HER2/neu 655 polymorphism, trastuzumab-induced cardiotoxicity, and survival in HER2-positive breast cancer patients.

PURPOSE: HER2 overexpression in breast cancer correlates with poor outcomes. The incorporation of Trastuzumab into the treatment regimen has notably improved patient prognoses. However, cardiotoxicity emerges in approximately 20% of patients treated with the drug. This study aims to investigate the association between the HER2 655 A > G polymorphism, Trastuzumab-induced cardiotoxicity, and patient survival. METHODS: The study involved 88 patients treated with Trastuzumab. Cardiotoxicity, defined as a reduction in left ventricular ejection fraction (LVEF) from baseline or the emergence of clinical signs of congestive heart failure, was identified during treatment follow-up. Genotyping of HER2 655 A > G employed TaqMan SNP technology. RESULTS: Genotype frequencies of HER2/neu 655 (53 AA, 32 AG, and 3 GG) were consistent with Hardy-Weinberg equilibrium. No significant differences were observed in mean baseline LVEF between patients who developed cardiotoxicity and those who did not. Within these groups, neither AA nor AG genotypes showed an association with changes in mean baseline or reduced LVEF levels. Logistic regression analysis, adjusted for hormonal status and anthracycline treatment, revealed that AG genotype carriers face a significantly higher risk of cardiotoxicity compared to AA carriers (OR = 4.42; p = 0.037). No association was found between the HER2/neu 655 A > G polymorphism and disease-free or overall survival, regardless of whether the data was adjusted for stage or not. CONCLUSION: HER2 655 A > G polymorphism is significantly linked to an increased risk of Trastuzumab-induced cardiotoxicity but does not correlate with variations in disease-free survival or overall survival rates.

Discovery of a synthetic taiwaniaquinoid with potent in vitro and in vivo antitumor activity against breast cancer cells.

Taiwaniaquinoids are a unique family of diterpenoids predominantly isolated from Taiwania cryptomerioides Hayata. Previously, we evaluated the antiproliferative effect of several synthetic taiwaniaquinoids against human lung (A-549), colon (T-84), and breast (MCF-7) tumor cell lines. Herein, we report the in vitro and in vivo antitumor activity of the most potent compounds. Their cytotoxic activity against healthy peripheral blood mononuclear cells (PBMCs) has also been examined. We underscore the limited toxicity of compound C36 in PBMCs and demonstrate that it exerts its antitumor effect in MCF-7 cells (IC50 = 1.8 µM) by triggering an increase in reactive oxygen species, increasing the cell population in the sub-G1 phase of the cell cycle (90 %), and ultimately activating apoptotic (49.6 %) rather than autophagic processes. Western blot results suggested that the underlying mechanism of the C36 apoptotic effects was linked to caspase 9 activation and a rise in the Bax/Bcl-2 ratio. In vivo analyses showed normal behavior and hematological parameters in C57BL/6 mice post C36 treatment. Moreover, no significant impact was observed on the biochemical parameters of these animals, indicating that C36 did not induce liver toxicity. Furthermore, C36 demonstrated a significant reduction in tumor growth in immune-competent C57BL/6 mice implanted with E0771 mouse mammary tumor cells, effectively improving survival rates. These findings position taiwaniaquinoids, particularly compound C36, as promising therapeutic candidates for human breast cancer.

Dynamic Output Feedback and Neural Network Control of a Non-Holonomic Mobile Robot.

This paper presents the design and synthesis of a dynamic output feedback neural network controller for a non-holonomic mobile robot. First, the dynamic model of a non-holonomic mobile robot is presented, in which these constraints are considered for the mathematical derivation of a feasible representation of this kind of robot. Then, two control strategies are provided based on kinematic control for this kind of robot. The first control strategy is based on driftless control; this means that considering that the velocity vector of the mobile robot is orthogonal to its restriction, a dynamic output feedback and neural network controller is designed so that the control action would be zero only when the velocity of the mobile robot is zero. The Lyapunov stability theorem is implemented in order to find a suitable control law. Then, another control strategy is designed for trajectory-tracking purposes, in which similar to the driftless controller, a kinematic control scheme is provided that is suitable to implement in more sophisticated hardware. In both control strategies, a dynamic control law is provided along with a feedforward neural network controller, so in this way, by the Lyapunov theory, the stability and convergence to the origin of the mobile robot position coordinates are ensured. Finally, two numerical experiments are presented in order to validate the theoretical results synthesized in this research study. Discussions and conclusions are provided in order to analyze the results found in this research study.

