high-risk populations. It has been suggested to use ivermectin and tafenoquine in combination, but the safety of these drugs in combination has not been evaluated. Early derivatives of 8-aminoquinolones (8-AQ) were neurotoxic, and ivermectin is an inhibitor of the P-glycoprotein (P-gp) blood brain barrier (BBB) transporter. Thus, there is concern that co-administration of these drugs could be neurotoxic. This study aimed to evaluate the safety and pharmacokinetic interaction of tafenoquine, ivermectin, and chloroquine (CQ) in Rhesus macaques. No clinical, biochemistry, or hematological outcomes of concern were observed. The Cambridge Neuropsychological Test Automated Battery (CANTAB) was employed to assess potential neurological deficits following drug administration. Some impairment was observed with tafenoquine alone and in the same monkeys with subsequent co-administrations. Co-administration of chloroquine and tafenoquine resulted in increased plasma exposure to tafenoquine. Urine concentrations of the 5,6 orthoquinone TQ metabolite were increased with co-administration of tafenoquine and ivermectin. There was an increase in ivermectin plasma exposure when co-administered with chloroquine. No interaction of tafenoquine on ivermectin was observed in vitro. Chloroquine and trace levels of ivermectin, but not tafenoquine, were observed in the cerebrospinal fluid. The 3''-O-demethyl ivermectin metabolite was observed in macaque plasma but not in urine or cerebrospinal fluid. Overall, the combination of ivermectin, tafenoquine, and chloroquine did not have clinical, neurological, or pharmacological interactions of concern in macaques; therefore, this combination could be considered for evaluation in human trials.

Impact of Balloon Guide Catheters in Elderly Patients Treated with Mechanical Thrombectomy: Insights from the ROSSETTI Registry.

BACKGROUND AND PURPOSE: Several nonrandomized studies have demonstrated the effectiveness of balloon guide catheters in treating patients with anterior circulation large-vessel occlusion. However, their impact on the elderly populations has been underreported. We aimed to analyze the effect of balloon guide catheters in a cohort of elderly patients (80 years of age or older) with anterior circulation large-vessel occlusion. MATERIALS AND METHODS: Consecutive patients from June 2019 to June 2022 were collected from the ROSSETTI Registry. Demographic and clinical data, angiographic endovascular technique, and clinical outcome were compared between balloon guide catheter and non-balloon guide catheter groups. We studied the association between balloon guide catheters and the rate of complete recanalization after a single first-pass effect modified TICI 2c-3, as well as their association with functional independence at 3 months. RESULTS: A total of 808 patients were included during this period, 465 (57.5%) of whom were treated with balloon guide catheters. Patients treated with balloon guide catheters were older, had more neurologic severity at admission and lower baseline ASPECTS, and were less likely to receive IV fibrinolytics. No differences were observed in terms of the modified first-pass effect between groups (45.8 versus 39.9%, P = .096). In the multivariable regression analysis, balloon guide catheter use was not independently associated with a modified first-pass effect or the final modified TICI 2c-3, or with functional independence at 3 months. CONCLUSIONS: In our study, balloon guide catheter use during endovascular treatment of anterior circulation large-vessel occlusion in elderly patients did not predict the first-pass effect, near-complete final recanalization, or functional independence at 3 months. Further studies, including randomized clinical trials, are needed to confirm these results.

Impact of sleep deprivation on neurocognition and inflammation in rhesus macaques.

Sleep deprivation in humans is associated with both cognitive impairment and immune dysregulation. An animal model of neuropathogenesis may provide insight to understand the effects of sleep deprivation on the brain. Human neurocognition is more closely mirrored by nonhuman primates (NHP) than other animals. As such, we developed an NHP model to assess the impact of sleep deprivation on neurocognition and markers of systemic immune activation. Six male rhesus macaques underwent three rounds of sleep deprivation (48 h without sleep) at days 0, 14, and 28. We performed domain specific cognitive assessments using the Cambridge Neuropsychological Test Automated Battery (CANTAB) via a touch screen before and after 24 and 48 h of sleep deprivation. Immune activation markers were measured in the blood by multiplex assay and flow cytometry. Although we observed variability in cognitive performance between the three rounds of sleep deprivation, cognitive impairments were identified in all six animals. We noted more cognitive impairments after 48 h than after 24 h of sleep deprivation. Following 48 h of sleep deprivation, elevations in markers of immune activation in the blood were observed in most animals. The observed impairments largely normalized after sleep. The co-occurrence of systemic immune alterations and cognitive impairment establishes this model as useful for studying the impact of sleep deprivation on neurobehavior and immune perturbations in rhesus macaques.

