Excess Mortality and Loss of Life Expectancy After Myocardial Infarction: A Registry-Based Matched Cohort Study.

BACKGROUND: The effect of myocardial infarction (MI) on life expectancy is difficult to study because the prevalence of MI hinders direct comparison with the life expectancy of the general population. We sought to assess this in relation to age, sex, and left ventricular ejection fraction (LVEF) by comparing individuals with MI with matched comparators without previous MI. METHODS: We included patients with a first MI between 1991 and 2022 from the nationwide SWEDEHEART registry (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies), each matched with up to 5 comparators on age, sex, and region of residence. Flexible parametric survival models were used to estimate excess mortality risk and mean loss of life expectancy (LOLE) depending on index year, age, sex, and LVEF, and adjusted for differences in characteristics. RESULTS: A total of 335 748 cases were matched to 1 625 396 comparators. A higher LOLE was observed in younger individuals, women, and those with reduced LVEF (<50%). In 2022, the unadjusted and adjusted mean LOLE spanned from 11.1 and 9.5 years in 50-year-old women with reduced LVEF to 5 and 3.7 months in 80-year-old men with preserved LVEF. Between 1992 and 2022, the adjusted mean LOLE decreased by 36% to 55%: from 4.4 to 2.0 years and from 3.3 to 1.9 years in 50-year-old women and men, respectively, and from 1.7 to 1.0 years and from 1.4 to 0.9 years in 80-year-old women and men, respectively. CONCLUSIONS: LOLE is higher in younger individuals, women, and those with reduced LVEF, but is attenuated when adjusting for comorbidities and risk factors. Advances in MI treatment during the past 30 years have almost halved LOLE, with no clear sign of leveling off to a plateau.

The effect of acute respiratory demand on postural control: A systematic review.

BACKGROUND: Postural control can be challenged by breathing. RESEARCH QUESTION: What is the effect of an acute increase in respiratory demand on postural control compared to quiet breathing? METHODS: A systematic review was conducted. Electronic databases were systematically searched until October 18, 2022 on studies reporting changes in center of pressure (CoP) motion related to an acute manipulation of respiratory demand compared to quiet breathing during upright standing in healthy participants and/or participants with a clinical condition. RESULTS: Twenty-one studies in healthy participants showed that voluntary (not metabolic-induced) hyperventilation or inspiratory resistive loading significantly increased CoP motion, while breath-holding decreased CoP motion, compared to quiet breathing (p< 0.05). Manipulating respiratory rate or breathing patterns did not reveal consistent results. Four studies showed that people with low back pain showed similar CoP responses to increasing respiratory demand (p> 0.05), except for breathing at different rates, whereas they showed greater CoP motion during quiet breathing. SIGNIFICANCE: The extent of postural disturbance depended on the breathing mode and how it was quantified (i.e., CoP coupled with breathing movement or overall CoP measures). Voluntary hyperventilation and inspiratory resistive loading increased postural sway. For voluntary hyperventilation, this could be explained by CoP motion being directly coupled to chest wall movements whereas metabolic-induced hyperventilation did not increase CoP motion or CoP coupling with breathing. Breath-holding decreased postural sway. Patients with low back pain show greater postural sways than pain-free individuals during quiet breathing, although they exhibit similar postural adaptations to respiratory-related challenges as controls.

Current Concepts in the Epigenetic Regulation of Cardiac Fibrosis.

