RNA aggregates harness the danger response for potent cancer immunotherapy.

Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.

Expanded specific T cells to hypomutated regions of the SARS-CoV-2 using mRNA electroporated antigen-presenting cells.

The COVID-19 pandemic has caused about seven million deaths worldwide. Preventative vaccines have been developed including Spike gp mRNA-based vaccines that provide protection to immunocompetent patients. However, patients with primary immunodeficiencies, patients with cancer, or hematopoietic stem cell transplant recipients are not able to mount robust immune responses against current vaccine approaches. We propose to target structural SARS-CoV-2 antigens (i.e., Spike gp, Membrane, Nucleocapsid, and Envelope) using circulating human antigen-presenting cells electroporated with full length SARS-CoV-2 structural protein-encoding mRNAs to activate and expand specific T cells. Based on the Th1-type cytokine and cytolytic enzyme secretion upon antigen rechallenge, we were able to generate SARS-CoV-2 specific T cells in up to 70% of unexposed unvaccinated healthy donors (HDs) after 3 subsequent stimulations and in 100% of recovered patients (RPs) after 2 stimulations. By means of SARS-CoV-2 specific TCRß repertoire analysis, T cells specific to Spike gp-derived hypomutated regions were identified in HDs and RPs despite viral genomic evolution. Hence, we demonstrated that SARS-CoV-2 mRNA-loaded antigen-presenting cells are effective activating and expanding COVID19-specific T cells. This approach represents an alternative to patients who are not able to mount adaptive immune responses to current COVID-19 vaccines with potential protection across new variants that have conserved genetic regions.

Vaccines: a promising therapy for myelodysplastic syndrome.

Myelodysplastic neoplasms (MDS) define clonal hematopoietic malignancies characterized by heterogeneous mutational and clinical spectra typically seen in the elderly. Curative treatment entails allogeneic hematopoietic stem cell transplant, which is often not a feasible option due to older age and significant comorbidities. Immunotherapy has the cytotoxic capacity to elicit tumor-specific killing with long-term immunological memory. While a number of platforms have emerged, therapeutic vaccination presents as an appealing strategy for MDS given its promising safety profile and amenability for commercialization. Several preclinical and clinical trials have investigated the efficacy of vaccines in MDS; these include peptide vaccines targeting tumor antigens, whole cell-based vaccines and dendritic cell-based vaccines. These therapeutic vaccines have shown acceptable safety profiles, but consistent clinical responses remain elusive despite robust immunological reactions. Combining vaccines with immunotherapeutic agents holds promise and requires further investigation. Herein, we highlight therapeutic vaccine trials while reviewing challenges and future directions of successful vaccination strategies in MDS.

Evaluation of the osmoregulatory capacity and three stress biomarkers in white shrimp Penaeus vannamei exposed to different temperature and salinity conditions: Na+/K+ ATPase, Heat Shock Proteins (HSP), and Crustacean Hyperglycemic Hormones (CHHs).

Salinity and temperature influence growth, survival, and reproduction of crustacean species such as Penaeus vannamei where Na +/K+-ATPase plays a key role in maintaining osmotic homeostasis in different salinity conditions. This ability is suggested to be mediated by other proteins including neuropeptides such as the crustacean hyperglycemic hormones (CHHs), and heat shock proteins (HSPs). The mRNA expression of Na+/K+-ATPase, HSP60, HSP70, CHH-A, and CHH-B1, was analyzed by qPCR in shrimp acclimated to different salinities (10, 26, and 40 PSU) and temperature conditions (20, 23, 26, 29, and 32 °C) to evaluate their uses as molecular stress biomarkers. The results showed that the hemolymph osmoregulatory capacity in shrimp changed with exposure to the different salinities. From 26 to 32 °C the Na+/K+-ATPase expression increased significantly at 10 PSU relative to shrimp acclimated at 26 PSU and at 20 °C increased at similar values independently of salinity. The highest HSP expression levels were obtained by HSP70 at 20 °C, suggesting a role in protecting proteins such as Na+/K+ -ATPase under low-temperature and salinity conditions. CHH-A was not expressed in the gill under any condition, but CHH-B1 showed the highest expression at the lowest temperatures and salinities, suggesting its participation in the Na+/K+-ATPase induction. Since Na+/K+-ATPase, HSPs, and CHHs seem to participate in maintaining the osmo-ionic balance and homeostasis in P. vannamei, their expression levels may be used as a stress biomarkers to monitor marine crustacean health status when acclimated in low salinity and temperature conditions.

mRNA-based precision targeting of neoantigens and tumor-associated antigens in malignant brain tumors.

