Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity.

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit, receiving strong input from the indirect pathway and regulating a variety of functions, including locomotor output and habit formation. We recently showed that it also acts as a gatekeeper of cocaine-induced behavioral plasticity, as inhibition of parvalbumin-positive cells in the GPe (GPe PV ) prevents the development of cocaine-induced reward and sensitization. However, the molecular and circuit mechanisms underlying this function are unknown. Here we show that GPe PV cells control cocaine reward and sensitization by inhibiting GABAergic neurons in the substantia nigra pars reticulata (SNr GABA ), and ultimately, selectively modulating the activity of ventral tegmental area dopamine (VTA DA ) cells projecting to the lateral shell of the nucleus accumbens (NAcLat). A major input to GPe PV cells is the indirect pathway of the dorsomedial striatum (DMS D 2 ), which receives DAergic innervation from collaterals of VTA DA →NAcLat cells, making this a closed-loop circuit. Cocaine likely facilitates reward and sensitization not directly through actions in the GPe, but rather in the upstream DMS, where the cocaine-induced elevation of DA triggers a depression in DMS D 2 cell activity. This cocaine-induced elevation in DA levels can be blocked by inhibition of GPe PV cells, closing the loop. Interestingly, the level of GPe PV cell activity prior to cocaine administration is correlated with the extent of reward and sensitization that animals experience in response to future administration of cocaine, indicating that GPe PV cell activity is a key predictor of future behavioral responses to cocaine. Single nucleus RNA-sequencing of GPe cells indicated that genes encoding voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability are downregulated in GPe PV cells following a single cocaine exposure, contributing to the elevation in GPe PV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPe PV cell excitability and also impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its potential as a therapeutic to counteract psychostimulant use disorder. Our findings illuminate the molecular and circuit mechanisms by which the GPe orchestrates brain-wide changes in response to cocaine that are required for reward, sensitization, and self-administration behaviors.

Magnon Sensing of NO, NO2 and NH3 Gas Capture on CrSBr Monolayer.

Air pollution and greenhouse emissions are significant problems across various sectors, urging the need for advanced technologies to detect and capture harmful gases. In recent years, two-dimensional (2D) materials have attracted increasing attention due to their large surface-to-volume ratio and reactivity. Herein, we investigate the potential of single-layer CrSBr for gas sensing and capturing by means of first-principles calculations. We explore the adsorption behaviour of different pollutant gases (H2S, NH3, NO, NO2, CO and CO2) on this 2D ferromagnet and the impact of intrinsic defects on its magnetic properties. Interestingly, we find that Br vacancies enhance the adsorption of NH3, NO and NO2 and induce a selective frequency shift on the magnon dispersion. This work motivates the creation of novel magnonic gas sensing devices based on 2D van der Waals magnetic materials.

Boundary of ecosystem services: Differentiating between ecosystem services and geosystem services is needed.

Geosystem services (GSs) and ecosystem services (ESs) are interconnected, both representing nature's contributions to people. Whether GSs are a subset of ESs depends on the definition of ESs. The answer would be "not necessarily" (i.e., some GSs are, while other GSs are not), if ESs are the benefits humans derive from ecological functions, processes, or characteristics. The boundary proposed by Chen et al. (2023) to differentiate ESs from other ecosystem-related benefits adopted this definition, and suggested that ESs are renewable and affected by biotic elements to occur. Gray et al. (2024) criticized this boundary for separating out bits of nature and ignoring the contributions of GSs and abiotic elements to ESs and human wellbeing. In fact, highlighting that ESs are affected by biotic elements to occur does not deny that ESs' occurrence is also affected by abiotic elements. However, ESs' dependence on abiotic elements cannot be a criterion to differentiate ESs from other benefits because abiotic elements are integral to geosystems, ecosystems, and many other natural and artificial systems, as well as to these systems' services. Conversely, while geosystems might persist without biotic elements, ecosystems cannot. Chen et al. (2023) only excluded those (not the whole) abiotic benefits, such as wind energy, that may occur independently of biotic elements, while allowing for integrating certain GSs into ESs. For example, geological structures can offer flood protection and water storage as GSs, which can also be classified as ESs when their qualities or quantities are affected by biotic elements. Differentiation between GSs and ESs should not be misinterpreted as splitting their interconnections or undervaluing or dividing nature. Instead, such differentiation and classification of nature's benefits serve to facilitate communication, management, education, research, and policy-making associated with nature's benefits, while also highlighting the richness and diversity of nature's benefits.

