Norm conflicts and epistemic modals.

Statements containing epistemic modals (e.g., "by spring 2023 most European countries may have the Covid-19 pandemic under control") are common expressions of epistemic uncertainty. In this paper, previous published findings (Knobe & Yalcin, 2014; Khoo & Phillips, 2018) on the opposition between Contextualism and Relativism for epistemic modals are re-examined. It is found that these findings contain a substantial degree of individual variation. To investigate whether participants differ in their interpretations of epistemic modals, an experiment with multiple phases and sessions is conducted to classify participants according to the three semantic theories of Relativism, Contextualism, and Objectivism. Through this study, some of the first empirical evidence for the kind of truth-value shifts postulated by semantic Relativism is presented. It is furthermore found that participants' disagreement judgments match their truth evaluations and that participants are capable of distinguishing between truth and justification. In a second experimental session, it is investigated whether participants thus classified follow the norm of retraction which Relativism uses to account for argumentation with epistemic modals. Here the results are less favorable for Relativism. In a second experiment, these results are replicated and the normative beliefs of participants concerning the norm of retraction are investigated following work on measuring norms by Bicchieri (2017). Again, it is found that on average participants show no strong preferences concerning the norm of retraction for epistemic modals. Yet, it was found that participants who had committed to Objectivism and had training in logic applied the norm of retraction to might-statements. These results present a substantial challenge to the account of argumentation with epistemic modals presented in MacFarlane (2014), as discussed.

Pivotal Trial of the Neuroform Atlas Stent for Treatment of Anterior Circulation Aneurysms: One-Year Outcomes.

BACKGROUND AND PURPOSE: Stent-assisted coil embolization using the new generation Neuroform Atlas Stent System has shown promising safety and efficacy. The primary study results of the anterior circulation aneurysm cohort of the treatment of wide-neck, saccular, intracranial, aneurysms with the Neuroform Atlas Stent System (ATLAS trial [Safety and Effectiveness of the Treatment of Wide Neck, Saccular Intracranial Aneurysms With the Neuroform Atlas Stent System]) are presented. METHODS: ATLAS IDE trial (Investigational Device Exemption) is a prospective, multicenter, single-arm, open-label study of wide-neck (neck ≥4 mm or dome-to-neck ratio <2) intracranial aneurysms in the anterior circulation treated with the Neuroform Atlas Stent and approved coils. The primary efficacy end point was complete aneurysm occlusion (Raymond-Roy class 1) on 12-month angiography, in the absence of retreatment or parent artery stenosis (>50%) at the target location. The primary safety end point was any major stroke or ipsilateral stroke or neurological death within 12 months. Adjudication of the primary end points was performed by an independent Imaging Core Laboratory and the Clinical Events Committee. RESULTS: A total of 182 patients with wide-neck anterior circulation aneurysms at 25 US centers were enrolled. The mean age was 60.3±11.4 years, 73.1% (133/182) women, and 80.8% (147/182) white. Mean aneurysm size was 6.1±2.2 mm, mean neck width was 4.1±1.2 mm, and mean dome-to-neck ratio was 1.2±0.3. The most frequent aneurysm locations were the anterior communicating artery (64/182, 35.2%), internal carotid artery ophthalmic artery segment (29/182, 15.9%), and middle cerebral artery bifurcation (27/182, 14.8%). Stents were placed in the anticipated anatomic location in all patients. The study met both primary safety and efficacy end points. The composite primary efficacy end point of complete aneurysm occlusion (Raymond-Roy 1) without parent artery stenosis or aneurysm retreatment was achieved in 84.7% (95% CI, 78.6%-90.9%) of patients. Overall, 4.4% (8/182, 95% CI, 1.9%-8.5%) of patients experienced a primary safety end point of major ipsilateral stroke or neurological death. CONCLUSIONS: In the ATLAS IDE anterior circulation aneurysm cohort premarket approval study, the Neuroform Atlas stent with adjunctive coiling met the primary end points and demonstrated high rates of long-term complete aneurysm occlusion at 12 months, with 100% technical success and <5% morbidity. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02340585.

