Widespread alteration of protein autoinhibition in human cancers.

Autoinhibition is a prevalent allosteric regulatory mechanism in signaling proteins. Reduced autoinhibition underlies the tumorigenic effect of some known cancer drivers, but whether autoinhibition is altered generally in cancer remains elusive. Here, we demonstrate that cancer-associated missense mutations, in-frame insertions/deletions, and fusion breakpoints are enriched within inhibitory allosteric switches (IASs) across all cancer types. Selection for IASs that are recurrently mutated in cancers identifies established and unknown cancer drivers. Recurrent missense mutations in IASs of these drivers are associated with distinct, cancer-specific changes in molecular signaling. For the specific case of PPP3CA, the catalytic subunit of calcineurin, we provide insights into the molecular mechanisms of altered autoinhibition by cancer mutations using biomolecular simulations, and demonstrate that such mutations are associated with transcriptome changes consistent with increased calcineurin signaling. Our integrative study shows that autoinhibition-modulating genetic alterations are positively selected for by cancer cells.

TGF-ß induces matrisome pathological alterations and EMT in patient-derived prostate cancer tumoroids.

Extracellular matrix (ECM) tumorigenic alterations resulting in high matrix deposition and stiffening are hallmarks of adenocarcinomas and are collectively defined as desmoplasia. Here, we thoroughly analysed primary prostate cancer tissues obtained from numerous patients undergoing radical prostatectomy to highlight reproducible structural changes in the ECM leading to the loss of the glandular architecture. Starting from patient cells, we established prostate cancer tumoroids (PCTs) and demonstrated they require TGF-ß signalling pathway activity to preserve phenotypical and structural similarities with the tissue of origin. By modulating TGF-ß signalling pathway in PCTs, we unveiled its role in ECM accumulation and remodelling in prostate cancer. We also found that TGF-ß-induced ECM remodelling is responsible for the initiation of prostate cell epithelial-to-mesenchymal transition (EMT) and the acquisition of a migratory, invasive phenotype. Our findings highlight the cooperative role of TGF-ß signalling and ECM desmoplasia in prompting prostate cell EMT and promoting tumour progression and dissemination.

YAP Signaling Regulates the Cellular Uptake and Therapeutic Effect of Nanoparticles.

Interactions between living cells and nanoparticles are extensively studied to enhance the delivery of therapeutics. Nanoparticles size, shape, stiffness, and surface charge are regarded as the main features able to control the fate of cell-nanoparticle interactions. However, the clinical translation of nanotherapies has so far been limited, and there is a need to better understand the biology of cell-nanoparticle interactions. This study investigates the role of cellular mechanosensitive components in cell-nanoparticle interactions. It is demonstrated that the genetic and pharmacologic inhibition of yes-associated protein (YAP), a key component of cancer cell mechanosensing apparatus and Hippo pathway effector, improves nanoparticle internalization in triple-negative breast cancer cells regardless of nanoparticle properties or substrate characteristics. This process occurs through YAP-dependent regulation of endocytic pathways, cell mechanics, and membrane organization. Hence, the study proposes targeting YAP may sensitize triple-negative breast cancer cells to chemotherapy and increase the selectivity of nanotherapy.

Adverse Pregnancy Outcomes Among Women with Human Immunodeficiency Virus Taking Isoniazid Preventive Therapy During the First Trimester.