Admission systolic blood pressure and effect of endovascular treatment in patients with ischaemic stroke: an individual patient data meta-analysis.

BACKGROUND: Current guidelines for ischaemic stroke treatment recommend a strict, but arbitrary, upper threshold of 185/110 mm Hg for blood pressure before endovascular thrombectomy. Nevertheless, whether admission blood pressure influences the effect of endovascular thrombectomy on outcome remains unknown. Our aim was to study the influence of admission systolic blood pressure (SBP) on functional outcome and on the effect of endovascular thrombectomy. METHODS: We used individual patient data from seven randomised controlled trials (MR CLEAN, ESCAPE, EXTEND-IA, SWIFT PRIME, REVASCAT, PISTE, and THRACE) that randomly assigned patients with anterior circulation ischaemic stroke to endovascular thrombectomy (predominantly using stent retrievers) or standard medical therapy (control) between June 1, 2010, and April 30, 2015. We included all patients for whom SBP data were available at hospital admission. The primary outcome was functional outcome (modified Rankin Scale) at 90 days. We assessed the association of SBP with outcome in both the endovascular thrombectomy group and the control group using multilevel regression analysis and tested for non-linearity and for interaction between SBP and effect of endovascular thrombectomy, taking into account treatment with intravenous thrombolysis. FINDINGS: We included 1753 patients (867 assigned to endovascular thrombectomy, 886 assigned to control) after excluding 11 patients for whom SBP data were missing. We found a non-linear association between SBP and functional outcome with an inflection point at 140 mm Hg (732 [42%] of 1753 patients had SBP <140 mm Hg and 1021 [58%] had SBP ≥140 mm Hg). Among patients with SBP of 140 mm Hg or higher, admission SBP was associated with worse functional outcome (adjusted common odds ratio [acOR] 0·86 per 10 mm Hg SBP increase; 95% CI 0·81-0·91). We found no association between SBP and functional outcome in patients with SBP less than 140 mm Hg (acOR 0·97 per 10 mm Hg SBP decrease, 95% CI 0·88-1·05). There was no significant interaction between SBP and effect of endovascular thrombectomy on functional outcome (p=0·96). INTERPRETATION: In our meta-analysis, high admission SBP was associated with worse functional outcome after stroke, but SBP did not seem to negate the effect of endovascular thrombectomy. This finding suggests that admission SBP should not form the basis for decisions to withhold or delay endovascular thrombectomy for ischaemic stroke, but randomised trials are needed to further investigate this possibility. FUNDING: Medtronic.

Derivo embolization device for intracranial aneurysms: a Spanish multicenter retrospective study.

BACKGROUND: Flow diverters have emerged in recent years as a safe and effective treatment for intracranial aneurysms, with expanding indications. The Derivo embolization device (DED) is a second-generation flow diverter with a surface finish that may reduce thrombogenicity. We report our multicenter experience evaluating its safety and efficacy. METHODS: We retrospectively analyzed all patients treated with the DED in eight centers in Spain between 2016 and 2020. Demographics, clinical data, procedural complications, morbidity and aneurysm occlusion rates were collected. RESULTS: A total of 209 patients with 250 aneurysms were treated (77.5% women). The majority of aneurysms were located in the internal carotid artery (86.8%) and most (69.2%) were small (<10 mm) with a median maximum diameter of 5.85 mm and median neck size of 4 mm. DED deployment was successful in all cases, despite two malfunctioning devices (1%). Major complications occurred in nine patients (4.3%), while mild neurologic clinical events were registered in 23 (11%); four patients died (1.9%). A total of 194 aneurysms had an angiographic follow-up at 6 months and showed complete aneurysm occlusion in 75% of cases. Twelve-month follow-up was available for 112 of the treated aneurysms, with a total occlusion rate of 83%. CONCLUSION: The DED is a second-generation surface-modified flow diverter that presents an option for treatment of intracranial aneurysms with comparable safety and efficacy to other available flow diverter devices. Nonetheless, risks are not negligible, and must be balanced against the natural history risk of cerebral aneurysms, considering the tendency to widen indications for treatment of smaller and less complex lesions in day-to-day use.

