Individual variability in neural representations of mind-wandering.

Mind-wandering is a frequent, daily mental activity, experienced in unique ways in each person. Yet neuroimaging evidence relating mind-wandering to brain activity, for example in the default mode network (DMN), has relied on population- rather than individual-based inferences owing to limited within-person sampling. Here, three densely sampled individuals each reported hundreds of mind-wandering episodes while undergoing multi-session functional magnetic resonance imaging. We found reliable associations between mind-wandering and DMN activation when estimating brain networks within individuals using precision functional mapping. However, the timing of spontaneous DMN activity relative to subjective reports, and the networks beyond DMN that were activated and deactivated during mind-wandering, were distinct across individuals. Connectome-based predictive modeling further revealed idiosyncratic, whole-brain functional connectivity patterns that consistently predicted mind-wandering within individuals but did not fully generalize across individuals. Predictive models of mind-wandering and attention that were derived from larger-scale neuroimaging datasets largely failed when applied to densely sampled individuals, further highlighting the need for personalized models. Our work offers novel evidence for both conserved and variable neural representations of self-reported mind-wandering in different individuals. The previously unrecognized interindividual variations reported here underscore the broader scientific value and potential clinical utility of idiographic approaches to brain-experience associations.

While everyone experiences that their mind "wanders" throughout daily life, the content and form of inner experience is different in different people. In this study, we found that brain activity representing mind-wandering is different in each person, reflecting unique mental experiences. While people consistently engaged the brain's default mode network (DMN) during mind-wandering, there were inconsistencies in the way that the DMN was engaged and in the other networks throughout the brain that were engaged. Our study highlights that personalized approaches, which require that individuals are sampled more densely than is common in current practice, enable accurate insights into relationships between brain activity and inner experience.

Bidirectional Associations Between Cardiometabolic Multimorbidity and Depression and Mediation of Lifestyles: A Multicohort Study.

Background: Cardiometabolic multimorbidity (CMM) and depression are major health concerns, and the onset of either condition may heighten the risk of developing the other. Objectives: The goal of this study was to characterize the reciprocal associations between CMM and depression among middle-aged and older adults. Methods: This multicohort study used harmonized data from 5 prospective cohorts from China, South Korea, the United States, the United Kingdom, and Europe. Cardiometabolic diseases (CMDs) (including diabetes, heart diseases, and stroke) and depression were assessed at baseline and at 7 to 8 years' follow-up. Lifestyle factors, including physical activity, alcohol consumption, and smoking status, were regarded as potential mediators. Two sets of analyses, CMM-depression analyses (n = 67,188) and depression-CMM analyses (n = 65,738), were conducted to explore the bidirectional associations between CMM and depression. Results: In the CMM-depression analyses, 16,596 (24.7%) individuals developed depression. Participants with a single CMD (HR: 1.24; 95% CI:1.19-1.29) and CMM (HR: 1.52; 95% CI: 1.42-1.63) at baseline had higher risks of depression occurring. Physical activity and alcohol consumption significantly mediated 7.5% and 6.9% of the CMM-depression association, respectively. In the depression-CMM analyses, 1,461 (2.2%) participants developed CMM. The HR for developing CMM was 1.31 (95% CI: 1.14-1.50) in patients with depression, with increased risk of developing more CMDs. Physical activity and alcohol consumption mediated 12.0% and 7.1% of the depression-CMM association. The bidirectional relationships were more pronounced in Western countries than in Asian countries. Conclusions: CMM and depression were bidirectionally associated. The mediated effects of lifestyle factors were larger in the depression-lifestyle-CMM pathway than in the CMM-lifestyle-depression pathway.

GDF-15 levels in patients with polycystic ovary syndrome treated with metformin: a combined clinical and in silico pathway analysis.

