A Boolean model explains phenotypic plasticity changes underlying hepatic cancer stem cells emergence.

In several carcinomas, including hepatocellular carcinoma, it has been demonstrated that cancer stem cells (CSCs) have enhanced invasiveness and therapy resistance compared to differentiated cancer cells. Mathematical-computational tools could be valuable for integrating experimental results and understanding the phenotypic plasticity mechanisms for CSCs emergence. Based on the literature review, we constructed a Boolean model that recovers eight stable states (attractors) corresponding to the gene expression profile of hepatocytes and mesenchymal cells in senescent, quiescent, proliferative, and stem-like states. The epigenetic landscape associated with the regulatory network was analyzed. We observed that the loss of p53, p16, RB, or the constitutive activation of ß-catenin and YAP1 increases the robustness of the proliferative stem-like phenotypes. Additionally, we found that p53 inactivation facilitates the transition of proliferative hepatocytes into stem-like mesenchymal phenotype. Thus, phenotypic plasticity may be altered, and stem-like phenotypes related to CSCs may be easier to attain following the mutation acquisition.

Evaluating Noncovalent Interactions in Halogenated Molecules with Double-Hybrid Functionals and a Dedicated Small Basis Set.

We present here an extension of our recently developed PBE-QIDH/DH-SVPD basis set to halogen atoms, with the aim of obtaining, for weakly interacting halogenated molecules, interaction energies close to those provided by a large basis set (def2-TZVPP) coupled to empirical dispersion potential. The core of our approach is the split-valence basis set, DH-SVPD, that has been developed for F, Cl, Br, and I atoms using a self-consistent formula, containing only energy terms computed for dimers and the corresponding monomers at the same level of theory. The basis set developed considering four systems, one for each halogen atoms, has been then tested on the X40, X4 × 10 benchmarks as well as on other two, less standard, data sets. Finally, a large system (380 atoms) has been also considered as a "crash" test. Our results show that the simple and nonempirical PBE-QIDH/DH-SVPD approach is able to provide accurate results for interaction energies of all the considered systems and can thus be considered as a cheaper alternative to DH functionals paired with empirical dispersion corrections and a large basis set of triple-ζ quality.

Engineering principles for rationally design therapeutic strategies against hepatocellular carcinoma.

The search for new therapeutic strategies against cancer has favored the emergence of rationally designed treatments. These treatments have focused on attacking cell plasticity mechanisms to block the transformation of epithelial cells into cancerous cells. The aim of these approaches was to control particularly lethal cancers such as hepatocellular carcinoma. However, they have not been able to control the progression of cancer for unknown reasons. Facing this scenario, emerging areas such as systems biology propose using engineering principles to design and optimize cancer treatments. Beyond the possibilities that this approach might offer, it is necessary to know whether its implementation at a clinical level is viable or not. Therefore, in this paper, we will review the engineering principles that could be applied to rationally design strategies against hepatocellular carcinoma, and discuss whether the necessary elements exist to implement them. In particular, we will emphasize whether these engineering principles could be applied to fight hepatocellular carcinoma.

Systematic Review on the Impact of Mobile Applications with Augmented Reality to Improve Health.

Physical inactivity represents a significant public health challenge globally. Mobile applications, particularly those utilizing augmented reality (AR), have emerged as innovative tools for promoting physical activity. However, a systematic evaluation of their efficacy is essential. This systematic review aims to evaluate and synthesize the evidence regarding the effectiveness and benefits of mobile applications with augmented reality in enhancing physical activity and improving health outcomes. A comprehensive search was conducted in Scopus, PubMed, WOS, and the Cochrane Library databases following PRISMA guidelines. Observational and interventional studies evaluating AR mobile applications for physical exercise were included, without restrictions on publication date or language. The search terms included "Mobile Applications", "Augmented Reality", "Physical Fitness", "Exercise Therapy", and "Health Behavior". The methodological quality was assessed using the ROBINS tool. The review identified twelve eligible studies encompassing 5,534,661 participants. The findings indicated significant increases in physical activity and improvements in mental health associated with the use of AR applications, such as Pokémon GO. However, potential risk behaviors were also noted. The evidence suggests that AR interventions can effectively promote physical activity and enhance health. Nonetheless, further research is needed to address limitations and optimize their efficacy. Future interventions should be tailored to diverse cultural contexts to maximize benefits and mitigate risks. AR mobile applications hold promise for promoting physical activity and improving health outcomes. Strategies to optimize their effectiveness and address identified risks should be explored to fully realize their potential.