Influence of donor capnometry on renal graft evolution in uncontrolled donation after circulatory death.

AIM: To analyse the association between donor capnometry data and the short-term evolution of kidney grafts in cases of uncontrolled donation after circulatory death (uDCD). METHOD: We used an ambispective observational study design, conducted in the Community of Madrid between January and December 2019, inclusive. Patients who suffered out-of-hospital cardiac arrest (CA) with no response to advanced cardiopulmonary resuscitation (CPR) were selected as potential donors. Donor capnometry levels were measured at the start, midpoint and transfer to hospital then compared with indicators of renal graft evolution. RESULTS: The initial selection included 34 possible donors, of which 12 (35.2%) were viable donors from whom 22 (32.3%) kidneys were recovered. There was a correlation between the highest capnometry values and less need for post-transplant dialysis (≥24 mmHg, p < 0.017), fewer dialysis sessions and fewer days to recover correct renal function (Rho -0.47, p < 0.044). There was a significant inverse correlation between the capnometry values at transfer and 1-month post-transplant creatinine levels (Rho -0.62, p < 0.033). There were no significant differences between the capnometry values at transfer and primary nonfunction (PNF) or warm ischaemia time. One-year patient survival was 100% for patient receiving organ donation, while graft survival was 95%. CONCLUSIONS: Capnometry levels at transfer are a useful predictor of the short-term function and viability of kidney transplants from uncontrolled donations after circulatory death.

A Multifaceted Educational Intervention in the Doctor-Patient Relationship for Medical Students to Incorporate Patient Agendas in Simulated Encounters.

From the beginning of their clinical training, medical students demonstrate difficulties when incorporating patient perspectives. This study aimed to assess if students, after an instructional programme, increased their sensitivity towards patients' needs and carried out bidirectional conversations. An observational study involving 109 medical students prior to their clerkships was designed. They attended a five-step training programme designed to encourage the use of communication skills (CSs) to obtain patients' perspectives. The course developed experiential and reflective educational strategies. The students improved their use of CSs throughout three sessions, and the overall score for these patient consultations went up in the opinions of both the external observer (EO) (5; 6.6; 7.5) and the simulated patients SPs (5.3; 6.6; 7.8). Most of the students (83.9%) considered that the CSs addressed were useful for clinical practice, particularly the interviews and the feedback received by the SP and the lecturer. The programme seems to help the students use CSs that facilitate a more bidirectional conversation in a simulated learning environment. It is feasible to integrate these skills into a broader training programme. More research is needed to assess whether the results are applicable to students in real settings and whether they influence additional outcomes.

A Paradoxical Clinical Coincidence: Benign Paroxysmal Positional Vertigo and Bilateral Vestibulopathy.

Benign paroxysmal positional vertigo (BPPV) and bilateral vestibulopathy (BVL) are two completely different forms of vestibular disorder that occasionally occur in the same patient. We conducted a retrospective review searching for that coincidence in our database of the patients seen over a 15-year period and found this disorder in 23 patients, that is 0.4%. More frequently they occurred sequentially (10/23) and BPPV was diagnosed first. Simultaneous presentation occurred in 9/23 patients. It was subsequently studied, but in a prospective manner, in patients with BPPV on all of whom a video head impulse test was performed to search for bilateral vestibular loss; we found it was slightly more frequent (6/405). Both disorders were treated accordingly, and it was found that the results follow the general trend in patients with only one of those disorders.

Early increase in tamoxifen dose in CYP2D6 poor metaboliser breast cancer patients and survival: A propensity score matching analysis.

PURPOSE: Tamoxifen is a drug used for hormone receptor-positive breast cancers, primarily metabolised by the CYP2D6 enzyme into active metabolites such as endoxifen. CYP2D6 displays varying degrees of activity depending on its genotype. This study aims to analyse the effect of an early increase in tamoxifen dose in poor metabolisers (PM) on survival. METHODS: We enrolled 220 patients diagnosed with breast cancer who were treated with tamoxifen. CYP2D6 polymorphisms were determined, and the phenotype was estimated according to the Clinical Pharmacogenetics Implementation Consortium. Disease-free survival (DFS) and overall survival (OS) were analysed considering the entire patient group, and a subgroup of 110 patients selected by Propensity Score Matching (PSM). All women were treated with 20 mg/day of tamoxifen for 5 years, except PM, who initially received 20 mg/day for 4 months, followed by 40 mg/day for 4 months and 60 mg/day for 4 months before returning to the standard dose of 20 mg/day until completing 5 years of treatment. RESULTS: The analysis of the influence of CYP2D6 polymorphisms in the complete group and in the PSM subgroup revealed no significant differences for DFS or OS. Furthermore, DFS and OS were analysed in relation to various covariates such as age, histological grade, nodal status, tumour size, HER-2, Ki-67, chemotherapy, and radiotherapy. Only age, histological grade, nodal status, and chemotherapy treatment demonstrated statistical significance. CONCLUSION: An early increase in tamoxifen dose in PM patients is not associated with survival differences among CYP2D6 phenotypes.

