Uneven response of phytoplankton-bacteria coupling under Saharan dust pulse and ultraviolet radiation in the south-western Mediterranean Sea.

The microbial carbon (C) flux in the ocean is a key functional process governed by the excretion of organic carbon by phytoplankton (EOC) and heterotrophic bacterial carbon demand (BCD). Ultraviolet radiation (UVR) levels in upper mixed layers and increasing atmospheric dust deposition from arid regions may alter the degree of coupling in the phytoplankton-bacteria relationship (measured as BCD:EOC ratio) with consequences for the C-flux through these compartments in marine oligotrophic ecosystem. Firstly, we performed a field study across the south-western (SW) Mediterranean Sea to assess the degree of coupling (BCD:EOC) and how it may be related to metabolic balance (total primary production: community respiration; PPT:CR). Secondly, we conducted a microcosm experiment in two contrasting areas (heterotrophic nearshore and autotrophic open sea) to test the impact of UVR and dust interaction on microbial C flux. In the field study, we found that BCD was not satisfied by EOC (i.e., BCD:EOC >1; uncoupled phytoplankton-bacteria relationship). BCD:EOC ratio was negatively related to PPT:CR ratio across the SW Mediterranean Sea. A spatial pattern emerged, i.e. in autotrophic open sea stations uncoupling was less severe (BCD:EOC ranged 1-2), whereas heterotrophic nearshore stations uncoupling was more severe (BCD:EOC > 2). In the experimental study, in the seawater both enriched with dust and under UVR, BCD:EOC ratio decreased by stimulating autotrophic processes (particulate primary production (PPP) and EOC) in the heterotrophic nearshore area, whereas BCD:EOC increased by stimulating heterotrophic processes [heterotrophic bacterial production (HBP), bacterial growth efficiency (BGE), bacterial respiration (BR)] in the autotrophic open sea. Our results show that this spatial pattern could be reversed under future UVR × Dust scenario. Overall, the impact of greater dust deposition and higher UVR levels will alter the phytoplankton-bacteria C-flux with consequences for the productivity of both communities, their standing stocks, and ultimately, the ecosystem's metabolic balance at the sea surface.

SEOM-GEINO clinical guidelines for grade 2 gliomas (2023).

The 2021 World Health Organization (WHO) classification has updated the definition of grade 2 gliomas and the presence of isocitrate dehydrogenase (IDH) mutation has been deemed the cornerstone of diagnosis. Though slow-growing and having a low proliferative index, grade 2 gliomas are incurable by surgery and complementary treatments are vital to improving prognosis. This guideline provides recommendations on the multidisciplinary treatment of grade 2 astrocytomas and oligodendrogliomas based on the best evidence available.

Clinical practice guideline on the management of vestibular schwannoma.

INTRODUCTION: Vestibular schwannoma (VS) is the most common tumour of the cerebellopontine angle. The greater accessibility to radiological tests has increased its diagnosis. Taking into account the characteristics of the tumour, the symptoms and the age of the patient, three therapeutic strategies have been proposed: observation, surgery or radiotherapy. Choosing the most appropriate for each patient is a frequent source of controversy. MATERIAL AND METHODS: This paper includes an exhaustive literature review of issues related to VS that can serve as a clinical guide in the management of patients with these lesions. The presentation has been oriented in the form of questions that the clinician usually asks himself and the answers have been written and/or reviewed by a panel of national and international experts consulted by the Otology Commission of the SEORL-CCC. RESULTS: A list has been compiled containing the 13 most controversial thematic blocks on the management of VS in the form of 50 questions, and answers to all of them have been sought through a systematic literature review (articles published on PubMed and Cochrane Library between 1992 and 2023 related to each thematic area). Thirty-three experts, led by the Otology Committee of SEORL-CCC, have analyzed and discussed all the answers. In Annex 1, 14 additional questions divided into 4 thematic areas can be found. CONCLUSIONS: This clinical practice guideline on the management of VS offers agreed answers to the most common questions that are asked about this tumour. The absence of sufficient prospective studies means that the levels of evidence on the subject are generally medium or low. This fact increases the interest of this type of clinical practice guidelines prepared by experts.

Winged resistance: Storks and gulls increase carriage of antibiotic resistance by shifting from paddy fields to landfills.