Endovascular reconstruction of extracranial traumatic internal carotid artery dissections: a systematic review.

Extracranial internal carotid artery dissection (ICAD) is a potential source of morbidity and mortality in trauma patients and requires high degree of suspicion for diagnosis after the initial presentation. Occasionally, if standard therapy is contraindicated, endovascular reconstruction is a treatment option. The aim of this systematic review was to report clinical and radiographic outcomes following endovascular repair of ICAD of traumatic and iatrogenic etiology. A comprehensive systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. PubMed and Cochrane Library databases were searched. Twenty-four studies comprising 191 patients (204 lesions) were included; 179 underwent traditional carotid artery stenting (CAS), whereas 12 patients underwent flow diversion with the pipeline embolization device (PED). In total, 75.7% of the CAS group and 66.6% of the PED group presented with ICAD-related symptomatology. Concomitant pseudoaneurysms were identified in 61.9% and 78.5% of lesions in the CAS and PED group, respectively. Adverse event rates among CAS-treated lesions after 30-day follow-up were below 2.2% for stroke, transient ischemic attack, and mortality. During follow-up in the CAS group, there was no incidence of ICAD-related stroke or death and 2.2% of patients underwent a repeat CAS procedure. In the PED group, no patient suffered stroke or death in the reported follow-up. In the PED cohort, there was an adequate occlusion rate and no patient had to be retreated. Endovascular reconstruction of traumatic or iatrogenic ICAD appears safe. This approach demonstrated acceptable short- and long-term clinical and radiographic outcomes in both groups.

Direct Transcervical Access vs the Transfemoral Approach for Carotid Artery Stenting: A Systematic Review and Meta-Analysis.

PURPOSE: To examine the safety profile of transcervical access (TCA) in comparison with the transfemoral approach (TFA) in carotid artery stenting. MATERIALS AND METHODS: A systematic review and meta-analysis was performed according to current guidelines. Eleven eligible studies including 11,592 patients (10,736 in the TFA group and 856 in the TCA group) were identified through a search of the PubMed, Scopus, and Cochrane databases up to October 2018. A random effects model meta-analysis was conducted, and the I2 statistic was used to assess heterogeneity. Publication bias was assessed using funnel plots and quantified using the Egger method. RESULTS: The TFA group had a statistically significantly higher risk of periprocedural (30-day) stroke compared with the TCA group (OR 1.98, 95% CI 1.08 to 3.63, p=0.027; I2=0%). Also, patients in the TFA group had a significantly higher risk of developing new ischemic lesions (OR 2.97, 95% CI 1.48 to 5.96, p=0.002; I2=0%) on diffusion-weighted magnetic resonance imaging (DW-MRI). No differences in terms of transient ischemic attack (OR 1.50, 95% CI 0.73 to 3.10, p=0.268; I2=5.9%), myocardial infarction (OR 0.64, 95% CI 0.30 to 1.35; p=0.242; I2=0%), local hematoma (OR 0.53, 95% CI 0.12 to 2.25, p=0.389; I2=0%), or mortality (OR 1.35, 95% CI 0.62 to 2.92, p=0.449; I2=0%) were identified between the groups. CONCLUSION: TCA is associated with a significantly lower risk for periprocedural stroke and DW-MRI ischemic lesions compared with TFA. Other periprocedural outcomes were similar between the groups.

Giant cell reparative granuloma of the pediatric cranium: case report and review of the literature.

PURPOSE: Giant cell reparative granulomas are rare bone tumors. Although benign, these tumors are locally destructive and can be highly vascular. They seldom occur in the cranial vault. We describe a multidisciplinary approach to a case of giant cell reparative granuloma of the cranium in a 3-year-old patient. CASE REPORT: A 3-year-old girl female referred to the pediatric neurosurgery department for evaluation of a retro-auricular mass. She had a history of recurrent otitis media with two subsequent courses of antibiotics without resolution. CT imaging revealed an expansive lesion located in the right mastoid region. Open surgical biopsy revealed a hemorrhagic tumor consistent with a giant cell reparative granuloma. Angiography identified a hypervascular tumor blush that was supplied by the occipital artery. Preoperative transcatheter embolization was performed followed by a multidisciplinary surgical resection and reconstruction. Blood loss was minimal, and the patient recovered well after surgery. CONCLUSION: Preoperative endovascular embolization and a multidisciplinary intraoperative approach with primary resection and cranial vault reconstruction is an effective approach to hypervascular giant cell reparative granulomas.