BACKGROUND: Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically "cold" tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines. mRNA-based immunotherapeutics have also garnered widespread interest for their potential to revolutionize cancer treatment. In this study, we developed a novel and scalable approach for the production of personalized mRNA-based therapeutics that target multiple tumor rejection antigens in a single therapy for the treatment of refractory brain tumors. METHODS: Tumor-specific neoantigens and aberrantly overexpressed tumor-associated antigens were identified for glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (O.R.A.N). Personalized tumor antigen-specific mRNA vaccine was developed for each individual tumor model using selective gene capture and enrichment strategy. The immunogenicity and efficacy of the personalized mRNA vaccines was evaluated in combination with anti-PD-1 immune checkpoint blockade therapy or adoptive cellular therapy with ex vivo expanded tumor antigen-specific lymphocytes in highly aggressive murine GBM models. RESULTS: Our results demonstrate the effectiveness of the antigen-specific mRNA vaccines in eliciting robust anti-tumor immune responses in GBM hosts. Our findings substantiate an increase in tumor-infiltrating lymphocytes characterized by enhanced effector function, both intratumorally and systemically, after antigen-specific mRNA-directed immunotherapy, resulting in a favorable shift in the tumor microenvironment from immunologically cold to hot. Capacity to generate personalized mRNA vaccines targeting human GBM antigens was also demonstrated. CONCLUSIONS: We have established a personalized and customizable mRNA-therapeutic approach that effectively targets a plurality of tumor antigens and demonstrated potent anti-tumor response in preclinical brain tumor models. This platform mRNA technology uniquely addresses the challenge of tumor heterogeneity and low antigen burden, two key deficiencies in targeting the classically immunotherapy-resistant CNS malignancies, and possibly other cold tumor types.

Reducing the Gap in Neurosurgical Education in LMICs: A Report of a Non-Profit Educational Program.

INTRODUCTION: Central to neurosurgical care, neurosurgical education is particularly needed in low- and middle-income countries (LMICs), where opportunities for neurosurgical training are limited due to social and economic constraints and an inadequate workforce. The present paper aims (1) to evaluate the validity and usability of a cadaver-free hybrid system in the context of LMICs and (2) to report their learning needs and whether the courses meet those needs via a comprehensive survey. METHODS: From April to November 2021, a non-profit initiative consisting of a series of innovative cadaver-free courses based on virtual and practical training was organized. This project emerged from a collaboration between the Young Neurosurgeons Forum of the World Federation of Neurological Societies (WFNS), the NIHR Global Health Research Group on Neurotrauma, and UpSurgeOn, an Italian hi-tech company specialized in simulation technologies, creator of the UpSurgeOn Box, a hyper-realistic simulator of cranial approaches fused with augmented reality. Over that period, 11 cadaver-free courses were held in LMICs using remote hands-on Box simulators. RESULTS: One hundred sixty-eight participants completed an online survey after course completion of the course. The anatomical accuracy of simulators was overall rated high by the participant. The simulator provided a challenging but manageable learning curve, and 86% of participants found the Box to be very intuitive to use. When asked if the sequence of mental training (app), hybrid training (Augmented Reality), and manual training (the Box) was an effective method of training to fill the gap between theoretical knowledge and practice on a real patient/cadaver, 83% of participants agreed. Overall, the hands-on activities on the simulators have been satisfactory, as well as the integration between physical and digital simulation. CONCLUSIONS: This project demonstrated that a cadaver-free hybrid (virtual/hands-on) training system could potentially participate in accelerating the learning curve of neurosurgical residents, especially in the setting of limited training possibilities such as LMICs, which were only worsened during the COVID-19 pandemic.