Transparent, plasticized cellulose-glycerol bioplastics for food packaging applications.

Free-standing films have been obtained by drop-casting cellulose-glycerol mixtures (up to 50 wt% glycerol) dissolved in trifluoroacetic acid and trifluoroacetic anhydride (TFA:TFAA, 2:1, v:v). A comprehensive examination of the optical, structural, mechanical, thermal, hydrodynamic, barrier, migration, greaseproof, and biodegradation characteristics of the films was conducted. The resulting cellulose-glycerol blends exhibited an amorphous molecular structure and a reinforced H-bond network, as evidenced by X-ray diffraction analysis and infrared spectroscopy, respectively. The inclusion of glycerol exerted a plasticizing influence on the mechanical properties of the films, while keeping their transparency. Hydrodynamic and barrier properties were assessed through water uptake and water vapor/oxygen transmission rates, respectively, and obtained values were consistent with those of other cellulose-based materials. Furthermore, overall migration levels were below European regulation limits, as stated by using Tenax® as a dry food simulant. In addition, these bioplastics demonstrated good greaseproof performance, particularly at high glycerol content, and potential as packaging materials for bakery products. Biodegradability assessments were carried out by measuring the biological oxygen demand in seawater and high biodegradation rates induced by glycerol were observed.

Decrease in platelet count in patients with AKI and its association with major adverse kidney events.

INTRODUCTION: A reduction in platelet count in critically ill patients is a marker of severity of the clinical condition. However, whether this association holds true in acute kidney injury (AKI) is unknown. We analyzed the association between platelet reduction in patients with AKI and major adverse kidney events (MAKE). METHODS: In this retrospective cohort, we included AKI patients at the Hospital Civil of Guadalajara, in Jalisco, Mexico. Patients were divided according to whether their platelet count fell >21% during the first 10 days. Our objectives were to analyze the associations between a platelet reduction >21% and MAKE at 10 days (MAKE10) or at 30-90 days (MAKE30-90) and death. RESULTS: From 2017 to 2023, 400 AKI patients were included, 134 of whom had a > 21% reduction in platelet count. The mean age was 54 years, 60% were male, and 44% had sepsis. The mean baseline platelet count was 194 x 103 cells/µL, and 65% of the KDIGO3 patients met these criteria. Those who underwent hemodialysis (HD) had lower platelet counts. After multiple adjustments, a platelet reduction >21% was associated with MAKE10 (OR 4.2, CI 2.1-8.5) but not with MAKE30-90. The mortality risk increased 3-fold (OR 2.9, CI 1.1-7.7, p = 0.02) with a greater decrease in the platelets (<90 x 103 cells/µL). As the platelets decreased, the incidence of MAKE was more likely to increase. These associations lost significance when accounting for starting HD. CONCLUSION: In our retrospective cohort of patients with AKI, a > 21% reduction in platelet count was associated with MAKE. Our results are useful for generating hypotheses and motivating us to continue studying this association with a more robust design.

A reduction in platelet count in critically ill patients has been associated with a worse prognosis, but it is not yet known whether this relationship also exists in patients with acute kidney injury, who are more susceptible to platelet decrease due to the syndrome or due to the onset of hemodialysis. In our study of acute kidney injury patients, we found that those whose platelet count decreased >21% during the first days were more likely to experience a major kidney event. In addition, the greater the decrease in platelet count was, the more likely these events were to occur. The significance of this association was lost in patients who start hemodialysis. Our conclusions could serve to generate hypotheses about this interesting relationship.

Polarimetric measurement of temporal coherence in electromagnetic light beams.

We present a method to determine the degree of temporal coherence of a quasimonochromatic vectorial light beam by polarimetric measurements. More specifically, we employ Michelson's interferometer in which the polarization Stokes parameters of the output (interference) beam are measured as a function of the time delay. Such a measurement enables us to deduce the magnitudes of the coherence (two-time) Stokes parameters, and hence the degree of coherence, of the input beam. Compared to existing methods the current technique has the benefits that neither optical elements in the arms of the interferometer nor visibility measurements are needed. The method is demonstrated with a laser diode and a filtered halogen source of various degrees of polarization.

