TALEN-edited Allogeneic Inducible Dual CAR T-cells Enable Effective Targeting of Solid Tumors while Mitigating Off-Tumor Toxicity.

Adoptive cell therapy using chimeric antigen receptor (CAR) T-cells has proven to be lifesaving for many cancer patients. However, its therapeutic efficacy has been limited in solid tumors. One key factor for this are cancer-associated fibroblasts (CAFs), that modulate the tumor microenvironment (TME) to inhibit T cell infiltration and induce "T cell dysfunction". Additionally, the sparsity of tumor-specific antigens (TSA) and expression of CAR-directed tumor-associated antigens (TAA) on normal tissues often results in "on-target off-tumor" cytotoxicity, raising safety concerns. Using TALEN-mediated gene editing, we present here an innovative CAR-T cell engineering strategy to overcome these challenges. Our allogeneic "Smart CAR T-cells" are designed to express a constitutive CAR, targeting FAP+ CAFs in solid tumors. Additionally, a second CAR targeting a Tumor Associated Antigen (TAA) such as mesothelin is specifically integrated at a TCR signaling-inducible locus like PDCD1. FAPCAR-mediated CAF targeting induces expression of the mesothelin-CAR, establishing an IF/THEN-gated circuit sensitive to dual antigen sensing. Using this approach, we observe enhanced anti-tumor cytotoxicity, while limiting "on-target off-tumor" toxicity. Our study thus demonstrates TALEN-mediated gene editing capabilities for design of allogeneic IF/THEN-gated Dual CAR T-cells which efficiently target immunotherapy-recalcitrant solid tumors while mitigating potential safety risks, encouraging clinical development of this strategy.

Advances in the medical treatment and diagnosis of intracranial hemorrhage associated with oral anticoagulation.

INTRODUCTION: With the increasing prevalence of atrial fibrillation (AF), it entails expanding oral anticoagulants (OACs) use, carrying a higher risk of associated hemorrhagic events, including intracranial hemorrhage (ICH). Despite advances in OACs development with a better safety profile and reversal agent for these anticoagulants, there is still no consensus on the optimal management of patients with OACs-associated ICH. AREAS COVERED: In this review, the authors have carried out an exhaustive search on the advances in recent years. The authors provide an update on the management of ICH in anticoagulated patients, as well as an update on the latest evidence on anticoagulation resumption, recent therapeutic strategies, and investigational drugs that could play a role in the future. EXPERT OPINION: Following an ICH event in an anticoagulated patient, a comprehensive clinical evaluation is imperative. Anticoagulation should be promptly withdrawn and reversed. Once the patient is stabilized, a reintroduction of anticoagulation should be considered, typically within a timeframe of 4-8 weeks, if feasible. If re-anticoagulation is not possible, alternative options such as Left Atrial Appendage Occlusion are available.

First-attempt awake tracheal intubation success rate using a hyperangulated unchannelled videolaryngoscope vs. a channelled videolaryngoscope in patients with anticipated difficult airway: a randomised controlled trial.