Waterbirds are vectors for the dissemination of antimicrobial resistance across environments, with some species increasingly reliant on highly anthropized habitats for feeding. However, data on the impact of their feeding habits on the carriage of antibiotic resistance genes (ARGs) are still scarce. To fill this gap, we examined the microbiota (16S rRNA amplicon gene sequencing) and the prevalence of ARG (high-throughput qPCR of 47 genes) in faeces from white storks (Ciconia ciconia) and lesser black-backed gulls (Larus fuscus) feeding in highly (landfill) and less (paddy fields) polluted habitats. Faecal bacterial richness and diversity were higher in gulls feeding upon landfills and showed a greater abundance of potential pathogens, such as Staphylococcus. In contrast, faecal bacterial communities from storks were similar regardless of habitat preferences, maybe due to a less intense habitat use compared to gulls. In addition, birds feeding in the landfill carried a higher burden of ARGs compared to the surrounding soil and surface waters. Network analysis revealed strong correlations between ARGs and potential pathogens, particularly between tetM (resistance to tetracyclines), blaCMY (beta-lactam resistance), sul1 (sulfonamide resistance) and members of the genera Streptococcus, Peptostreptococcus, and Peptoclostridium. Our work demonstrates how transitioning from paddy fields to landfills fosters the carriage of ARGs and potential pathogens in the bird gut, shedding light on the ecological role of these avian vectors in antimicrobial resistance dissemination.

Characterization of cardiac arrhythmias and maternal-fetal outcomes in pregnant women: A prospective cohort study.

INTRODUCTION AND OBJECTIVES: Cardiovascular disease is a common cause of morbidity and mortality in pregnant women. Arrhythmias are common complications during pregnancy; however, the data are limited. Our goal was to characterize the epidemiology, clinical presentation, and impact of cardiac arrhythmias on maternal-fetal outcomes. METHODS: A prospective cohort study from the Colombian Registry of Pregnancy and Cardiovascular Disease was carried out from 2016 to 2019. All patients with tachyarrhythmia or bradyarrhythmia and a minimum follow-up of six months after delivery were included. The primary outcome was a composite of cardiac events defined as pulmonary edema, symptomatic sustained arrhythmia requiring specific therapy, stroke, cardiac arrest, or maternal death. Secondary outcomes were other cardiac, neonatal, and obstetric events. RESULTS: Arrhythmias were the most common cause of referral to our dedicated cardio-obstetric clinic. A total of 92 patients were included, mean age 27±6 years; 8.7% had previous structural heart disease, and cardiology consultation was delayed in 79.4%. The most common arrhythmias were premature ventricular contractions (33%) and paroxysmal reentrant supraventricular tachycardias (15%); 11 patients (12%) had cardiac implantable electronic devices. Cardiac events occurred in 18.4% of patients, obstetric events occurred in 6.5%, and one caesarean was indicated in the context of symptomatic severe mitral stenosis. Adverse neonatal outcomes were observed in 24.3% of newborns. CONCLUSIONS: Arrhythmias were the most common cause of referral to a dedicated cardio-obstetric clinic; most had a benign course. Adverse maternal cardiovascular outcomes were significant and there was a high rate of obstetric and neonatal adverse events, underlining the importance of multidisciplinary care.

A Short-Term Evaluation of Foot Pronation Tendency in Healthy Recreational Runners.

Running is a highly physical activity, and it is related to injuries when there is an excessive pronation of the foot. This study evaluates, from a sample group of healthy recreational runners, if the foot tends to pronate after a period of running activity and when, with respect to a period of running compared to walking, evaluated during several phases: after 30, 45, and 60 min. This quasi-experimental study has been carried out on a total of 36 healthy recreational subjects. The subjects were evaluated during two different activities: running activity for a period of an hour with respect to normal walking activity. The main outcome measures were the foot posture index (FPI) and the navicular drop test (NDT), which were evaluated at p1 (the screening day), after 30 min of activity (p2), after 45 min of activity (p3), and finally after 60 min (p4) during running or walking activity. The analysis showed significant differences for the FPI and NDT variables in both groups and on both feet, comparing p1 and p4. These changes showed a significant relationship comparing p1 and p3 for the FPI variable, and for the NDT variable (p < 0.001) of the left foot and, with respect to the right foot, significance was shown to the FPI comparing the p1 and p2. A significant difference was found in the tendency to pronate the foot after a period of running compared to the same period of walking after 60 min of activity. Running produced an excessive pronation of the foot after 45 min of activity, evaluated with the FPI for both feet.