On the Origin of the Above-Room-Temperature Magnetism in the 2D van der Waals Ferromagnet Fe3GaTe2.

2D magnetic materials have attracted growing interest driven by their unique properties and potential applications. However, the scarcity of systems exhibiting magnetism at room temperature has limited their practical implementation into functional devices. Here we focus on the van der Waals ferromagnet Fe3GaTe2, which exhibits above-room-temperature magnetism (Tc = 350-380 K) and strong perpendicular anisotropy. Through first-principles calculations, we examine the magnetic properties of Fe3GaTe2 and compare them with those of Fe3GeTe2. Our calculations unveil the microscopic mechanisms governing their magnetic behavior, emphasizing the pivotal role of ferromagnetic in-plane couplings in the stabilization of the elevated Tc in Fe3GaTe2. Additionally, we predict the stability, substantial perpendicular anisotropy, and high Tc of the single-layer Fe3GaTe2. We also demonstrate the potential of strain engineering and electrostatic doping to modulate its magnetic properties. Our results incentivize the isolation of the monolayer and pave the way for the future optimization of Fe3GaTe2 in magnetic and spintronic nanodevices.

Knee-Loading Predictions with Neural Networks Improve Finite Element Modeling Classifications of Knee Osteoarthritis: Data from the Osteoarthritis Initiative.

Physics-based modeling methods have the potential to investigate the mechanical factors associated with knee osteoarthritis (OA) and predict the future radiographic condition of the joint. However, it remains unclear what level of detail is optimal in these methods to achieve accurate prediction results in cohort studies. In this work, we extended a template-based finite element (FE) method to include the lateral and medial compartments of the tibiofemoral joint and simulated the mechanical responses of 97 knees under three conditions of gait loading. Furthermore, the effects of variations in cartilage thickness and failure equation on predicted cartilage degeneration were investigated. Our results showed that using neural network-based estimations of peak knee loading provided classification performances of 0.70 (AUC, p < 0.05) in distinguishing between knees that developed severe OA or mild OA and knees that did not develop OA eight years after a healthy radiographic baseline. However, FE models incorporating subject-specific femoral and tibial cartilage thickness did not improve this classification performance, suggesting there exists an optimal point between personalized loading and geometry for discrimination purposes. In summary, we proposed a modeling framework that streamlines the rapid generation of individualized knee models achieving promising classification performance while avoiding motion capture and cartilage image segmentation.

Coinfections and comorbidities observed in COVID-19 during the influenza season in the pediatric patient.

OBJECTIVE: To evaluate if the comorbidity and coinfections presented by SARS-CoV-2 infection vs. COVID-19 impact our Mexican children. METHOD: Prospective and observational study that included the 2020-2021 peak influenza season. All patients with a diagnosis of infection by SARS-CoV-2 vs. COVID-19 who were admitted to the Hospital Infantil de Mexico were analyzed. Real-time RT-PCR for SARS-CoV-2 was performed in all patients, determining E, RdRp and RP genes and protein N, as well as RT-PCR for detection of respiratory viruses. RESULTS: The inclusion criteria were met by 163 patients. The group with the highest risk of becoming ill was adolescents (40.4%), followed by schoolchildren and preschoolers (21.4% and 19.6% of the cases, respectively). There were three cases with viral coinfection: two (1.2%) with parvovirus B-19 and one (0.6%) with herpes type I; another two (1.2%) showed bacterial coinfection. The main comorbidity were obesity, acute lymphoblastic leukemia and arterial hypertension. Regarding mortality, we only had four cases (2.4%). CONCLUSIONS: Obesity, cancer, hypertension, heart disease and diabetes are comorbidity present in our patients, as referred to in literature, but not coinfections. In our study, we did not have any associated mortality related to comorbidity.