Influence of Basic Life Support on Donor Organs in Uncontrolled Donors After Cardiac Death.

BACKGROUND: The aim of this study was to determine whether the application of basic life support (BLS) in patients who have experienced cardiac arrest and are subsequently referred to as uncontrolled asystole donors has any influence on the achievement of organs for subsequent transplantation. METHODS: Demographic data, BLS, cause of death, emergency response times, and organ donations were collected. The analysis of quantitative variables following normal distribution is shown as mean (SD), and Student t distribution was used for comparison purposes. The analysis of variables that did not follow the normal distribution is shown as median (IQR), and Wilcoxon test was applied for comparison purposes. RESULTS: A total of 91 cases of possible uncontrolled donor transfers were analyzed. Basic life support was provided to 61 patients (67.7%), whereas no BLS was provided to 27 patients (23.3%). Of the group that received BLS, 39 (73.6%) were effective donors compared with the non-BLS group, in which 22 (62.9%) were effective donors (P = .28). CONCLUSIONS: We did not find an association between performing BLS compared with non-BLS and organ donation.

Endovascular Technique for Ascending Aorta Repair Based on TEVAR and TAVI Procedures.

PURPOSE: Ascending aorta (AAo) acute pathology still has an open-surgery indication with a high mortality rate associated to cardiopulmonary bypass and circulatory arrest. In these cases, the endovascular aortic approach could be an excellent option. The aim of the present study is to detail an optimized technique for the endovascular treatment of AAo diseases, based on thoracic endovascular aortic repair (TEVAR) and transcatheter aortic valve implantation (TAVI) procedures. TECHNIQUE: The procedure implies the usual preparation for TEVAR and TAVI implants. A transient pacemaker lead is necessary to deliver the prosthesis under "rapid pacing." As in the TAVI technique, a final high-support guidewire is placed at the left ventricle. The proximal landing zone is the sinotubular junction (zone 0B). Transesophageal echocardiography is essential to ensure aortic valve function and patency in coronary arteries during the delivery. To assess a potential occlusion of the brachiocephalic artery, a guidewire is positioned in the descending aorta from the axillary artery. Finally, a noncovered stent is implanted to stabilize the AAo prosthesis. CONCLUSION: The technique presented here can standardize a safe and reproducible procedure to endovascular repair of AAo diseases. However, new devices specifically designed for the AAo could facilitate the transcatheter approach. CLINICAL IMPACT: Ascending aorta acute pathology still has an open-surgery indication with high mortality rate associated to cardiopulmonary bypass and circulatory arrest. Moreover, near 30% of patients are not considered suitable for surgery because of age, critical situation or the presence of severe comorbidities. The present study provides a detailed and optimized technique for the endovascular treatment of ascending aorta disease, based on TEVAR and TAVI procedures.

Poppers maculopathy: A quantitative review of previous literature.

AIM: To review the available literature on poppers maculopathy (PM). MATERIAL AND METHODS: Sixty-four patients (60 with bilateral and 4 with unilateral involvement), for a total of 124 eyes were reported in PubMed, Google Scholar and Embase. Patterns were analyzed according to country, age, gender, sexual orientation, HIV status, consumption habits, visual acuity at presentation (VAP), final visual acuity (VAF) and optical coherence tomography (OCT). RESULTS: Most cases (110 eyes) of PM were reported in European countries and affected middle-aged men (only 8 eyes from female users). The median age was 38.7 years (SD = 10.5 years). Final visual acuity (Median = 0.8; Interquartile range: 0.67-1) was higher than visual acuity at presentation (Median = 0.67; Interquartile range: 0.4-0.8). Many articles lack data on sexual orientation and HIV status as this is considered very personal information. One third of the eyes (40 eyes) developed PM after a single exposure. No significant differences were found between eyes that developed PM after a single exposure and those which developed the condition after several exposures. The most commonly reported pattern was an interruption of the ellipsoid line (68 eyes). CONCLUSION: PM is more prevalent in Europe or European ophthalmologists are more likely to diagnose PM. PM usually affects middle-aged men given that this condition generally appears with chronic exposure to poppers. VAF was higher than VAP, suggesting that this toxicity is in part reversible. Information about HIV status was not provided in most recent articles, thus it is not possible to make inferences about the possible implication of HIV drugs as cofactors for the development of this retinal toxicity.