Endovascular management of cerebral vasospasm.

Cerebral vasospasm remains a feared complication from subarachnoid hemorrhage. Vasospasm typically occurs from three to fourteen days post-aneurysm rupture, with peak risk on Day 7. Up to 50% of patients with angiographic vasospasm will subsequently develop delayed cerebral ischemia; 15-20% of this subset will develop stroke or death despite maximal medical therapy. We define symptomatic vasospasm as the presence of neurological worsening after exclusion of other identifiable causes, such as seizure, hydrocephalus, intracerebral hemorrhage, or metabolic dysfunction. This video demonstrates the set-up and treatment protocol for endovascular intervention of symptomatic vasospasm not responsive to maximal medical management. The video can be found here: http://youtu.be/q7YvxLzIDnU .

Scaffold-based discovery of indeglitazar, a PPAR pan-active anti-diabetic agent.

In a search for more effective anti-diabetic treatment, we used a process coupling low-affinity biochemical screening with high-throughput co-crystallography in the design of a series of compounds that selectively modulate the activities of all three peroxisome proliferator-activated receptors (PPARs), PPARalpha, PPARgamma, and PPARdelta. Transcriptional transactivation assays were used to select compounds from this chemical series with a bias toward partial agonism toward PPARgamma, to circumvent the clinically observed side effects of full PPARgamma agonists. Co-crystallographic characterization of the lead molecule, indeglitazar, in complex with each of the 3 PPARs revealed the structural basis for its PPAR pan-activity and its partial agonistic response toward PPARgamma. Compared with full PPARgamma-agonists, indeglitazar is less potent in promoting adipocyte differentiation and only partially effective in stimulating adiponectin gene expression. Evaluation of the compound in vivo confirmed the reduced adiponectin response in animal models of obesity and diabetes while revealing strong beneficial effects on glucose, triglycerides, cholesterol, body weight, and other metabolic parameters. Indeglitazar has now progressed to Phase II clinical evaluations for Type 2 diabetes mellitus (T2DM).

Intentional partial coiling dome protection of complex ruptured cerebral aneurysms prevents acute rebleeding and produces favorable clinical outcomes.

BACKGROUND: The coiling of ruptured cerebral aneurysms protects against acute rebleeding; however, whether partially coiling a ruptured cerebral aneurysm protects against acute rebleeding has never been demonstrated. OBJECTIVE: This study was performed to test our hypothesis that intentional partial coiling of complex ruptured cerebral aneurysms, which are unfavorable for clipping and cannot be completely coiled primarily, prevents acute rebleeding to allow for clinical and neurological recovery until definitive treatment and produces favorable clinical outcomes. METHODS: Data were collected from the prospective databases of three centers. Only subarachnoid hemorrhage patients that were treated with a strategy of intentional partial coiling for dome protection were included. This did not include patients in whom the goal was complete coiling but only subtotal coil occlusion was achieved. RESULTS: Fifteen patients [aged 51 ± 13 years; HH 3-5 (n = 7); Fisher 3-4 (n = 9)] were treated with intentional partial dome protection. Aneurysm size was 12.8 ± 5.4 mm; neck size 4.9 ± 3 mm; 12 anterior circulation. Four intentional partial coilings were performed with balloon assistance. Definitive treatment was performed 92 ± 90 days later, with no case of rebleeding. Definitive treatment was clipping (n = 8), stent-coiling (n = 5), Onyx (n = 1), further coiling (n = 1). Clinical outcome was favorable in 13 cases (GOS 4-5), fair in one (GOS 3), and death in one (GOS 1). CONCLUSIONS: Judicious use of a treatment strategy of intentional partial dome protection for complex aneurysms that are not favorable for clipping and in which complete coiling primarily is not possible may prevent acute rebleeding and produce favorable clinical outcomes.