Comparison of Resorbable and Non-Resorbable Osteosynthesis Material in Hallux Surgery: A Systematic Review.

There are various pathologies that involve the hallux, among which hallux valgus is the most common. When conservative treatment fails, it is necessary to resort to a surgical approach. The fixation elements for osteotomies in the hallux are usually composed of metallic materials; however, today, there are numerous resorbable materials that offer numerous advantages over conventional materials. In this article, the objective is to analyze the scientific evidence through the systematic analysis of the existing literature in relation to the effectiveness of resorbable versus non-resorbable osteosynthesis material in the surgical correction of hallux deformities and compare the complications as well as the patient satisfaction and quality of life between both fixation methods. A systematic review of the literature available in the PubMed, EMBASE, Web of Science and Scopus databases and 10 studies were included. The documents were chosen following the eligibility and exclusion criteria, including experimental and observational studies evaluated with the Jadad and Newcastle-Ottawa methodological quality scale, respectively. Data were extracted from valid studies for the review, and the variables functionality, pain, angular corrections, complications, satisfaction and quality of life were observed. In conclusion, there is limited scientific evidence regarding the effectiveness of resorbable versus non-resorbable osteosynthesis material in the surgical correction of hallux deformities. All observed variables are similar regardless of the surgical technique and osteosynthesis material used.

Circular and L50-like leaderless enterocins share a common ABC-transporter immunity gene.

Microbes live within complex communities of interacting populations, either free-living in waters and soils or symbionts of animals and plants. Their interactions include the production of antimicrobial peptides (bacteriocins) to antagonize competitors, and these producers must carry their own immunity gene for self-protection. Whether other coexisting populations are sensitive or resistant to the bacteriocin producer will be key for the population dynamics within the microbial community. The immunity gene frequently consists of an ABC transporter to repel its own bacteriocin but rarely protects against a nonrelated bacteriocin. A case where this cross-resistance occurs mediated by a shared ABC transporter has been shown between enterocins MR10A/B and AS-48. The first is an L50-like leaderless enterocin, while AS-48 is a circular enterocin. In addition, L50-like enterocins such as MR10A/B have been found in E. faecalis and E. faecium, but AS-48 appears only in E. faecalis. Thus, using the ABC transporter of the enterocin MR10A/B gene cluster of Enterococcus faecalis MRR10-3 as a cross-resistance model, we aimed to unravel to what extent a particular ABC transporter can be shared across multiple bacteriocinogenic bacterial populations. To this end, we screened the MR10A/B-ABC transporters in available microbial genomes and analyzed their sequence homologies and distribution. Overall, our main findings are as follows: (i) the MR10A/B-ABC transporter is associated with multiple enterocin gene clusters; (ii) the different enterocins associated with this transporter have a saposin-like fold in common; (iii) the Mr10E component of the transporter is more conserved within its associated enterocin, while the Mr10FGH components are more conserved within the carrying species. This is the least known component of the transporter, but it has shown the greatest specificity to its corresponding enterocin. Bacteriocins are now being investigated as an alternative to antibiotics; hence, the wider or narrower distribution of the particular immunity gene should be taken into account for clinical applications to avoid the selection of resistant strains. Further research will be needed to investigate the mechanistic interactions between the Mr10E transporter component and the bacteriocin as well as the specific ecological and evolutionary mechanisms involved in the spread of the immunity transporter across multiple bacteriocins.

Lactiplantibacillus paraplantarum BPF2 and Pediococcus acidilactici ST6, Two Bacteriocinogenic Isolated Strains from Andalusian Spontaneous Fermented Sausages.