INTRODUCTION: There is uncertainty about the optimal videolaryngoscope for awake tracheal intubation in patients with anticipated difficult airway. The use of channelled and unchannelled videolaryngoscopy has been reported, but there is a lack of evidence on which is the best option. METHODS: We conducted a randomised clinical trial to compare the efficacy of the C-MAC D-Blade® vs. Airtraq® in adult patients (aged ≥ 18 y) scheduled for elective or emergency surgery under general anaesthesia with anticipated difficult airway who required awake tracheal intubation under local anaesthesia and conscious sedation. The primary endpoint was the first-attempt tracheal intubation success rate. Secondary outcomes included the overall success rate; number of tracheal intubation attempts; Cormack and Lehane glottic view; level of difficulty (visual analogue score); patient discomfort (visual analogue score); and incidence of complications. RESULTS: Ninety patients (70/90 male (78%); mean (SD) age 65 (12) y) with anticipated difficult airways were randomly allocated to C-MAC D-Blade or Airtraq videolaryngoscopy. First-attempt successful tracheal intubation rate was higher in patients allocated to the C-MAC D-Blade group compared with those allocated to the Airtraq group (38/45 (84%) vs. 28/45 (62%), respectively; p = 0.006). The proportion of patients' tracheas that were intubated at the second and third attempt was 4/45 (9%) and 3/45 (7%) in those allocated to the C-MAC D-Blade group compared with 14/45 (31%) and 1/45 (2%) in those allocated to the Airtraq group (p = 0.006). There was no significant difference in overall tracheal intubation success rate (C-MAC D-Blade group 45/45 (100%) vs. Airtraq group 43/45 (96%), p = 0.494). DISCUSSION: In patients with anticipated difficult airway, first-attempt awake tracheal intubation success rate was higher with the C-MAC D-Blade compared with Airtraq laryngoscopy. No difference was found between the two videolaryngoscopes in overall tracheal intubation success rate.

Early mutational signatures and transmissibility of SARS-CoV-2 Gamma and Lambda variants in Chile.

Genomic surveillance (GS) programmes were crucial in identifying and quantifying the mutating patterns of SARS-CoV-2 during the COVID-19 pandemic. In this work, we develop a Bayesian framework to quantify the relative transmissibility of different variants tailored for regions with limited GS. We use it to study the relative transmissibility of SARS-CoV-2 variants in Chile. Among the 3443 SARS-CoV-2 genomes collected between January and June 2021, where sampling was designed to be representative, the Gamma (P.1), Lambda (C.37), Alpha (B.1.1.7), B.1.1.348, and B.1.1 lineages were predominant. We found that Lambda and Gamma variants' reproduction numbers were 5% (95% CI: [1%, 14%]) and 16% (95% CI: [11%, 21%]) larger than Alpha's, respectively. Besides, we observed a systematic mutation enrichment in the Spike gene for all circulating variants, which strongly correlated with variants' transmissibility during the studied period (r = 0.93, p-value = 0.025). We also characterised the mutational signatures of local samples and their evolution over time and with the progress of vaccination, comparing them with those of samples collected in other regions worldwide. Altogether, our work provides a reliable method for quantifying variant transmissibility under subsampling and emphasises the importance of continuous genomic surveillance.

First report of silverleaf caused by Chondrostereum purpureum in hazelnut (Corylus avellana) in Chile.

Hazelnut is among the most important nut crops in Chile, currently covering 46,000 ha. In 2023, the country exported 30,000-ton. In recent years the incidence of plants with internal discoloration, cankers and dieback has been increasing. In some cases, the trees died and had to be removed and, after a year, purple resupinate fruiting bodies were observed growing from the stumps. To determine the etiology of the symptoms and signs, wood samples (n=318) were collected since 2020, from 38 symptomatic orchards from Maule to La Araucanía Regions, primarily from the cvs. Tonda di Giffoni and Lewis. Wood sections 0.5 cm diameter were cut from the symptomatic tissues, disinfected using a sodium hypochlorite (10%) solution, and plated on a quarter-strength acidified potato dextrose agar (aPDA1/4). The plates were incubated and purified on PDA. Subsequently, isolates were identified by morphological and molecular means. Almost half of the isolates (47%) were preliminarily identified as basidiomycetes, based on mycelial features such as the presence of clamp connections, with 45% of them exhibiting abundant whitish cottony fast-growth mycelia, resembling Chondrostereum purpureum (Grinbergs et al., 2020). DNA was extracted and the 500-bp fragment, located between 5S and 18S ribosomal regions, was amplified using APN1 specific primers (Becker et al. 1999), identifying the isolates as C. purpureum. In addition, 5.8S gene of RGM1 (35°13'40.9"S 71°25'14.1"W), RGM2 (36°31'27.95"S 71°46'58.31"W), RGM3 (37°10'54.8"S 72°03'39.6"W), RGM4 (35°19'25.2"S 71°19'54.7"W) and RGM5 (36°35'30.8"S 72°05'18.8"W) isolates, representing different locations within the hazelnut growing area, was amplified using ITS1/ITS4 primers (White et al., 1990). The PCR product was sequenced, and the analysis showed 100% homology among isolates (Genebank codes: PP839283, PP839284, PP839285, PP839286 and PP839287, respectively). To determine the pathogenicity of the isolates, 30-cm healthy cuttings cv. Lewis were inoculated with mycelial plugs, while control shoots were inoculated with sterile agar plugs. Cuttings were vertically arranged in pots with 3-cm water and incubated for 60-d at 22°C. In addition, fresh cuts of 3-y potted plants cv. Lewis were inoculated with mycelial plugs and incubated for 137-d in a shadehouse. After incubation, bark was removed from inoculated cuttings and the length of necrotic lesions was measured. Although discoloration was reproduced by all the isolates in both pathogenicity tests, RGM1 isolate was the most aggressive, causing the complete discoloration of the cuttings and the death of the inoculated plants. To our knowledge this is the first report of C. purpureum causing wood disease in hazelnut. These findings are significant because the disease may not only reduce orchard longevity but also decrease fruit yield and quality, as observed in other fruit crops (Grinbergs et al., 2021).