Objective: Polycystic ovary syndrome (PCOS) is an endocrine disease characterized by metabolic, reproductive, and psychological manifestations. Growth and differentiation factor 15 (GDF-15) is a cytokine associated with metabolic and inflammatory disorders. Metformin is commonly used for the treatment of PCOS. We investigated the relationship between GDF-15 levels and PCOS, the effect of metformin on GDF-15 levels, and potential biologic pathways related to GDF-15. Subjects and methods: The study included 35 women with PCOS and 32 women without PCOS (controls). Both groups were compared in terms of GDF-15 levels. Additional analysis was conducted on samples from 22 women with PCOS who were treated with either metformin (n = 7) or placebo (n = 15), retrieved from a previous randomized, controlled trial. Levels of GDF-15 were measured using MILLIPLEX. The biologic pathways related to GDF-15 were evaluated using the databases STRING, SIGNOR, and Pathway Commons. The statistical analysis was conducted using the software SPSS. Results: Levels of GDF-15 were higher in the PCOS group compared with the non-PCOS group (p = 0.039). Among women with PCOS, GDF-15 levels were higher in those treated with metformin compared with placebo (p = 0.007). The proteins related to GDF-15 overlapped between the databases, and a significant interaction was found between GDF-15 and proteins related to PCOS and its complications, including those related to estrogen response, oxidative stress, ovarian infertility, interleukin (IL)-18, IL-4, the ratio of advanced glycation end products to their receptor (AGE/RAGE), leptin, transforming growth factor beta (TGF-ß), adipogenesis, and insulin. Conclusion: The findings of the present study suggest a relationship between GDF-15 and PCOS and a potential increase in GDF-15 levels with metformin treatment. An additional finding was that GDF-15 could be involved in biologic pathways related to PCOS complications.

Electrochemically assisted remediation of a highly chlorinated organic polluted sludge: A full-scale case study.

Electrochemical technology has emerged as an effective method to remediate soils in a laboratory environment. However, its practical application is often challenging due to the complexity of adopting small-scale parameters and identifying all the potential problems during the operation of electrokinetic plants. Here, a prototype demonstration in a space environment (Technology Readiness Level 7) is reported to remediate a 5 × 5 m2 plot of a leachate pond from a landfill containing dense sludge contaminated with chlorinated organic compounds. Bench-scale tests (50 kg per mock-up) were initially carried out to evaluate the effects of the key parameters (electric field, surfactants, and electrode materials) and demonstrated the feasibility of reducing contaminant concentrations in the sludge through dehalogenation and volatilisation. The average electro-osmotic flux was 0.23 cm day-1, comparable to that reported for silty soils. Iron electrodes enhanced electrokinetic water transport and reduced acidification, while glassy carbon electrodes increased water volatilisation, acidity near the anode, and dehalogenation of chlorinated hydrocarbons. Based on these findings, the full-scale design and operating conditions were selected. After 590 h of operation, the total pollutant concentration was reduced by 34 %, mainly due to volatilisation, using a sequence of six iron-electrode arrays at 1 V cm-1, which increased the sludge temperature over 60 °C. An evaporation rate of 0.021 cm d-1 and an electro-osmotic flux of 0.62 cm d-1 were achieved, consistent with the bench tests. These findings demonstrate the potential of electrokinetic plants for the remediation of sludges and provide expertise applicable to future remediation at other contaminated sites.

Modified Beer-Lambert algorithm to measure pulsatile blood flow, critical closing pressure, and intracranial hypertension.

We introduce a frequency-domain modified Beer-Lambert algorithm for diffuse correlation spectroscopy to non-invasively measure flow pulsatility and thus critical closing pressure (CrCP). Using the same optical measurements, CrCP was obtained with the new algorithm and with traditional nonlinear diffusion fitting. Results were compared to invasive determination of intracranial pressure (ICP) in piglets (n = 18). The new algorithm better predicted ICP elevations; the area under curve (AUC) from logistic regression analysis was 0.85 for ICP ≥ 20 mmHg. The corresponding AUC for traditional analysis was 0.60. Improved diagnostic performance likely results from better filtering of extra-cerebral tissue contamination and measurement noise.

Trends in body mass index for people with and without HIV: Pooled analysis of nationally-representative health surveys from 10 countries and 173,800 adults in Africa.