Bioconjugated liquid-like solid enhances characterization of solid tumor - chimeric antigen receptor T cell interactions.

Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable success as an immunotherapy for hematological malignancies, and its potential for treating solid tumors is an active area of research. However, limited trafficking and mobility of T cells within the tumor microenvironment (TME) present challenges for CAR T cell therapy in solid tumors. To gain a better understanding of CAR T cell function in solid tumors, we subjected CD70-specific CAR T cells to a challenge by evaluating their immune trafficking and infiltration through a confined 3D microchannel network in a bio-conjugated liquid-like solid (LLS) medium. Our results demonstrated successful CAR T cell migration and anti-tumor activity against CD70-expressing glioblastoma and osteosarcoma tumors. Through comprehensive analysis of cytokines and chemokines, combined with in situ imaging, we elucidated that immune recruitment occurred via chemotaxis, and the effector-to-target ratio plays an important role in overall antitumor function. Furthermore, through single-cell collection and transcriptomic profiling, we identified differential gene expression among the immune subpopulations. Our findings provide valuable insights into the complex dynamics of CAR T cell function in solid tumors, informing future research and development in this promising cancer treatment approach. STATEMENT OF SIGNIFICANCE: The use of specialized immune cells named CAR T cells to combat cancers has demonstrated remarkable success against blood cancers. However, this success is not replicated in solid tumors, such as brain or bone cancers, mainly due to the physical barriers of these solid tumors. Currently, preclinical technologies do not allow for reliable evaluation of tumor-immune cell interactions. To better study these specialized CAR T cells, we have developed an innovative in vitro three-dimensional model that promises to dissect the interactions between tumors and CAR T cells at the single-cell level. Our findings provide valuable insights into the complex dynamics of CAR T cell function in solid tumors, informing future research and development in this promising cancer treatment approach.

Beta-Lactam Antibiotics Can Be Measured in the Exhaled Breath Condensate in Mechanically Ventilated Patients: A Pilot Study.

Different techniques have been proposed to measure antibiotic levels within the lung parenchyma; however, their use is limited because they are invasive and associated with adverse effects. We explore whether beta-lactam antibiotics could be measured in exhaled breath condensate collected from heat and moisture exchange filters (HMEFs) and correlated with the concentration of antibiotics measured from bronchoalveolar lavage (BAL). We designed an observational study in patients undergoing mechanical ventilation, which required a BAL to confirm or discard the diagnosis of pneumonia. We measured and correlated the concentration of beta-lactam antibiotics in plasma, epithelial lining fluid (ELF), and exhaled breath condensate collected from HMEFs. We studied 12 patients, and we detected the presence of antibiotics in plasma, ELF, and HMEFs from every patient studied. The concentrations of antibiotics were very heterogeneous over the population studied. The mean antibiotic concentration was 293.5 (715) ng/mL in plasma, 12.3 (31) ng/mL in ELF, and 0.5 (0.9) ng/mL in HMEF. We found no significant correlation between the concentration of antibiotics in plasma and ELF (R2 = 0.02, p = 0.64), between plasma and HMEF (R2 = 0.02, p = 0.63), or between ELF and HMEF (R2 = 0.02, p = 0.66). We conclude that beta-lactam antibiotics can be detected and measured from the exhaled breath condensate accumulated in the HMEF from mechanically ventilated patients. However, no correlations were observed between the antibiotic concentrations in HMEF with either plasma or ELF.

Needs, Roles, and Challenges of Young Latin American and Caribbean Neurosurgeons.