Differences in circulating alpha-calcitonin gene-related peptide levels in inflammatory bowel disease and its relation to migraine comorbidity: A cross-sectional study.

OBJECTIVE: To analyze the specificity of calcitonin gene-related peptide (CGRP) levels, we measured alpha-CGRP circulating levels in a large series of patients with a recent diagnosis of inflammatory bowel disease (IBD) who were interviewed regarding comorbid headache. BACKGROUND: Several studies have found an association between migraine and IBD. METHODS: In this cross-sectional study performed in an IBD clinic, morning serum alpha-CGRP levels were measured by enzyme-linked immunosorbent assay in 96 patients who were recently diagnosed with IBD and compared to those from 50 similar patients with chronic migraine (CM) and 50 healthy controls (HC). RESULTS: Alpha-CGRP levels were higher in patients with IBD (median [interquartile range] 56.9 [35.6-73.9] pg/mL) and patients with CM (53.0 [36.7-73.9] pg/mL) compared to HC (37.2 [30.0-51.8] pg/mL; p = 0.003; p = 0.019, respectively). Regarding IBD diagnostic subtypes, alpha-CGRP levels for ulcerative colitis (67.2 ± 49.3 pg/mL; 57.0 [35.6-73.4] pg/mL) and Crohn's disease (54.9 ± 27.5 pg/mL; 57.7 [29.1-76.1] pg/mL) were significantly higher than those of HC (p = 0.013, p = 0.040, respectively). Alpha-CGRP levels were further different in patients with IBD with migraine (70.9 [51.8-88.7] pg/mL) compared to HC (p < 0.001), patients with IBD without headache (57.5 [33.3-73.8] pg/mL; p = 0.049), and patients with IBD with tension-type headache but without migraine (41.7 [28.5-66.9] pg/mL; p = 0.004), though alpha-CGRP levels in patients with IBD without migraine (53.7 [32.9-73.5] pg/mL) remained different over HC (p = 0.028). CONCLUSION: Together with CM, circulating alpha-CGRP levels are different in patients with IBD, perhaps reflecting a chronic inflammatory state. IBD is an example of how alpha-CGRP levels are not a totally specific migraine biomarker. However, alpha-CGRP levels were further increased in patients with IBD who have a history of migraine, which reinforces its role as a biomarker in migraine patients, always bearing in mind their comorbidities.

Methodological and Practical Challenges in Synthesizing Occupational Cancer Studies.

