Recent Advances in Therapeutics and Manufacturing Processes of Recombinant Adeno-Associated Virus for the Treatment of Lung Diseases.

Developing delivery vectors capable of transducing genetic material across the lung epithelia and mucus barrier is a major challenge and of great interest to enable gene therapies to treat pulmonary diseases. Recombinant Adeno-associated Viruses (rAAVs) have emerged as attractive candidates among viral and non-viral vectors due to their broad tissue tropism, ability to transduce dividing and quiescent cells, and their safety profile in current human applications. While rAAVs have demonstrated safety in earlier clinical trials for lung disease applications, there are still some limitations regarding rAAV-transgene delivery in pulmonary cells. Thus, further improvements in rAAV engineering are needed to enhance the effectiveness of rAAV-based therapies for lung diseases. Such therapies could benefit patients with chronic lung diseases, such as asthma, chronic obstructive pulmonary disease, pulmonary hypertension, and cystic fibrosis, among others, by regulating hereditary gene mutations or acquired gene deregulations causing these conditions. Alongside therapeutic development, advances in the rAAV production process are essential to meet increasing production demands, while reducing manufacturing costs. This review discusses current challenges and recent advances in the field of rAAV engineering and manufacturing to encourage the clinical development of new pulmonary gene therapy treatments.

Zephyr 375 urinary sphincter implant by unical perineal incision. Initial experience.

The treatment of male severe stress incontinence (MUI) after surgery is the implantation of an artificial urinary sphincter (AUS). Traditionally you need two incisions: perineal and inguinal. Our objetive is present a series of patients treated with the Zephyr 375 EUA implant through a single perineal incision. We present six men operated on for MUI after Transuretral resection of the prostate (TURP) (1) and radical prostatectomy (5). Preoperatively we perform Pad-Test and cystoscopy. Under epidural anesthesia, a vertical perineal incision was made and dissection up to the bulbospongiosus muscle was divided and we dissected the bulbar urethra. After removing the probe, we place the cuff, checking that it reaches the appropriate pressure, leaving it deactivated. To place the pump-reservoir, we digitally develop a scrotal dartos pocket from the perineum that we close with Vicryl 3/0. After closing the muscle with 3/0 Vicryl, we left a suction drain and a bladder catheter. The mean age was 63 years (55-72). Mean surgical time was 68 minutes (60-85). All were discharged the next day without catheter and drain. All patients comfortably palpated the scrotal reservoir-pump. After activation, all patients were continent without needing additional adjustment, using 3 a safety pad. The degree of satisfaction was very high, all of them affirmed that they would undergo the same intervention again. The Zephyr 375 urinary sphincter allows placement through a single perineal incision, reducing surgical time, simplifying the technique, and reducing morbidity without compromising the functional outcome.

Microsurgical clipping of unruptured intracranial aneurysms: Clinical and radiological outcomes.

BACKGROUND AND OBJECTIVES: The prevalence of unruptured intracranial aneurysms is 1-3%. The annual rupture rate increases in patients with multiple aneurysms that presented a previous hemorrhage from another aneurysm. OBJECTIVES: To evaluate outcomes of clipping unruptured aneurysms, comparing patients with single or multiple aneurysms clipped, describe the complications related to surgery and to identify risk factors predicting an unfavorable outcome. MATERIALS AND METHODS: Retrospective study including patients who underwent clipping of unruptured aneurysms between 2020-2023 at our center. Occlusion rate, complications, and functional outcome were analyzed. Risk factors for poor prognosis are identified using univariate model. RESULTS: 82 patients with 114 aneurysms were treated with microsurgery. Multiple aneurysms were clipped in 22 patients. A mini-open approach was used in 86,5% of cases. Complete occlusion in angio3D was found in 78.6% of clipped aneurysms. Complication rate was 12.2%, including asymptomatic cases. Mortality was 0%. The probability of 1 point mRS worsening was 7.3% and 2 or more points was 1.2%, with a good functional outcome in 98.9%. Clipping multiple aneurysms, miniopen approaches, or surgery in patients with previous subarachnoid hemorrhage did not increase the risk of complications. Posterior circulation aneurysms surgery increased the risk of ischemia. CONCLUSIONS: The management for unruptured intracranial aneurysms should be multimodal and based on clinical and radiological outcomes. Microsurgery is a valid and safe technique, with 0% mortality and bleeding rates and 1,2% rate of severe morbidity in our series.