OBJETIVO: Evaluar el impacto de la comorbilidad y de las coinfecciones presentadas por la infección por SARS-CoV-2 vs. COVID-19 en niños mexicanos. MÉTODO: Estudio prospectivo y observacional que comprendió la temporada alta de influenza 2020-2021, analizando todos los pacientes con diagnóstico de infección vs. enfermedad por SARS-CoV-2 vs. COVID-19 que ingresaron al Hospital Infantil de México. Se realizó en todos RT-PCR en tiempo real para SARS-CoV-2, determinando gen E, gen RdRp, gen RP y proteína N, y RT-PCR multiplex para detección de virus respiratorios. RESULTADOS: Los criterios de inclusión los cumplieron 163 pacientes. El grupo con mayor riesgo de enfermar fueron los adolescentes (40.4%), seguidos de los escolares y preescolares (21.4% y 19.6% de los casos, respectivamente). Hubo tres casos con coinfección viral: dos (1.2%) con parvovirus B-19 y uno (0.6%) con herpes tipo I; hubo otros dos (1.2%) con coinfección bacteriana. La principal comorbilidad correspondió a obesidad, leucemia linfoblástica aguda e hipertensión arterial. En cuanto a mortalidad, solo hubo cuatro casos (2.4%). CONCLUSIONES: Obesidad, cáncer, hipertensión, cardiopatías y diabetes constituyen la comorbilidad en nuestros pacientes, como se refiere en la literatura, no así las coinfecciones. En nuestro estudio no hubo casos de mortalidad relacionada con la comorbilidad.

Theoretical Investigation of the Lattice Thermal Conductivities of II-IV-V2 Pnictide Semiconductors.

Ternary pnictide semiconductors with II-IV-V2 stoichiometry hold potential as cost-effective thermoelectric materials with suitable electronic transport properties, but their lattice thermal conductivities (κ) are typically too high. Insights into their vibrational properties are therefore crucial to finding strategies to reduce κ and achieve improved thermoelectric performance. We present a theoretical exploration of the lattice thermal conductivities for a set of pnictide semiconductors with ABX2 composition (A = Zn, Cd; B = Si, Ge, Sn; and X = P, As) using machine-learning-based regression algorithms to extract force constants from a reduced number of density functional theory simulations and then solving the Boltzmann transport equation for phonons. Our results align well with available experimental data, decreasing the mean absolute error by ∼3 W m-1 K-1 with respect to the best previous set of theoretical predictions. Zn-based ternary pnictides have, on average, more than double the thermal conductivity of the Cd-based compounds. Anisotropic behavior increases with the mass difference between A and B cations, but while the nature of the anion does not affect the structural anisotropy, the thermal conductivity anisotropy is typically higher for arsenides than for phosphides. We identify compounds such as CdGeAs2, for which nanostructuring to an affordable range of particle sizes could lead to κ values low enough for thermoelectric applications.

Salivary biomarkers as pioneering indicators for diagnosis and severity stratification of pediatric long COVID.

Introduction: Long COVID, or post-acute sequelae of SARS-CoV-2 infection (PASC), manifests as persistent and often debilitating symptoms enduring well beyond the initial COVID-19 infection. This disease is especially worrying in children since it can seriously alter their development. Presently, a specific diagnostic test or definitive biomarker set for confirming long COVID is lacking, relying instead on the protracted presence of symptoms post-acute infection. Methods: We measured the levels of 13 biomarkers in 105 saliva samples (49 from children with long COVID and 56 controls), and the Pearson correlation coefficient was used to analyse the correlations between the levels of the different salivary biomarkers. Multivariate logistic regression analyses were performed to determine which of the 13 analysed salivary biomarkers were useful to discriminate between children with long COVID and controls, as well as between children with mild and severe long COVID symptoms. Results: Pediatric long COVID exhibited increased oxidant biomarkers and decreased antioxidant, immune response, and stress-related biomarkers. Correlation analyses unveiled distinct patterns between biomarkers in long COVID and controls. Notably, a multivariate logistic regression pinpointed TOS, ADA2, total proteins, and AOPP as pivotal variables, culminating in a remarkably accurate predictive model distinguishing long COVID from controls. Furthermore, total proteins and ADA1 were instrumental in discerning between mild and severe long COVID symptoms. Discussion: This research sheds light on the potential clinical utility of salivary biomarkers in diagnosing and categorizing the severity of pediatric long COVID. It also lays the groundwork for future investigations aimed at unravelling the prognostic value of these biomarkers in predicting the trajectory of long COVID in affected individuals.

Design Principles Guided by DFT Calculations and High-Throughput Frameworks for the Discovery of New Diamond-like Chalcogenide Thermoelectric Materials.