BACKGROUND: Barriers to neurosurgery training and practice in Latin American and Caribbean countries (LACs) have been scarcely documented. The World Federation of Neurosurgical Societies Young Neurosurgeons Forum survey sought to identify young neurosurgeons' needs, roles, and challenges. We present the results focused on Latin America and the Caribbean. METHODS: In this cross-sectional study, we analyzed the Young Neurosurgeons Forum survey responses from LACs, following online survey dissemination through personal contacts, social media, and neurosurgical societies' e-mailing lists between April and November 2018. Data analysis was performed using Jamovi version 2.0 and STATA version 16. RESULTS: There were 91 respondents from LACs. Three (3.3%) respondents practiced in high-income countries, 77 (84.6%) in upper middle-income countries, 10 (11%) in lower middle-income countries, and 1 (1.1%) in an unclassified country. The majority (77, or 84.6%) of respondents were male, and 71 (90.2%) were younger than 40. Access to basic imaging modalities was high, with access to computed tomography scan universal among the survey respondents. However, only 25 (27.5%) of respondents reported having access to imaging guidance systems (navigation), and 73 (80.2%) reported having access to high-speed drills. A high GDP per capita was associated with increased availability of high-speed drills and more time dedicated to educational endeavors in neurosurgery, such as didactic teaching and topic presentation (P < 0.05). CONCLUSIONS: This survey found that neurosurgery trainees and practitioners of Latin America and the Caribbean face many barriers to practice. These include inadequate state-of-the-art neurosurgical equipment, a lack of standardized training curricula, few research opportunities, and long working hours.

Three-Dimensional Bioconjugated Liquid-Like Solid (LLS) Enhance Characterization of Solid Tumor - Chimeric Antigen Receptor T cell interactions.

Cancer immunotherapy offers lifesaving treatments for cancers, but the lack of reliable preclinical models that could enable the mechanistic studies of tumor-immune interactions hampers the identification of new therapeutic strategies. We hypothesized 3D confined microchannels, formed by interstitial space between bio-conjugated liquid-like solids (LLS), enable CAR T dynamic locomotion within an immunosuppressive TME to carry out anti-tumor function. Murine CD70-specific CAR T cells cocultured with the CD70-expressing glioblastoma and osteosarcoma demonstrated efficient trafficking, infiltration, and killing of cancer cells. The anti-tumor activity was clearly captured via longterm in situ imaging and supported by upregulation of cytokines and chemokines including IFNg, CXCL9, CXCL10, CCL2, CCL3, and CCL4. Interestingly, target cancer cells, upon an immune attack, initiated an "immune escape" response by frantically invading the surrounding microenvironment. This phenomenon however was not observed for the wild-type tumor samples which remained intact and produced no relevant cytokine response. Single cells collection and transcriptomic profiling of CAR T cells at regions of interest revealed feasibility of identifying differential gene expression amongst the immune subpopulations. Complimentary 3D in vitro platforms are necessary to uncover cancer immune biology mechanisms, as emphasized by the significant roles of the TME and its heterogeneity.

mRNA challenge predicts brain cancer immunogenicity and response to checkpoint inhibitors.

To prospectively determine whether brain tumors will respond to immune checkpoint inhibitors (ICIs), we developed a novel mRNA vaccine as a viral mimic to elucidate cytokine release from brain cancer cells in vitro. Our results indicate that cytokine signatures following mRNA challenge differ substantially from ICI responsive versus non-responsive murine tumors. These findings allow for creation of a diagnostic assay to quickly assess brain tumor immunogenicity, allowing for informed treatment with ICI or lack thereof in poorly immunogenic settings.

mRNA aggregates harness danger response for potent cancer immunotherapy.

Messenger RNA (mRNA) has emerged as a remarkable tool for COVID-19 prevention but its use for induction of therapeutic cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Herein, we develop a facile approach for substantially enhancing immunogenicity of tumor-derived mRNA in lipid-particle (LP) delivery systems. By using mRNA as a molecular bridge with ultrapure liposomes and foregoing helper lipids, we promote the formation of 'onion-like' multi-lamellar RNA-LP aggregates (LPA). Intravenous administration of RNA-LPAs mimics infectious emboli and elicits massive DC/T cell mobilization into lymphoid tissues provoking cancer immunogenicity and mediating rejection of both early and late-stage murine tumor models. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for toll-like receptor engagement, RNA-LPAs stimulate intracellular pathogen recognition receptors (RIG-I) and reprogram the TME thus enabling therapeutic T cell activity. RNA-LPAs were safe in acute/chronic murine GLP toxicology studies and immunologically active in client-owned canines with terminal gliomas. In an early phase first-in-human trial for patients with glioblastoma, we show that RNA-LPAs encoding for tumor-associated antigens elicit rapid induction of pro-inflammatory cytokines, mobilization/activation of monocytes and lymphocytes, and expansion of antigen-specific T cell immunity. These data support the use of RNA-LPAs as novel tools to elicit and sustain immune responses against poorly immunogenic tumors.