High-Content Phenotypic Screen of a Focused TCAMS Drug Library Identifies Novel Disruptors of the Malaria Parasite Calcium Dynamics.

The search for new antimalarial drugs with unexplored mechanisms of action is currently one of the main objectives to combat the resistance already in the clinic. New drugs should target specific mechanisms that once initiated lead inevitably to the parasite's death and clearance and cause minimal toxicity to the host. One such new mode of action recently characterized is to target the parasite's calcium dynamics. Disruption of the calcium homeostasis is associated with compromised digestive vacuole membrane integrity and release of its contents, leading to programmed cell death-like features characterized by loss of mitochondrial membrane potential and DNA degradation. Intriguingly, chloroquine (CQ)-treated parasites were previously reported to exhibit such cellular features. Using a high-throughput phenotypic screen, we identified 158 physiological disruptors (hits) of parasite calcium distribution from a small subset of approximately 3000 compounds selected from the GSK TCAMS (Tres Cantos Anti-Malarial Set) compound library. These compounds were then extensively profiled for biological activity against various CQ- and artemisinin-resistant Plasmodium falciparum strains and stages. The hits were also examined for cytotoxicity, speed of antimalarial activity, and their possible inhibitory effects on heme crystallization. Overall, we identified three compounds, TCMDC-136230, -125431, and -125457, which were potent in inducing calcium redistribution but minimally inhibited heme crystallization. Molecular superimposition of the molecules by computational methods identified a common pharmacophore, with the best fit assigned to TCMDC-125457. There were low cytotoxicity or CQ cross-resistance issues for these three compounds. IC50 values of these three compounds were in the low micromolar range. In addition, TCMDC-125457 demonstrated high efficacy when pulsed in a single-dose combination with artesunate against tightly synchronized artemisinin-resistant ring-stage parasites. These results should add new drug options to the current armament of antimalarial drugs as well as provide promising starting points for development of drugs with non-classical modes of action.

Robust Stabilization and Synchronization of a Novel Chaotic System with Input Saturation Constraints.

In this paper, the robust stabilization and synchronization of a novel chaotic system are presented. First, a novel chaotic system is presented in which this system is realized by implementing a sigmoidal function to generate the chaotic behavior of this analyzed system. A bifurcation analysis is provided in which by varying three parameters of this chaotic system, the respective bifurcations plots are generated and evinced to analyze and verify when this system is in the stability region or in a chaotic regimen. Then, a robust controller is designed to drive the system variables from the chaotic regimen to stability so that these variables reach the equilibrium point in finite time. The robust controller is obtained by selecting an appropriate robust control Lyapunov function to obtain the resulting control law. For synchronization purposes, the novel chaotic system designed in this study is used as a drive and response system, considering that the error variable is implemented in a robust control Lyapunov function to drive this error variable to zero in finite time. In the control law design for stabilization and synchronization purposes, an extra state is provided to ensure that the saturated input sector condition must be mathematically tractable. A numerical experiment and simulation results are evinced, along with the respective discussion and conclusion.

Stabilization and Synchronization of a Complex Hidden Attractor Chaotic System by Backstepping Technique.

In this paper, the stabilization and synchronization of a complex hidden chaotic attractor is shown. This article begins with the dynamic analysis of a complex Lorenz chaotic system considering the vector field properties of the analyzed system in the Cn domain. Then, considering first the original domain of attraction of the complex Lorenz chaotic system in the equilibrium point, by using the required set topology of this domain of attraction, one hidden chaotic attractor is found by finding the intersection of two sets in which two of the parameters, r and b, can be varied in order to find hidden chaotic attractors. Then, a backstepping controller is derived by selecting extra state variables and establishing the required Lyapunov functionals in a recursive methodology. For the control synchronization law, a similar procedure is implemented, but this time, taking into consideration the error variable which comprise the difference of the response system and drive system, to synchronize the response system with the original drive system which is the original complex Lorenz system.

