Extra-Skeletal Osteosarcoma of the Prostate After Treated Prostatic Acinar Adenocarcinoma: A Case Report and Review of the Literature.

Extra-skeletal osteosarcoma is a rare form of malignant soft tissue sarcoma. Its occurrence in the prostate gland is particularly uncommon. In this case report, we present a patient diagnosed with osteosarcoma arising within the prostatic gland. A 58-year-old man was initially diagnosed with Gleason 8 prostate acinar adenocarcinoma following a transurethral resection (TUR) of the prostate. This diagnosis was accompanied by locoregional involvement and multiple bone metastases. The patient underwent a treatment regimen including complete androgen blockade, chemotherapy, greenlight laser prostate vaporization, and palliative radiotherapy. After treatment, he achieved a complete biochemical response, and his bone metastases remained stable. However, at 16 months post-diagnosis, clinical follow-up by means of radiological examinations revealed an increase in the size of the prostatic lesion, along with additional infiltration of the tumor into the rectum and bladder walls. Remarkably, a mesenchymal tumor proliferation with intratumor calcifications was observed. A subsequent TUR biopsy of the prostate showed a malignant tumor spindle and ovoid cell proliferation with high-grade nuclear atypia, necrosis, and islets of osteoid formation, leading to a final diagnosis of high-grade prostatic extra-skeletal osteosarcoma. Despite undergoing chemotherapy, the patient's condition progressed with the development of pulmonary and liver metastases, culminating in his demise.

Frailty and Medication Appropriateness in Rural Adults: Proposing Interventions through Pharmacist-Physician Collaborative Efforts.

Background: Frailty and polymedication are closely interrelated. Addressing these concurrent conditions in primary care settings relies on the utilization of potentially inappropriate medication (PIM) lists and medication reviews (MRs), particularly in rural areas, where healthcare professionals serve as the sole point of access to the medical system. The aim of this study was to examine the relationship between medication appropriateness and variables related to frailty in a rural municipality in order to propose potential strategies for therapy optimization. Methods: This cross-sectional study included all adult community dwellers aged 50 and above officially registered in the municipality of Tiriez (Albacete, Spain) in 2023 (n = 241). The primary outcome variable was frailty (assessed using the fatigue, resistance, ambulation, illness, and loss of weight (FRAIL) scale). The independent variables were age, gender, medication regimen, history of falls, comorbidities, PIMs (evaluated using the screening tool of older persons' prescriptions (STOPP) 2023 criteria), fall-risk-increasing drugs (FRID), and anticholinergic burden (ACB). Results: The prevalence of frailty was approximately 20%. FRID and ACB scores were statistically associated (p-value < 0.001) with frailty, 1.1 ± 1.3 vs. 2.5 ± 1.7, and 1.0 ± 1.3 vs. 2.8 ± 2.5, respectively. Regardless of age, frailty was observed to be more prevalent among females (odds ratio (OR) [95% confidence interval (CI)]: 3.5 [1.5, 9.0]). On average, 2.1 ± 1.6 STOPP criteria were fulfilled, with the prolonged use of anxiolytics and anti-peptic-ulcer agents being the most frequent. Priority interventions (PIs) included opioid dose reduction, benzodiazepine withdrawal, and the assessment of antidepressant and antiplatelet treatment plans. Conclusions: The optimization of medication in primary care is of paramount importance for frail patients. Interventional measures should focus on ensuring the correct dosage and combination of drugs for each therapeutic regimen.

Binary mixtures of Vanderbilt University allosteric agonist thermolysis components act as volatile spatial repellents for malaria vector mosquitoes.