Studies examining occupational exposures and cancer risk frequently report mixed findings; it is thus imperative for researchers to synthesize study results and identify any potential sources that explain such variabilities in study findings. However, when synthesizing study results using meta-analytic techniques, researchers often encounter a number of practical and methodological challenges. These challenges include (1) an incomparability of effect size measures due to large variations in research methodology; (2) a violation of the independence assumption for meta-analysis; (3) a violation of the normality assumption of effect size measures; and (4) a variation in cancer definitions across studies and changes in coding standards over time. In this paper, we first demonstrate these challenges by providing examples from a real dataset collected for a large meta-analysis project that synthesizes cancer mortality and incidence rates among firefighters. We summarize how each of these challenges has been handled in our meta-analysis. We conclude this paper by providing practical guidelines for handling challenges when synthesizing study findings from occupational cancer literature.

Management of cytomegalovirus reactivation in patient with immunotherapy-induced gastritis.

We present the case of a 52-year-old woman diagnosed with stage IV clear cell renal cell carcinoma who received combination of surgery and systemic therapy with nivolumab (anti-PD1) and ipilimumab (anti-CTLA-4). During treatment, patient presented oral intolerance, vomiting and abdominal pain. Computed tomography (CT) and gastroscopy (EGD) were performed, identifying findings suggestive of severe gastro-duodenitis with friability and diffuse oedema of the mucosa and deep ulcers. A gastrointestinal immunotherapy-induced toxicity was suspected so patient was managed with proton pump inhibitors (PPIs) and intravenous corticosteroids 1mg/Kg. Three weeks later, corticosteroid treatment failed. EGD was repeated and gastric biopsies were taken for histological and microbiological tests. Gastric biopsies revealed the presence of cytomegalovirus (CMV) inclusion bodies by immunohistochemistry (IHC). CMV viral load by quantitative PCR in plasma was 2,000 IU/mL so intravenous ganciclovir was prescribed. Then, the patient presented poor clinical course with persistent vomiting due to a failure of first-line corticosteroid and antiviral treatment. Another EGD was performed. Last IHC reveals a low CMV viral load. Second-line treatment with Anti-TNF was performed using a single-dose regimen of intravenous infliximab 5 mg/Kg. Finally, the patient presented a clinical and endoscopic response and a negative CMV DNA test in the blood after completing the antiviral treatment.

Photocatalytic functionalization of thin-layer membranes using a monomer truncation strategy.

We present the design and synthesis of two new organic polymer films making use of a liquid-liquid interfacial amine-acid chloride polymerization strategy. One of them was additionally functionalized in situ by the anchoring of N-phenyl-phenothiazine through a monomer truncation strategy, which endowed it with photocatalytic activity. This photoactive film displays interesting luminescence phenomena that were used for the oxidation of a variety of sulphides to their corresponding sulfoxides and reduction of aryl bromines.

Effect of early vs. delayed extubation on functional outcome among patients with acute ischemic stroke treated with endovascular thrombectomy under general anesthesia: the prospective, randomized controlled EDESTROKE trial study protocol.