BACKGROUND: Isoniazid preventive therapy (IPT) is recommended for tuberculosis prevention yet data on the safety of first-trimester pregnancy exposure are limited. METHODS: Planned secondary analysis in a TB prevention trial of adverse pregnancy outcomes among participants assigned to 9-month IPT who became pregnant during (IPT-exposed) or after (unexposed) IPT. Regression models compared binary outcomes of a composite adverse outcome (any non-live birth, excluding induced abortion); preterm delivery <37 weeks; and low birth weight <2500 g) among exposure groups. Models were adjusted for latent TB infection, maternal age, CD4 count, and antiretroviral therapy (ART). RESULTS: In total, 128 participants had a known pregnancy outcome; 39 IPT-exposed and 89 unexposed. At pregnancy outcome, ART use was lower in IPT-exposed (79%) than unexposed women (98%). Overall, 29 pregnancies ended in a composite adverse outcome (25 spontaneous abortions, 2 stillbirths and 2 ectopic pregnancies), 15 preterm deliveries, and 10 infants with low birth weight. IPT was associated with the composite adverse outcome adjusting for covariates at enrollment (adjusted relative risk [aRR] 1.98; 95% confidence interval [CI] 1.15, 3.41), but the effect was attenuated when adjusted for covariates at pregnancy outcome (aRR 1.47; 95% CI .84, 2.55); IPT was not associated with preterm delivery (relative risk [RR] 0.87; 95% CI .32-2.42) or low birth weight (RR 1.01; 95% CI .29, 3.56). CONCLUSIONS: First-trimester IPT exposure was associated with nearly two-fold increased risk of fetal demise, mostly spontaneous abortion, though the association was attenuated when adjusted for covariates proximal to pregnancy outcome including ART use. Further study is needed to inform TB prevention guidelines.

Association of Polymorphisms of the IL-17A and IL-17F Genes with Increased Risk of Hypertension and Obesity in Mexican Patients with COVID-19.

Coronavirus disease 2019 (COVID-19) is caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV2). COVID-19 can cause a cytokine release syndrome in which cytokines, including interleukin 17 (IL-17), are massively secreted in response to a specific stimulus. This can contribute to mortality and severe forms of COVID-19. The study aimed to determine the association of SARS-CoV2 infection with the IL-17A rs2275913 and IL-17F rs763780 variants, as well as with the associated comorbidities in COVID-19-positive Mexican patients. The study included 178 patients positive to COVID-19 and 177 COVID-19 negative subjects. For genotyping, the samples were amplified with a TaqMan® probe. There was no association between the AA genotype and A allele of IL-17A variant or the IL-17F C allele with the presence of COVID-19. In regard to comorbidities, a statistically significant association was found between IL-17A rs2275913 AA genotype and hypertension, as well as with the presence of obesity (P = 0.003, OR 23, 95% CI: 2.97-178.092 and P = 0.025, OR 28, 95% CI: 1.52-178.029, respectively) in patients with COVID-19. In conclusion, rs2275913 IL-17A polymorphism in COVID-19 patients seems to confer a higher susceptibility to the presence of hypertension and obesity, increasing the risk of premature cardiovascular disease in this population. However, more studies should be conducted for a better understanding of their relation.

Evolving the Era of 5D Ultrasound? A Systematic Literature Review on the Applications for Artificial Intelligence Ultrasound Imaging in Obstetrics and Gynecology.

Artificial intelligence (AI) has gained prominence in medical imaging, particularly in obstetrics and gynecology (OB/GYN), where ultrasound (US) is the preferred method. It is considered cost effective and easily accessible but is time consuming and hindered by the need for specialized training. To overcome these limitations, AI models have been proposed for automated plane acquisition, anatomical measurements, and pathology detection. This study aims to overview recent literature on AI applications in OB/GYN US imaging, highlighting their benefits and limitations. For the methodology, a systematic literature search was performed in the PubMed and Cochrane Library databases. Matching abstracts were screened based on the PICOS (Participants, Intervention or Exposure, Comparison, Outcome, Study type) scheme. Articles with full text copies were distributed to the sections of OB/GYN and their research topics. As a result, this review includes 189 articles published from 1994 to 2023. Among these, 148 focus on obstetrics and 41 on gynecology. AI-assisted US applications span fetal biometry, echocardiography, or neurosonography, as well as the identification of adnexal and breast masses, and assessment of the endometrium and pelvic floor. To conclude, the applications for AI-assisted US in OB/GYN are abundant, especially in the subspecialty of obstetrics. However, while most studies focus on common application fields such as fetal biometry, this review outlines emerging and still experimental fields to promote further research.