Rational design principles are one pathway to discovering new materials. However, technological breakthroughs rarely occur in this way because these design principles are usually based on incremental advances that seldom lead to disruptive applications. The emergence of machine-learning (ML) and high-throughput (HT) techniques has changed the paradigm, opening up new possibilities for efficiently screening large chemical spaces and creating on-the-fly design principles for the discovery of novel materials with desired properties. In this work, the approach is used to discover novel thermoelectric (TE) materials based on quaternary diamond-like chalcogenides. A HT framework that integrates density functional theory calculations, ML, and the solution of the Boltzmann transport equation is used to efficiently rationalize the transport properties of these compounds and identify those with potential as TE materials, achieving ZT values above 2.

Evaluation of deep oscillation therapy for the treatment of lumbar pain syndrome using motion capture systems: A systematic review.

Low back pain is a painful disorder that prevents normal mobilization, increases muscle tension and whose first-line treatment is usually non-steroidal anti-inflammatory drugs, together with non-invasive manual therapies, such as deep oscillation therapy. This systematic review aims to investigate and examine the scientific evidence of the effectiveness of deep oscillation therapy in reducing pain and clinical symptomatology in patients with low back pain, through the use of motion capture technology. To carry out this systematic review, the guidelines of the PRISMA guide were followed. A literature search was performed from 2013 to March 2022 in the PubMed, Elsevier, Science Director, Cochrane Library, and Springer Link databases to collect information on low back pain, deep oscillation, and motion capture. The risk of bias of the articles was assessed using the Cochrane risk of bias tool. Finally, they were included 16 articles and 5 clinical trials which met the eligibility criteria. These articles discussed the effectiveness of deep oscillation therapy in reducing pain, eliminating inflammation, and increasing lumbar range of motion, as well as analyzing the use of motion capture systems in the analysis, diagnosis, and evaluation of a patient with low back pain before, during and after medical treatment. There is no strong scientific evidence that demonstrates the high effectiveness of deep oscillation therapy in patients with low back pain, using motion capture systems. This review outlines the background for future research directed at the use of deep oscillation therapy as a treatment for other types of musculoskeletal injuries.

Mimicking opioid analgesia in cortical pain circuits.

The anterior cingulate cortex plays a pivotal role in the cognitive and affective aspects of pain perception. Both endogenous and exogenous opioid signaling within the cingulate mitigate cortical nociception, reducing pain unpleasantness. However, the specific functional and molecular identities of cells mediating opioid analgesia in the cingulate remain elusive. Given the complexity of pain as a sensory and emotional experience, and the richness of ethological pain-related behaviors, we developed a standardized, deep-learning platform for deconstructing the behavior dynamics associated with the affective component of pain in mice-LUPE (Light aUtomated Pain Evaluator). LUPE removes human bias in behavior quantification and accelerated analysis from weeks to hours, which we leveraged to discover that morphine altered attentional and motivational pain behaviors akin to affective analgesia in humans. Through activity-dependent genetics and single-nuclei RNA sequencing, we identified specific ensembles of nociceptive cingulate neuron-types expressing mu-opioid receptors. Tuning receptor expression in these cells bidirectionally modulated morphine analgesia. Moreover, we employed a synthetic opioid receptor promoter-driven approach for cell-type specific optical and chemical genetic viral therapies to mimic morphine's pain-relieving effects in the cingulate, without reinforcement. This approach offers a novel strategy for precision pain management by targeting a key nociceptive cortical circuit with on-demand, non-addictive, and effective analgesia.

Strategies to enhance the response of liver cancer to pharmacological treatments.

In contrast to other types of cancers, there is no available efficient pharmacological treatment to improve the outcomes of patients suffering from major primary liver cancers, i.e., hepatocellular carcinoma and cholangiocarcinoma. This dismal situation is partly due to the existence in these tumors of many different and synergistic mechanisms of resistance, accounting for the lack of response of these patients, not only to classical chemotherapy but also to more modern pharmacological agents based on the inhibition of tyrosine kinase receptors (TKIs) and the stimulation of the immune response against the tumor using immune checkpoint inhibitors (ICIs). This review summarizes the effort to develop strategies to overcome this severe limitation, including searching for novel drugs derived from synthetic, semisynthetic, or natural products with vectorial properties against therapeutic targets to increase drug uptake or reduce drug export from cancer cells. Besides, immunotherapy is a promising line of research that is already starting to be implemented in clinical practice. Although less successful than in other cancers, the foreseen future for this strategy in treating liver cancers is considerable. Similarly, the pharmacological inhibition of epigenetic targets is highly promising. Many novel "epidrugs", able to act on "writer", "reader" and "eraser" epigenetic players, are currently being evaluated in preclinical and clinical studies. Finally, gene therapy is a broad field of research in the fight against liver cancer chemoresistance, based on the impressive advances recently achieved in gene manipulation. In sum, although the present is still dismal, there is reason for hope in the non-too-distant future.