BACKGROUND: Recent meta-analyses and randomized studies have shown that among patients with acute ischemic stroke undergoing endovascular thrombectomy, general anesthesia with mechanical ventilation is associated with better functional status compared to local anesthesia and sedation, and they recommend its use. But once the procedure is completed, when is the optimal moment for extubation? Currently, there are no guidelines recommending the optimal moment for extubation. Prolonged mechanical ventilation time could potentially be linked to increased complications such as pneumonia or disturbances in cerebral blood flow due to the vasodilatation produced by most anesthetic drugs. However, premature extubation in a patient who has suffered a stroke could led to complications such as agitation, disorientation, abolished reflexes, sudden fluctuations in blood pressure, alterations in cerebral blood flow, respiratory distress, bronchial aspiration, and the need for reintubation. We therefore designed a randomized study hypothesizing that early compared with delayed extubation is associated with a better functional outcome 3 months after endovascular thrombectomy treatment under general anesthesia for acute ischemic stroke. METHODS: This investigator-initiated, single-center, prospective, parallel, evaluated blinded, superiority, randomized controlled trial will include 178 patients with a proximal occlusion of the anterior circulation treated with successful endovascular thrombectomy (TICI 2b-3) under general anesthesia. Patients will be randomly allocated to receive early (< 6 h) or delayed (6-12 h) extubation after the procedure. The primary outcome measure is functional independence (mRS of 0-2) at 90 days, measured with the modified Rankin Score (mRS), ranging from 0 (no symptoms) to 6 (death). DISCUSSION: This will be the first trial to compare the effect of mechanical ventilation duration (early vs delayed extubation) after satisfactory endovascular thrombectomy for acute ischemic stroke under general anesthesia. TRIAL REGISTRATION: The study protocol was approved April 11, 2023, by the by the Santiago-Lugo Research Ethics Committee (CEI-SL), number 2023/127, and was registered into the clinicaltrials.gov clinical trials registry with No. NCT05847309. Informed consent is required. Participant recruitment begins on April 18, 2023. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences.

Implications of Prenatal Exposure to Endocrine-Disrupting Chemicals in Offspring Development: A Narrative Review.

During the last decades, endocrine-disrupting chemicals (EDCs) have attracted the attention of the scientific community, as a result of a deepened understanding of their effects on human health. These compounds, which can reach populations through the food chain and a number of daily life products, are known to modify the activity of the endocrine system. Regarding vulnerable groups like pregnant mothers, the potential damage they can cause increases their importance, since it is the health of two lives that is at risk. EDCs can affect the gestation process, altering fetal development, and eventually inducing the appearance of many disorders in their childhood and/or adulthood. Because of this, several of these substances have been studied to clarify the influence of their prenatal exposure on the cognitive and psychomotor development of the newborn, together with the appearance of non-communicable diseases and other disorders. The most novel research on the subject has been gathered in this narrative review, with the aim of clarifying the current knowledge on the subject. EDCs have shown, through different studies involving both animal and human investigation, a detrimental effect on the development of children exposed to the during pregnancy, sometimes with sex-specific outcomes. However, some other studies have failed to find these associations, which highlights the need for deeper and more rigorous research, that will provide an even more solid foundation for the establishment of policies against the extended use of these chemicals.

Marcadores trombogénicos en pacientes con trombofilia hereditaria

Fundamento: la trombofilia hereditaria se define como la tendencia genéticamente determinada al tromboembolismo venoso, entidad con una incidencia importante a nivel mundial. Desde el laboratorio pudieran explicarse un gran porcentaje de estos eventos de trombosis. Objetivo: caracterizar desde el punto de vista clínico humoral las trombofilias hereditarias e identificar la posible relación entre marcadores bioquímicos alterados de trombosis y su recurrencia. Método: se realizó un estudio descriptivo y transversal en el laboratorio de hemostasia del Hospital Provincial Docente Saturnino Lora de Santiago de Cuba, en el periodo de un año. Se tuvo como referencia 39 pacientes: 26 con eventos trombóticos egresados de los Servicios de Angiología, Cirugía Cardiovascular y Neurología, y 13 sin evento conocido, familiares de primera línea de aquellos pacientes que resultaron con marcadores de trombofilia positivos durante el estudio. Las variables clínicas analizadas fueron: edad, sexo, antecedentes personales y familiares de trombosis y número de eventos trombóticos en el paciente. Se calcularon media, desviación estándar y porcentajes. Resultados: el déficit de proteína S ocupó el primer lugar con 22 (56,4 %). La combinación de parámetros alterados que predominó fue el déficit de proteína C y S con 8 (20,5 %). En el 64,1 % se encontraron dos o más marcadores alterados; se muestran similares porcentajes en pacientes con 1, con 2 dos o más eventos de trombosis. Conclusión: la trombofilia se presentó como una enfermedad que afecta fundamentalmente a mujeres, en edades intermedias de la vida. En pacientes asintomáticos con antecedentes familiares de evento trombótico, sin aparente causa, los marcadores de laboratorio orientan el enfoque diagnóstico. La presencia de dos o más marcadores trombogénicos positivos inclina a la ocurrencia de eventos trombóticos en esta población.