Impact of the Mexican education system and age on basic knowledge about ischemic heart disease in the pre-COVID-19 era.

BACKGROUND AND OBJECTIVE: To assess general population's knowledge about ischemic heart disease (IHD) and its relationship to years of schooling in Mexico. METHOD: Analysis of surveys designed to measure knowledge about IHD applied in Mexico City. RESULTS: 530 surveys were analyzed. 51.7% were women. The median age was 43 years (IQR: 15-92) and the median of schooling was 18 years (IQR: 15-18). 64.5% of respondents scored less than 50% of correct answers. A slight increase in the knowledge level and years of study (p < 0.001) and age (p = 0.101) was observed, but with low correlation indexes (r = 0.215 and r = 0.071, respectively). CONCLUSIONS: Knowledge about IHD in general population is deficient and doesn't increase adequately neither with age nor academic studies. It is necessary to review our health education strategies.

ANTECEDENTES Y OBJETIVO: Evaluar los conocimientos sobre cardiopatía isquémica (CI) de la población general y relacionarlos con los años de escolaridad y la edad. MÉTODO: Análisis de encuestas diseñadas para medir conocimientos sobre CI aplicadas en Ciudad de México. RESULTADOS: Se analizaron 530 encuestas. El 51.7% fueron mujeres. La mediana de edad fue 43 años (RIC: 15 a 92) y la de años de estudio fue de 18 años (RIC: 15-18). El 64.5% de los encuestados obtuvo menos del 50% de aciertos. Se documentó un ligero incremento en el nivel de conocimiento con los años de estudio (p < 0.001) y con la edad (p = 0.101), pero con bajos índices de correlación (r = 0.215 y r = 0.071, respectivamente). CONCLUSIONES: Los conocimientos sobre CI en la población general son deficientes y no se incrementan adecuadamente con la edad ni con los años de estudios académicos. Es necesario revisar nuestras estrategias de educación en salud.

Comparison of Three Scores of Collateral Status for Their Association With Clinical Outcome: The HERMES Collaboration.

BACKGROUND: Leptomeningeal collateral status on baseline computed tomographic angiography (CTA) is associated with clinical outcome after acute ischemic stroke treatment. However, assessment of collateral status is not uniform. To compare 3 different CTA collateral scores (CS) and imaging techniques about their association with clinical outcome. METHODS: Pooled analysis of patient-level data from the Highly Effective Reperfusion Using Multiple Endovascular Devices collaboration. Patients with large vessel occlusion from 7 randomized controlled trials that compared endovascular thrombectomy with standard medical care were included. Three different CS (Tan CS, regional CS [rCS], and regional Alberta Stroke Program Early CT Score CS) and 2 imaging techniques (single-phase [sCTA] and multiphase/dynamic CTA) were evaluated. Functional independence (modified Rankin Scale score 0-2) at 3 months poststroke was the primary outcome. Furthermore, we assessed the effect of sCTA image acquisition time on collateral status assessment using an adjusted ordinal logistic regression model to obtain predicted values for the trichotomized rCS. RESULTS: Among 1147 pooled patients, 948 (82.7%) had sCTA and 199 (17.3%) multiphase/dynamic CTA as baseline angiography. With all 3 collateral scales, better CSs were associated with better 3-month functional outcome. With sCTA images, the rCS (area under the curve [AUC] 0.63) and regional Alberta Stroke Program Early CT Score CS (AUC 0.62) better predicted functional outcome than the Tan CS (AUC 0.60, respectively; P<0.001 and P=0.02). With multiphase/dynamic CTA images, all collateral scales performed similarly in predicting functional outcome (rCS [AUC 0.61]; regional Alberta Stroke Program Early CT Score CS [AUC 0.61] versus Tan CS [AUC 0.61], respectively; P=0.93 and P=0.91). Overall, no endovascular thrombectomy treatment effect modification by collateral status (rCS) was demonstrated (P=0.41). sCTA timing independently influenced CS assessment. On earlier timed sCTA, the predicted proportions of scans with poor collaterals was higher and vice versa. CONCLUSIONS: In this data set of highly selected patients with stroke, using a regional CS on sCTA likely allows for the most accurate prediction of functional outcome while on time-resolved CTA, the type of CS did not matter. Patients across all collateral grades benefit from endovascular thrombectomy. sCTA timing independently influenced CS assessment.