Evolution and Revolution of Imaging Technologies in Neurosurgery.

We understand only a small fraction of the events happening in our brains; therefore, despite all the progress made thus far, a whole array of questions remains. Nonetheless, neurosurgeons invented new tools to circumvent the challenges that had plagued their predecessors. With the manufacturing boom of the 20th century, technological innovations blossomed enabling the neuroscientific community to study and operate upon the living brain in finer detail and with greater precision while avoiding harm to the nervous system. The purpose of this chronological review is to 1) raise awareness among future neurosurgeons about the latest advances in the field, 2) become familiar with innovations such as augmented reality (AR) that should be included in education given their ready applicability in surgical training, and 3) be comfortable with customizing these technologies to real-life cases like in the case of mixed reality.

CAR T Cell Locomotion in Solid Tumor Microenvironment.

The promising outcomes of chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies potentiates its capability in the fight against many cancers. Nevertheless, this immunotherapy modality needs significant improvements for the treatment of solid tumors. Researchers have incrementally identified limitations and constantly pursued better CAR designs. However, even if CAR T cells are armed with optimal killer functions, they must overcome and survive suppressive barriers imposed by the tumor microenvironment (TME). In this review, we will discuss in detail the important role of TME in CAR T cell trafficking and how the intrinsic barriers contribute to an immunosuppressive phenotype and cancer progression. It is of critical importance that preclinical models can closely recapitulate the in vivo TME to better predict CAR T activity. Animal models have contributed immensely to our understanding of human diseases, but the intensive care for the animals and unreliable representation of human biology suggest in vivo models cannot be the sole approach to CAR T cell therapy. On the other hand, in vitro models for CAR T cytotoxic assessment offer valuable insights to mechanistic studies at the single cell level, but they often lack in vivo complexities, inter-individual heterogeneity, or physiologically relevant spatial dimension. Understanding the advantages and limitations of preclinical models and their applications would enable more reliable prediction of better clinical outcomes.

Effects of immune checkpoint blockade on antigen-specific CD8+ T cells for use in adoptive cellular therapy.

Adoptive T-cell therapies have been successfully used as prophylaxis or treatment for immunocompromised patients at risk of viral infections or advanced cancers. Unfortunately, for some refractory cancers, they have failed. To overcome this, checkpoint inhibitors are used to rescue immune antitumor responses. We hypothesized that in vitro checkpoint blockade during T-cell stimulation and expansion with messenger RNA (mRNA)-pulsed DCs may enhance the activity of antigen-specific T cells and improve the efficacy of adoptive cellular therapy platforms. Human peripheral blood mononuclear cells were isolated from cytomegalovirus (CMV)-seropositive donors to generate DCs. These were pulsed with CMV matrix phosphoprotein 65 (CMVpp65)-mRNA to educate T cells in coculture for 15 days. Three checkpoint blockade conditions were evaluated (anti-PD1, anti-Tim3, and anti-PD1 + Tim3). IL-2 and antibodies blockades were added every 3 days. Immunophenotyping was performed on Day 0 and Day 15. Polyfunctional antigen-specific responses were evaluated upon rechallenge with CMVpp65 peptides. CMVpp65-activated CD8+ T cells upregulate Lag3 and Tim3 (P ≤ 0.0001). Tim3 antibody blockade alone or in combination led to a significant upregulation of Lag3 expression on CD8+ pp65Tetramer+ central memory, effector memory, and terminal effector memory cells re-expressing RA (TEMRA) T cells. This latter T-cell subset uniquely maintains double-positive Tim3/Lag3 expression after checkpoint blockade. By contrast, PD1 blockade had minimal effects on Tim3 or Lag3 expression. In addition, IFN-γ secretion was reduced in T cells treated with Tim3 blockade in a dose-dependent manner (P = 0.004). In this study, we have identified a potential activating component of Tim3 and linkage between Tim3 and Lag3 signaling upon blocking the Tim3 axis during T-cell-antigen-presenting cell interactions that should be considered when targeting immune checkpoints for clinical use.