Foundation: hereditary thrombophilia is defined as the genetically determined tendency to venous thromboembolism, an entity with a significant incidence worldwide. A large percentage of these thrombosis events could be explained from the laboratory. Objective: to characterize hereditary thrombophilias from a humoral clinical point of view and to identify the possible relationship between altered biochemical markers of thrombosis and its recurrence. Method: a descriptive and cross-sectional study was carried out in the hemostasis laboratory of the Saturnino Lora Provincial Teaching Hospital of Santiago de Cuba, over a period of one year. 39 patients were used as a reference: 26 with thrombotic events discharged from the Angiology, Cardiovascular Surgery and Neurology Services, and 13 without a known event, first-line relatives of those patients who had positive thrombophilia markers during the study. The clinical variables analyzed were: age, sex, personal and family history of thrombosis and number of thrombotic events in the patient. Mean, standard deviation and percentages were calculated. Results: protein S deficiency ranked first with 22 (56.4 %). The combination of altered parameters that predominated was protein C and S deficiency with 8 (20.5 %). Two or more altered markers were found in 64.1 %; similar percentages are shown in patients with 1, 2 or more thrombosis events. Conclusion: thrombophilia was presented as a disease that mainly affects women, at intermediate ages of life. In asymptomatic patients with a family history of thrombotic event, without apparent cause, laboratory markers guide the diagnostic approach. The presence of two or more positive thrombogenic markers suggests the occurrence of thrombotic events in this population.

Immune responses during COVID-19 breakthrough cases in vaccinated children and adolescents.

Background: Vaccine effectiveness against SARS-CoV-2 infection has been somewhat limited due to the widespread dissemination of the Omicron variant, its subvariants, and the immune response dynamics of the naturally infected with the virus. Methods: Twelve subjects between 3-17 years old (yo), vaccinated with two doses of CoronaVac®, were followed and diagnosed as breakthrough cases starting 14 days after receiving the second dose. Total IgGs against different SARS-CoV-2 proteins and the neutralizing capacity of these antibodies after infection were measured in plasma. The activation of CD4+ and CD8+ T cells was evaluated in peripheral blood mononuclear cells stimulated with peptides derived from the proteins from the wild-type (WT) virus and Omicron subvariants by flow cytometry, as well as different cytokines secretion by a Multiplex assay. Results: 2 to 8 weeks post-infection, compared to 4 weeks after 2nd dose of vaccine, there was a 146.5-fold increase in neutralizing antibody titers against Omicron and a 38.7-fold increase against WT SARS-CoV-2. Subjects showed an increase in total IgG levels against the S1, N, M, and NSP8 proteins of the WT virus. Activated CD4+ T cells showed a significant increase in response to the BA.2 subvariant (p<0.001). Finally, the secretion of IL-2 and IFN-γ cytokines showed a discreet decrease trend after infection in some subjects. Conclusion: SARS-CoV-2 infection in the pediatric population vaccinated with an inactivated SARS-CoV-2 vaccine produced an increase in neutralizing antibodies against Omicron and increased specific IgG antibodies for different SARS-CoV-2 proteins. CD4+ T cell activation was also increased, suggesting a conserved cellular response against the Omicron subvariants, whereas Th1-type cytokine secretion tended to decrease. Clinical Trial Registration: clinicaltrials.gov #NCT04992260.

Implementing Standard Diagnosis and Treatment for Locally Advanced Breast Cancer Through Global Research in Latin America: Results From a Multicountry Pragmatic Trial.