Trend from 2001 to 2015 in the prevalence of bronchiectasis among patients hospitalized for asthma and effect of bronchiectasis on the in-hospital mortality.

OBJECTIVE: We aimed to analyze the prevalence of bronchiectasis among patients hospitalized with asthma and to assess the effect of suffering bronchiectasis on in-hospital mortality (IHM). METHODS: We used the Spanish National Hospital Discharge Database from 2000 to 2015 to evaluate all admissions for asthma exacerbation as the main diagnosis, dividing them according to the presence or absence of associated bronchiectasis. We assessed time trends in the prevalence, clinical characteristics, length of hospital stay, costs, and IHM. RESULTS: Of 342,644 admissions for asthma, 10,377 (3.02%) had bronchiectasis. The prevalence of bronchiectasis increased from 2.16% in 2001 to 4.47% in 2015 (p < 0.001). Compared to patients without bronchiectasis, those with bronchiectasis were more frequently women (77.06% vs. 22.94%, p < 0.001), were older (68.87 ± 15.16 vs. 47.05 ± 30.66 years, p < 0.001) and had more comorbid conditions (Charlson comorbidity index ≥ 2: 9.45% vs. 6.58%, p < 0.001). Pseudomonas (8% vs. 0.66%, p < 0.001), Aspergillus (0.93% vs. 0.15%, p < 0.001), eosinophilia (0.29% vs. 0.17%, p = 0.005) and IHM (2.07% vs. 1.2%, p < 0.001) were more frequent in patients with bronchiectasis. After multivariable adjustments, IHM was not associated with bronchiectasis. The presence of bronchiectasis was associated with a longer length of hospital stay and higher costs. CONCLUSIONS: Admissions for asthma with bronchiectasis have increased over time in Spain. In our investigation, the presence of bronchiectasis was not associated with higher IHM, but it increased the length of hospital stay and costs.

Genitourinary Systems Entangled with Shifting Environments in a Salvadoran Subsistence Farming Community.

Diseases of the genitourinary system are the leading cause of hospital deaths in El Salvador, and chronic kidney disease of unknown origin has been gaining attention as a public health problem among farmers in particular. Epidemiological studies point, in part, to environmental risk factors, which have shifted over time with the deployment of modern agricultural science and ongoing climate change. We examined how diseases of the genitourinary system were situated at several margins of an epidemic in one rural Salvadoran municipality where these environmental and epidemiological changes are occurring, albeit relatively slow. By using this approach to study diseases of the genitourinary system, we illustrate one way in which shifting human/environment entanglements can be experimentally "known" in the context of human diseases associated with them. Our approach offers a unique perspective in thinking with ethnographic data to compliment ongoing epidemiological investigations of kidney disease in El Salvador.

[All Roads Lead to Rome: Results of Non-Invasive Respiratory Therapies Applied in a Tertiary-Care Hospital Without an Intermediate Care Unit During the COVID-19 Pandemic]. / Todos los caminos llevan a Roma: resultados de las terapias respiratorias no invasivas aplicadas en un centro terciario sin Unidad de Cuidados Intermedios durante la pandemia de COVID-19.

Introduction: Non-invasive respiratory therapies (NRT) were widely used in the first wave of the COVID-19 pandemic in different settings, depending on availability. The objective of our study was to present 90-day survival and associated factors in patients treated with NRT in a tertiary hospital without an Intermediate Respiratory Care Unit. The secondary objective was to compare the outcomes of the different therapies. Methods: Observational study of patients treated with NRT outside of an intensive care or intermediate respiratory care unit setting, diagnosed with COVID-19 and acute respiratory distress syndrome by radiological criteria and SpO2/FiO2 ratio. A multivariate logistic regression model was developed to determine independently associated variables, and the outcomes of high flow nasal cannula and continuous positive airway pressure were compared. Results: In total, 107 patients were treated and 85 (79.4%) survived at 90 days. Before starting NRT, the mean SpO2/FiO2 ratio was 119.8 ± 59.4. A higher SOFA score was significantly associated with mortality (OR 2,09; 95% CI 1.34-3.27), while self-pronation was a protective factor (OR 0.23; 95% CI 0.06-0.91). High flow nasal cannula was used in 63 subjects (58.9%), and continuous positive airway pressure in 41 (38.3%), with no differences between them. Conclusion: Approximately 4 out of 5 patients treated with NRT survived to 90 days, and no significant differences were found between high flow nasal cannula and continuous positive airway pressure.