Citotoxicidad in vitro del polipéptido antimicrobiano nisina sobre células tumorales sanguíneas / In vitro cytotoxicity of the antimicrobial polypeptide nisin on blood tumor cells

RESUMEN: Las bacteriocinas son péptidos antimicrobianos de síntesis ribosomal secretadas por bacterias. Dentro de estas destaca nisina que posee potenciales usos en terapias antibióticas, como biopreservante de alimentos y probióticos. También se ha descrito que nisina posee citotoxicidad sobre líneas celulares neoplásicas, pero existe poca información de su efecto sobre células tumorales sanguíneas. Debido al potencial uso que presenta nisina, es relevante determinar la toxicidad que presenta sobre líneas celulares tumorales del tipo sanguíneo. Para esto, se realizaron ensayos de actividad hemolítica sobre eritrocitos humanos y de toxicidad sobre células mononucleares de sangre periférica humanas, determinándose que nisina no posee efecto citotóxico sobre este tipo de células normales humanas sanguíneas. Se realizaron también, ensayos de citotoxicidad con líneas celulares tumorales (K562 y U937), con el fin de determinar dosis, tiempo de exposición y selectividad en el efecto tóxico de nisina sobre las células tumorales humanas. Estos ensayos muestran que nisina presenta actividad citotóxica sobre líneas celulares K562 y U937 a las 72 h de exposición, a una concentración de 40 µg/mL, que corresponde a 100 veces la concentración mínima inhibitoria (MIC) usada para su acción sobre bacterias. Al comparar el efecto de nisina sobre células mononucleares de sangre periférica humanas con las líneas tumorales linfoides y mieloides (K562 y U937 respectivamente), se observa un efecto selectivo de nisina sobre las células tumorales sanguíneas.

SUMMARY: Bacteriocins are antimicrobial peptides of ribosomal synthesis secreted by bacteria. Among these, nisin stands out, which has potential uses in antibiotic therapies, as a food bio preservative and probiotics. Nisin has also been reported to have cytotoxicity on neoplastic cell lines, but there is little information on its effect on blood tumor cells. Due to the potential use that nisin presents, it is relevant to determine the toxicity it presents on tumor cell lines of the blood type. For this, hemolytic activity tests were carried out on human erythrocytes and toxicity on human peripheral blood mononuclear cells, determining that nisin does not have a toxic effect on this type of normal human blood cells. Cytotoxicity tests were also carried out with tumor cell lines (K562 and U937), to determine dose, exposure time and selectivity in the toxic effect of nisin on human tumor cells. These tests show that nisin shows cytotoxic activity on K562 and U937 cell lines at 72 h of exposure, at a concentration of 40 µg / mL, which corresponds to 100 times the minimum inhibitory concentration (MIC) used for its action on bacteria. When comparing the effect of nisin on human peripheral blood mononuclear cells with lymphoid and myeloid tumor lines (K562 and U937 respectively), a selective effect of nisin on blood tumor cells is observed.

Descending thoracic aorta to bilateral femoral artery bypass and thoracic endovascular aortic repair in the management of atypical aortoiliac occlusive disease.

Despite recent advancements in endovascular technology and the proven durability of open surgery, extensive thoracoabdominal aortoiliac occlusive disease (AIOD) remains challenging to treat. In the present report, we have described the case of a 58-year-old woman with AIOD and multiple medical comorbidities. She successfully underwent a novel intraoperative transesophageal echocardiography-guided combined treatment with concurrent descending thoracic aorta to bilateral femoral artery bypass and thoracic endovascular aortic repair. We have shown that this approach, which combines descending thoracic aorta to bilateral femoral artery bypass with thoracic endovascular aortic repair, is an effective treatment alternative for future cases of complex AIOD.