PURPOSE: Breast cancer mortality rates in Latin America (LA) are higher than those in the United States, possibly because of advanced disease presentation, health care disparities, or unfavorable molecular subtypes. The Latin American Cancer Research Network was established to address these challenges and to promote collaborative clinical research. The Molecular Profiling of Breast Cancer Study (MPBCS) aimed to evaluate the clinical characteristics and treatment outcomes of LA participants with locally advanced breast cancer (LABC). PATIENTS AND METHODS: The MPBCS enrolled 1,449 participants from Argentina, Brazil, Chile, Mexico, and Uruguay. Through harmonized procedures and quality assurance measures, this study evaluated clinicopathologic characteristics, neoadjuvant chemotherapy response, and survival outcomes according to residual cancer burden (RCB) and the type of surgery. RESULTS: Overall, 711 and 480 participants in the primary surgery and neoadjuvant arms, respectively, completed the 5-year follow-up period. Overall survival was independently associated with RCB (worse survival for RCBIII-adjusted hazard ratio, 8.19, P < .001, and RCBII [adjusted hazard ratio, 3.69, P < .008] compared with RCB0 [pathologic complete response or pCR]) and type of surgery (worse survival in mastectomy than in breast-conserving surgery [BCS], adjusted hazard ratio, 2.97, P = .001). The hormone receptor-negative-human epidermal growth factor receptor 2-positive group had the highest proportion of pCR (48.9%). The analysis of the ASCO Quality Oncology Practice Initiative breast module revealed high compliance with pathologic standards but lower adherence to treatment administration standards. Notably, compliance with trastuzumab administration varied widely among countries (33.3%-88.7%). CONCLUSION: In LABC, we demonstrated the survival benefit of BCS and the prognostic effect of the response to available neoadjuvant treatments despite an important variability in access to key treatments. The MPBCS represents a significant step forward in understanding the real-world implementation of oncologic procedures in LA.

Metastases Affecting Cranial Nervous Structures in Male Breast Cancer: Two Case Reports.

INTRODUCTION: Breast cancer in males is a very rare entity, and survival is mainly influenced by the stage at diagnosis. The lack of early detection tools in men results in a diagnostic delay of about 5-10 years and a higher percentage of metastatic disease at diagnosis. However, the characteristics of head metastases are not well defined. CASE REPORTS: We present 2 cases of male breast cancer with metastases affecting cranial nervous structures and we provide imaging and histologic data. Both were middle-aged patients with ductal-type, HER-2- negative, and androgen receptor-positive primary tumors. CONCLUSION: Although central nervous system involvement is uncommon, this entity should be considered in middle-aged males with focal neurologic symptoms. More cases would be necessary to better understand the biology of this condition in order to establish an adequate diagnosis and treatment.

Impact of Universal Use of the McGrath Videolaryngoscope as a Device for All Intubations in the Cardiac Operating Room. A Prospective Before-After VIDEOLAR-CAR Study.

OBJECTIVE: Tracheal intubation in cardiac surgery patients has a higher incidence of difficult laryngoscopic views compared with patients undergoing other types of surgery. The authors hypothesized that using the McGrath Mac videolaryngoscope as the first intubation option for cardiac surgery patients improves the percentage of patients with "easy intubation" compared with using a direct Macintosh laryngoscope. DESIGN: A prospective, observational, before-after study. SETTING: At a tertiary-care hospital. PARTICIPANTS: One thousand one hundred nine patients undergoing cardiac surgery. INTERVENTION: Consecutive patients undergoing cardiac surgery were intubated using, as the first option, a Macintosh laryngoscope (preinterventional phase) or a McGrath Mac videolaryngoscope (interventional phase). MEASUREMENTS AND MAIN RESULTS: The main objective was to assess whether the use of the McGrath videolaryngoscope, as the first intubation option, improves the percentage of patients with "easy intubation," defined as successful intubation on the first attempt, modified Cormack-Lehane grades of I or IIa, and the absence of the need for adjuvant airway devices. A total of 1,109 patients were included, 801 in the noninterventional phase and 308 in the interventional phase. The incidence of "easy intubation" was 93% in the interventional phase versus 78% in the noninterventional phase (p < 0.001). First-success-rate intubation was higher in the interventional phase (304/308; 98.7%) compared with the noninterventional phase (754/801, 94.1%; p = 0.005). Intubation in the interventional phase showed decreases in the incidence of difficult laryngoscopy (12/308 [3.9%] v 157/801 [19.6%]; p < 0.001), as well as moderate or difficult intubation (5/308 [1.6%] v 57/801 [7.1%]; p < 0.001). CONCLUSIONS: The use of the McGrath videolaryngoscope as the first intubation option for tracheal intubation in cardiac surgery improves the percentage of patients with "easy" intubation," increasing glottic view and first-success-rate intubation and decreasing the incidence of moderate or difficult intubation.