Navigating a medical mystery in an elite athlete-severe dystonia induced by swimming.

Dystonia is a state of involuntary muscle contractions that cause repetitive or twisting movements. It may affect one or more parts of the body and sometimes the entire body. The condition can be mild or severe. In this unusual case, high-intensity swimming triggered the episodes of atypical functional movement disorder.

Neurosurgical Causes of Pulsatile Tinnitus: Contemporary Update.

Traditionally in the domain of the otolaryngologist, pulsatile tinnitus (PT) has become increasingly relevant to neurosurgeons. PT may prove to be a harbinger of life-threatening pathology; however, often, it is a marker of a more benign process. Irrespectively, the neurosurgeon should be familiar with the many potential etiologies of this unique and challenging patient population. In this review, we discuss the myriad causes of PT, categorized by pulse-phase rhythmicity.

First-Line Stent Retriever versus Direct Aspiration for Acute Basilar Artery Occlusions: A Systematic Review and Meta-analysis.

BACKGROUND: Mechanical thrombectomy (MT) for anterior circulation stroke has been proven to be highly effective. In comparison, MT for basilar artery occlusion (BAO) continues to lack definitive evidence of efficacy. The main MT modalities are stent retriever (SR) and direct aspiration (DA). Several studies have been published comparing the 2 approaches. OBJECTIVE: We sought to directly compare and synthesize safety and efficacy outcomes with SR versus DA for acute BAO. METHODS: A systematic review and meta-analysis was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Overall, 8 studies comprising 693 patients with BAO were included (SR: 457; DA: 236). The SR group was associated with statistically significant lower odds of modified Thrombolysis in Cerebral Infarction (mTICI) 2b/3 (odds ratio [OR]: 0.54; 95% confidence interval [CI]: 0.31-0.94) and mTICI3 (OR: 0.47; 95% CI: 0.23-0.95) compared with DA. Favorable outcome rates were similar between the 2 groups (OR: 0.83; 95% CI: 0.60-1.16). The rates of symptomatic intracerebral hemorrhage (OR: 3.57; 95% CI: 0.75-16.95), subarachnoid hemorrhage (SAH) (OR: 4.71; 95% CI: 0.82-26.90), and vessel perforation (OR: 2.64; 95% CI: 0.43-16.33) were higher in the SR group, but statistical significance was not reached. The rates of 90-day mortality were similar between the 2 groups (OR: 1.07; 95% CI: 0.67-1.70). Procedure duration was significantly shorter when DA was used compared with SR (weighted mean difference: 26.10 minutes; 95% CI: 13.28-38.92). CONCLUSIONS: SR is associated with statistically significant lower odds of mTICI 2b/3 and mTICI 3 recanalization rates compared with DA. SR appears to be associated with a higher complication rate, but significance was not reached.

Pivotal trial of the Neuroform Atlas stent for treatment of posterior circulation aneurysms: one-year outcomes.

BACKGROUND: Stent-assisted coiling of wide-necked intracranial aneurysms (IAs) using the Neuroform Atlas Stent System (Atlas) has shown promising results. OBJECTIVE: To present the primary efficacy and safety results of the ATLAS Investigational Device Exemption (IDE) trial in a cohort of patients with posterior circulation IAs. METHODS: The ATLAS trial is a prospective, multicenter, single-arm, open-label study of unruptured, wide-necked, IAs treated with the Atlas stent and adjunctive coiling. This study reports the results of patients with posterior circulation IAs. The primary efficacy endpoint was complete aneurysm occlusion (Raymond-Roy (RR) class I) on 12-month angiography, in the absence of re-treatment or parent artery stenosis >50%. The primary safety endpoint was any major ipsilateral stroke or neurological death within 12 months. Adjudication of the primary endpoints was performed by an imaging core laboratory and a Clinical Events Committee. RESULTS: The ATLAS trial enrolled and treated 116 patients at 25 medical centers with unruptured, wide-necked, posterior circulation IAs (mean age 60.2±10.5 years, 81.0% (94/116) female). Stents were placed in all patients with 100% technical success rate. A total of 95/116 (81.9%) patients had complete angiographic follow-up at 12 months, of whom 81 (85.3%) had complete aneurysm occlusion (RR class I). The primary effectiveness outcome was achieved in 76.7% (95% CI 67.0% to 86.5%) of patients. Overall, major ipsilateral stroke and secondary persistent neurological deficit occurred in 4.3% (5/116) and 1.7% (2/116) of patients, respectively. CONCLUSIONS: In the ATLAS IDE posterior circulation cohort, the Neuroform Atlas Stent System with adjunctive coiling demonstrated high rates of technical and safety performance. Trial registration number https://clinicaltrials.gov/ct2/show/NCT02340585.

Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity.

BRAF(V600E) is the most frequent oncogenic protein kinase mutation known. Furthermore, inhibitors targeting "active" protein kinases have demonstrated significant utility in the therapeutic repertoire against cancer. Therefore, we pursued the development of specific kinase inhibitors targeting B-Raf, and the V600E allele in particular. By using a structure-guided discovery approach, a potent and selective inhibitor of active B-Raf has been discovered. PLX4720, a 7-azaindole derivative that inhibits B-Raf(V600E) with an IC(50) of 13 nM, defines a class of kinase inhibitor with marked selectivity in both biochemical and cellular assays. PLX4720 preferentially inhibits the active B-Raf(V600E) kinase compared with a broad spectrum of other kinases, and potent cytotoxic effects are also exclusive to cells bearing the V600E allele. Consistent with the high degree of selectivity, ERK phosphorylation is potently inhibited by PLX4720 in B-Raf(V600E)-bearing tumor cell lines but not in cells lacking oncogenic B-Raf. In melanoma models, PLX4720 induces cell cycle arrest and apoptosis exclusively in B-Raf(V600E)-positive cells. In B-Raf(V600E)-dependent tumor xenograft models, orally dosed PLX4720 causes significant tumor growth delays, including tumor regressions, without evidence of toxicity. The work described here represents the entire discovery process, from initial identification through structural and biological studies in animal models to a promising therapeutic for testing in cancer patients bearing B-Raf(V600E)-driven tumors.

A Consensus Study: Generational Differences in Neurosurgeons' Perception of Retirement and Practice Limits.

BACKGROUND: Concerns about the changing demographics in the United States and the aging of the neurosurgical workforce exist. Both the importance and inherent risk of surgical responsibilities suggest that thought be given to whether workloads should change later in surgeons' careers. We sought to assess current neurosurgeons' expectations concerning their late-stage careers. METHODS: A survey was sent to 3317 U.S. board-certified neurosurgeons. It was designed to assess surgeons' perceptions of call and operative responsibilities in the later stages of their careers. Statistical analyses were completed in R version 3.6.1, with an alpha set to 0.05. RESULTS: Six-hundred and fifty-nine neurosurgeons completed the questionnaire. Seventy-seven percent believed that the call burden should decrease later in practice, and 66% planned to decrease their own call burden later in their career. The most common age range for planned retirement was 65 to 69 years (36%), followed by 70+ years (33%). Most (67%) believed that there should not be a mandatory age to stop operating. More recent year of residency completion was negatively associated with the belief that call burden should decrease at older age groups and positively associated with support for a mandatory age to stop operating as well as an earlier retirement age. CONCLUSIONS: This study suggests that neurosurgeons have differing views on how workloads should change later in their careers. Younger neurosurgeons support an earlier decrease in workload or even a policy-mandated stop to operating after a certain age. These results may give insight into future trends and turnover in neurosurgery and provide a valuable tool to help practices anticipate workforce changes.

Carotid cavernous fistula (CCF) treatment approaches: A systematic literature review and meta-analysis of transarterial and transvenous embolization for direct and indirect CCFs.