Risk Factors for Severe Pain and Impairment of Daily Life Activities after Cesarean Section-A Prospective Multi-Center Study of 11,932 Patients.

Cesarean section (CS) is the most widely performed and one of the most painful surgeries. This study investigated postoperative pain after CS using patient-related outcomes (PROs) to identify risk factors for severe pain. The secondary outcome was to evaluate the influence of surgery indication (primary CS (PCS) vs. urgent CS (UCS)). This multi-center, prospective cohort study included data submitted to the pain registry "quality improvement in postoperative pain treatment" (QUIPS) between 2010 and 2020. In total, 11,932 patients were evaluated. Median of maximal pain was 7.0 (numeric rating scale (NRS) 0 to 10); 53.9% suffered from severe pain (NRS ≥ 7), this being related to impairment of mood, ambulation, deep breathing and sleep, as well as more vertigo, nausea and tiredness (p < 0.001). Distraction, relaxation, mobilization, having conversations, patient-controlled analgesia (PCA) and pain monitoring were shown to be protective for severe pain (p < 0.001). Maximal pain in PCS and UCS was similar, but UCS obtained more analgesics (p < 0.001), and experienced more impairment of ambulation (p < 0.001) and deep breathing (p < 0.05). Severe pain has a major effect on daily-life activities and recovery after CS, and depends on modifiable factors. More effort is needed to improve the quality of care after CS.

Dual-Mode Conical Horn Antenna with 2-D Azimuthal Monopulse Pattern for Millimeter-Wave Applications.

In this paper, a novel concept of a three-dimensional full metal system including a Dual-Mode Converter (DMC) network integrated with a high-gain Conical Horn Antenna (CHA) is presented. This system is designed for 5G millimeter wave applications requiring monopulse operation at K-band (37.5-39 GHz). The DMC integrates two mode converters. They excite either the TE11cir or the TE01cir modes of the circular waveguide of the CHA. The input of the mode converters is the TE10rec mode of two independent WR-28 standard rectangular waveguide ports. By integrating the DMC with the CHA, the whole system, called a Dual-Mode Conical Horn Antenna (DM-CHA), is formed, radiating the sum (Σ) and difference (Δ) patterns associated to the monopulse operation. To adequately prevent the propagation of higher order modes and mode mutual coupling, this integration procedure is carefully designed and fabricated. To prove the performance of the design, the DMC network was fabricated using subtractive manufacturing by Computer Numerical Control (CNC) technology. The CHA was fabricated using additive manufacturing by Direct Metal Laser Sintering (DLMS) technology. Finally, the simulation and measurement results were exhaustively compared, including return loss, isolation, radiation pattern, and gain of the full DM-CHA structure. It is noteworthy that this system provided up to ±11° per beam in the angular of arrival detection to support the high data rate operation for 5G satellite communications in the millimeter-wave band.

Molecular Bases of Protein Antigenicity and Determinants of Immunogenicity, Anergy, and Mitogenicity.

BACKGROUND: The immune system is able to recognize substances that originate from inside or outside the body and are potentially harmful. Foreign substances that bind to immune system components exhibit antigenicity and are defined as antigens. The antigens exhibiting immunogenicity can induce innate or adaptive immune responses and give rise to humoral or cell-mediated immunity. The antigens exhibiting mitogenicity can cross-link cell membrane receptors on B and T lymphocytes leading to cell proliferation. All antigens vary greatly in physicochemical features such as biochemical nature, structural complexity, molecular size, foreignness, solubility, and so on. OBJECTIVE: Thus, this review aims to describe the molecular bases of protein-antigenicity and those molecular bases that lead to an immune response, lymphocyte proliferation, or unresponsiveness. CONCLUSION: The epitopes of an antigen are located in surface areas; they are about 880-3,300 Da in size. They are protein, carbohydrate, or lipid in nature. Soluble antigens are smaller than 1 nm and are endocytosed less efficiently than particulate antigens. The more the structural complexity of an antigen increases, the more the antigenicity increases due to the number and variety of epitopes. The smallest immunogens are about 4,000-10,000 Da in size. The more phylogenetically distant immunogens are from the immunogen-recipient, the more immunogenicity increases. Antigens that are immunogens can trigger an innate or adaptive immune response. The innate response is induced by antigens that are pathogen-associated molecular patterns. Exogenous antigens, T Dependent or T Independent, induce humoral immunogenicity. TD protein-antigens require two epitopes, one sequential and one conformational to induce antibodies, whereas, TI non-protein-antigens require only one conformational epitope to induce low-affinity antibodies. Endogenous protein antigens require only one sequential epitope to induce cell-mediated immunogenicity.