BACKGROUND: The development of economically viable and environmentally neutral tools to control insects that consume or damage over 20% of global agriculture or vector human and animal disease represents one of the most important challenges of the 21st century. The suite of chemical-based strategies currently employed to control insect populations rely primarily on insecticides, which are subject to rapid resistance and often have harmful off-target environmental and health-related impacts, and, to a lesser degree, repellents, which typically rely on masking attractive odors. The discovery and characterization of Vanderbilt University allosteric agonists (VUAAs), a family of small-molecule agonists that target the highly conserved, insect-specific odorant receptor coreceptor (Orco), raise the potential for the development of a novel repellent paradigm for vector/pest management. VUAAs have the potential to target nearly all insect olfactory sensory neurons, leading to highly aversive behavioral responses, but importantly have limited volatility, thereby reducing their utility as spatial repellents. RESULTS: We have characterized VUAA thermolysis components and identified a suite of volatiles (VUAA-based active ingredients, VUAIs) that act specifically in novel binary combinations as robust and long-lasting spatial repellents against Anopheline mosquitoes. In mobility-based behavioral experiments, VUAIs act synergistically as effective spatial repellents and outperform parent VUAA compounds against host-seeking Anopheline mosquitoes. CONCLUSIONS: VUAIs are volatile alternatives to Vanderbilt University allosteric agonists (VUAAs) that have the potential for use as spatial repellents in disease vector and agricultural pest control. The repellency observed is odorant receptor coreceptor (Orco)-dependent, supporting the hypothesis that VUAIs and VUAAs similarly target an allosteric Orco recognition site. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Placental mitochondrial impairment and its association with maternal metabolic dysfunction.

The placenta plays an essential role in pregnancy, leading to proper fetal development and growth. As an organ with multiple physiological functions for both mother and fetus, it is a highly energetic and metabolically demanding tissue. Mitochondrial physiology plays a crucial role in the metabolism of this organ and thus any alteration leading to mitochondrial dysfunction has a severe outcome in the development of the fetus. Pregnancy-related pathological states with a mitochondrial dysfunction outcome include preeclampsia and gestational diabetes mellitus. In this review, we address the role of mitochondrial morphology, metabolism and physiology of the placenta during pregnancy, highlighting the roles of the cytotrophoblast and syncytiotrophoblast. We also describe the relationship between preeclampsia, gestational diabetes, gestational diabesity and pre-pregnancy maternal obesity with mitochondrial dysfunction.

Performance of the First-Trimester Cervical Consistency Index to Predict Preterm Birth.

Background/Objectives: Preterm birth (PTB) remains a significant global health challenge. Previous attempts to predict preterm birth in the first trimester using cervical length have been contradictory. The cervical consistency index (CCI) was introduced to quantify early cervical changes and has shown promise across various clinical scenarios in the mid-trimester, though testing in the first trimester is lacking. This study aims to assess the cervical consistency index performance in predicting preterm birth during the first trimester of pregnancy. Methods: In this prospective cohort study, focused exclusively on research, women with singleton pregnancies, both with and without a history of spontaneous preterm birth (sPTB), were included. The primary outcome was sPTB before 37 weeks, with a secondary outcome of sPTB before 34 weeks. CCI measurements were taken between 11+0 to 13+6 weeks of gestation. Receiver operating characteristic (ROC) curves were generated, and sensitivity and specificity were calculated for the optimal cut-off and for the 5th, 10th, and 15th percentile. Intraobserver and interobserver agreements were assessed using the intraclass correlation coefficient (ICC). Results: Among the 667 patients analyzed, the rates of sPTB before 37 and 34 weeks were 9.2% (61/667) and 1.8% (12/667), respectively. The detection rates (DRs) for CCI predicting PTB before 37 and 34 weeks were 19.7% (12/61) and 33.3% (4/12). Negative predictive values were 91.8% (546/595) and 98.7% (588/596), while the areas under the curve (AUC) for sPTB before 37 and 34 weeks were 0.62 (95% CI: 0.54-0.69) and 0.80 (95% CI: 0.71-0.89), respectively. Of the 61 patients with preterm birth, 13 (21.3%) had a preterm birth history; in this group, the CCI percentile 10th identified 39% (5/13). Intraobserver ICC was 0.862 (95% CI: 0.769-0.920), and interobserver ICC was 0.833 (95% CI: 0.722-0.902). Conclusions: This study suggests that utilizing CCI in the first trimester of pregnancy could serve as a valuable tool for predicting preterm birth before 34 weeks of gestation, demonstrating robust intraobserver and interobserver reliability.