Traditional spontaneously fermented foods are well known for their sensory and safety properties, which is mainly due to their indigenous microflora. Within this group of food, Mediterranean dry-cured sausages stand out as a significant source of lactic-acid bacterial strains (LAB) with biotechnological properties, such as their antimicrobial activity. The aim of this study was to investigate the biodiversity of antagonistic LAB strains from different Andalusian traditional sausages, such as salchichón and chorizo. First, a screening was carried out focusing on the antimicrobial activity against foodborne pathogens, such as Listeria monocytogenes, Escherichia coli, Clostridium perfringens, and Staphylococcus aureus, selecting two strains due to their higher antibiosis properties, both in agar and liquid media. These bacteria were identified as Lactiplantibacillus paraplantarum BPF2 and Pediococcus acidilactici ST6. In addition, genomic studies confirmed the presence of certain structural genes related to the production of bacteriocins. Finally, the culture supernatants of both strains were purified and analyzed by LC-MS/MS, obtaining the relative molecular mass and the amino acid sequence and identifying the peptides as the bacteriocins Pediocin-PA and Leucocin K. In conclusion, genomes and antimicrobial substances of P. acidilactici ST6, a Pediocin-PA producer, and Lpb. paraplantarum BPF2, a Leucocin K producer, isolated from Andalusian salchichón and chorizo, respectively, are presented in this work. Although further studies are required, these strains could be used alone or in combination as starters or protective cultures for the food industry.

The vestibular system: Contributions of Lorente de Nó.

BACKGROUND: Rafael Lorente de Nó was a neuroscientist that worked alongside two of the giants of Medicine, the Nobel Prize winners Cajal and Bárány. OBJECTIVE: To describe the contributions of Lorente de Nó to vestibular neuroscience. METHODS: Detailed review of the publications of Lorente de Nó and analysis of the archives from Junta para Ampliación de Estudios e Investigaciones Científicas at Residencia de Estudiantes (Madrid, Spain), Casa de Salud Valdecilla at Hospital Universitario Marqués de Valdecilla (Santander, Spain), Becker Medical Library at Washington University (St. Louis, MO, USA), Rockefeller Archive Center (Sleepy Hollow, New York, NY, USA), Archivo Fernando de Castro (Madrid, Spain), Biblioteca Nacional de España (Madrid, Spain) and Legado Cajal at Instituto Cajal (Madrid, Spain). Most of this material is unpublished and includes over a hundred letters to or from Lorente. RESULTS: Lorente de Nó made a substantial contribution to our understanding of the vestibular system. Amongst these, he meticulously detailed the course of the vestibular nerve and its central projections. He described the vestibulo-ocular reflex as the consequence of an integration of the various nuclei and connections across the vestibular system, rather than a simple three-neuron arc. He also highlighted the role of the reticular formation in the generation of the fast phase of the nystagmus. CONCLUSIONS: Lorente de Nó was a pioneer of modern neuro-otology, having made outstanding contributions to vestibular neuroscience, forging novel discoveries that still burn true today.

The Importance of Cajal's and Lorente de Nó's Neuroscience to the Birth of Cybernetics.

The beginnings of cybernetics were marked by the publication of two papers in 1943. In the first one, Rosenblueth, Wiener, and Bigelow claimed that purposeful behavior is a circular process controlled by negative feedback. In the second seminal paper, McCulloch and Pitts proposed that neurons are interconnected working as logical operators. Both articles raised human-machine analogies and mathematically formulated cognitive mechanisms. These ideas ignited the interest of von Neumann, who was developing the first stored-program computer. Thus, after a preliminary meeting in 1945, a series of meetings were held between 1946 and 1953. The role of the Spanish neurophysiologist Rafael Lorente de Nó in the beginnings of cybernetics is attested not only by his participation in the core members of these Macy conferences but also for his previous description of reverberating circuits formed by a closed chain of internuncial neurons. This was the first neurobiologic demonstration of a feedback loop. Most researchers considered the central nervous system as a mere reflex organ until then; nevertheless, he demonstrated a self-sustained central activity in the nervous system, supporting the idea of self-regulating mechanisms as a key concept not just in machines but also in the brain.

Pediatric Palliative Care at Home: A Prospective Study on Subcutaneous Drug Administration.