Adjunct Thrombolysis Enhances Brain Reperfusion following Successful Thrombectomy.

OBJECTIVE: This study was undertaken to investigate whether adjunct alteplase improves brain reperfusion following successful thrombectomy. METHODS: This single-center, randomized, double-blind, placebo-controlled study included 36 patients (mean [standard deviation] = 70.8 [13.5] years old, 18 [50%] women) with large vessel occlusion undergoing thrombectomy resulting in near-normal (expanded Thrombolysis in Cerebral Infarction [eTICI] b50/67/2c, n = 23, 64%) or normal angiographic reperfusion (eTICI 3, n = 13, 36%). Seventeen patients were randomized to intra-arterial alteplase (0.225mg/kg), and 19 received placebo. At 48 hours, patients had brain perfusion/diffusion-weighted magnetic resonance imaging (MRI) and MRI-spectroscopy. The primary outcome was the difference in the proportion of patients with areas of hypoperfusion on MRI. Secondary outcomes were the infarct expansion ratio (final to initial infarction volume), and the N-acetylaspartate (NAA) peak relative to total creatine as a marker of neuronal integrity. RESULTS: The prevalence of hypoperfusion was 24% with intra-arterial alteplase, and 58% with placebo (adjusted odds ratio = 0.20, 95% confidence interval [CI] = 0.04-0.91, p = 0.03). Among 14 patients with final eTICI 3 scores, hypoperfusion was found in 1 of 7 (14%) in the alteplase group and 3 of 7 (43%) in the placebo group. Abnormal brain perfusion was associated with worse functional outcome at day 90. Alteplase significantly reduced the infarct expansion ratio compared with placebo (median [interquartile range (IQR)] = 0.7 [0.5-1.2] vs 3.2 [1.8-5.7], p = 0.01) and resulted in higher NAA peaks (median [IQR] = 1.13 [0.91-1.36] vs 1.00 [0.74-1.22], p < 0.0001). INTERPRETATION: There is a high prevalence of areas of hypoperfusion following thrombectomy despite successful reperfusion on angiography. Adjunct alteplase enhances brain reperfusion, which results in reduced expansion of the infarction and improved neuronal integrity. ANN NEUROL 2022;92:860-870.

Intestinal Ewing sarcoma: An unusual presentation in the pediatric age.

BACKGROUND: Ewing's Sarcoma (ES) is the second most common type of bone cancer, with an annual incidence of 2.9:100,000. Extraosseous cases represent 15%; however, there are no reported cases of ES located in the intestine in the pediatric population. CASE REPORT: We describe the case of a 14-year-old male patient, previously healthy, who started with an anemic syndrome, weight loss, and diaphoresis of 8 weeks of evolution. After visiting a physician, who documented the presence of anemia, the patient was referred to the National Institute of Pediatrics. Physical examination showed grade III-IV systolic murmur, splenomegaly, and pain in the left hemiabdomen with no irradiation. Computed axial tomography showed a mass-dependent on the peritoneum and intestinal loop. A biopsy of the lesion showed intestinal ES. The lesion was completely resected, and the patient was treated with chemotherapy and radiotherapy. Thirty months after diagnosis, the patient has no evidence of tumor activity. CONCLUSIONS: Extraosseous presentation of ES in pediatric age is rare. There are no reports of intestinal ES in the Latin American pediatric population, although eight case reports were found in adults. ES is curable by a combination of chemotherapy, radiotherapy, and surgery. The medical literature indicates that the extraosseous presentation should receive the same treatment as the osseous presentation, which can provide a survival rate of up to 70% if there is no evidence of metastasis (which most frequently is observed in the lung).