It remains unclear if and how body mass index (BMI) levels have changed over time in HIV endemic regions. We described trends in mean BMI and prevalence of overweight between 2003-2019 in 10 countries in Africa including people living with (PLWH) and without (PLWoH) HIV. We pooled Demographic and Health Surveys (DHS) from countries where ≥2 surveys >4 years apart were available with height/weight measurements and HIV tests. HIV status was ascertained with a finger-prick dried blood spot (DBS) specimen tested in a laboratory. The DBS is taken as part of the regular DHS procedures. We summarized age and socioeconomic status standardized sex-specific mean BMI (kg/m2) and prevalence of overweight (BMI ≥25 kg/m2) by HIV status. We fitted country-level meta-regressions to ascertain if changes in ART coverage were correlated with changes in BMI. Before 2011, women LWH (22.9 [95% CI: 22.2-23.6]) and LWoH (22.6 [95% CI: 22.3-22.8]) had similar mean BMI. Over time, mean BMI increased more in women LWH (+0.8 [95% CI: 0.7-0.8] BMI units) than LWoH (+0.2 [95% CI: 0.2-0.3]). Before 2013, the mean BMI was similar between men LWH (21.1 (95% CI: 20.3-21.9)) and LWoH (20.8 (95% CI: 20.6-21.1)). Over time, mean BMI increased more in men LWoH (+0.3 [95% CI: 0.3-0.3]) than LWH (+0.1 [95% CI: 0.1-0.1]). The same profile was observed for prevalence of overweight. ART coverage was not strongly associated with BMI changes. Mean BMI and prevalence of overweight were similar in PLWH and PLWoH, yet in some cases the estimates for PWLH were on track to catch up with those for PLWoH. BMI monitoring programs are warranted in PLWH to address the rising BMI trends.

Estimating the prevalence, factors, and conditions associated with Parkinson disease: a population-based study in Peru.

This study aimed to estimate the population-based Parkinson disease prevalence, and to explore potentially associated factors and conditions. A population-based survey was conducted in Northern Peru. Symptoms compatible with Parkinson's were defined using a validated Spanish questionnaire (≥ 42 points suggest Parkinson's). Potential factors (e.g., age, sex, etc.) and clinical conditions (e.g., depressive symptoms, perceived stress, etc.) associated with Parkinson's were assessed. In total, 1,609 subjects were included, mean age of participants was 48.2 (SD: 10.6), and 810 (50.3%) were women. Parkinson's prevalence was 1.6% (95%CI: 1.0; 2.4). Those aged ≥ 55 years, and those who reported using wood as fuel for household cooking had a Parkinson's prevalence from 3.5 to 4 times greater than those who did not. The presence of depressive symptoms, anxiety symptoms, perceived stress, poor sleep quality, and cognitive impairment was more common among those with Parkinson's, and quality of life in these participants was lower than those without Parkinson's. In conclusion, 1.6% of the population shows symptoms compatible with Parkinson's. Age and use of wood for household cooking were factors associated with Parkinson's. Several mental health conditions and lower quality of life were more frequent among those with Parkinson's. Appropriate strategies are required to detect, prevent, and manage Parkinson's cases.

Comparison of wild-type and high-risk PNPLA3 variants in a human biomimetic liver microphysiology system for metabolic dysfunction-associated steatotic liver disease precision therapy.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a worldwide health epidemic with a global occurrence of approximately 30%. The pathogenesis of MASLD is a complex, multisystem disorder driven by multiple factors, including genetics, lifestyle, and the environment. Patient heterogeneity presents challenges in developing MASLD therapeutics, creating patient cohorts for clinical trials, and optimizing therapeutic strategies for specific patient cohorts. Implementing pre-clinical experimental models for drug development creates a significant challenge as simple in vitro systems and animal models do not fully recapitulate critical steps in the pathogenesis and the complexity of MASLD progression. To address this, we implemented a precision medicine strategy that couples the use of our liver acinus microphysiology system (LAMPS) constructed with patient-derived primary cells. We investigated the MASLD-associated genetic variant patatin-like phospholipase domain-containing protein 3 (PNPLA3) rs738409 (I148M variant) in primary hepatocytes as it is associated with MASLD progression. We constructed the LAMPS with genotyped wild-type and variant PNPLA3 hepatocytes, together with key non-parenchymal cells, and quantified the reproducibility of the model. We altered media components to mimic blood chemistries, including insulin, glucose, free fatty acids, and immune-activating molecules to reflect normal fasting (NF), early metabolic syndrome (EMS), and late metabolic syndrome (LMS) conditions. Finally, we investigated the response to treatment with resmetirom, an approved drug for metabolic syndrome-associated steatohepatitis (MASH), the progressive form of MASLD. This study, using primary cells, serves as a benchmark for studies using "patient biomimetic twins" constructed with patient induced pluripotent stem cell (iPSC)-derived liver cells using a panel of reproducible metrics. We observed increased steatosis, immune activation, stellate cell activation, and secretion of pro-fibrotic markers in the PNPLA3 GG variant compared to the wild-type CC LAMPS, consistent with the clinical characterization of this variant. We also observed greater resmetirom efficacy in the PNPLA3 wild-type CC LAMPS compared to the GG variant in multiple MASLD metrics, including steatosis, stellate cell activation, and the secretion of pro-fibrotic markers. In conclusion, our study demonstrates the capability of the LAMPS platform for the development of MASLD precision therapeutics, enrichment of patient cohorts for clinical trials, and optimization of therapeutic strategies for patient subgroups with different clinical traits and disease stages.