CONTEXT: The subcutaneous route is a useful alternative for drug administration in palliative care. Although there is scientific evidence on its use in adult patients, the literature in pediatric palliative care is almost nonexistent. OBJECTIVES: To describe the experience of a pediatric palliative care unit (PPCU) with in-home subcutaneous drug administration symptom control. METHODS: Prospective observational study of patients receiving home-based subcutaneous treatment administered as part of a PPCU treatment regimen over 16 months. Analysis includes demographic and clinical variables and treatment received. RESULTS: Fifty-four different subcutaneous lines were inserted in the 15 patients included, mainly in the thigh (85.2%). The median time of needle in situ was 5.5 days (range: 1-36 days). A single drug was administered in 55.7% of treatments. The most frequently used drugs were morphine chloride (82%) and midazolam (55.7%). Continuous subcutaneous infusion was the predominant administration route (96.7%), with infusion rates oscillating between 0.1 mL/h and 1.5 mL/h. A statistically significant relationship was found between the maximum infusion rate and induration onset. Of the 54 lines placed, 29 (53.7%) had an associated complication requiring line removal. The primary cause for removal was insertion-site induration (46.3%). Subcutaneous lines were mainly used to manage pain, dyspnea, and epileptic seizures. CONCLUSION: In the pediatric palliative care patients studied, the subcutaneous route is most frequently used for administering morphine and midazolam in continuous infusion. The main complication was induration, especially with longer dwell times or higher infusion rates. However, further studies are required to optimize management and prevent complications.

Seed Size, Not Dispersal Syndrome, Determines Potential for Spread of Ricefield Weeds by Gulls.

Recent field data suggest that migratory gulls disperse many rice field weeds by gut passage (endozoochory), most of which are dry fruited and widely assumed to have no long-distance dispersal mechanisms, except via human activity. We investigated this mechanism with a feeding experiment, in which seeds of five common rice field weeds (in order of increasing seed size: Juncus bufonius, Cyperus difformis, Polypogon monspeliensis, Amaranthus retroflexus, and the fleshy-fruited Solanum nigrum) were fed to seven individuals of lesser black-backed gulls Larus fuscus held in captivity. We quantified seed survival after collecting faeces at intervals for 33 h after ingestion, then extracting intact seeds and running germination tests, which were also conducted for control seeds. All five species showed high seed survival after gut passage, of >70%. Gut retention times averaged 2-4 h, but maxima exceeded 23 h for all species. Germinability after gut passage was 16-54%, and gut passage accelerated germination in J. bufonius and S. nigrum, but slowed it down in the other species. All species had lower germinability after gut passage compared to control seeds (likely due to stratification prior to the experiment), but the loss of germinability was higher in smaller seeds. There was no evidence that the different dispersal syndromes assigned to the five species (endozoochory, epizoochory or barochory) had any influence on our results. In contrast, mean gut retention time was strongly and positively related to seed size, likely because small seeds pass more quickly from the gizzard into the intestines. Non-classical endozoochory of dry-fruited seeds by waterbirds is a major but overlooked mechanism for potential long-distance dispersal, and more research into this process is likely essential for effective weed management.

Clinical outcomes and complications following percutaneous closure of patent foramen ovale

Introduction: patent foramen ovale (PFO) has been associated with systemic embolic events, and evidence in favor of its closure is increasing. Our objective is to describe the main clinical outcomes and complications of percutaneous closure of patent foramen ovale. Materials and methods: patients who underwent percutaneous PFO closure from January 1, 2016, through September 1, 2021, were recorded retrospectively. Immediate outcomes (<72 hours), and early and late-onset clinical outcomes were evaluated. In-hospital and follow-up mortality were evaluated through medical chart reviews or telephone calls. Results: forty patients who underwent percutaneous PFO closure were included. There was a mean follow up of 2.3 years, the mean age was 43 ± 13.6 years, 7% were over 60 years old, 72.5% were women, 25% were hypertensive, 20% had diabetes, and 10% had a history of migraines. The mean RoPE score was 6, and 50% had a score greater than 7. Out of all the cases, three (7.5%) had serious adverse events and four had immediate complications. During follow-up, 2.5% had early-onset events consisting of atrial fibrillation and 2.5% had late-onset events due to CVA recurrence. There were no deaths from neurological causes and we reported a 100% survival. Discussion: From our experience, we highlight a low percentage of serious adverse events, and a low number of immediate, early and late-onset events, with a 100% survival, showing excellent results for percutaneous PFO closure. (Acta Med Colomb 2022; 48. DOI:https://doi.org/10.36104/amc.2023.2585).

Allium-Derived Compound Propyl Propane Thiosulfonate (PTSO) Reduces Vibrio Populations and Increases Body Weight of European Seabass (Dicentrarchus labrax) Juveniles.