Germline ERG haploinsufficiency defines a new syndrome with cytopenia and hematological malignancy predisposition.

The genomics era has facilitated discovery of new genes predisposing to bone marrow failure (BMF) and hematological malignancy (HM). We report the discovery of ERG as a novel autosomal dominant BMF/HM predisposition gene. ERG is a highly constrained transcription factor critical for definitive hematopoiesis, stem cell function and platelet maintenance. ERG colocalizes with other transcription factors including RUNX1 and GATA2 on promoters/enhancers of genes orchestrating hematopoiesis. We identified a rare heterozygous ERG missense variant in 3 thrombocytopenic individuals from one family and 14 additional ERG variants in unrelated individuals with BMF/HM including 2 de novo cases and 3 truncating variants. Phenotypes associated with pathogenic germline ERG variants included cytopenias (thrombocytopenia, neutropenia, pancytopenia) and HMs (acute myeloid leukemia, myelodysplastic syndrome, acute lymphoblastic leukemia) with onset before 40 years. Twenty ERG variants (19 missense, 1 truncating) including 3 missense population variants were functionally characterized. Thirteen potentially pathogenic ETS domain missense variants displayed loss-of-function characteristics disrupting transcriptional transactivation, DNA-binding and/or nuclear localization. Selected variants overexpressed in mouse fetal liver cells failed to drive myeloid differentiation and cytokine-independent growth in culture, and to promote acute erythroleukemia when transplanted into mice, concordant with these variants being loss-of-function. Four individuals displayed somatic genetic rescue by copy neutral loss of heterozygosity. Identification of predisposing germline ERG variants has clinical implications for patient/family diagnosis, counselling, surveillance, and treatment strategies including selection of bone marrow donors or cell/gene therapy.

The Combined Immunohistochemical Expression of GLI1 and BCOR in Synovial Sarcomas for the Identification of Three Risk Groups and Their Prognostic Outcomes: A Study of 52 Patients.

Synovial sarcoma (SS) is a rare soft-tissue tumor characterized by a monomorphic blue spindle cell histology and variable epithelial differentiation. Morphologically, SSs may be confused with other sarcomas. Systemic treatment is more effective for patients with high-risk SSs, patients with advanced disease, and younger patients. However, further studies are required to find new prognostic biomarkers. Herein, we describe the morphological, molecular, and clinical findings, using a wide immunohistochemical panel, of a series of SS cases. We studied 52 cases confirmed as SSs by morphological diagnosis and/or molecular studies. Clinical data (gender, age, tumor size, tumor location, resection margins, adjuvant treatment, recurrences, metastasis, and survival) were also retrieved for each patient. All the available H&E slides were examined by four pathologists. Three tissue microarrays (TMAs) were constructed for each of the tumors, and a wide immunohistochemical panel was performed. For time-to-event variables, survival analysis was performed using Kaplan-Meier curves and log-rank testing, or Cox regression. Statistical significance was considered at p < 0.05. The mean age of our patients was 40.33, and the median was 40.5 years. We found a predominance of males versus females (1.7:1). The most frequent morphological subtype was monophasic. TRPS1, SS18-SSX, and SSX-C-terminus were positive in 96% of cases. GLI1 expression was strong in six and focal (cytoplasmic) in twenty patients. Moreover, BCOR was expressed in more than half of SSs. Positive expression of both proteins, BCOR and GLI1, was correlated with a worse prognosis. Multivariate analysis was also performed, but only BCOR expression appeared to be significant. The combination of GLI1 and BCOR antibodies can be used to group SSs into three risk groups (low, intermediate, and high risk). We hypothesize that these findings could identify which patients would benefit from receiving adjuvant treatment and which would not. Moreover, these markers could represent therapeutic targets in advanced stages. However, further, larger series of SSs and molecular studies are necessary to corroborate our present findings.

Serine Depletion Promotes Antitumor Immunity by Activating Mitochondrial DNA-Mediated cGAS-STING Signaling.