Lower Microscopy Sensitivity with Decreasing Malaria Prevalence in the Urban Amazon Region, Brazil, 2018-2021.

Malaria is increasingly diagnosed in urban centers across the Amazon Basin. In this study, we combined repeated prevalence surveys over a 4-year period of a household-based random sample of 2,774 persons with parasite genotyping to investigate the epidemiology of malaria in Mâncio Lima, the main urban transmission hotspot in Amazonian Brazil. We found that most malarial infections were asymptomatic and undetected by point-of-care microscopy. Our findings indicate that as malaria transmission decreases, the detection threshold of microscopy rises, resulting in more missed infections despite similar parasite densities estimated by molecular methods. We identified genetically highly diverse populations of Plasmodium vivax and P. falciparum in the region; occasional shared lineages between urban and rural residents suggest cross-boundary propagation. The prevalence of low-density and asymptomatic infections poses a significant challenge for routine surveillance and the effectiveness of malaria control and elimination strategies in urbanized areas with readily accessible laboratory facilities.

Coffee Oil Extraction Methods: A Review.

Green and roasted coffee oils are products rich in bioactive compounds, such as linoleic acid and the diterpenes cafestol and kahweol, being a potential ingredient for food and cosmetic industries. An overview of oil extraction techniques most applied for coffee beans and their influence on the oil composition is presented. Both green and roasted coffee oil extractions are highlighted. Pressing, Soxhlet, microwave, and supercritical fluid extraction were the most used techniques used for coffee oil extraction. Conventional Soxhlet is most used on a lab scale, while pressing is most used in industry. Supercritical fluid extraction has also been evaluated mainly due to the environmental approach. One of the highlighted activities in Brazilian agribusiness is the industrialization of oils due to their increasing use in the formulation of cosmetics, pharmaceuticals, and foods. Green coffee oil (raw bean) has desirable bioactive compounds, increasing the interest of private companies and research institutions in its extraction process to preserve the properties contained in the oils.

Associations between socioeconomic inequalities and progression to psychological and cognitive multimorbidities after onset of a physical condition: a multicohort study.

Background: Chronic physical conditions (e.g., heart diseases, diabetes) increase with population ageing, contributing to psychological and cognitive multimorbidities. Yet, little is known about socioeconomic inequalities in this process. We examined the associations between socioeconomic status (SES) and progression to psychological and cognitive multimorbidities after onset of a physical condition. Methods: We used harmonized individual-level data from five prospective cohort studies across 24 countries in the US, Europe and Asia, with repeated morbidity measurements between 2002 and 2021. Participants with at least one new-onset physical conditions (hypertension, diabetes, heart diseases, stroke, chronic lung diseases, cancer, or arthritis) were followed up for progression to physical-psychological multimorbidity, physical-cognitive multimorbidity, and physical-psychological-cognitive multimorbidity. SES was determined based on educational level and total household wealth at the onset of a physical condition. Time to and incidence rates of progressing psychological and cognitive multimorbidities were estimated in analyses stratified by SES. Fine-Gray subdistribution hazard models and multi-state models were used to estimate the associations between SES and progression to psychological and cognitive multimorbidities. Findings: Among 20,250 participants aged ≥45 years (mean age at a physical condition onset 65.38 years, standard deviation 8.37) with at least one new-onset physical conditions in the analysis, 7928 (39.2%) progressed to psychological and cognitive multimorbidities during a median follow-up of 8.0 years (168,575 person-years). The mean survival time free from physical-psychological-cognitive multimorbidity was 11.96 years (95% confidence interval 11.57-12.34) in low SES individuals, compared to 15.52 years (15.40-15.63) in high SES individuals, with the corresponding incidence rate of 18.44 (16.32-20.82) and 3.15 (2.48-4.01) per 1000 person-years, respectively. The associations of education, household wealth and SES with multimorbidities followed a dose-dependent relation, with subdistribution hazard ratios per decreasing SES category being 1.24 (1.19-1.29) for physical-psychological multimorbidity, 1.47 (1.40-1.54) for physical-cognitive multimorbidity, and 1.84 (1.72-1.97) for physical-psychological-cognitive multimorbidity. The strongest SES-multimorbidities associations were observed in participants with arthritis, hypertension or diabetes. In multi-state models SES was linked to all five transitions from physical condition to physical-psychological multimorbidity, physical-cognitive multimorbidity and physical-psychological-cognitive multimorbidity. Interpretation: Socioeconomic inequalities are associated with the progression of a chronic physical condition, with the lower SES groups had both an earlier time to and a higher incidence of psychological and cognitive multimorbidities. These findings underscore the need for more effective equity-oriented policies and healthcare practices to address reduced psychological wellness and cognitive maintenance among individuals with low SES and physical conditions. Funding: Zhejiang University Hundred Talents Program Research Initiation Fund, Fundamental Research Funds for the Central Universities in China, Wellcome Trust, Medical Research Council, National Institute on Aging, Academy of Finland.