Beam Steering 3D Printed Dielectric Lens Antennas for Millimeter-Wave and 5G Applications.

Two types of cost-efficient antennas based on dielectric gradient index dielectric lens have been designed for 5G applications at 28 GHz. The first is a linearly polarized flat lens antenna (LP-FLA) for terrestrial 5G communications. The second is a novel circularly polarized stepped lens antenna (CP-SLA) for 5G satellite services. An efficient design method is presented to optimize and conform the lens topology to the radiation pattern coming from the antenna feeder. The LP-FLA is fed by a traditional linearly polarized pyramidal horn antenna (PHA). The CP-SLA is fed by an open-ended bow-tie waveguide cavity (BCA) antenna. This cavity feeder (BCA), using cross-sections with bow-tie shapes, allows having circular polarization at the desired frequency bandwidth. The two types of presented antennas have been manufactured in order to verify their performance by an easy, low-cost, three-dimensional (3D) printing technique based on stereolithography. The peak realized gain value for the flat (LP-FLA) and stepped (CP-SLA) lens antennas have been increased at 28 GHz to 25.2 and 24.8 dBi, respectively, by disposing the lens structures at the appropriated distance from the feeders. Likewise, using an array of horns (PHA) or open-ended bow-tie waveguide cavity (BCA) antenna feeders, it is possible to obtain a maximum steering angle range of 20° and 35°, for a directivity over 15 dBi and 10 dBi, in the planar and stepped lens antennas, respectively.

Hepatic steatosis and nonalcoholic fatty liver disease are common and associated with cardiometabolic risk in a primary prevention cohort of people with HIV.

BACKGROUND: Hepatic steatosis, including nonalcoholic fatty liver disease (NAFLD), is common among people with HIV (PWH). We present baseline steatosis prevalence and cardiometabolic characteristics among REPRIEVE substudy participants. METHODS: REPRIEVE is an international, primary cardiovascular disease prevention, randomized, controlled trial of pitavastatin calcium vs. placebo among 7769 PWH ages 40-75 years on antiretroviral therapy (ART) and with low-to-moderate cardiovascular risk. A subset of participants underwent noncontrast computed tomography, with hepatic steatosis defined as mean hepatic attenuation less than 40 HU or liver/spleen ratio less than 1.0, and NAFLD defined as steatosis in the absence of frequent alcohol use or viral hepatitis. RESULTS: Of 687 evaluable persons, median age was 51 years, BMI 27 kg/m 2 , CD4 + T-cell count 607 cells/µl; 17% natal female sex, 36% Black, 24% Hispanic, and 98% HIV-1 RNA less than 400 copies/ml. Hepatic steatosis prevalence was 22% (149/687), and NAFLD 21% (96/466). Steatosis/NAFLD prevalence was higher in men and with older age, non-Black race, and higher BMI and waist circumference. Both were associated with BMI greater than 30 kg/m 2 , metabolic syndrome components, higher atherosclerotic cardiovascular disease (ASCVD) risk score, HOMA-IR, LpPLA-2 and hs-CRP, and lower high-density lipoprotein cholesterol. Of HIV-specific/ART-specific characteristics, only history of an AIDS-defining illness was more common among persons with steatosis/NAFLD. After adjusting for age, sex and race/ethnicity, BMI greater than 30 kg/m 2 , HOMA-IR greater than 2.0, Metabolic syndrome and each of its components were associated with NAFLD prevalence. CONCLUSION: In this cohort with controlled HIV and low-to-moderate cardiovascular risk, hepatic steatosis and NAFLD were common and associated with clinically relevant metabolic and inflammatory disturbances but not current HIV-related or ART-related factors.