Probing Quantum Efficiency: Exploring System Hardness in Electronic Ground State Energy Estimation.

We consider the question of how correlated the system hardness is between classical algorithms of electronic structure theory in ground state estimation and quantum algorithms. To define the system hardness for classical algorithms, we employ empirical criterion based on the deviation of electronic energies produced by coupled cluster and configuration interaction methods from the exact ones along multiple bonds dissociation in a set of molecular systems. For quantum algorithms, we have selected the Variational Quantum Eigensolver (VQE) and Quantum Phase Estimation (QPE) methods. As characteristics of the system hardness for quantum methods, we analyzed circuit depths for the state preparation, the number of quantum measurements needed for the energy expectation value, and various cost characteristics for the Hamiltonian encodings via Trotter approximation and linear combination of unitaries (LCU). Our results show that the quantum resource requirements are mostly unaffected by classical hardness, with the only exception being the state preparation part, which contributes to both VQE and QPE algorithm costs. However, there are clear indications that constructing the initial state with a significant overlap with the true ground state is easier than obtaining the state with an energy expectation value within chemical precision. These results support optimism regarding the identification of a molecular system where a quantum algorithm excels over its classical counterpart, as quantum methods can maintain efficiency in classically challenging systems.

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.

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.

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.

Cost Evaluation of Professional Services in a Rural Community Pharmacy: A Monocentric Exploratory Approach.

The increasing pressure on healthcare systems (HCSs) is a cause for concern worldwide. Rising costs, uncertainty about sustainability, and aging populations are the main issues that make it challenging to allocate scarce resources to the needs of HCSs. Clinical professional pharmacy services (PSs) have been shown to help alleviate system stress and to reach the entire population, although a cost of provision is borne. The objective of this study was to evaluate the provision costs of three PSs, a medicine-dispensing service (MDS), a multicompartmental compliance aid system service (MCAS), and a cognitive impairment screening service (CISS), in a rural community pharmacy. A cost analysis was performed using a time-driven activity-based costing model. The time dedicated to PS provision was appropriately recorded, and the corresponding expenses were extracted from the accounting records. A provision time of 4.80 min and a cost of EUR 2.24 were estimated for the MDS, while 18.33 min and EUR 8.73 were calculated for the MCAS, and 122.20 min and EUR 56.72 were calculated for the CISS. The total provision time represented 85% of the pharmacist's effective working time. Tailored cost analysis is a useful tool for making decisions on the implementation of a PS. Larger studies including a variety of pharmacies and locations are necessary to accurately assess costs and engage in discussions on funding and remuneration.

Uso y abuso de los criterios de inclusión y exclusión en el proyecto de investigación

Uno de los aspectos metodológicos esenciales de una investigación es la delimitación de los sujetos a estudiar. Este artìculo aborda la tendencia actual a una excesiva e injustificada declaración de los criterios de inclusión y de exclusión en todo tipo de investigación. Se defiende la idea de que una adecuada utilización de las categorías universo y muestra hace innecesaria la declaración de criterios de inclusión y de exclusión en el diseño metodológico de la mayoría de los proyectos de trabajo de terminación de la especialidad que presentan nuestros residentes.

One of the essential methodological aspects of an investigation is the delimitation of the subjects to be studied. This article addresses the current trend towards an excessive and unjustified statement of inclusion and exclusion criteria in all types of research. The idea is defended that an adequate use of the universe and sample categories makes it unnecessary to declare inclusion and exclusion criteria in the methodological design of most of the specialty completion work projects presented by our residents.

Cellular shortening and calcium dynamics are improved by noisy stimulus in a model of cardiomyopathy.