GLR-dependent calcium and electrical signals are not coupled to systemic, oxylipin-based wound-induced gene expression in Marchantia polymorpha.

In angiosperms, wound-derived signals travel through the vasculature to systemically activate defence responses throughout the plant. In Arabidopsis thaliana, activity of vasculature-specific Clade 3 glutamate receptor-like (GLR) channels is required for the transmission of electrical signals and cytosolic Ca2+ ([Ca2+]cyt) waves from wounded leaves to distal tissues, triggering activation of oxylipin-dependent defences. Whether nonvascular plants mount systemic responses upon wounding remains unknown. To explore the evolution of systemic defence responses, we investigated electrical and calcium signalling in the nonvascular plant Marchantia polymorpha. We found that electrical signals and [Ca2+]cyt waves are generated in response to mechanical wounding and propagated to nondamaged distal tissues in M. polymorpha. Functional analysis of MpGLR, the only GLR encoded in the genome of M. polymorpha, indicates that its activity is necessary for the systemic transmission of wound-induced electrical signals and [Ca2+]cyt waves, similar to vascular plants. However, spread of these signals is neither coupled to systemic accumulation of oxylipins nor to a transcriptional defence response in the distal tissues of wounded M. polymorpha plants. Our results suggest that lack of vasculature prevents translocation of additional signalling factors that, together with electrical signals and [Ca2+]cyt waves, contribute to systemic activation of defences in tracheophytes.

A Principled Approach to Characterize and Analyze Partially Observed Confounder Data from Electronic Health Records.

Objective: Partially observed confounder data pose challenges to the statistical analysis of electronic health records (EHR) and systematic assessments of potentially underlying missingness mechanisms are lacking. We aimed to provide a principled approach to empirically characterize missing data processes and investigate performance of analytic methods. Methods: Three empirical sub-cohorts of diabetic SGLT2 or DPP4-inhibitor initiators with complete information on HbA1c, BMI and smoking as confounders of interest (COI) formed the basis of data simulation under a plasmode framework. A true null treatment effect, including the COI in the outcome generation model, and four missingness mechanisms for the COI were simulated: completely at random (MCAR), at random (MAR), and two not at random (MNAR) mechanisms, where missingness was dependent on an unmeasured confounder and on the value of the COI itself. We evaluated the ability of three groups of diagnostics to differentiate between mechanisms: 1)-differences in characteristics between patients with or without the observed COI (using averaged standardized mean differences [ASMD]), 2)-predictive ability of the missingness indicator based on observed covariates, and 3)-association of the missingness indicator with the outcome. We then compared analytic methods including "complete case", inverse probability weighting, single and multiple imputation in their ability to recover true treatment effects. Results: The diagnostics successfully identified characteristic patterns of simulated missingness mechanisms. For MAR, but not MCAR, the patient characteristics showed substantial differences (median ASMD 0.20 vs 0.05) and consequently, discrimination of the prediction models for missingness was also higher (0.59 vs 0.50). For MNAR, but not MAR or MCAR, missingness was significantly associated with the outcome even in models adjusting for other observed covariates. Comparing analytic methods, multiple imputation using a random forest algorithm resulted in the lowest root-mean-squared-error. Conclusion: Principled diagnostics provided reliable insights into missingness mechanisms. When assumptions allow, multiple imputation with nonparametric models could help reduce bias.