A Systematic Review of Congenital Insensitivity to Pain, a Rare Disease.

INTRODUCTION: Pain perception, far from being a pathological mechanism, is a crucial protective stimulus to prevent additional injuries. Any disturbance in this complex system poses significant risks to individuals, affecting their quality of life and even their survival. OBJECTIVE: This review aims to explore congenital insensitivity to pain, an extremely rare genetic disorder with an autosomal recessive pattern that results in the inability to perceive pain. We will focus on the well-known subtype, congenital insensitivity to pain with anhidrosis (CIPA). Our research seeks to update existing knowledge through a comprehensive literature review. METHODOLOGY: The review employs a systematic literature review, analyzing various sources and scientific documents, primarily emphasizing CIPA. The review follows the PROSPERO protocol, registered under CRD42023394489. The literature search was performed on the Scopus, PubMed, and Cinahl databases. RESULTS: Our review reveals secondary complications associated with CIPA, such as recurrent bone fractures, temperature insensitivity, self-mutilation, and, occasionally, intellectual disabilities. The limited available information underscores the need for expanding our knowledge. CONCLUSIONS: In summary, CIPA, particularly, presents a significant medical challenge with adverse impacts on quality of life. Early diagnosis, education for families and healthcare professionals, and appropriate nursing care are essential for effective management. This review highlights the necessity of further research and awareness to enhance support for those affected.

Comparative Analysis of Therapeutic Showers and Bathtubs for Pain Management and Labor Outcomes-A Retrospective Cohort Study.

Hydrotherapy, including the use of therapeutic showers and bathtubs, has been studied for its potential benefits in labor pain management. Previous research has indicated that hydrotherapy can alleviate pain, but comparative studies between therapeutic showers and bathtubs are scarce. Objective: This study aims to compare the effects of therapeutic showers and bathtubs on pain perception, labor duration, use of epidural analgesia, and maternal and neonatal outcomes during labor. Methods: A total of 124 pregnant women were included in this study. Participants were divided into two groups: those who used a therapeutic shower and those who used a bathtub during labor. Pain levels were measured using a visual analog scale (VAS). Labor duration, use of epidural analgesia, types of delivery, maternal outcomes (postpartum hemorrhage, perineal status, maternal hypotension, fever, and breastfeeding), and neonatal outcomes (APGAR scores, fetal heart rate, complications, and neonatal unit admissions) were recorded and analyzed. Results: Both the therapeutic shower and the bathtub effectively reduced pain perception, with the bathtub showing a greater reduction in VAS scores. The therapeutic shower group experienced a significantly shorter labor duration compared to the bathtub group. The majority of participants in both groups did not require epidural analgesia, with no significant differences between the groups. There were no significant differences in the types of delivery. Maternal outcomes indicated a lower incidence of perineal tears and episiotomies in the therapeutic shower group. Neonatal outcomes, including APGAR scores and fetal heart rate, were similar between the groups, with no significant differences in complications or neonatal unit admissions. Conclusions: Both therapeutic showers and bathtubs are effective for pain relief during labor, with the bathtub showing a higher reduction in pain intensity. The therapeutic shower is associated with a shorter labor duration and a lower incidence of perineal tears and episiotomies. Both methods are safe for neonatal well-being, making hydrotherapy a viable non-pharmacological option for pain management in labor. However, the therapeutic shower may offer additional benefits in terms of labor duration and maternal outcomes.