INTRODUCCIÓN: El sarcoma de Ewing (SE) es el segundo tipo cáncer más común de hueso, cuya incidencia anual es de 2.9:100,000. Los casos extraóseos representan el 15%; sin embargo, no existen reportes en la literatura de casos de SE ubicados en el intestino en la población pediátrica. CASO CLÍNICO: Se describe el caso de un paciente de sexo masculino de 14 años, previamente sano, que inició con síndrome anémico, pérdida de peso y diaforesis de 8 semanas de evolución. Acudió con un médico, quien documentó la presencia de anemia y lo refirió al Instituto Nacional de Pediatría. A la exploración física presentaba soplo sistólico grado III-IV, esplenomegalia y dolor en hemiabdomen izquierdo sin irradiaciones. La tomografía axial computarizada mostró una masa dependiente del peritoneo y asa intestinal. La biopsia de la lesión reportó SE intestinal. Se resecó por completo la lesión y el paciente recibió tratamiento con quimioterapia y radioterapia. Después de 30 meses del diagnóstico, el paciente se encuentra sin datos de actividad tumoral. CONCLUSIONES: La presentación extraósea del SE en edad pediátrica es rara. No existen reportes de presentación de SE intestinal en la población pediátrica latinoamericana, aunque se encontraron ocho reportes de caso en adultos. El SE es curable mediante la combinación de quimioterapia, radioterapia y cirugía. La literatura médica indica que la presentación extraósea debe recibir el mismo tratamiento que la ósea, lo cual puede proporcionar una sobrevida de hasta el 70% si no hay evidencia de metástasis (que ocurre más frecuentemente a pulmón).

Intestinal Ewing sarcoma: An unusual presentation in the pediatric age / Sarcoma de Ewing intestinal: presentación inusual en la edad pediátrica

Abstract Background: Ewing's Sarcoma (ES) is the second most common type of bone cancer, with an annual incidence of 2.9:100,000. Extraosseous cases represent 15%; however, there are no reported cases of ES located in the intestine in the pediatric population. Case report: We describe the case of a 14-year-old male patient, previously healthy, who started with an anemic syndrome, weight loss, and diaphoresis of 8 weeks of evolution. After visiting a physician, who documented the presence of anemia, the patient was referred to the National Institute of Pediatrics. Physical examination showed grade III-IV systolic murmur, splenomegaly, and pain in the left hemiabdomen with no irradiation. Computed axial tomography showed a mass-dependent on the peritoneum and intestinal loop. A biopsy of the lesion showed intestinal ES. The lesion was completely resected, and the patient was treated with chemotherapy and radiotherapy. Thirty months after diagnosis, the patient has no evidence of tumor activity. Conclusions: Extraosseous presentation of ES in pediatric age is rare. There are no reports of intestinal ES in the Latin American pediatric population, although eight case reports were found in adults. ES is curable by a combination of chemotherapy, radiotherapy, and surgery. The medical literature indicates that the extraosseous presentation should receive the same treatment as the osseous presentation, which can provide a survival rate of up to 70% if there is no evidence of metastasis (which most frequently is observed in the lung).

Resumen Introducción: El sarcoma de Ewing (SE) es el segundo tipo cáncer más común de hueso, cuya incidencia anual es de 2.9:100,000. Los casos extraóseos representan el 15%; sin embargo, no existen reportes en la literatura de casos de SE ubicados en el intestino en la población pediátrica. Caso clínico: Se describe el caso de un paciente de sexo masculino de 14 años, previamente sano, que inició con síndrome anémico, pérdida de peso y diaforesis de 8 semanas de evolución. Acudió con un médico, quien documentó la presencia de anemia y lo refirió al Instituto Nacional de Pediatría. A la exploración física presentaba soplo sistólico grado III-IV, esplenomegalia y dolor en hemiabdomen izquierdo sin irradiaciones. La tomografía axial computarizada mostró una masa dependiente del peritoneo y asa intestinal. La biopsia de la lesión reportó SE intestinal. Se resecó por completo la lesión y el paciente recibió tratamiento con quimioterapia y radioterapia. Después de 30 meses del diagnóstico, el paciente se encuentra sin datos de actividad tumoral. Conclusiones: La presentación extraósea del SE en edad pediátrica es rara. No existen reportes de presentación de SE intestinal en la población pediátrica latinoamericana, aunque se encontraron ocho reportes de caso en adultos. El SE es curable mediante la combinación de quimioterapia, radioterapia y cirugía. La literatura médica indica que la presentación extraósea debe recibir el mismo tratamiento que la ósea, lo cual puede proporcionar una sobrevida de hasta el 70% si no hay evidencia de metástasis (que ocurre más frecuentemente a pulmón).

Chimeric Virus-like Particle-Based COVID-19 Vaccine Confers Strong Protection against SARS-CoV-2 Viremia in K18-hACE2 Mice.