Noise is present in cell biology. The capability of cells to respond to noisy environment have become essential. This study aimed to investigate whether noise can enhance the contractile response and Ca2+ handling in cardiomyocytes from a cardiomyopathy model. Experiments were conducted in an experimental setup with Gaussian white noise, frequency, and amplitude control to stimulate myocytes. Cell shortening, maximal shortening velocity, time to peak shortening, and time to half relaxation variables were recorded to cell shortening. Ca2+ transient amplitude and raise rate variables were registered to measure Ca2+ transients. Our results for cell shortening, Ca2+ transient amplitude, and raise rate suggest that cell response improve when myocytes are noise stimulated. Also, cell shortening, maximal shortening velocity, Ca2+ transient amplitude, and raise improves in control cells. Altogether, these findings suggest novel characteristics in how cells improve their response in a noisy environment.

Correction: How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosoma brucei cell.

[This corrects the article DOI: 10.1371/journal.ppat.1011522.].

¿Mi estudio es transversal o longitudinal?

La clasificación de los estudios en transversales o longitudinales constituye uno de los aspectos metodológicos que se declaran en los proyectos de investigación correspondientes a los trabajos de terminación de la especialidad. En este artículo se ofrecen elementos esclarecedores para la distinción entre ambos tipos de estudios; en este sentido, se considera que la esencia definitoria del estudio longitudinal radica en el interés del investigador por los cambios en el tiempo del fenómeno investigado.

The studies' classification as cross-sectional or longitudinal constitutes one of the methodological aspects that are declared in the research projects corresponding to the specialty's completion works. This article offers clarifying elements for the distinction between both types of studies; In this sense, it is considered that the longitudinal study's defining essence lies in the researcher's interest in the changes over time of the investigated phenomenon.

How much (ATP) does it cost to build a trypanosome? A theoretical study on the quantity of ATP needed to maintain and duplicate a bloodstream-form Trypanosoma brucei cell.

ATP hydrolysis is required for the synthesis, transport and polymerization of monomers for macromolecules as well as for the assembly of the latter into cellular structures. Other cellular processes not directly related to synthesis of biomass, such as maintenance of membrane potential and cellular shape, also require ATP. The unicellular flagellated parasite Trypanosoma brucei has a complex digenetic life cycle. The primary energy source for this parasite in its bloodstream form (BSF) is glucose, which is abundant in the host's bloodstream. Here, we made a detailed estimation of the energy budget during the BSF cell cycle. As glycolysis is the source of most produced ATP, we calculated that a single parasite produces 6.0 x 1011 molecules of ATP/cell cycle. Total biomass production (which involves biomass maintenance and duplication) accounts for ~63% of the total energy budget, while the total biomass duplication accounts for the remaining ~37% of the ATP consumption, with in both cases translation being the most expensive process. These values allowed us to estimate a theoretical YATP of 10.1 (g biomass)/mole ATP and a theoretical [Formula: see text] of 28.6 (g biomass)/mole ATP. Flagellar motility, variant surface glycoprotein recycling, transport and maintenance of transmembrane potential account for less than 30% of the consumed ATP. Finally, there is still ~5.5% available in the budget that is being used for other cellular processes of as yet unknown cost. These data put a new perspective on the assumptions about the relative energetic weight of the processes a BSF trypanosome undergoes during its cell cycle.

Long-term potentiation and its neurotrophin-dependent modulation in the superior cervical ganglion of the rat are influenced by KCNQ channel function.

Ganglionic long-term potentiation (gLTP) in the rat superior cervical ganglion (SCG) is differentially modulated by neurotrophic factors (Nts): brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF). KCNQ/M channels, key regulators of neuronal excitability, and firing pattern are modulated by Nts; therefore, they might contribute to gLTP expression and to the Nts-dependent modulation of gLTP. In the SCG of rats, we characterized the presence of the KCNQ2 isoform and the effects of opposite KCNQ/M channel modulators on gLTP in control condition and under Nts modulation. Immunohistochemical and reverse transcriptase polymerase chain reaction analyses showed the expression of the KCNQ2 isoform. We found that 1 µmol/L XE991, a channel inhibitor, significantly reduced gLTP (∼50%), whereas 5 µmol/L flupirtine, a channel activator, significantly increased gLTP (1.3- to 1.7-fold). Both modulators counterbalanced the effects of the Nts on gLTP. Data suggest that KCNQ/M channels are likely involved in gLTP expression and in the modulation exerted by BDNF and NGF.