Risk versus Benefit of Tyrosine Kinase Inhibitors for Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Although the treatment landscape has rapidly evolved over the last years, hepatocellular carcinoma (HCC) is one of the most lethal cancers. With recent advances, both immunotherapy and tyrosine kinase inhibitors (TKIs)-based chemotherapy constitute the standard treatment for advanced HCC. A systematic search of randomized clinical trials employing TKIs was performed in 17 databases, obtaining 25 studies evaluating the prognosis, tumor response, and presence of adverse events (AEs) related to TKIs in HCC. Overall effect sizes were estimated for the hazard ratios (HR) and odds ratios (OR) with 95% confidence interval (CI), either extracted or calculated with the Parmar method, employing STATA 16. Heterogeneity was assessed by Chi-square-based Q-test and inconsistency (I2) statistic; source of heterogeneity by meta-regression and subgroup analysis; and publication bias by funnel plot asymmetry and Egger's test. The research protocol was registered in PROSPERO (CRD42023397263). Meta-analysis revealed a correlation between survival and tumor response parameters and TKI treatment vs. placebo, despite detecting high heterogeneity. Combined TKI treatment showed a significantly better objective response rate (ORR) with no heterogeneity, whereas publication bias was only detected with time to progression (TTP). Few gastrointestinal and neurological disorders were associated with TKI treatment vs. placebo or with combined treatment. However, a higher number of serious AEs were related to TKI treatment vs. sorafenib alone. Results show positive clinical benefits from TKI treatment, supporting the approval and maintenance of TKI-based therapy for advanced HCC, while establishing appropriate strategies to maximize efficacy and minimize toxicity.

Detrimental Impact of Atrial Fibrillation among Patients Hospitalized for Acute Exacerbation of COPD: Results of a Population-Based Study in Spain from 2016 to 2021.

Background/Objectives: To analyze changes in the prevalence of atrial fibrillation (AF) in patients hospitalized for acute exacerbation of chronic obstructive pulmonary disease (AE-COPD); to evaluate hospital outcomes according to AF status, assessing sex differences; to identify factors associated with AF presence; and to analyze variables associated with in-hospital mortality (IHM) in AE-COPD patients with AF. Methods: We used data from the Registry of Specialized Care Activity-Basic Minimum Data Set (RAE-CMBD) to select patients aged ≥40 years with COPD in Spain (2016-2021). We stratified the study population according to AF presence and sex. The propensity score matching (PSM) methodology was employed to create comparable groups based on age, admission year, and comorbidities at the time of hospitalization. Results: We identified 399,196 hospitalizations that met the inclusion criteria. Among them, 20.58% had AF. The prevalence of AF rose from 2016 to 2021 (18.26% to 20.95%), though the increase was only significant in men. The median length of hospital stay (LOHS) and IHM were significantly higher in patients with AF than in those without AF. After PSM, IHM remained significantly higher for man and women with AF. Older age, male sex, and several comorbidities were factors associated with AF. Additionally, older age, male sex, different comorbidities including COVID-19, hospitalization in the year 2020, mechanical ventilation, and intensive care unit (ICU) admission were associated with higher IHM in patients with AE-COPD and AF. Conclusions: AF prevalence was high in patients hospitalized for AE-COPD, was higher in men than in women, and increased over time. AF presence was associated with worse outcomes. The variables associated with IHM in hospitalized AE-COPD patients with AF were older age, male sex, different comorbidities including COVID-19 presence, hospitalization in the year 2020, need of mechanical ventilation, and ICU admission.

PGPB Consortium Formulation to Increase Fermentable Sugar in Agave tequilana Weber var. Blue: A Study in the Field.

Agave tequilana Weber var. Blue is used as the primary raw material in tequila production due to its fructans (inulin) content. This study evaluates the formulation of a plant-growth-promoting bacteria (PGPB) consortium (Pseudomonas sp. and Shimwellia sp.) to increase sugars in A. tequilana under field conditions. A total of three doses were tested: low (5 L ha-1), medium (10 L ha-1), and high (15 L ha-1), with a cellular density of 1 × 108 CFU mL-1 and one control treatment (without application). Total reducing sugars (TRS), inulin, sucrose, glucose, fructose, and plant growth were measured in agave plants aged 4-5 years at 0 (T0), 3 (T3), 6 (T6), and 12 (T12) months. Yield was recorded at T12. The TRS increased by 3%, and inulin by 5.3% in the high-dose treatment compared to the control at T12. Additionally, a low content of sucrose, glucose, and fructose (approximately 1%) was detected. At T12, the weight of agave heads increased by 31.2% in the medium dose and 22.3% in the high dose compared to the control. The high dose provided a higher inulin content. The A. tequilana plants were five years old and exhibited growth comparable to the standards for 6-7-year-old plants. This study demonstrates a sustainable strategy for tequila production, optimizing the use of natural resources and enhancing industry performance through increased sugar content and yield.