Pitavastatin to Prevent Cardiovascular Disease in HIV Infection.

BACKGROUND: The risk of cardiovascular disease is increased among persons with human immunodeficiency virus (HIV) infection, so data regarding primary prevention strategies in this population are needed. METHODS: In this phase 3 trial, we randomly assigned 7769 participants with HIV infection with a low-to-moderate risk of cardiovascular disease who were receiving antiretroviral therapy to receive daily pitavastatin calcium (at a dose of 4 mg) or placebo. The primary outcome was the occurrence of a major adverse cardiovascular event, which was defined as a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral arterial ischemia, revascularization, or death from an undetermined cause. RESULTS: The median age of the participants was 50 years (interquartile range, 45 to 55); the median CD4 count was 621 cells per cubic millimeter (interquartile range, 448 to 827), and the HIV RNA value was below quantification in 5250 of 5997 participants (87.5%) with available data. The trial was stopped early for efficacy after a median follow-up of 5.1 years (interquartile range, 4.3 to 5.9). The incidence of a major adverse cardiovascular event was 4.81 per 1000 person-years in the pitavastatin group and 7.32 per 1000 person-years in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.48 to 0.90; P = 0.002). Muscle-related symptoms occurred in 91 participants (2.3%) in the pitavastatin group and in 53 (1.4%) in the placebo group; diabetes mellitus occurred in 206 participants (5.3%) and in 155 (4.0%), respectively. CONCLUSIONS: Participants with HIV infection who received pitavastatin had a lower risk of a major adverse cardiovascular event than those who received placebo over a median follow-up of 5.1 years. (Funded by the National Institutes of Health and others; REPRIEVE ClinicalTrials.gov number, NCT02344290.).

Formación de los estudiantes de Medicina Integral Comunitaria durante el enfrentamiento a la COVID-19

Se realizó un estudio observacional, descriptivo y transversal en colaboración entre profesionales cubanos y venezolanos involucrados en la dirección del proceso de formación de la carrera Medicina Integral Comunitaria en la Universidad de Ciencias de la Salud Hugo Rafael Chávez, con el propósito de valorar el impacto de la actividad comunitaria en la formación de los estudiantes de Medicina Integral Comunitaria en el enfrentamiento a la COVID-19 en el Estado Falcón, en el período de febrero a septiembre de 2020. El universo lo representa 508 estudiantes de la carrera y la muestra estuvo conformada por 244 que se incorporaron en las actividades comunitaria en el enfrentamiento a la COVID-19. Se utilizó la observación participativa e informes diarios de actividad de pesquisa, la revisión documental, encuesta y técnicas de estadística descriptiva. Se emplearon medidas resúmenes como media, porcentaje que permitieron la búsqueda y procesamiento de la información. Los principales resultados fueron la transformación del personal pedagógico en los diferentes niveles de dirección y la organización del sistema de influencia en los estudiantes, la introducción de un nuevo estilo de trabajo en función de elevar la calidad del proceso docente educativo a partir de la educación a distancia, la integración de los estudiantes a las actividades comunitarias en la contingencia y su impacto en la formación integral de los futuros profesionales de la salud, así como la solución de los problemas de salud de las comunidades del territorio.