Metal(triphenylphosphine)-atovaquone Complexes: Synthesis, Antimalarial Activity, and Suppression of Heme Detoxification.

To ascertain the bioinorganic chemistry of metals conjugated with quinones, the complexes [Ag(ATV)(PPh3)2] (1), [Au(ATV)(PPh3)]·2H2O (2), and [Cu(ATV)(PPh3)2] (3) were synthesized by the coordination of the antimalarial naphthoquinone atovaquone (ATV) to the starting materials [Ag(PPh3)2]NO3, [Au(PPh3)Cl], and [Cu(PPh3)2NO3], respectively. These complexes were characterized by analytical and spectroscopical techniques. X-ray diffraction of single crystals precisely confirmed the coordination mode of ATV to the metals, which was monodentate or bidentate, depending on the metal center. Both coordination modes showed high stability in the solid state and in solution. All three complexes showed negative log D values at pH 5, but at pH 7.4, while complex 2 continued to have a negative log D value, complexes 1 and 3 displayed positive values, indicating a more hydrophilic character. ATV and complexes 1-3 could bind to ferriprotoporphyrin IX (FePPIX); however, only complexes 1-3 could inhibit ß-hematin crystal formation. Phenotype-based activity revealed that all three metal complexes are able to inhibit the growth of P. falciparum with potency and selectivity comparable to those of ATV, while the starting materials lack this activity. The outcomes of this chemical design may provide significant insights into structure-activity relationships for the development of new antimalarial agents.

Effectiveness of intracuff alkalinized lidocaine associated with intravenous dexamethasone in reducing laryngotracheal morbidity in children undergoing general anesthesia for tonsillectomy: a randomized controlled trial.

BACKGROUND: Postoperative sore throat is one of the main postoperative complaints in patients undergoing tonsillectomy. As the primary outcome, we aimed to determine whether endotracheal tube cuffs filled with alkalinized lidocaine are associated with a lower incidence of postoperative sore throat and anesthesia emergence phenomena in children undergoing tonsillectomy or adenotonsillectomy. We also assessed the potential additional benefits of IV dexamethasone in reducing postoperative laryngotracheal morbidity. METHODS: This is a clinical prospective, randomized, controlled trial. Patients were randomly allocated to one of four groups, as follows: air - endotracheal tube cuff filled with air; air/dex - endotracheal tube cuff filled with air and intravenous dexamethasone; lido - endotracheal tube cuff filled with alkalinized lidocaine; and lido/dex - endotracheal tube cuff filled with alkalinized lidocaine and intravenous dexamethasone. Perioperative hemodynamic parameters and the incidence of postoperative nausea and vomiting, coughing and hoarseness were recorded. Postoperative sore throat was assessed in the postanesthetic care unit and 24 hours post tracheal extubation. RESULTS: In total, 154 children aged 4-12 years, ASA physical status I or II, undergoing general anesthesia for elective tonsillectomy and adenotonsillectomy, were assessed for postoperative sore throat in this study. The incidence of postoperative sore throat 24 hours after tracheal extubation was significantly lower in the lido/dex group compared to groups air and air/dex (p = 0.01). However, no additional reduction in these symptoms was observed from the intravenous administration of dexamethasone when comparing the lido and lido/dex groups. Similarly, there were no differences among groups regarding perioperative hemodynamic variables or postoperative nausea and vomiting, coughing, and hoarseness during the study period. CONCLUSION: Intracuff alkalinized lidocaine, associated with intravenous dexamethasone, might be effective in reducing sore throat 24 hours post-tonsillectomy or adenotonsillectomy in children when compared to the use of air as the cuff insufflation media.