BACKGROUND: Carotid Cavernous Fistulas (CCFs) are the result of an abnormal communication between the carotid artery and its branches and the venous system of the cavernous sinus. The mainstay of therapy for CCFs consists of transarterial or transvenous embolization, while other treatment options such as open surgery or radiosurgery are still utilized as second-line or adjuvant therapeutic options. OBJECTIVE: Our aim was to systematically review and summarize available data regarding short- and long-term outcomes of all available treatment modalities for CCFs. METHODS: This systematic review was conducted according to the PRISMA guidelines. A random effects model meta-analysis was conducted. RESULTS: Fifty-seven studies comprising 1575 patients were included in this systematic review. Transarterial embolization for direct and indirect CCFs offered a complete obliteration rate of 93.93% (N = 589/627) and 81.51% (N = 119/146), respectively. Transvenous embolization for direct and indirect lesions achieved obliteration in 91.67% (N = 33/36) and 86.03% (N = 425/494) of patients, respectively. Comparison between transarterial and transvenous embolization did not reveal statistically significant differences in terms of fistula obliteration for direct (OR: 1.42; 95% CI: 0.23-8.90; I2 0.0%) and indirect CCFs (OR: 0.62; 95% CI: 0.31-1.23; I2 0.0%). CONCLUSIONS: Endovascular embolization techniques are the preferred treatment modality for the management of CCFs. No differences were identified between transarterial and transvenous embolization by synthesizing studies with available data. Future prospective cohorts are warranted to compare the different materials and techniques implemented especially within the rapidly expanding realm of endovascular approaches.

Neuroform Atlas Stent for Treatment of Middle Cerebral Artery Aneurysms: 1-Year Outcomes From Neuroform Atlas Stent Pivotal Trial.

BACKGROUND: Heterogeneous effect of endovascular aneurysm therapy has been observed across different anatomic locations. There is a paucity of data for stent-assisted coiling of middle cerebral artery (MCA) aneurysms. OBJECTIVE: To present the results of the MCA aneurysm group from the Neuroform Atlas (Stryker Neurovascular) investigational device exemption (IDE) trial. METHODS: The Atlas IDE trial is a prospective, multicenter, single-arm, open-label study of wide-neck aneurysms (neck ≥ 4 mm or dome-to-neck ratio < 2) in the anterior circulation treated with the Neuroform Atlas Stent and approved coils. Follow-up was obtained immediately postprocedure and 2, 6, and 12 mo postoperatively. We herein describe safety and efficacy outcomes, and functional independence of the subjects with aneurysms from all segments of MCA. RESULTS: A total of 35 patients were included (27 MCA bifurcation, 5 M1, 3 M2). The mean aneurysm size was 6.0 ± 1.8 mm, and the mean neck was 4.4 ± 1.2 mm. Technical procedural success was achieved in all patients. A total of 26 patients had follow-up digital subtraction angiography available at 12 mo, with 80.8% (21/26) having complete aneurysm occlusion. Twelve-month safety data were collected for 91.4% (32/35), 8.5% (3/35) had primary safety endpoint, all 3 major ischemic strokes. Mortality occurred in 2 patients beyond 30 d unrelated to procedure (1 gallbladder cancer and 1 fentanyl intoxication). At 1 yr, modified Rankin Score was 0 to 2 in 84.4% (27/32), 3 in 9.4%, and 3 patients were missing. Approximately 5.7% (2/35) of patients were retreated at 12 mo. CONCLUSION: Stent-assisted coiling with the Neuroform Atlas Stent is a viable alternative to clipping for selected MCA aneurysms. Complete aneurysm occlusion rates have improved compared to historical data. Proper case selection can lead to acceptable endovascular results.

The local co-evolution of firms and governments in the Information Age.