An observational, descriptive and cross-sectional study was carried out in collaboration between Cuban and Venezuelan professionals involved in the direction of the training process of the Comprehensive Community Medicine career at the Hugo Rafael Chávez University of Health Sciences, with the purpose of assessing the impact of the community activity in the comprehensive training of Comprehensive Community Medicine students in the confrontation with COVID-19 in Falcón State, from February to September 2020. The universe is represented by 508 students from the Comprehensive Community Medicine career and The sample consisted of 244 students who joined community activities in the fight against COVID-19. Participatory observation and daily reports of research activity, documentary review, survey and descriptive statistical techniques were used using summary measures such as average, percentage, which allowed the search remains and information processing, the main results obtained were the transformation of the pedagogical personnel at the different levels of management and the organization of the system of influence on the students, the introduction of a new style of work in order to raise the quality of the process educational teacher from distance education, the integration of students into community activities in the contingency and its impact on the comprehensive training of future health professionals and the solution of health problems in the communities of the territory.

Graphene-based 3D-Printed nanocomposite bioelectronics for monitoring breast cancer cell adhesion.

This work examines the suitability of graphene-based 3D-printed nanocomposite bioelectronics as innovative systems to in situ monitor and evaluate both breast cancer cell adhesion and the chemosensitivity of anti-cancer drugs. With this aim, 3D-printed nanocomposite graphene electrodes (3D-nGEs) -made of a commercially available graphene/polylactic acid filament- have been covalently biofunctionalized with an extracellular matrix protein (i.e., fibronectin) by exploiting the carbon reactivity of 3D-nGEs. The specificity and selectivity of the developed electrochemical system to monitor breast cancer cell adhesion has been tested via electrochemical impedance spectroscopy (EIS). Importantly, the resulting 3D-printed bioelectronic system displayed excellent accuracy for the rapid screening of anti-cancer drugs, which exactly corresponded with the results achieved by the standard optical method, while having the advantage of employing a label-free approach. In light of the current state-of-the-art in the field, this proof-of-concept connects electronics to biological systems within 3D printing technology, providing the bases for the sustainable and cost-effective manufacturing of graphene-based 3D-printed nanocomposite bioelectronics to simulate in vivo microenvironments using in situ and real time electronic output signals.

Following Evidence-Based Recommendations for Perioperative Pain Management after Cesarean Section Is Associated with Better Pain-Related Outcomes: Analysis of Registry Data.

Women who have had a Cesarean Section (CS) frequently report severe pain and pain-related interference. One reason for insufficient pain treatment might be inconsistent implementation of evidence-based guidelines. We assessed the association between implementing three elements of care recommended by guidelines for postoperative pain management and pain-related patient-reported outcomes (PROs) in women after CS. The analysis relied on an anonymized dataset of women undergoing CS, retrieved from PAIN OUT. PAIN OUT, an international perioperative pain registry, provides clinicians with treatment assessment methodology and tools for patients to assess multi-dimensional pain-related PROs on the first postoperative day. We examined whether the care included [i] regional anesthesia with a neuraxial opioid OR general anesthesia with wound infiltration or a Transvesus Abdominis Plane block; [ii] at least one non-opioid analgesic at the full daily dose; and [iii] pain assessment and recording. Credit for care was given only if all three elements were administered (= "full"); otherwise, it was "incomplete". A "Pain Composite Score-total" (PCStotal), evaluating outcomes of pain intensity, pain-related interference with function, and side-effects, was the primary endpoint in the total cohort (women receiving GA and/or RA) or a sub-group of women with RA only. Data from 5182 women was analyzed. "Full" care was administered to 20% of women in the total cohort and to 21% in the RA sub-group. In both groups, the PCStotal was significantly lower compared to "incomplete" care (p < 0.001); this was a small-to-moderate effect size. Administering all three elements of care was associated with better pain-related outcomes after CS. These should be straightforward and inexpensive for integration into routine care after CS. However, even in this group, a high proportion of women reported poor outcomes, indicating that additional work needs to be carried out to close the evidence-practice gap so that women who have undergone CS can be comfortable when caring for themselves and their newborn.

The importance of methods for site performance evaluation in REPRIEVE, a longitudinal, global, multicenter trial.