Hydrotherapy in Pain Management in Pregnant Women: A Meta-Analysis of Randomized Clinical Trials.

Background: the benefits of water are significant during the birth process. Improved maternal experience of labor, less use of epidurals, better pain management, shorter labor, and a greater sense of control are observed during the birth process. Objective: This report aims to determine the benefits of hydrotherapy in clinical childbirth approaches and its applicability in pain control. Methods: A meta-analysis of randomized clinical trials selected from various databases with no publication date limits was conducted, comparing groups that did not use hydrotherapy with groups that did during labor. Results: Seven articles met the inclusion criteria, with five articles using hot water immersion and two using hot water shower as hydrotherapy treatments. This study identified 840 participants, with the intervention groups including 417 term pregnant women and the control groups including 423 pregnant women. The effect size of hydrotherapy on pain was calculated using the visual analog scale in five articles and analgesic use in the other two articles. Hydrotherapy significantly reduced pain during labor with a mean difference of -0.97 (95% CI: -1.91 to -0.03; I2 = 97.32%, p < 0.001). The duration of the first stage of labor was not significantly affected, with a mean difference of -0.17 h (95% CI: -0.55 to 0.21; I2 = 56.75%, p = 0.059). Additionally, hydrotherapy did not significantly impact the newborns' Apgar scores at 5 min, with a mean difference of 0.18 (95% CI: -0.48 to 0.85; I2 = 2.15%, p = 0.939). Conclusions: Hydrotherapy is beneficial for pain control in the first stage of labor and does not increase its duration or negatively affect the Apgar score of newborns.

Effects of Hydrotherapy on the Management of Childbirth and Its Outcomes-A Retrospective Cohort Study.

The use of hydrotherapy during childbirth has gained relevance due to the demand for natural childbirth and greater respect for the woman's choice. Studies have shown benefits such as less use of epidural analgesia, increased ability to cope with pain, shorter labor, and a better overall birth experience. OBJECTIVE: The main objective of this study was to generate further evidence on maternal and birth outcomes associated with the use of hydrotherapy during labor, specifically aiming to describe the effects of water immersion during all stages of labor (first, second, and third) on women. METHODOLOGY: A retrospective cohort study was carried out on a random sample of women who gave birth at the Costa del Sol Hospital between January 2010 and December 2020. The calculated sample size was 377 women and the data were extracted from their partograms. After data extraction, two groups were formed: one group used hydrotherapy during childbirth (n = 124), while the other group included women who did not use hydrotherapy during the childbirth process (n = 253). RESULTS: The results highlight significant differences in pain perception, analgesia use, types of labor, and delivery times between the two groups. Women who did not use hydrotherapy reported higher pain perception, with a median (IQR) of 8 (7-9) on a numerical scale, compared to a median (IQR) of 6 (5-7) for the hydrotherapy group. Furthermore, the group without hydrotherapy required epidural analgesia in 40% of cases, while in the hydrotherapy group, it was only necessary in 20%. In terms of the type of delivery, the hydrotherapy group had more spontaneous vaginal deliveries compared to the non-hydrotherapy group, which had more operative vaginal deliveries. The overall duration of labor was longer in the hydrotherapy group, especially in women who arrived at the hospital late in labor. CONCLUSIONS: Hydrotherapy is associated with a longer time to delivery. Women with a higher pain tolerance tend to opt for hydrotherapy instead of epidural analgesia.

The Effect of Ultrasound on the Extraction and Functionality of Proteins from Duckweed (Lemna minor).