Novel High-tech, Low-cost Ventilation for Military Use, Mass Casualty Incidents, Stockpiling, and Underserved Communities.

INTRODUCTION: Despite the significant need for mechanical ventilation in- and out-of-hospital, mechanical ventilators remain inaccessible in many instances because of cost or size constraints. Mechanical ventilation is especially critical in trauma scenarios, but the impractical size and weight of standard mechanical ventilators restrict first responders from carrying them in medical aid bags, leading to reliance on imprecise manual bag-mask ventilation. This is particularly important in combat-related injury, where airway compromise and respiratory failure are leading causes of preventable death, but medics are left without necessary mechanical ventilation. To address the serious gaps in mechanical ventilation accessibility, we are developing an Autonomous, Modular, and Portable Ventilation platform (AMP-Vent) suitable for austere environments, prolonged critical care, surgical applications, mass casualty incidents, and stockpiling. The core system is remarkably compact, weighing <2.3 kg, and can fit inside a shoebox (23.4 cm × 17.8 cm × 10.7 cm). Notably, this device is 65% lighter than standard transport ventilators and astoundingly 96% lighter than typical intensive care unit ventilators. Beyond its exceptional portability, AMP-Vent can be manufactured at less than one-tenth the cost of conventional ventilators. Despite its reduced size and cost, the system's functionality is uncompromised. The core system is equipped with closed-loop sensors and advanced modes of ventilation (pressure-control, volume-control, and synchronized intermittent mandatory ventilation), enabling quality care in a portable form factor. The current prototype has undergone preliminary preclinical testing and optimization through trials using a breathing simulator (ASL 5000) and in a large animal model (swine). This report aims to introduce a novel ventilation system and substantiate its promising performance through evidence gathered from preclinical studies. MATERIALS AND METHODS: Lung simulator testing was performed using the ASL 5000, in accordance with table 201.105 "pressure-control inflation-type testing" from ISO 80601-2-12:2020. Following simulations, AMP-Vent was tested in healthy 10-kg female domestic piglets. The Children's Hospital of Philadelphia Institutional Animal Care and Use Committee approved all animal procedures. Swine received 4-min blocks of alternating ventilation, where AMP-Vent and a conventional anesthesia ventilator (GE AISYS CS2) were used to titrate to varied end-tidal carbon dioxide (EtCO2) goals with the initial ventilator switching for each ascending target (35, 40, 45, 50, 55 mmHg). RESULTS: During ASL 5000 simulations, AMP-Vent exhibited consistent performance under varied conditions, maintaining a coefficient of variation of 2% or less within each test. In a large animal study, AMP-Vent maintained EtCO2 and SpO2 targets with comparable performance to a conventional anesthesia ventilator (GE AISYS CS2). Furthermore, the comparison of minute ventilation (Ve) distributions between the conventional anesthesia ventilator and AMP-Vent at several EtCO2 goals (35, 40, 45, 50, and 55 mmHg) revealed no statistically significant differences (p = 0.46 using the Kruskal-Wallis rank sum test). CONCLUSIONS: Preclinical results from this study highlight AMP-Vent's core functionality and consistent performance across varied scenarios. AMP-Vent sets a benchmark for portability with its remarkably compact design, positioning it to revolutionize trauma care in previously inaccessible medical scenarios.

Human induced pluripotent stem cell based hepatic-modeling of lipid metabolism associated TM6SF2 E167K variant.

BACKGROUND AND AIMS: TM6SF2 rs58542926 (E167K) is related to increased prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD). Conflicting mouse study results highlight the need for a human model to understand this mutation's impact. This study aims to create and characterize a reliable human in vitro model to mimic the effects of the TM6SF2-E167K mutation for future studies. APPROACH AND RESULTS: We used gene editing on human human-induced pluripotent stem cells (iPSC) from a healthy individual to create cells with the TM6SF2-E167K mutation. After hepatocyte directed differentiation, we observed decreased TM6SF2 protein expression, increased intracellular lipid droplets and total cholesterol in addition to reduced VLDL secretion. Transcriptomics revealed upregulation of genes involved in lipid, fatty acid, and cholesterol transport, flux, and oxidation. Global lipidomics showed increased lipid classes associated with ER stress, mitochondrial dysfunction, apoptosis, and lipid metabolism. Additionally, the TM6SF2-E167K mutation conferred a pro-inflammatory phenotype with signs of mitochondria and ER stress. Importantly, by facilitating protein folding within the ER of hepatocytes carrying TM6SF2-E167K mutation, VLDL secretion and ER stress markers improved. CONCLUSIONS: Our findings indicate that induced hepatocytes generated from iPSCs carrying the TM6SF2-E167K recapitulate the effects observed in human hepatocytes from individuals with the TM6SF2 mutation. This study characterizes an in vitro model that can be used as a platform to identify potential clinical targets and highlights the therapeutic potential of targeting protein misfolding to alleviate ER stress and mitigate the detrimental effects of the TM6SF2-E167K mutation on hepatic lipid metabolism.