Serine is critical for supporting cancer metabolism, and depriving malignant cells of this nonessential amino acid exerts antineoplastic effects, in large part, through disrupting metabolic pathways. Given the intricate relationship between cancer metabolism and the immune system, the metabolic defects imposed by serine deprivation might impact tumor-targeting immunity. In this study, we demonstrated that restricting endogenous and exogenous sources of serine in colorectal cancer cells results in mitochondrial dysfunction, leading to mitochondrial DNA (mtDNA) accumulation in the cytosol and consequent cGAS-STING1-driven type I IFN secretion. Depleting mtDNA or blocking its release attenuated cGAS-STING1 activation during serine deprivation. In vivo studies revealed that serine deprivation limits tumor growth, accompanied by enhanced type I IFN signaling and intratumoral infiltration of immune effector cells. Notably, the tumor-suppressive and immune-enhancing effects of serine restriction were impaired by T-cell depletion and IFN receptor blockade. Moreover, disrupting cGAS-STING1 signaling in colorectal cancer cells limited the immunostimulatory and tumor-suppressive effects of serine deprivation. Lastly, serine depletion increased the sensitivity of tumors to an immune checkpoint inhibitor targeting PD-1. Taken together, these findings reveal a role for serine as a suppressor of antitumor immunity, suggesting that serine deprivation may be employed to enhance tumor immunogenicity and improve responsiveness to immune checkpoint inhibitors. Significance: Depriving cancer cells of serine provokes mitochondrial perturbations that induce cytosolic mitochondrial DNA accumulation and subsequent activation of cGAS-STING signaling, stimulating tumor-targeting immune responses that can be enhanced with PD-1 targeted therapy. See related commentary by Borges and Garg, p. 2569.

Effect of silica-sprayed collection tubes on synovial fluid bacterial culture.

INTRODUCTION: Silica-sprayed tubes (SSTs) are often used to transport synovial fluid samples in equine practice. They promote the coagulation of the sample. The objective of the study is to evaluate the effect of SST on bacterial culture. MATERIALS AND METHODS: The study was divided into two parts: sterile saline (Part A) and synovial fluid (Part B). Four common bacteria associated with equine synovial sepsis were used: Streptococcus pyogenes, Escherichia coli, Staphylococcus aureus and methicillin-resistant S. aureus (MRSA). Three collection tubes were used: STT, plain (no-additives) and brain and heart infusion (BHI) broth. Bacteria were cultured in horse blood agar plates for 48 h. Outcome variables were negative culture, positive culture and total number of colony-forming units (CFUs). Statistical analysis was performed using Mann-Whitney U test, and significance was set at p < 0.05. RESULTS: The total number of agar plates read was 1557 (779 saline; 778 synovial fluid). Total negative cultures were 25/779 on saline and 3/778 on synovial fluid. In broth, maximum growth CFU was achieved after 8 h for both saline and synovial fluid for all bacteria. S. pyogenesand E. coli produced a significantly lower number of CFU when in SST compared to plain or broth after 4 h, whereas S. aureus (American Type Culture Collection [ATCC] and MRSA) only after 24 h. DISCUSSION: Silica-containing tubes reduced bacterial proliferation, whereas the use of a BHI broth provided the highest bacterial load in the sample. The use of SST may have a negative effect on bacterial proliferation in samples obtained from clinical cases.

Genomic and Transcriptomic Analysis of a Patient with Early-Onset Colorectal Cancer and Therapy-Induced Focal Nodular Hyperplasia: A Case Report.

Early-onset colorectal cancer (EOCRC), defined as colorectal cancer in individuals under 50 years of age, has shown an alarming increase in incidence worldwide. We report a case of a twenty-four-year-old female with a strong family history of colorectal cancer (CRC) but without an identified underlying genetic predisposition syndrome. Two years after primary surgery and adjuvant chemotherapy, the patient developed new liver lesions. Extensive diagnostic imaging was conducted to investigate suspected liver metastases, ultimately leading to a diagnosis of focal nodular hyperplasia. The young age of the patient has prompted comprehensive genomic and transcriptomic profiling in order to identify potential oncogenic drivers and inform further clinical management of the patient. Besides a number of oncogenic mutations identified in the patient's tumour sample, including KRAS G12D, TP53 R248W and TTN L28470V, we have also identified a homozygous deletion of 24.5 MB on chromosome 8. A multivariate Cox regression analysis of this patient's mutation profile conferred a favourable prognosis when compared with the TCGA COADREAD database. Notably, the identified deletion on chromosome 8 includes the WRN gene, which could contribute to the patient's overall positive response to chemotherapy. The complex clinical presentation, including the need for emergency surgery, early age at diagnosis, strong family history, and unexpected findings on surveillance imaging, necessitated a multidisciplinary approach involving medical, radiation, and surgical oncologists, along with psychological support and reproductive medicine specialists. Molecular profiling of the tumour strongly indicates that patients with complex mutational profile and rare genomic rearrangements require a prolonged surveillance and personalised informed interventions.