COVID-19 and Pregnancy: A Dangerous Mix for Bone Turnover and Metabolism Biomarkers in Placenta and Colostrum.

Background: In pregnant women, COVID-19 can alter the metabolic environment, cell metabolism, and oxygen supply of trophoblastic cells and, therefore, have a negative influence on essential mechanisms of fetal development. The purpose of this study was to investigate, for the first time, the effects of COVID-19 infection during pregnancy with regard to the bone turnover and endocrine function of several metabolic biomarkers in colostrum and placenta. Methods: One hundred and twenty-four pregnant mothers were recruited from three hospitals between June 2020 and August 2021 and assigned to two groups: Control group and COVID-19 group. Metabolism biomarkers were addressed in placental tissue and colostrum. Results: Lipocalin-2 and resistin levels were higher in the placenta, revealing an underlying pro-inflammatory status in the gestation period for mothers suffering from COVID-19; a decrease in GLP-1 and leptin was also observed in this group. As for adiponectin, resistin, and insulin, their concentrations showed an increase; a decrease in GLP-1, leptin, and PYY was also reported in the colostrum of mothers suffering from COVID-19 compared with the control group. Conclusions: As for bone turnover, placental samples from mothers with COVID-19 showed lower levels of OPG, while DKK-1 increased compared with the control group. Colostrum samples showed higher levels of OPG, SOST, and PTH in the COVID-19 group, a fact that could have noteworthy implications for energy metabolism, fetal skeletal development, and postnatal bone density and mineralization. Further research is needed to explain the pathogenic mechanism of COVID-19 that may affect pregnancy, so as to assess the short-term and long-term outcomes in infants' health.

Presence of Zonula Occludens Toxin-Coding Genes among Vibrio parahaemolyticus Isolates of Clinical and Environmental Origin.

In recent studies, emphasis has been placed on the zonula occludens toxin (Zot) from the non-toxigenic Vibrio parahaemolyticus strain PMC53.7 as an agent inducing alterations in the actin cytoskeleton of infected Caco-2 cells and which appears as a relevant virulence factor. Universal zot primers were designed by the alignment of different types of zot gene and identification of conserved sequences to investigate the presence in diverse environmental and clinical V. parahaemolyticus isolates, in co-occurrence with virulence factors, such a hemolysins and secretion systems. The study screened a total of 390 isolates from environmental sources from Chile and Italy and 95 Chilean clinical isolates. The results revealed that around 37.2% of Chilean environmental strains and 25.9% of Italian strains, and 24.2% of clinical isolates carried the zot gene. The Zot-C2 cluster was present in 71.4% of Chilean environmental strains but absent in clinical isolates, while the Zot-C4 cluster was identified in 28.6% of environmental and 100% of clinical isolates. Understanding the role of zot in V. parahaemolyticus virulence is crucial, especially considering the risk associated with consuming diverse isolates from bivalves and the co-occurrence with virulence factors such as TDH, TRH or T3SS2.