Impact of Tricuspid Repair on Surgical Death in Patients Undergoing Mitral Valve Surgery Due to Rheumatic Disease.

Background: Tricuspid valve repair during mitral valve replacement surgery remains a controversial topic. The risk-benefit ratio in some populations remains uncertain, especially in rheumatic heart disease patients. Therefore, we aimed to evaluate the impact of concomitant tricuspid repair on surgical mortality in patients undergoing cardiac surgery due to rheumatic mitral valve disease who have moderate to severe functional tricuspid regurgitation. Methods: This is a prospective cohort study from January 1, 2017, to December 30, 2022. All patients over 18 years of age who underwent cardiac surgery to correct rheumatic mitral valve disease with concomitant moderate to severe tricuspid regurgitation were included. The primary outcome was a surgical death. In an exploratory analysis, clinical and echocardiographic data were obtained 2 years after the procedure. Results: Of the 144 patients included, 83 (57.6%) underwent tricuspid valve repair. The mean age was 46.2 (±12.3) years with 107 (74.3%) female individuals, the median left ventricular ejection fraction was 61.0% (55-67), and systolic pulmonary artery pressure (sPAP) was 55.0 mmHg (46-74), with 45 (31.3%) individuals with right ventricular dysfunction. The total in-hospital mortality was 15 (10.4%) individuals, and there was no difference between the groups submitted or not to tricuspid repair: 10 (12.0%) vs. 5 (7.5%); p = 0.46, respectively. There was an association with one variable independently: the sPAP value, relative risk 1.04 (1.01-1.07), p = 0.01. The estimated cut-off value of sPAP that indicates higher early mortality through the receiver operating characteristic curve (area 0.70, p = 0.012) was 73.5 mmHg. Conclusions: Performing tricuspid repair in individuals who were undergoing cardiac surgery to correct rheumatic mitral valve disease was not associated with increased surgical mortality. Our results suggest the safety of tricuspid repair even in this high-risk population, reinforcing the recommendations in current guidelines.

Next-generation chemotherapy treatments based on black hole algorithms: From cancer remission to chronic disease management.

PROBLEM: Therapeutic planning strategies have been developed to enhance the effectiveness of cancer drugs. Nevertheless, their performance is highly limited by the inefficient biological representativeness of predictive tumor growth models, which hinders their translation to clinical practice. OBJECTIVE: This study proposes a disruptive approach to oncology based on nature-inspired control using realistic Black Hole physical laws, in which tumor masses are trapped to experience attraction dynamics on their path to complete remission or to become a chronic disease. This control method is designed to operate independently of individual patient idiosyncrasies, including high tumor heterogeneities and highly uncertain tumor dynamics, making it a promising avenue for advancing beyond the limitations of the traditional survival probabilistic paradigm. DESIGN: Here, we provide a multifaceted study of chemotherapy therapeutic planning that includes: (1) the design of a pioneering controller algorithm based on physical laws found in the Black Holes; (2) investigation of the ability of this controller algorithm to ensure stable equilibrium treatments; and (3) simulation tests concerning tumor volume dynamics using drugs with significantly different pharmacokinetics (Cyclophosphamide and Atezolizumab), tumor volumes (200 mm3 and 12 732 mm3) and modeling characterizations (Gompertzian and Logistic tumor growth models). RESULTS: Our results highlight the ability of this new astrophysical-inspired control algorithm to perform effective chemotherapy treatments for multiple tumor-treatment scenarios, including tumor resistance to chemotherapy, clinical scenarios modelled by time-dependent parameters, and highly uncertain tumor dynamics. CONCLUSIONS: Our findings provide strong evidence that cancer therapy inspired by phenomena found in black holes can emerge as a disruptive paradigm. This opens new high-impacting research directions, exploring synergies between astrophysical-inspired control algorithms and Artificial Intelligence applied to advanced personalized cancer therapeutics.