Virus-like particles (VLPs) are highly immunogenic and versatile subunit vaccines composed of multimeric viral proteins that mimic the whole virus but lack genetic material. Due to the lack of infectivity, VLPs are being developed as safe and effective vaccines against various infectious diseases. In this study, we generated a chimeric VLP-based COVID-19 vaccine stably produced by HEK293T cells. The chimeric VLPs contain the influenza virus A matrix (M1) proteins and the SARS-CoV-2 Wuhan strain spike (S) proteins with a deletion of the polybasic furin cleavage motif and a replacement of the transmembrane and cytoplasmic tail with that of the influenza virus hemagglutinin (HA). These resulting chimeric S-M1 VLPs, displaying S and M1, were observed to be enveloped particles that are heterogeneous in shape and size. The intramuscular vaccination of BALB/c mice in a prime-boost regimen elicited high titers of S-specific IgG and neutralizing antibodies. After immunization and a challenge with SARS-CoV-2 in K18-hACE2 mice, the S-M1 VLP vaccination resulted in a drastic reduction in viremia, as well as a decreased viral load in the lungs and improved survival rates compared to the control mice. Balanced Th1 and Th2 responses of activated S-specific T-cells were observed. Moderate degrees of inflammation and viral RNA in the lungs and brains were observed in the vaccinated group; however, brain lesion scores were less than in the PBS control. Overall, we demonstrate the immunogenicity of a chimeric VLP-based COVID-19 vaccine which confers strong protection against SARS-CoV-2 viremia in mice.

Correlation Between Computed Tomography-Based Tissue Net Water Uptake and Volumetric Measures of Cerebral Edema After Reperfusion Therapy.

BACKGROUND: Cerebral edema after large hemispheric infarction is associated with poor functional outcome and mortality. Net water uptake (NWU) quantifies the degree of hypoattenuation on unenhanced-computed tomography (CT) and is increasingly used to measure cerebral edema in stroke research. Hemorrhagic transformation and parenchymal contrast staining after thrombectomy may confound NWU measurements. We investigated the correlation of NWU measured postthrombectomy with volumetric markers of cerebral edema and association with functional outcomes. METHODS: In a pooled individual patient level analysis of patients presenting with anterior circulation large hemispheric infarction (core 80-300 mL or Alberta Stroke Program Early CT Score ≤5) in the HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke trials) data set, cerebral edema was defined as the volumetric expansion of the ischemic hemisphere expressed as a ratio to the contralateral hemisphere(rHV). NWU and midline-shift were compared with rHV as the reference standard on 24-hour follow-up CT, adjusted for hemorrhagic transformation and the use of thrombectomy. Association between edema markers and day 90 functional outcomes (modified Rankin Scale) was assessed using ordinal logistic regression. RESULTS: Overall (n=144), there was no correlation between NWU and rHV (rs=0.055, P=0.51). In sub-group analyses, a weak correlation between NWU with rHV was observed after excluding patients with any degree of hemorrhagic transformation (rs=0.211, P=0.015), which further improved after excluding thrombectomy patients (rs=0.453, P=0.001). Midline-shift correlated strongly with rHV in all sub-group analyses (rs>0.753, P=0.001). Functional outcome at 90 days was negatively associated with rHV (adjusted common odds ratio, 0.46 [95% CI, 0.32-0.65]; P<0.001) and midline-shift (adjusted common odds ratio, 0.85 [95% CI, 0.78-0.92]; P<0.001) but not NWU (adjusted common odds ratio, 1.00 [95% CI, 0.97-1.03]; P=0.84), adjusted for age, baseline National Institutes of Health Stroke Scale, and thrombectomy. Prognostic performance of NWU improved after excluding patients with hemorrhagic transformation and thrombectomy (adjusted odds ratio, 0.90 [95% CI, 0.80-1.02]; P=0.10). CONCLUSIONS: NWU correlated poorly with conventional markers of cerebral edema and was not associated with clinical outcome in the presence of hemorrhagic transformation and thrombectomy. Measuring NWU postthrombectomy requires validation before implementation into clinical research. At present, the use of NWU should be limited to baseline CT, or follow-up CT only in patients without hemorrhagic transformation or treatment with thrombectomy.

Equex STM paste improves post-thawed epididymal sperm motility and acrosome integrity in rhesus monkey (Macaca mulatta).