The governance structures of the value-creating activities of MNEs have evolved towards more networked forms that are geographically highly concentrated and involve partnering with diverse actors. The experimentation that takes place within these corporate networks has a parallel on the government side, where subnational governments, and particularly cities as hubs of economic activity, have increased their profile and level of cooperative activity. We argue that engagement in these partnerships is an essential way in which firms and governments co-evolve and create the basis for sustainable economic growth in the Information Age. While the origins of this collaborative form of governance reside in the increasing knowledge intensity of value creation, its implications go far beyond MNE value creation and capture, extending to issues of global governance such as climate change and sustainable development goals. We examine the implications of this process of co-evolution both in terms of the costs of developing the requisite corporate capabilities as well as the legitimacy of these efforts as part of a deliberative democracy.

Les structures de gouvernance des activités de création de valeur des EMN ont évolué vers des formes plus réticulaires qui sont géographiquement très concentrées et qui impliquent des partenariats avec divers acteurs. L'expérimentation qui a lieu au sein de ces réseaux d'entreprises a un parallèle du côté gouvernemental, où les gouvernements infranationaux, et en particulier les villes en tant que centres d'activité économique, ont accru leur profil et leur niveau d'activité coopérative. Nous soutenons que l'engagement dans ces partenariats est un moyen essentiel pour les entreprises et les gouvernements de co-évoluer et de créer les bases d'une croissance économique durable à l'ère de l'information. Bien que les origines de cette forme de gouvernance collaborative résident dans l'intensité croissante des connaissances en matière de création de valeur, ses implications vont bien au-delà de la création et de la récupération de valeur par les EMN, s'étendant aux questions de gouvernance mondiale telles que le changement climatique et les objectifs de développement durable. Nous examinons les implications de ce processus de co-évolution à la fois en termes de coûts de développement des capacités d'entreprise requises, ainsi que de légitimité de ces efforts dans le cadre d'une démocratie délibérative.

Las estructuras de gobernanza en las actividades de creación de valor de las empresas multinacionales han evolucionado hacia formas más interconectadas que están altamente concentradas geográficamente y que implican asociarse con diversos actores. La experimentación que se lleva a cabo dentro de estas redes corporativas tiene un paralelo con el lado gubernamental en donde los gobiernos sub-nacionales, y en particular las ciudades como centros de actividad económica, han aumentado su perfil y nivel de actividad cooperativa. Argumentamos que la participación en estas asociaciones es una manera esencial en que las empresas y los gobiernos co-evolucionan y crean las bases para el crecimiento económico sostenible en la Era de la Información. Mientras que los orígenes de esta forma colaborativa de gobernanza residen en la creciente intensidad de conocimiento de la creación de valor, sus implicaciones van más allá de la creación y captura de valor de las empresas multinacionales, extendiéndose a los asuntos de gobernanza global como son el cambio climático y los objetivos de desarrollo sostenible. Examinamos las implicaciones de este proceso de co-evolución tanto en términos de los costos de desarrollar las capacidades corporativas necesarias, como de la legitimidad de estos esfuerzos como parte de una democracia deliberativa.

As estruturas de governança das atividades de criação de valor de MNEs evoluíram para formas mais interligadas que são geograficamente altamente concentradas e que envolvem parcerias com diversos atores. A experimentação que ocorre dentro dessas redes empresariais tem um paralelo no lado governamental, onde governos subnacionais, e particularmente cidades como pólos de atividade econômica, têm aumentado seu perfil e nível de atividade cooperativa. Argumentamos que o envolvimento nessas parcerias é uma forma essencial pela qual empresas e governos coevoluem e criam a base para crescimento econômico sustentável na Era da Informação. Embora as origens dessa forma colaborativa de governança residam na crescente intensidade de conhecimento da criação de valor, suas implicações vão muito além da criação e captura de valor da MNE, estendendo-se a questões de governança global, como mudanças climáticas e metas de desenvolvimento sustentável. Examinamos as implicações desse processo de coevolução, tanto em termos dos custos de desenvolvimento das capacidades corporativas necessárias, como da legitimidade desses esforços como parte de uma democracia deliberativa.

Biochemical Characterization of Respiratory Syncytial Virus RNA-Dependent RNA Polymerase Complex.