The inclusion of protein in the regular human diet is important for the prevention of several chronic diseases. In the search for novel alternative protein sources, plant-based proteins are widely explored from a sustainable and ecological point of view. Duckweed (Lemna minor), also known as water lentil, is an aquatic plant with potential applications for human consumption due to its protein content and carbohydrate contents. Among all the conventional and novel protein extraction methods, the utilization of ultrasound has attracted the attention of scientists because of its effects on improving protein extraction and its functionalities. In this work, a Box-Behnken experimental design was proposed to optimize the alkaline extraction of protein from duckweed. In addition, an exploration of the effects of ultrasound on the morphological, structural, and functional properties of the extracted protein was also addressed. The optimal extraction parameters were a pH of 11.5 and an ultrasound amplitude and processing time of 60% and 20 min, respectively. These process conditions doubled the protein content extracted in comparison to the value from the initial duckweed sample. Furthermore, the application of ultrasound during the extraction of protein generated changes in the FTIR spectra, color, and structure of the duckweed protein, which resulted in improvements in its solubility, emulsifying properties, and foaming capacity.

Association between Gut Microbiota and Inflammation: Mediation Analysis Using Waist Circumference.

Chronic low-grade inflammation (CLI) is implicated in the development of multiple metabolic diseases. The gut microbiota (GM) activates different signaling pathways and induces phenotypic changes, offering an exciting opportunity to treat CLI. We evaluated the mediation of waist circumference on the association of GM with serum cytokines. In this cross-sectional study of 331 children, we measured 5 gut bacterial species, namely, Lactobacillus (L.) casei, L. paracasei, L. reuteri, Staphylococcus (S.) aureus, and Akkermansia (A.) muciniphila, as well as anthropometry, serum cytokines, and other covariates. We evaluated adjusted regression models, path analysis, and structural equation modeling to obtain path coefficients (PCs) for direct, indirect (waist circumference-mediated), and total effects. We found that L. paracasei was directly associated with lower interleukin-10 (IL-10) levels (PC = -173.5 pg/mL). We also observed indirect associations between S. aureus with lower adiponectin levels (PC = -0.1 µg/mL and -0.09 µg/mL). Finally, A. muciniphila was indirectly associated with higher adiponectin levels (PC = 0.1 µg/mL). Our findings suggest the importance of considering the GM composition and waist circumference when evaluating inflammatory-related factors, providing a basis for future research to identify potential strategies to intervene in inflammatory processes and prevent metabolic diseases in childhood. [Figure: see text].

Evolution of the impact of the COVID-19 pandemic on heart transplant recipients: Decreasing risk, improving perspective.

BACKGROUND AND METHODS: Heart transplant recipients (HTr) have a higher probability of suffer from severe coronavirus disease-2019 (COVID-19) in comparison to general population, but their risk has changed over the course of the pandemic in relation to various factors. We conducted a prospective study including all HTr at risk of COVID-19 in a tertiary center between February 2020 and October 2022. The aim was to analyze how the prognosis (incidence of pneumonia and mortality) of COVID-19 in HTr has evolved over time, contextualizing variants, vaccination, and other treatments. RESULTS: Of 308 HTr included, 124 got the infection (39.2%). COVID and non-COVID HTr had similar baseline characteristics. COVID-19 patients with pneumonia had a poorer prognosis than those with less severe presentations, with a higher rate of hospitalization (93.3 vs. 14.1%, p < .001) and death (41.0 vs. 1.2%, p < .001). Multivariate analysis identified age ≥60 years (odds ratio [OR] 3.65, 95% confidence interval [CI] 1.16-11.49, p = .027), and chronic kidney disease ≥3a (OR 4.95, 95% CI 1.39-17.54, p = .014) as predictors of pneumonia. Two-dose vaccination (OR 0.20, CI 95% 0.05-0.72, p = .02) and early remdesivir administration (OR 0.17, CI 0.03-0.90, p = .037) were protective factors. Over the course of the pandemic considering three periods in the follow-up (prevaccination February-December 2020, postvaccination January-December 2021, and post early remdesivir indication January-October 2022), we observed a reduction in pneumonia incidence from 62% to 19% (p < .001); and mortality (from 23% to 4%, p < .001). CONCLUSIONS: The prognosis of COVID-19 in HTr has improved over time, likely due to vaccination and early administration of remdesivir.

Systematic Reviews and Synthesis without Meta-Analysis on Hydrotherapy for Pain Control in Labor.