Equex STM paste, a water-soluble detergent, exerts the protective effect of egg-yolk during sperm cryopreservation. This study aims to evaluate the post-thaw quality of rhesus monkeys' epididymal spermatozoa in the Tris-citric-glucose egg-yolk extender, supplemented with or without Equex STM paste (0.5%, v/v) (n = 6). Sperm motility, progressive motility, motion characteristics, viability, acrosome integrity and mitochondrial activity were compared immediately post-thaw. Equex STM paste supplementation significantly improved sperm motility (35.0 ± 4.5 vs. 23.7 ± 5.0%), progressive motility (15.4 ± 2.1 vs. 9.8 ± 2.7%) and percentage of sperm with intact acrosome (30.4 ± 4.5 vs. 26.3 ± 4.6%) compared to the controls, respectively. This is the first report applying Equex STM paste for monkey epididymal sperm cryopreservation and is expected to be beneficial as a model for endangered non-human primates.

Effect of Intra-arterial Alteplase vs Placebo Following Successful Thrombectomy on Functional Outcomes in Patients With Large Vessel Occlusion Acute Ischemic Stroke: The CHOICE Randomized Clinical Trial.

Importance: It is estimated that only 27% of patients with acute ischemic stroke and large vessel occlusion who undergo successful reperfusion after mechanical thrombectomy are disability free at 90 days. An incomplete microcirculatory reperfusion might contribute to these suboptimal clinical benefits. Objective: To investigate whether treatment with adjunct intra-arterial alteplase after thrombectomy improves outcomes following reperfusion. Design, Setting, and Participants: Phase 2b randomized, double-blind, placebo-controlled trial performed from December 2018 through May 2021 in 7 stroke centers in Catalonia, Spain. The study included 121 patients with large vessel occlusion acute ischemic stroke treated with thrombectomy within 24 hours after stroke onset and with an expanded Treatment in Cerebral Ischemia angiographic score of 2b50 to 3. Interventions: Participants were randomized to receive intra-arterial alteplase (0.225 mg/kg; maximum dose, 22.5 mg) infused over 15 to 30 minutes (n = 61) or placebo (n = 52). Main Outcomes and Measures: The primary outcome was the difference in proportion of patients achieving a score of 0 or 1 on the 90-day modified Rankin Scale (range, 0 [no symptoms] to 6 [death]) in all patients treated as randomized. Safety outcomes included rate of symptomatic intracranial hemorrhage and death. Results: The study was terminated early for inability to maintain placebo availability and enrollment rate because of the COVID-19 pandemic. Of 1825 patients with acute ischemic stroke treated with thrombectomy at the 7 study sites, 748 (41%) patients fulfilled the angiographic criteria, 121 (7%) patients were randomized (mean age, 70.6 [SD, 13.7] years; 57 women [47%]), and 113 (6%) were treated as randomized. The proportion of participants with a modified Rankin Scale score of 0 or 1 at 90 days was 59.0% (36/61) with alteplase and 40.4% (21/52) with placebo (adjusted risk difference, 18.4%; 95% CI, 0.3%-36.4%; P = .047). The proportion of patients with symptomatic intracranial hemorrhage within 24 hours was 0% with alteplase and 3.8% with placebo (risk difference, -3.8%; 95% CI, -13.2% to 2.5%). Ninety-day mortality was 8% with alteplase and 15% with placebo (risk difference, -7.2%; 95% CI, -19.2% to 4.8%). Conclusions and Relevance: Among patients with large vessel occlusion acute ischemic stroke and successful reperfusion following thrombectomy, the use of adjunct intra-arterial alteplase compared with placebo resulted in a greater likelihood of excellent neurological outcome at 90 days. However, because of study limitations, these findings should be interpreted as preliminary and require replication. Trial Registration: ClinicalTrials.gov Identifier: NCT03876119; EudraCT Number: 2018-002195-40.

Chronic Wound Infection Model of Acinetobacter baumannii in Outbred Mice.