The global demand for fish products is continuously increasing as the population grows, and aquaculture plays an important role in supplying this demand. However, industrial antibiotic misuse has contributed to the spread of antimicrobial resistance among pathogenic bacteria, therefore, several antibiotic alternatives have been proposed. In this study, we have analyzed the effects of Allium-derived propyl propane thiosulfonate (PTSO) in European seabass juveniles' growth and performance. These effects were tested by measuring the body weight and analyzing the gut microbiome of fish after 89 days of feeding trial. The relative abundance of potentially pathogenic Vibrio in the foregut and hindgut of supplemented fish decreased, while Pseudomonas and Kocuria increased significantly. Alpha diversity indices significantly decreased in both gut regions of fish fed with Allium-derived PTSO supplemented diet, as well as between bacterial community composition. These results may indicate a positive effect of the supplementation in the diet with Allium-derived PTSO, reducing potentially pathogenic Vibrio and increasing body weight at the end of the experiment (89 days). However, this supplementation with Allium-derived PTSO produces changes in the diversity and composition of microbial communities, so further experiments would be necessary to explore bacterial community composition and health relationship.

Active in situ and passive airborne fluorescence measurements for water stress detection on a fescue field.

Ledflex is a fluorometer adapted to measure chlorophyll fluorescence at the canopy level. It has been described in detail by Moya et al. (2019), Photosynthesis Research. https://doi.org/10.1007/s11120-019-00642-9 . We used this instrument to determine the effect of water stress on the fluorescence of a fescue field under extreme temperature and light conditions through a 12 days campaign during summer in a Mediterranean area. The fescue field formed part of a lysimeter station in "las Tiesas," near Albacete-Spain. In addition to the fluorescence data, the surface temperature was measured using infrared radiometers. Furthermore, "Airflex," a passive fluorometer measuring the filling-in of the atmospheric oxygen absorption band at 760 nm, was installed in an ultralight plane and flown during the most critical days of the campaign. We observed with the Ledflex fluorometer a considerable decrease of about 53% of the stationary chlorophyll fluorescence level at noon under water stress, which was well correlated with the surface temperature difference between the stressed and control plots. Airflex data also showed a decrease in far-red solar-induced fluorescence upon water stress in agreement with surface temperature data and active fluorescence measurements after correction for PS I contribution. Notwithstanding, the results from airborne remote sensing are not as precise as in situ active data.

Domingo Sánchez y Sánchez (1860-1947): Cajal's man on the nervous system of invertebrates.

Domingo Sánchez y Sánchez (1860-1947), a distinguished disciple of Santiago Ramón y Cajal, played a fundamental role in the Spanish School of Neurohistology through the meticulous use of diverse staining and microscopic techniques in the study of the histology and physiology of the invertebrate nervous system, generating valuable contributions that were recognized and cited by the scientific community. His research covered a wide range of areas: he was initially an anthropologist and zoologist, later earning a doctorate in Medicine and specializing in the neurohistology of invertebrates, including the detailed study of the retina and nerve centers of insects, and the discovery of histolysis in nerve centers of insect larvae during metamorphosis, challenging scientific paradigms of the time. Furthermore, Sánchez's work on the neurofibrils of insects was crucial in supporting Cajal's neuronal theory and refuting Bethe and Apathy's reticularist hypothesis. Additionally, he also made preliminary observations of the Golgi apparatus, the lysosomal system, the endoplasmic reticulum, and the sarcoplasmic reticulum of skeletal muscles (Cajal-Fusari network). Domingo Sánchez y Sánchez's exceptional scientific research and contributions to neurohistology in 20th century Spain continue to serve as a significant legacy. Life science identifiers: Apis mellifera: urn:lsid:zoobank.org:act:9082C709-6347-4768-A0DC-27DC44400CB2Helix aspersa: urn:lsid:zoobank.org:act:9099927E-24DF-4F89-B352-6B7902CD4A38.

Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma: The CANTATA Randomized Clinical Trial.