BACKGROUND: Although there is scientific evidence regarding the use of water immersion during labor, this evidence is primarily focused on the first stage of labor. There is limited scientific evidence on water immersion during the second stage of labor. OBJECTIVE: The objective of this study was to conduct a comprehensive systematic review and synthesis of contemporary evidence related to water birth, with a specific focus on the second stage of labor. METHODS: A systematic review of the scientific literature published between January 2018 and October 2023 was carried out. A synthesis of the results was conducted following the Synthesis without Meta-Analysis (SWiM) guidelines. PubMed, Scopus, and the Cochrane Library were utilized as information sources. The search strategy was designed using the keywords "immersion" and "parturition", along with their relevant synonyms. Inclusion criteria encompassed studies employing randomized controlled trials (RCTs), systematic reviews, and quantitative and qualitative approaches focusing on pregnant women undergoing water immersion at any stage of the labor process. RESULTS: Eleven articles were selected: two systematic reviews (one quantitative and one qualitative), five cohort studies, one case-control study, one cross-sectional observational study, and two qualitative studies. A thorough assessment of the methodology was performed using several specific tools: the Cochrane RoB 2 (Risk of Bias 2) tool for systematic reviews, JBI Critical Appraisal Checklist for Qualitative Research for qualitative studies, STROBE for observational descriptive studies, and CASPe for qualitative studies. The results provided fundamental insights that will contribute to conceptual standardization regarding the effects of water birth on maternal and fetal health. Additionally, a synthesis of the results was performed concerning types of delivery, analgesia use, pain perception, and maternal satisfaction with the water birth experience. CONCLUSIONS: In this study, we conclude that the results regarding delivery types, labor durations, and analgesia use found in the literature, along with statistically significant maternal/fetal effects, are crucial for making recommendations regarding the use of water during labor in any of its stages if the woman desires it safely.

Axial-equatorial equilibrium in substituted cyclohexanes: a DFT perspective on a small but complex problem.

In Chemistry, complexity is not necessarily associated to large systems, as illustrated by the textbook example of axial-equatorial equilibrium in mono-substituted cyclohexanes. The difficulty in modelling such a simple isomerization is related to the need for reproducing the delicate balance between two forces, with opposite effects, namely the attractive London dispersion and the repulsive steric interactions. Such balance is a stimulating challenge for density-functional approximations and it is systematically explored here by considering 20 mono-substituted cyclohexanes. In comparison to highly accurate CCSD(T) reference calculations, their axial-equatorial equilibrium is studied with a large set of 48 exchange-correlation approximations, spanning from semilocal to hybrid to more recent double hybrid functionals. This dataset, called SAV20 (as Steric A-values for 20 molecules), allows to highlight the difficulties encountered by common and more original DFT approaches, including those corrected for dispersion with empirical potentials, the 6-31G*-ACP model, and our cost-effective PBE-QIDH/DH-SVPD protocol, in modeling these challenging interactions. Interestingly, the performance of the approaches considered in this contribution on the SAV20 dataset does not correlate with that obtained with other more standard datasets, such as S66, IDISP or NC15, thus indicating that SAV20 covers physicochemical features not already considered in previous noncovalent interaction benchmarks.

Physical Exercise and Dietary Supplementation in Middle-Aged and Older Women: A Systematic Review.

With the aging of the population in developed countries, the number of middle-aged and older women is progressively increasing. During this stage, women suffer from a number of signs and symptoms that could be reduced or treated with physical exercise and dietary supplements. The main objective of this study was to analyse the benefits of exercise and dietary supplements during menopause. MATERIALS AND METHODS: A systematic review of the scientific literature was performed according to the PRISMA 2020 protocol, searching the PubMed, Cochrane, Scopus, and WOS databases. Studies that met the inclusion criteria were assessed for methodological quality using the PEDro or AMSTAR-2 scales. RESULTS: The searches yielded a total of 104 results, of which 10 were selected, with methodological quality ranging from fair to excellent. Each article examined the combination of a dietary supplement plan versus a placebo; plus an exercise routine versus another routine or a sedentary lifestyle. The results showed the benefits of combining a nutritional supplementation plan with an exercise routine during menopause. CONCLUSIONS: The practice of weekly strength and endurance exercises, together with the consumption of certain dietary supplements, may be a good resource for coping with menopause in a healthy way.