Backup Frontal Drainage System for Urgent Tension Pneumocephalus Management After Chronic Subdural Hematoma Surgery: A Retrospective Cohort Study.

OBJECTIVE: To describe a simple variation of burr hole craniostomy for the management of chronic subdural hematoma (CSDH) that uses a frontal drainage system to facilitate timely decompression in the event of tension pneumocephalus and spares the need for additional surgery. METHODS: We conducted a retrospective analysis of 20 patients with CSDH who underwent burr hole craniostomy and 20 patients who underwent the same procedure alongside the placement of a 5 Fr neonatal feeding tube as a backup drainage for the anterior craniostomy. Depending on the situation, the secondary drain stayed for a maximum of 72 hours to be opened and used in emergency settings for drainage, aspiration, or as a 1-way valve with a water seal. RESULTS: The outcomes of 20 patients who underwent this procedure and 20 controls are described. One patient from each group presented tension pneumocephalus. One was promptly resolved by opening the backup drain under a water seal to evacuate pneumocephalus and the other patient had to undergo a reopening of the craniostomy. CONCLUSIONS: The described variation of burr hole craniostomy represents a low-cost and easy-to-implement technique that can be used for emergency decompression of tension pneumocephalus. It also has the potential to reduce reoperation rates and CSDH recurrence. Prospective controlled research is needed to validate this approach further.

Synthesis of Novel Triazine-Based Chalcones and 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines as Potential Leads in the Search of Anticancer, Antibacterial and Antifungal Agents.

This study presents the synthesis of four series of novel hybrid chalcones (20,21)a-g and (23,24)a-g and six series of 1,3,5-triazine-based pyrimido[4,5-b][1,4]diazepines (28-33)a-g and the evaluation of their anticancer, antibacterial, antifungal, and cytotoxic properties. Chalcones 20b,d, 21a,b,d, 23a,d-g, 24a-g and the pyrimido[4,5-b][1,4]diazepines 29e,g, 30g, 31a,b,e-g, 33a,b,e-g exhibited outstanding anticancer activity against a panel of 60 cancer cell lines with GI50 values between 0.01 and 100 µM and LC50 values in the range of 4.09 µM to >100 µM, several of such derivatives showing higher activity than the standard drug 5-fluorouracil (5-FU). On the other hand, among the synthesized compounds, the best antibacterial properties against N. gonorrhoeae, S. aureus (ATCC 43300), and M. tuberculosis were exhibited by the pyrimido[4,5-b][1,4]diazepines (MICs: 0.25-62.5 µg/mL). The antifungal activity studies showed that triazinylamino-chalcone 29e and triazinyloxy-chalcone 31g were the most active compounds against T. rubrum and T. mentagrophytes and A. fumigatus, respectively (MICs = 62.5 µg/mL). Hemolytic activity studies and in silico toxicity analysis demonstrated that most of the compounds are safe.

Esthetic crown lengthening in the treatment of gummy smile associated with altered passive eruption: A case report

Introduction: Excessive gummy smile affects the aesthetics of the patient and can be the result of several factors, including altered passive eruption, which can be surgically corrected by aesthetic crown lengthening. Case report: 22-year-old female patient, who was treated by aesthetic crown lengthening for the correction of type 1B altered passive eruption. Discussion: Considering the patient's age and periodontal phenotype, surgical correction of the gummy smile by aesthetic crown lengthening shows stable long-term results. Conclusion: Surgically correcting excessive gingival exposure through esthetic crown lengthening can help patients improve the appearance of their smile and regain their self-confidence.