Intubation timing as determinant of outcome in patients with acute respiratory distress syndrome by SARS-CoV-2 infection.

PURPOSE: To determine whether time-to-intubation was associated with higher ICU mortality in patients with COVID-19 on mechanical ventilation due to respiratory insufficiency. MATERIALS AND METHODS: We conducted an observational, prospective, single-center study of patients with confirmed SARS-CoV-2 infection hospitalized with moderate to severe ARDS, connected to mechanical ventilation in the ICU between March 17 and July 31, 2020. We examined their general and clinical characteristics. Time-to-intubation was the time from hospital admission to endotracheal intubation. RESULTS: We included 183 consecutive patients; 28% were female, and median age was 62 years old. Eighty-eight patients (48%) were intubated before 48 h (early) and ninety-five (52%) after 48 h (late). Patients intubated early had similar admission PaO2/FiO2 ratio (123 vs 99; p = 0.179) but were younger (59 vs 64; p = 0.013) and had higher body mass index (30 vs 28; p = 0.006) compared to patients intubated late. Mortality was higher in patients intubated late (18% versus 43%), with admission PaO2/FiO2 ratio < 100 mmHg (OR 5.2; p = 0.011), of older age (OR 1.1; p = 0.001), and with previous use of ACE inhibitors (OR 4.8; p = 0.026). CONCLUSIONS: In COVID-19 patients, late intubation, Pafi <100, older age, and previous ACE inhibitors use were associated with increased ICU mortality.

Women in Neurosurgery: First Neurosurgeon in Latin America and Current Mexican Leaders.

BACKGROUND: History has taught us that Mexican culture has been largely supported by women, despite gender prejudice from the society. Neurosurgery has not been the exception. Therefore, we investigated the challenges and influence of female neurosurgeons in Mexico. METHODS: We conducted a review of the literature and an analysis of the internal database of the Mexican Society of Neurological Surgery focusing on 3 topics: 1) the historical presence of women and gender inequality in Mexico; 2) the life and legacy of the woman who became the first neurosurgeon in Mexico and in Latin America; and 3) the participation of women in neurosurgery in the past 3 decades. RESULTS: In Latin America, the first woman in neurosurgery was María Cristina García-Sancho, who completed her neurosurgical training in 1951. Currently, women represent 6.2% of the total members of the Mexican Society of Neurological Surgery (MSNS). This percentage is still low, although data collected in this study suggest that it might increase in the next few years because 16.7% of Board Directors of the MSNS are women, the next elected president is a female neurosurgeon, and 14.5% of neurosurgery residents are women. CONCLUSIONS: Although a steady increase has occurred of women in neurosurgery in Mexico, there is still work to do, especially to overcome the barriers related to the old assumptions of the cultural and social roles of women.

A Novel Stress Fracture Rehabilitation Program: A Pilot Study.

INTRODUCTION: Stress fractures (SFx) of the tibia are common and limit military readiness, but there is presently no scientifically validated program that objectively fosters tibia SFx rehabilitation. Therefore, this pilot study evaluated the feasibility of a Graduated Exercise Program (GEP) based on the theory that programmed rest between exercise bouts improves the osteogenic response, which may enhance rehabilitation and military readiness. METHODS: Participants were randomly assigned to the GEP or standard-of-care exercise program. Both programs use a walk-jog-run progression, but the GEP splits daily exercise into morning and evening episodes and provides 5 days of programmed rest after each stage is completed. The GEP included autonomy support to foster program adherence. Outcome measures included adherence, subjective and ActiGraph-validated objective assessments of exercise duration and intensity, pain assessments, and autonomy support assessments. Participants offered suggestions for program improvement. RESULTS: Quantitative findings were mixed, but more importantly, this pilot study showed that the measurement, support, and self-reporting parameters were feasible, with high compliance by participants. Barriers to recruitment and retention were identified, along with solutions to overcome these barriers, starting with obtaining unit support for GEP participation. CONCLUSION: This pilot study demonstrated the feasibility of a GEP with autonomy support, along with challenges and their solutions, providing the foundation for a formal large-sample study.