RNA-dependent RNA polymerases (RdRPs) from nonsegmented negative strand (NNS) RNA viruses perform both mRNA transcription and genome replication, and these activities are regulated by their interactions with RNA and other accessory proteins within the ribonucleoprotein (RNP) complex. Detailed biochemical characterization of these enzymatic activities and their regulation is essential for understanding the life cycles of many pathogenic RNA viruses and for antiviral drug discovery. We developed biochemical and biophysical kinetic methods to study the RNA synthesis and RNA binding activities of respiratory syncytial virus (RSV) L/P RdRP. We determined that the intact L protein is essential for RdRP activity, and in truncated L protein constructs, RdRP activity is abrogated due to their deficiency in RNA template binding. These results are in agreement with the observation of an RNA template-binding tunnel at the interface of RdRP and capping domains in RSV and vesicular stomatitis virus (VSV) L protein cryo-EM structures. We also describe nonradiometric assays for measuring RNA binding and RNA polymerization activity of RSV RdRP, which are amenable to compound screening and profiling.

Prevalence of carotid stenosis following radiotherapy for head and neck cancer: A systematic review and meta-analysis.

BACKGROUND: Radiation to the head and neck is a well-established risk factor for the development of carotid artery stenosis. Our objective was to identify the prevalence, incidence, and degree of carotid stenosis in patients with a history of head and neck irradiation. METHODS: This study was performed according to the PRISMA guidelines. A random effects model meta-analysis was conducted. RESULTS: Nineteen studies comprising 1479 patients were included. The prevalence of carotid stenosis >50%, >70%, and carotid occlusion was 25% (95% CI: 19%-32%), 12% (95% CI: 7%-17%), and 4% (95% CI: 2%-8%), respectively. The cumulative 12-month incidence of carotid stenosis >50% was 4% (95% CI: 2%-5%), the 24-month was 12% (95% CI: 9%-15%), and the 36-month was 21% (95% CI: 9%-36%). CONCLUSIONS: The yearly incidence of carotid stenosis >50% increased every year during the first 3 years following radiotherapy. We propose routine yearly Doppler ultrasound screening beginning 1 year after head and neck radiotherapy.

Mechanical Thrombectomy in Acute Ischemic Stroke: A Meta-Analysis of Stent Retrievers vs Direct Aspiration vs a Combined Approach.

BACKGROUND: Recent randomized control trials (RCTs) established that mechanical thrombectomy is superior to medical therapy for patients with stroke due to a large vessel occlusion. OBJECTIVE: To compare the safety and efficacy profile of the different mechanical thrombectomy strategies. METHODS: A random-effects meta-analysis was performed and the I2 statistic was used to assess heterogeneity according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. RESULTS: Nineteen studies with a total of 2449 patients were included. No differences were identified between the stent retrieval and direct aspiration groups in terms of modified Thrombolysis in Cerebral Infarction (mTICI) 2b/3 and mTICI 3 recanalization rates, and favorable outcomes (modified Rankin Scale [mRS] ≤ 2). Adverse event rates, including 90-d mortality, symptomatic intracerebral hemorrhage (sICH), and subarachnoid hemorrhage (SAH), were similar between the stent retrieval and direct aspiration groups. The use of the stent retrieval was associated with a higher risk of vasospasm (odds ratio [OR]: 2.98; 95% confidence interval [CI]: 1.10-8.09; I2: 0%) compared to direct aspiration. When compared with the direct aspiration group, the subgroup of patients who underwent thrombectomy with the combined approach as a first-line strategy had a higher likelihood of successful mTICI 2b/3 (OR: 1.47; 95% CI: 1.02-2.12; I2: 0%) and mTICI 3 recanalization (OR: 3.65; 95% CI: 1.56-8.54), although with a higher risk of SAH (OR: 4.33; 95% CI: 1.15-16.32). CONCLUSION: Stent retrieval thrombectomy and direct aspiration did not show significant differences. Current available evidence is not sufficient to draw conclusions on the best surgical approach. The combined use of a stent retriever and aspiration as a first-line strategy was associated with higher mTICI 2b/3 and mTICI 3 recanalization rates, although with a higher risk of 24-h SAH, when compared with direct aspiration.