[Circulatory support with venovenous ECMO in a patient with reperfusion pulmonary edema after pulmonary artery thromboendarterectomy]. / Soporte circulatorio con ECMO venovenoso en paciente con síndrome de reperfusión pulmonar secundario a tromboendarterectomía arterial pulmonar.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a subtype of pulmonary hypertension characterized by the obstruction of pulmonary arteries secondary to chronic thromboembolism. Pulmonary thromboendarterectomy surgery (PTE) is the main treatment for patients with CTEPH, as it removes the chronic thrombi from the pulmonary arteries. Pulmonary reperfusion syndrome is a common complication of the surgery, which involves the development of pulmonary edema in the area where blood perfusion improves after the surgery. The incidence of this syndrome varies from 8 to 91% depending on the criteria used for diagnosis, and it is one of the most serious complications of pulmonary thromboendarterectomy. In such cases, circulatory support with extracorporeal membrane oxygenation (ECMO) has become a valuable therapeutic modality. We present the case of a 60-year-old woman with a history of acute pulmonary embolism due to deep vein thrombosis of the right pelvic limb who was diagnosed later with CTEPH who was admitted for scheduled surgical treatment involving bilateral PTE. However, during the immediate postoperative period, she developed cardiogenic shock and refractory hypoxemia secondary to pulmonary reperfusion syndrome following the surgical procedure. As a result, she required veno-venous ECMO circulatory support for 6 days, leading to resolution of the pulmonary condition and clinical improvement.

La hipertensión pulmonar tromboembólica crónica (HPTEC) es un subtipo de hipertensión pulmonar caracterizada por la obstrucción de las arterias pulmonares secundaria a tromboembolias crónicas. La cirugía de tromboendarterectomía pulmonar (TEAP) es el tratamiento principal para los pacientes con HPTEC, elimina los trombos crónicos de las arterias pulmonares. El síndrome de reperfusión pulmonar es una complicación común de la cirugía, se trata del desarrollo de edema pulmonar en el área en la que la perfusión sanguínea mejora después de la cirugía. La incidencia del síndrome varía del 8 al 91% según los criterios utilizados para diagnosticarlo y es una de las complicaciones más graves de la tromboendarterectomía pulmonar. En tales casos, el soporte circulatorio con oxigenación por membrana extracorpórea (ECMO) se ha convertido en una valiosa modalidad terapéutica. Presentamos el caso de una paciente de 60 años de edad con antecedente de tromboembolia pulmonar aguda secundaria a trombosis venosa profunda de miembro pélvico derecho a quien durante el seguimiento se realizó el diagnóstico de HPTEC e ingresó de manera programada para tratamiento quirúrgico con realización de TEAP bilateral, sin embargo durante el posquirúrgico inmediato presentó choque cardiogénico e hipoxemia refractaria secundarios a síndrome de reperfusión pulmonar, por lo cual requirió soporte circulatorio con ECMO venovenosa durante seis días, con resolución del cuadro pulmonar y mejoría clínica.

Partial Cranial Reconstruction Using Titanium Mesh after Craniectomy: An Antiadhesive and Protective Barrier with Improved Aesthetic Outcomes.

OBJECTIVE: Describe a new, safe, technique that uses titanium mesh to partially cover skull defects immediately after decompressive craniectomy (DC). METHODS: This study is a retrospective review of 8 patients who underwent DC and placement of a titanium mesh. The mesh partially covered the defect and was placed between the temporalis muscle and the dura graft. The muscle was sutured to the mesh. All patients underwent cranioplasty at a later time. The study recorded and analyzed demographic information, time between surgeries, extra-axial fluid collections, postoperative infections, need for reoperation, cortical hemorrhages, and functional and aesthetic outcomes. RESULTS: After craniectomy, all patients underwent cranioplasty within an average of 112.5 days (30-240 days). One patient reported temporalis muscle atrophy, which was the only complication observed. During the cranioplasties, no adhesions were found between temporalis muscle, titanium mesh, and underlying dura. None of the patients showed complications in the follow-up computerized tomography scans. All patients had favorable aesthetic and functional results. CONCLUSIONS: Placing a titanium mesh as an extra step during DC could have antiadhesive and protective properties, facilitating subsequent cranioplasty by preventing adhesions and providing a clear surgical plane between the temporalis muscle and intracranial tissues. This technique also helps preserve the temporalis muscle and enhances functional and aesthetic outcomes postcranioplasty. Therefore, it represents a safe alternative to other synthetic anti-adhesive materials. Further studies are necessary to draw definitive conclusions and elucidate long-term outcomes, however, the results obtained hold great promise for the safety and efficacy of this technique.

Un acercamiento a las variables y su escala de clasificación, a través de la "edad" como variable de estudio

La operacionalización de las variables constituye una acción investigativa de gran importancia metodológica. En este artículo se repasan, someramente, aspectos teóricos acerca de las variables de estudio, con el propósito de fundamentar la mayor utilidad y conveniencia de declarar, en el proyecto de investigación, el tipo de escala que será empleada para la agrupación de los datos provenientes de las unidades de análisis, en lugar del tipo de variable, como suele hacerse. Esta idea adquiere un evidente sentido práctico cuando se trabaja con variables cuantitativas.