Importance: Dysregulated metabolism is a hallmark of renal cell carcinoma (RCC). Glutaminase is a key enzyme that fuels tumor growth by converting glutamine to glutamate. Telaglenastat is an investigational, first-in-class, selective, oral glutaminase inhibitor that blocks glutamine utilization and downstream pathways. Preclinically, telaglenastat synergized with cabozantinib, a VEGFR2/MET/AXL inhibitor, in RCC models. Objective: To compare the efficacy and safety of telaglenastat plus cabozantinib (Tela + Cabo) vs placebo plus cabozantinib (Pbo + Cabo). Design, Setting, and Participants: CANTATA was a randomized, placebo-controlled, double-blind, pivotal trial conducted at sites in the US, Europe, Australia, and New Zealand. Eligible patients had metastatic clear-cell RCC following progression on 1 to 2 prior lines of therapy, including 1 or more antiangiogenic therapies or nivolumab plus ipilimumab. The data cutoff date was August 31, 2020. Data analysis was performed from December 2020 to February 2021. Interventions: Patients were randomized 1:1 to receive oral cabozantinib (60 mg daily) with either telaglenastat (800 mg twice daily) or placebo until disease progression or unacceptable toxicity. Main Outcomes and Measures: The primary end point was progression-free survival (Response Evaluation Criteria in Solid Tumors version 1.1) assessed by blinded independent radiology review. Results: A total of 444 patients were randomized: 221 to Tela + Cabo (median [range] age, 61 [21-81] years; 47 [21%] women and 174 [79%] men) and 223 to Pbo + Cabo (median [range] age, 62 [29-83] years; 68 [30%] women and 155 [70%] men). A total of 276 (62%) patients had received prior immune checkpoint inhibitors, including 128 with prior nivolumab plus ipilimumab, 93 of whom had not received prior antiangiogenic therapy. Median progression-free survival was 9.2 months for Tela + Cabo vs 9.3 months for Pbo + Cabo (HR, 0.94; 95% CI, 0.74-1.21; P = .65). Overall response rates were 31% (69 of 221) with Tela + Cabo vs 28% (62 of 223) with Pbo + Cabo. Treatment-emergent adverse event (TEAE) rates were similar between arms. Grade 3 to 4 TEAEs occurred in 160 patients (71%) with Tela + Cabo and 172 patients (79%) with Pbo + Cabo and included hypertension (38 patients [17%] vs 40 patients [18%]) and diarrhea (34 patients [15%] vs 29 patients [13%]). Cabozantinib was discontinued due to AEs in 23 patients (10%) receiving Tela + Cabo and 33 patients (15%) receiving Pbo + Cabo. Conclusions and Relevance: In this randomized clinical trial, telaglenastat did not improve the efficacy of cabozantinib in metastatic RCC. Tela + Cabo was well tolerated with AEs consistent with the known risks of both agents. Trial Registration: ClinicalTrials.gov Identifier: NCT03428217.

Drip and ship and mothership models of mechanical thrombectomy result in similar outcomes in acute ischemic stroke of the anterior circulation.

BACKGROUND: Stroke therapy has been transformed in recent years due to the availability of thrombolysis and mechanical thrombectomy (MT). Whether transferring the patient directly to a comprehensive stroke center (CSC, mothership model) is better than taking them to a primary stroke center (PSC) and then to a CSC for MT (drip and ship) is unclear but has important implications. We compared the performance of both models in a district of the Basque country, Spain. METHODS: This is a retrospective analysis of prospectively collected data of all acute ischemic stroke patients consecutively admitted to the Neurology Department of two institutions and eligible for MT over a 36-month period with anterior circulation large vessel occlusion (LVO). One center applied the mothership model and the other the drip-and-ship. The two models were compared in terms of mortality and functional status assessed by modified Rankin (mRS) scale at 90 days. As a surrogate of the effectiveness of the two models, all times pertinent to stroke therapy were recorded. RESULTS: A total of 187 patients were evaluated subjected to MT with the drip-and-ship model and 188 with mothership, with a median NIHSS of 15. Prior to MT, 17% of the drip-and-ship patients received thrombolysis and 26% in the mothership. Neither mortality rate nor mRS showed statistically significant differences 90 days after stroke. The time lapse from stroke to MT was optimal in both models; albeit being 10 minutes longer in the drip-and-ship model, it had no impact on patients' outcomes. CONCLUSIONS: Drip-and-ship and mothership models can provide optimal and similar results in acute stroke patients in terms of mortality and functional status at 90 days. Their coexistence may alleviate the burden of CSC thus facilitating the access of more stroke patients to advanced therapies in an equitable manner.