INTRODUCTION: We established a murine wound infection model with doxycycline treatment against multidrug-resistant Acinetobacter baumannii (AB5075) in Institute of Cancer Research (ICR) outbred mice. METHODS: Using three groups of neutropenic ICR mice, two full-thickness dorsal dermal wounds (6 mm diameter) were made on each mouse. In two groups, wounds were inoculated with 7.0 × 104 colony-forming units of AB5075. Of these two groups, one received a 6-day regimen of doxycycline while the other was sham treated with phosphate-buffered saline as placebo control. Another uninfected/untreated group served as a control. Wound closure, clinical symptoms, bacterial burden in wound beds and organs, and wound histology were investigated. RESULTS: Doxycycline-treated wounds completely healed by day 21, but untreated, infected wounds failed to heal. Compared to controls, wound infections without treatment resulted in significant reductions in body weight and higher bacterial loads in wound beds, lung, liver, and spleen by day 7. Histological evaluation of wounds on day 21 revealed ulcerated epidermis, muscle necrosis, and bacterial presence in untreated wounds, while wounds treated with doxycycline presented intact epidermis. CONCLUSIONS: Compared to the previously developed BALB/c dermal wound model, this study demonstrates that the mouse strain selected impacts wound severity and resolution. Furthermore, this mouse model accommodates two dorsal wounds rather than only one. These variations offer investigators increased versatility when designing future studies of wound infection. In conclusion, ICR mice are a viable option as a model of dermal wound infection. They accommodate two simultaneous dorsal wounds, and upon infection, these wounds follow a different pattern of resolution compared to BALB/c mice.

Neurocognitive impact of Zika virus infection in adult rhesus macaques.

BACKGROUND: Zika virus (ZIKV) is a mosquito-transmitted flavivirus that affects many regions of the world. Infection, in utero, causes microcephaly and later developmental and neurologic impairments. The impact of ZIKV infection on neurocognition in adults has not been well described. The objective of the study was to assess the neurocognitive impact of ZIKV infection in adult rhesus macaques. METHODS: Neurocognitive assessments were performed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) via a touch screen and modified Brinkman Board before and after subcutaneous ZIKV inoculation. Immune activation markers were measured in the blood and cerebral spinal fluid (CSF) by multiplex assay and flow cytometry. RESULTS: All animals (N = 8) had detectable ZIKV RNA in plasma at day 1 post-inoculation (PI) that peaked at day 2 PI (median 5.9, IQR 5.6-6.2 log10 genome equivalents/mL). In all eight animals, ZIKV RNA became undetectable in plasma by day 14 PI, but persisted in lymphoid tissues. ZIKV RNA was not detected in the CSF supernatant at days 4, 8, 14 and 28 PI but was detected in the brain of 2 animals at days 8 and 28 PI. Elevations in markers of immune activation in the blood and CSF were accompanied by a reduction in accuracy and reaction speed on the CANTAB in the majority of animals. CONCLUSIONS: The co-occurrence of systemic and CSF immune perturbations and neurocognitive impairment establishes this model as useful for studying the impact of neuroinflammation on neurobehavior in rhesus macaques, as it pertains to ZIKV infection and potentially other pathogens.

Experiences and Preferences of Opioid-Use-Disorder Patients Who Switched from Brand to Generic Buprenorphine/Naloxone Films: A Case Series.

PURPOSE: Differences in the suppression of withdrawal symptoms have been observed in opioid-use-disorder (OUD) patients who were switched from Suboxone (the brand name of buprenorphine/naloxone sublingual films) to either 1 of 2 generic versions. These descriptive observations evidence the need to further assess the use of these generics and its impact on the adherence to and outcomes of OUD treatments. The objective of this case series was to describe patient and provider experiences, perceptions, and preferences when said patients were abruptly switched from Suboxone to one of the generic versions manufactured by Sandoz or Alvogen. PATIENTS AND METHODS: A retrospective chart review of 24 Suboxone-maintained OUD patients from a single clinic who were forced to switch to a generic was performed to collect withdrawal and craving symptoms that occurred after the switch, as well as toxicology results and changes in dose (documented by the provider). RESULTS: The medical records of 9 (37.5%) of the 24 patients showed that they were suffering from withdrawal symptoms and/or cravings, had had their doses adjusted, and/or had had a positive urine toxicology screen. All 9 subjects communicated a preference for the brand formulation over that of either of the generic versions; few expressed a preference for one generic formulation over the other. None of patients were able to switch back to the brand formulation, nor were any of them able to choose the generic that worked best for them. Insomnia, muscle pain, and gooseflesh skin were the most common withdrawal symptoms reported by the patients using the generics. Better outcomes were observed in patients who received a buprenorphine dose increase (2 mg) to suppress the withdrawal symptoms experienced while using the generics. CONCLUSION: Our study serves as a reference to prescribers regarding approaches (eg, a small dose adjustment) that may potentially encourage OUD treatment adherence and even improve outcomes in patients who appear to be decompensating after the brand-to-generic switch.