De Novo Donor-Specific Antibodies after Heart Transplantation: A Comprehensive Guide for Clinicians.

Antibodies directed against donor-specific human leukocyte antigens (HLAs) can be detected de novo after heart transplantation and play a key role in long-term survival. De novo donor-specific antibodies (dnDSAs) have been associated with cardiac allograft vasculopathy, antibody-mediated rejection, and mortality. Advances in detection methods and international guideline recommendations have encouraged the adoption of screening protocols among heart transplant units. However, there is still a lack of consensus about the correct course of action after dnDSA detection. Treatment is usually started when antibody-mediated rejection is present; however, some dnDSAs appear years before graft failure is detected, and at this point, damage may be irreversible. In particular, class II, anti-HLA-DQ, complement binding, and persistent dnDSAs have been associated with worse outcomes. Growing evidence points towards a more aggressive management of dnDSA. For that purpose, better diagnostic tools are needed in order to identify subclinical graft injury. Cardiac magnetic resonance, strain techniques, or coronary physiology parameters could provide valuable information to identify patients at risk. Treatment of dnDSA usually involves plasmapheresis, intravenous immunoglobulin, immunoadsorption, and ritxumab, but the benefit of these therapies is still controversial. Future efforts should focus on establishing effective treatment protocols in order to improve long-term survival of heart transplant recipients.

SOS1-RSX-QIDH: A spin-opposite-scaled range-separated-exchange quadratic-integrand double-hybrid density functional.

We develop and validate the SOS1-RSX-QIDH density functional, a one-parameter spin-opposite-scaled variant of the range-separated-exchange quadratic-integrand double-hybrid (RSX-QIDH) model. By entering into the family of spin-biased double hybrids, this new density functional benefits from an improved computational scaling that rivals with the one of hybrids, still conserving the accuracy of its RSX-QIDH version. As part of the latter family, this density functional is well-adapted to treat molecular systems that are particularly prone to self-interaction errors in their ground and excited states. In particular, we show that the SOS1-RSX-QIDH model is a good compromise to treat ground-state problems dealing with kinetics and has a real added value when applied to the evaluation of the excited-state properties of equilibrium and out-of-equilibrium molecular complexes. Even if spin-biased double hybrids are recognized to strongly underestimate noncovalent interactions, we notice and recommend coupling SOS1-RSX-QIDH with a nonlocal van der Waals potential, a combination that is here proved to compete with the best density-functional approximations currently in use.

Total neoadjuvant therapy approach for the treatment of locally advanced rectal cancer. Where do we stand?

BACKGROUND: for the management of locally advanced rectal cancer (LARC), initial treatment with neoadjuvant chemoradiotherapy followed by surgery and chemotherapy in selected patients is considered one of the recommended options by the main international clinical guidelines. Nonetheless, the administration of all chemotherapy before definitive treatment (total neoadjuvant therapy or TNT) is an optimal alternative with a growing level of evidence that must be evaluated in multidisciplinary boards. This review summarizes the available data and controversies in this scenario. SUMMARY: we have analyzed the characteristics of the main published studies that assess the use of TNT in patients with LARC, evaluating their inclusion criteria and distinguishing between the employed radiotherapy fractionations, systemic agents, timing, and the implications of these treatments in regard to surgery and long-term oncological results. Our aim is to describe the evidence that supports the use of a specific regime in everyday clinical practice. KEY POINTS: there is solid evidence for the use of TNT in patients with LARC. There is no data indicating the superiority of one specific TNT scheme among all the existing options. International clinical guidelines leave the door open to choose the most adequate treatment based on the clinical and pathological characteristics of each patient. This review shows the different approaches to TNT and assesses the best options based on clinical evidence.