BACKGROUND: REPRIEVE, the Randomized Trial to Prevent Vascular Events in HIV, is a multicenter, primary prevention trial evaluating whether a statin can prevent major cardiovascular events in people with HIV. REPRIEVE is conducted at >100 clinical research sites (CRSs) globally. Detailed, comprehensive, and novel methods for evaluating and communicating CRS performance are required to ensure trial integrity and data quality. In this analysis we describe a comprehensive multidimensional methodology for evaluating CRS performance. METHODS: The REPRIEVE Data Coordinating and Clinical Coordinating Centers developed a robust system for evaluation of and communication with CRSs, designed to identify potential issues and obstacles to performance, provide real-time technical support, and make recommendations for process improvements to facilitate efficient trial execution. We describe these systems and evaluate their impact on participant retention, data management, and specimen management from 2019 to 2022, corresponding to the period from end of recruitment to present. This evaluation was based on pre-defined metrics, regular reviews, and bidirectional communication. RESULTS: Participant retention, data management, and specimen management all remained steady over the three-year period, although metrics varied by country of enrollment. Targeted messaging relating to certain performance metrics was effective. CONCLUSION: Site performance is vital to ensure trial integrity and achievement of key trial goals. This analysis demonstrates that utilization of a comprehensive approach allows for a thorough evaluation of CRS performance, facilitates data and specimen management, and enhances participant retention. Our approach may serve as a guidepost for maximizing future large-scale clinical trials' operational success and scientific rigor. CLINICALTRIALS: gov Identifier: NCT02344290.

Intrauterine transfusion in 103 fetuses with severe anemia caused by parvovirus infection. A multicenter retrospective study.

PURPOSE: Evaluating procedure-related complications and perinatal outcomes after intrauterine transfusion (IUT) before or after 20+0 weeks of gestation in fetuses with severe anemia due to intrauterine human parvovirus B19 infection. METHODS: A retrospective study investigating fetuses requiring IUT for fetal Parvo B19 infection in two tertiary referral centers between December 2002 and December 2021. Procedure-related complications, intrauterine fetal death (IUFD), and perinatal outcome were correlated to gestational age (GA) at first IUT, the presence of hydrops and fetal blood sampling results. RESULTS: A total of 186 IUTs were performed in 103 fetuses. The median GA at first IUT was 19+3 (13+0-31+4) weeks of gestation. IUFD occurred in 16/103 fetuses (15.5%). Overall survival was 84.5% (87/103). Hydrops (p = 0.001), lower mean hemoglobin at first IUT (p = 0.001) and low platelets (p = 0.002) were strongly associated with IUFD. There was no difference observed in fetuses transfused before or after 20+0 weeks of gestation. CONCLUSION: IUT is a successful treatment option in fetuses affected by severe anemia due to parvovirus B19 infection in specialized centers. In experienced hands, IUT before 20 weeks is not related to worse perinatal outcome.

NUSAP1 and PCLAF (KIA0101) Downregulation by Neoadjuvant Therapy is Associated with Better Therapeutic Outcomes and Survival in Breast Cancer.

Purpose: To evaluate whether changes in genomic expression that occur beginning with breast cancer (BC) diagnosis and through to tumor resection after neoadjuvant chemotherapy (NCT) reveal biomarkers that can help predict therapeutic response and survival. Materials and Methods: We determined gene expression profiles based on microarrays in tumor samples from 39 BC patients who showed pathologic complete response (pCR) or therapeutic failure (non-pCR) after NCT (cyclophosphamide-doxorubicin/epirubicin). Based on unsupervised clustering of gene expression, together with functional enrichment analyses of differentially expressed genes, we selected NUSAP1, PCLAF, MME, and DST. We evaluated the NCT response and the expression of these four genes in BC histologic subtypes. In addition, we study the presence of tumor-infiltrating lymphocytes. Finally, we analyze the correlation between NUSAP1 and PCLAF against disease-free survival (DFS) and overall survival (OS). Results: A signature of 43 differentially expressed genes discriminated pCR from non-pCR patients (|fold change >2|, false discovery rate <0.05) only in biopsies taken after surgery. Patients achieving pCR showed downregulation of NUSAP1 and PCLAF in tumor tissues and increased DFS and OS, while overexpression of these genes correlated with poor therapeutic response and OS. These genes are involved in the regulation of mitotic division. Conclusions: The downregulation of NUSAP1 and PCLAF after NCT is associated with the tumor response to chemotherapy and patient survival.