The variables' operationalization constitutes a research action of great methodological importance. This article briefly reviews theoretical aspects about the study variables, to substantiate the greatest usefulness and convenience of declaring, in the research project, the type of scale that will be used to group the data coming from of the units of analysis, instead of the type of variable, as is usually done. This idea takes on an obvious practical meaning when working with quantitative variables.

Síndrome de hipoventilación del obeso. Presentación de un caso

La obesidad se ha convertido en una importante causa de comorbilidades, por lo cual es importante reconocer de forma temprana las enfermedades asociadas a esta afección, así como su tratamiento. El síndrome de hipoventilación del obeso o también llamado síndrome de Pickwick se ha definido por la triada de obesidad, hipoventilación diurna y respiración alterada durante el sueño, en ausencia de otra enfermedad que explique las alteraciones respiratorias. Se presenta el caso de un paciente de 53 años de edad, de color de piel blanca, masculino, de procedencia urbana, con antecedentes patológicos personales de hipertensión arterial, artritis gotosa, obesidad mórbida, angina de pecho inestable, episodios previos de fibrilación auricular y síndrome de Pickwick sin tratamiento para ello. El día 12 de febrero del 2023 fue traído por sus familiares al Hospital Dr. Gustavo Aldereguía Lima de la provincia Cienfuegos, por presentar, desde hacía siete días atrás, dificultad para respirar, fiebre de 39 ºC, y el día anterior había comenzado a expectorar con sangre. Se describen los procedimientos realizados y tratamientos ante cada complicación, hasta su fallecimiento. Por la importancia que tiene el diagnóstico, control y seguimiento a estos pacientes obesos con comorbilidades, para evitar desenlaces fatales, se decidió la presentación del caso.

Obesity has become an important cause of comorbidities, it is important to recognize the diseases associated with this condition early, as well as its treatment. Obese hypoventilation syndrome, also called Pickwick syndrome, has been defined by the triad of obesity, daytime hypoventilation and altered breathing during sleep, in the absence of another disease that explains the respiratory alterations. The case of a 53-years-old patient, white skin color, male, from urban origin, with a personal pathological history of high blood pressure, gouty arthritis, morbid obesity, unstable angina pectoris, previous episodes of atrial fibrillation and Pickwick syndrome without treatment for it, it is presented. On February the 12th, 2023, he was brought by his family to the Dr. Gustavo Aldereguía Lima Hospital in the Cienfuegos province, because he had had difficulty breathing, a fever of 39ºC, for seven days, and the day before he had begun to expectorate blood. The performed procedures and treatments for each complication are described, until his death. Due to the importance of diagnosis, control and follow-up of these obese patients with comorbidities, to avoid fatal outcomes, it was decided to present the case.

Evaluation of the last 2 decades in the characteristics of presentation, management and prognosis of serious spontaneous intracerebral hemorrhage in a third level hospital.

OBJECTIVE: To analyze the change in the characteristics of presentation, evolution and treatment in the ICU, as well as the functional evolution at 12 months of spontaneous intracranial hemorrhages (ICHs) treated in an ICU reference center. PATIENT AND METHODS: Descriptive, retrospective study in a Neurocritical Reference Hospital. All admissions of patients with HICE during three periods are studied: 1999-2001 (I), 2015-2016 (II) and 2020-2021 (III). Evolution in the three periods of demographic variables, baseline characteristics of the patients, clinical variables and characteristics of bleeding, evolutionary data in the ICU are studied. At one year we assessed the GOS scale (Glasgow Outcome Score) according to whether they had a poor (GOS 1-3) or good (GOS 4-5) prognosis. RESULTS: 300 admitted patients, distributed in periods: I: 28.7%, II: 36.3% and III: 35%. 56.7% were males aged 66 (55.5-74) years; ICH score 2 (1-3). The ICU stay was 5 (2-14) days with a mortality of 36.8%. GOS 1-3 a year in 67.3% and GOS 4-5 in 32.7%. Comparing the three periods, we observed a higher prevalence in women, and the presence of cardiovascular factors; no changes in etiology; in relation to the location, it increases cerebellar hemorrhage and in the brainstem. Although the severity was greater, the stay in the ICU, the use of invasive mechanical ventilation and tracheostomy were lower. Open surgery has decreased its use by 50%. Mortality continues to be high, stagnating in the ICU at 35% and entails a high degree of disability one year after assessment. CONCLUSIONS: Severe ICH is a complex pathology that has changed some characteristics in the last two decades, with more severe patients, with more cardiovascular history and a greater predominance of brainstem and cerebellar hemorrhage. Despite the increase in severity, better parameters during the ICU stay, with open surgery used 50% less. Mortality remains stagnant at 35% with high disability per year.