Cardiovascular predicted risk: A population-based comparison of the pooled cohorts equation and PREVENT.

BACKGROUND: While the new cardiovascular risk score (PREVENT) has improvements, its implementation may lead to significant changes in the distribution of atherosclerotic cardiovascular diseases (ASCVD) in the United States. We aimed to quantify and characterize the distribution of the 10-year predicted absolute ASCVD risk using the Pooled Cohorts Equation (PCE) and PREVENT. METHODS: We utilized the latest (2017-March 2020) round of the National Health and Nutrition Examination Survey (NHANES). Accounting for the complex survey design of the NHANES, we computed the mean predicted ASCVD risk overall and by sex, race, and education; similarly, we computed the prevalence of cardiovascular risk groups (<5%, 5%-7.4%, 7.5%-19.9%, and ≥ 20%). RESULTS: The study included 3845 observations, representing 109,692,509 people. Using the PREVENT calculator resulted in a reduction of the mean 10-year ASCVD absolute risk by half compared to the PCE: 9.1% vs 4.7%. Under the PCE, the high-risk category accounted for 12.5% of the population, whereas under PREVENT it fell to 0.4%. Among those previously classified as high-risk under the PCE, 3.5% would remain in this category with PREVENT, while 93% would be reclassified as intermediate risk. CONCLUSIONS: The adoption of the novel cardiovascular risk score, PREVENT, could lower the average predicted ASCVD risk and reduce the prevalence of high-risk individuals. While this shift might suggest improved cardiovascular health, it could also lead to complacency, potentially undermining ongoing public health efforts aimed at preventing cardiovascular disease.

Fungemia due to opportunistic fungi in patients with cancer.

BACKGROUND: Fungemia due to uncommon fungi and secondary to multiple risk factors has become an emergent health problem, particularly in oncology patients. AIMS: This study shows the following data collected during an 11-year period in a tertiary care oncologic center from patients with fungemia: demographic data, clinical characteristics, and outcome. METHODS: A retrospective study was performed at Instituto Nacional de Cancerología, a 135-bed referral cancer center in Mexico City, from July 2012 to June 2023. All episodes of non-Candida fungemia were included. RESULTS: Sixteen cases with uncommon fungemia were found in the database, representing 0.3% from all the blood cultures positive during the study period, and 8.5% from all the fungi isolated. The most common pathogens identified in our series were Histoplasma capsulatum, Acremonium spp., Trichosporon asahii, and Saccharomyces cerevisiae. Eight patients had hematologic malignancies, and five had severe neutropenia. In eight cases fungemia was considered catheter-related, in four cases was classified as primary, and in the last four it was diagnosed as disseminated fungal diseases. Mortality at 30 days was 43.8%. CONCLUSIONS: The improved diagnostic tools have led to a better diagnosis of uncommon fungal infections. More aggressive therapeutic approaches, particularly in patients with malignancies, would increase survival rates in these potentially fatal diseases.

Progressive verbal apraxia of reading.

We identified a syndrome characterized by a relatively isolated progressive impairment of reading words that the patient was able to understand and repeat but without other components of speech apraxia. This cluster of symptoms fits a new syndrome designated Progressive Verbal Apraxia of Reading. A right-handed man (AB) came with a 2.5-year history of increasing difficulties in reading aloud. He was evaluated twice, 2 years apart, using multimodal neuroimaging techniques and quantitative neurolinguistic assessment. In the laboratory, reading difficulties arose in the context of intact visual and auditory word recognition as well as intact ability to understand and repeat words he was unable to read aloud. The unique feature was the absence of dysarthria or speech apraxia in tasks other than reading. Initial imaging did not reveal statistically significant atrophy. Structural magnetic resonance and FDG-PET imaging at the second assessment revealed atrophy and hypometabolism in the right posterior cerebellum, in areas shown to be part of his language network by task-based functional neuroimaging at initial assessment. This syndromic cluster can be designated Progressive Verbal Apraxia of Reading, an entity that has not been reported previously to the best of our knowledge. We hypothesize a selective disconnection of the visual word recognition system from the otherwise intact articulatory apparatus, a disconnection that appears to reflect the disruption of multisynaptic cerebello-cortical circuits.