Una mirada a las series de casos y sus unidades de análisis

Las series de casos constituyen un tipo particular de estudio de uso muy frecuente en la investigación clínica. En este artículo se pretende resaltar la utilidad y plena vigencia de estos estudios como propuestas de proyectos de terminación de la especialidad, así como abordar sus particularidades más importantes en la delimitación de sus unidades de análisis. Cuando son bien realizadas, estas investigaciones constituyen una excelente fuente de actualización del conocimiento médico y una magnífica oportunidad para que los investigadores jóvenes se entrenen en el campo de la investigación científica.

Case series are a particular type of study that is very frequently used in clinical research. This article intends to highlight the usefulness and full validity of these studies as proposals for completion projects of the specialty, as well as to address their most important particularities in the delimitation of their analysis units. When they are well carried out, these researches constitute an excellent source of updating medical knowledge and a magnificent opportunity for young researchers to train in the scientific research field.

The impact of COVID-19 infection on labor outcomes of Mexican formal workers.

The outbreak of the COVID-19 pandemic had an immediate and severe impact on the economy. However, we do not know whether the disease may have a longer-term effect on people's employment opportunities. In this study, we focus on the effects of COVID-19 infection on labor market outcomes 12 months after diagnosis. We use a unique dataset that includes all formal private sector workers in the Mexican social security system and that links health outcomes with administrative records. We implement two alternative identification strategies to estimate the impact: matching estimators and individual fixed effects models. Our study finds that COVID-19 infection does not harm employment probabilities or wages. On the contrary, we find that workers who had tested positive for COVID had a higher likelihood of keeping their formal sector jobs and higher wages than those who did not. Moreover, our results describe mostly low-income workers.

Las hipótesis en el proyecto de investigación: ¿cuándo si, cuándo no?

La utilización de hipótesis en los proyectos de trabajo de terminación de la especialidad constituye uno de los aspectos metodológicos que amerita un análisis. El artículo pretende esclarecer a los investigadores jóvenes cuándo en una investigación debe ser declarada esta categoría. Se sugiere utilizar el alcance de la investigación (exploratorio, descriptivo, correlacional o explicativo) para la decisión de empleo o no de hipótesis en un proyecto investigativo. Se detallan condiciones que determinan el uso de hipótesis específicamente en los estudios descriptivos, los más frecuentemente realizados por los residentes.

The use of hypotheses in the specialty finishing projects constitutes one of the methodological aspects that deserves an analysis. The article aims to clarify for young researchers when this category should be declared in a research. It is suggested to use the scope of the research (exploratory, descriptive, correlational or explanatory) for the decision of whether or not to use hypotheses in a research project. Conditions that determine the use of hypotheses specifically in descriptive studies, the most frequently carried out by residents are detailed.

p53 engages the cGAS/STING cytosolic DNA sensing pathway for tumor suppression.

Tumor suppression by TP53 involves cell-autonomous and non-cell-autonomous mechanisms. TP53 can suppress tumor growth by modulating immune system functions; however, the mechanistic basis for this activity is not well understood. We report that p53 promotes the degradation of the DNA exonuclease TREX1, resulting in cytosolic dsDNA accumulation. We demonstrate that p53 requires the ubiquitin ligase TRIM24 to induce TREX1 degradation. The cytosolic DNA accumulation resulting from TREX1 degradation activates the cytosolic DNA-sensing cGAS/STING pathway, resulting in induction of type I interferons. TREX1 overexpression sufficed to block p53 activation of the cGAS/STING pathway. p53-mediated induction of type I interferon (IFNB1) is suppressed by cGAS/STING knockout, and p53's tumor suppressor activities are compromised by the loss of signaling through the cGAS/STING pathway. Thus, our study reveals that p53 utilizes the cGAS/STING innate immune system pathway for both cell-intrinsic and cell-extrinsic tumor suppressor activities.