Efectos del reto de líquidos sobre el acople ventrículo arterial en un biomodelo porcino de choque endotóxico / The effect of fluid challenge on ventriculo-arterial coupling in an endotoxic shock swine bio-model

Introducción: el reto de líquidos es una prueba que consiste en administrarlos y medir la respuesta hemodinámica mediante el cambio del gasto cardíaco (GC), aunque solo medir el GC resulta insuficiente. El acople ventrículo-arterial (AVA) (elastancia arterial efectiva/ elastancia telesistólica: Eae/Ets) aparece como una variable que evalúa el estado cardiocirculatorio en forma integral. Objetivo: evaluar el AVA en un biomodelo de choque endotóxico y durante retos de líquidos. Materiales y métodos: biomodelo de choque endotóxico (9 porcinos). Se midieron variables hemodinámicas cada hora desde un tiempo 0 (T0) hasta T6. Se realizaron 5 retos de líquidos entre T0 y T4. El tiempo de hipotensión se denominó TH0. Se calcularon diferencias de medianas de variables entre T0-T4. Se clasificaron los retos en dos grupos según el delta del AVA (AVA posreto-AVA prerreto), en ΔAVA≤0 o >0, se midieron variables antes y después de cada reto. Se determinó la relación lactato/piruvato (L/P) en T0, T3 y T6, se establecieron correlaciones entre la diferencia LP T6-T0 y de variables hemodinámicas. Resultados: el AVA aumentó (1.58 a 2,02, p=0.042) por incremento en la Eae (1.74 a 2,55; p=0.017). El grupo ΔAVA≤0 elevó el GC (4.32 a 5,46, p=0.032) y el poder cardíaco (PC) (0.61 a 0,77, p=0,028). El Δ L/P se correlacionó con el Δ del índice de choque sistólico y diastólico (r=0.73), pero no con el del AVA. Conclusión: durante el choque endotóxico el AVA aumentó de manera significativa. Durante el reto de líquidos el grupo Δ AVA≤0, elevó el GC y PC. El Δ L/P no se correlacionó con variables del AVA.

Introduction: fluid challenges (FCs) consist of measuring hemodynamic response through changes in cardiac output (CO) after fluid administration, although only measuring CO proves insufficient. Ventriculo-arterial coupling (V-A) (effective arterial elastance / tele-systolic elastance: E(a)/Ets) are variables used for a comprehensive cardiac and circulatory status appraisal. Objective: to evaluate V-A in an endotoxic shock bio-model by FCs. Materials and methods: an endotoxic shock bio-model (9 pigs). Hemodynamic variables were measured every hour from time 0 (T0) to T6. Five FCs were performed between T0 and T4. Hypotension time was referred to as HT. The median differences in variables between T0-T4 were calculated. Challenges were classified into two groups according to V-A delta (post-challenge V-A - pre-challenge V-A). In ΔV-A≤0 o>0, variables were measured before and after each FC. The lactate to pyruvate (L/P) ratio was determined at T0, T3 and T6. Correlations between the LP T6-T0 difference and hemodynamic variables, were established. Results: V-A increased (1.58 to 2,02, p=0.042) as Eae increased (1.74 to 2.55; p=0.017). CO (4.32 to 5.46, p=0.032) and cardiac power (CP) (0.61 to 0.77, p=0,028) increased, in the ΔV-AC≤0 group. The ΔLP correlated with the systolic and diastolic shock index (r=0.73), but not with V-A. Conclusion: V-A increased significantly during endotoxic shock. The ΔAVA≤0 group, showed elevated CO and CP during FC. ΔLP did not correlate with any of the V-A variables.

Harnessing p53 to improve immunotherapy for lung cancer treatment.