El papel del cirujano moderno como líder de los equipos de atención sanitaria: una revisión narrativa sobre una facultad ubicua, pero poco definida.

OBJECTIVE: The objective is to describe the role of leadership in the training of the general surgeon and to point out its relevance. METHOD: A search of the medical literature was carried out to identify studies that reported on topics related to leadership in the context of medical education and surgery. We used the search engine of Medline/PubMed databases including related terms such as "leadership" AND "medicine" OR "surgery". RESULTS: Leadership is a valued characteristic in surgery, it implies professionalism, technical competence, motivation, innovation, teamwork, communication skills, decision making, emotional competence, resilience, and effective teaching. Leadership is measurable and can be developed through experience, observation, and education. CONCLUSIONS: Priority must be given to actions that improve leader traits. This has been shown to create a work environment where efficient work is performed, and failures are minimized. The current vision of the leader must be expanded to reduce the gender gap between the positions as leader occupy in this moment.

OBJETIVO: Describir el papel de liderazgo en la formación del cirujano general y puntualizar su relevancia en nuestro entorno. MÉTODO: Se realizó una búsqueda en la literatura médica para identificar estudios que informaran sobre temas relacionados al liderazgo en el contexto de la enseñanza médica y en cirugía. Se utilizó el motor de búsqueda de las bases de datos Medline/PubMed incluyendo términos relacionados como "leadership" AND "medicine" OR "surgery". RESULTADOS: El liderazgo es una característica valorada en cirugía, que implica profesionalismo, competencia técnica, motivación, innovación, trabajo en equipo, habilidades comunicativas, toma de decisiones, competencia emocional, resiliencia y enseñanza eficaz. Es medible y susceptible de desarrollarse a través de la experiencia, la observación y la educación. CONCLUSIONES: En la formación del cirujano general se deben priorizar las acciones que mejoren los rasgos de líder. Se ha demostrado que esto genera un ambiente de trabajo donde se realiza una labor eficiente y se minimizan las fallas. Se debe expandir la visión actual que se tiene de líder y permitir que se disminuya la brecha de género entre los puestos que hoy se ocupan.

Reporte de caso: vólvulo de sigmoides en un adulto joven, una manifestación de enfermedad de Hirschsprung.

BACKGROUND: Hirschsprung's disease is characterized by the absence of enteric ganglia in the distal digestive tract; being usually diagnosed in neonates, it rarely debuts during adulthood, where it presents as chronic constipation refractory to treatment. CASE REPORT: 24-year-old female patient with Hirschsprung's disease who arrives to the emergency room with a sigmoid volvulus requiring urgent surgical therapy. CONCLUSIONS: Hirschsprung's disease doesn't frequently debut in adulthood, presenting a diagnostic and therapeutic challenge for the general surgeon, especially when dealing with its complications.

ANTECEDENTES: La enfermedad de Hirschsprung se caracteriza por un defecto de las células nerviosas en el intestino distal. Suele diagnosticarse durante los primeros años de vida, rara vez debutando en adultos, en quienes se manifiesta como una constipación crónica refractaria al tratamiento. CASO CLÍNICO: Mujer de 24 años con enfermedad de Hirschsprung no diagnosticada, quien acude a urgencias por un cuadro de vólvulo de sigmoides que requiere intervención quirúrgica. CONCLUSIONES: La enfermedad de Hirschsprung rara vez debuta en la edad adulta y generalmente se diagnostica secundaria a sus complicaciones, por lo que supone un reto diagnóstico y terapéutico para el cirujano general.