Immunotherapy, especially immune checkpoint blockade (ICB), has become a critical therapy for lung cancer treatment in recent years. Tumor mutational burden (TMB) is one of the decisive biomarkers for predicting immune checkpoint blockade effect. Writing in Cancer Cell, Zhu and colleagues use autochthonous and syngeneic mouse models to show that p53 mutation and tumor heterogeneity may be responsible for resistance in lung cancer patients. Pole-induced high-TMB shows enhanced immunogenicity in KrasG12D mice, however, loss of p53 in KrasG12D PoleP286/+ mice can lead to an immune suppressive profile of lung tumors which diminishes immune response to ICB. Moreover, high TMB causes high shared mutations which helps promote immune protection and immune memory. Heterogeneity can drive immune escape to tumor cells causing resistance to ICB. Decreased cGAS/STING signaling may explain possible resistance to ICB. Based on the new model found by Zhu and colleagues for lung cancer, combined ICB with STING agonists or p53 inducers may be new therapeutic options to improve the efficacy of ICB for lung cancer patients with high TMB.

Harnessing p53 to Improve Immunotherapy for Lung Cancer Treatment.

Immunotherapy, especially immune checkpoint blockade (ICB), has become a critical therapy for lung cancer treatment in recent years. Tumor mutational burden (TMB) is one of the decisive biomarkers for predicting ICB effect. Writing in Cancer Cell, Zhu and colleagues use autochthonous and syngeneic mouse models to show that p53 mutation and tumor heterogeneity may be responsible for resistance in patients with lung cancer. Pole-induced high TMB shows enhanced immunogenicity in KrasG12D mice, however, loss of p53 in KrasG12D PoleP286/+ mice can lead to an immune suppressive profile of lung tumors, which diminishes immune response to ICB. Moreover, high TMB causes high shared mutations, which helps promote immune protection and immune memory. Heterogeneity can drive immune escape to tumor cells causing resistance to ICB. Decreased cGAS/STING signaling may explain possible resistance to ICB. On the basis of the new model found by Zhu and colleagues for lung cancer, combined ICB with STING agonists or p53 inducers may be new therapeutic options to improve the efficacy of ICB for patients with lung cancer with high TMB.

Contribución de la Facultad de Ciencias Médicas de Cienfuegos a la utilización de la tecnología computacional en la docencia médica superior. Reseña del empleo de simulaciones clínicas en el periodo 1990-2007

El artículo ha tenido como objetivo reseñar, de forma cronológica, los acontecimientos más relevantes relacionados con la utilización de simulaciones computarizadas en el proceso docente, en el contexto particular de la Facultad de Ciencias Médicas de Cienfuegos durante el periodo 1990-2007. Entre los acontecimientos identificados se encuentran los siguientes: la elaboración e introducción de simulaciones en la asignatura Medicina Interna correspondiente al tercer año de la carrera (curso 1990-1991); la introducción de la simulación, con fines evaluativos, en el internado de Medicina Interna (1997-2000); el desarrollo de un nuevo software para la elaboración de simulaciones (2002); y la extensión del uso de simulaciones a los seminarios de actualización terapéutica correspondientes al internado de Pediatría (2007). Se evidenció que la contribución realizada por la institución docente al tema abordado, no solo consistió en la elaboración de ejercicios de simulación y su introducción en la práctica formativa, sino también en la ejecución de acciones dirigidas a la capacitación de profesores, el perfeccionamiento de las herramientas utilizadas (programas, metodologías) y la socialización de las experiencias; todo lo cual se acompañó de una amplia actividad investigativa que mereció reconocimientos a diferentes niveles.

The objective of this article is to review chronologically, the most relevant events related to the use of computerized simulations in the teaching process, in the particular context of the Cienfuegos Medical Sciences Faculty from 1990 to 2007. Among the identified events are: the development and introduction of simulations in the Internal Medicine subject corresponding to the third year of the degree (course 1990-1991); the introduction of simulation, for evaluation purposes, in the Internal Medicine internship (1997-2000); the development of a new software for the elaboration of simulations (2002); and the extension of the use of simulations to therapeutic update seminars corresponding to the Pediatrics internship (2007). It was evidenced that the contribution made by the educational institution to the topic addressed, not only consisted in the preparation of simulation exercises and their introduction in the training practice, but also in the teacher training, the improvement of the tools used (programs, methodologies) and the sharing of experiences; all of which was accompanied by extensive research activity that deserved recognition at different levels.