Cardiac fibrosis is a significant driver of congestive heart failure, a syndrome that continues to affect a growing patient population globally. Cardiac fibrosis results from a constellation of complex processes at the transcription, receptor, and signaling axes levels. Various mediators and signaling cascades, such as the transformation growth factor-beta pathway, have been implicated in the pathophysiology of cardiac tissue fibrosis. Our understanding of these markers and pathways has improved in recent years as more advanced technologies and assays have been developed, allowing for better delineation of the crosstalk between specific factors. There is mounting evidence suggesting that epigenetic modulation plays a pivotal role in the progression of cardiac fibrosis. Transcriptional regulation of key pro- and anti-fibrotic pathways can accentuate or blunt the rate and extent of fibrosis at the tissue level. Exosomes, micro-RNAs, and long non-coding RNAs all belong to factors that can impact the epigenetic signature in cardiac fibrosis. Herein, we comprehensively review the latest literature about exosomes, their contents, and cardiac fibrosis. In doing so, we highlight the specific transcriptional factors with pro- or anti-fibrotic properties. We also assimilate the data supporting these mediators' potential utility as diagnostic or prognostic biomarkers. Finally, we offer insight into where further work can be done to fill existing gaps to translate pre-clinical findings better and improve clinical outcomes.

Anti-tumor withanolides as signal transducers and activators of transcription 3 (STAT3)-inhibition from Withania obtusifolia.

The Solanaceae family and the Withania genus specifically are rich sources of medicinal plants. Liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS/MS) revealed a predominance of withanolides from an organic extract of Withania obtusifolia. A constructed molecular network uncovered the presence of potentially novel withanolides. A series of withanolides were then isolated and structurally characterized from the extract including two new withanolides (withafolia A and withafolia B) and seven previously reported metabolites. Of the isolated compounds, cytotoxicity of withanolide J, physaperuvin G, and a commercial STAT3 inhibitor (S3I-201) were assessed against a human leukemia HL-60 cell line resulting in IC50 values of 26, 29, and 120 µM, respectively. In silico molecular docking simulations indicate that withanolide J and physaperuvin G can bind as an inhibitor in the active site of STAT3 with docking scores comparable to the selective STAT3 inhibitor, S3I-201.

Quantifying superimposed protein flow dynamics in live cells using spatial filtering and spatiotemporal image correlation spectroscopy.

Flow or collective movement is a frequently observed phenomenon for many cellular components including the cytoskeletal proteins actin and myosin. To study protein flow in living cells, we and others have previously used spatiotemporal image correlation spectroscopy (STICS) analysis on fluorescence microscopy image time series. Yet, in cells, multiple protein flows often occur simultaneously on different scales resulting in superimposed fluorescence intensity fluctuations that are challenging to separate using STICS. Here, we exploited the characteristic that distinct protein flows often occur at different spatial scales present in the image series to disentangle superimposed protein flow dynamics. We employed a newly developed and an established spatial filtering algorithm to alternatively accentuate or attenuate local image intensity heterogeneity across different spatial scales. Subsequently, we analysed the spatially filtered time series with STICS, allowing the quantification of two distinct superimposed flows within the image time series. As a proof of principle of our analysis approach, we used simulated fluorescence intensity fluctuations as well as time series of nonmuscle myosin II in endothelial cells and actin-based podosomes in dendritic cells and revealed simultaneously occurring contiguous and noncontiguous flow dynamics in each of these systems. Altogether, this work extends the application of STICS for the quantification of multiple protein flow dynamics in complex biological systems including the actomyosin cytoskeleton.

Positionally distinct interferon stimulated dermal immune acting fibroblasts promote neutrophil recruitment in Sweet's syndrome.

Sweet's syndrome is a poorly understood inflammatory skin disease characterized by neutrophil infiltration to the dermis. Single-nucleus and bulk transcriptomics of archival clinical samples of Sweet's syndrome revealed a prominent interferon signature in Sweet's syndrome skin that was reduced in tissue from other neutrophilic dermatoses. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured primary human dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, single-molecule resolution spatial transcriptomics of skin in Sweet's syndrome identified positionally distinct immune acting fibroblasts that included a CXCL1+ subset proximal to neutrophils and a CXCL12+ subset distal to the neutrophilic infiltrate. This study defines the cellular landscape of neutrophilic dermatoses and suggests dermal immune acting fibroblasts play a role in the pathogenesis of Sweet's syndrome through recognition of type I interferons.

Can we Predict Drug Excretion into Saliva? A Systematic Review and Analysis of Physicochemical Properties.

BACKGROUND AND OBJECTIVES: Saliva is a patient-friendly matrix for therapeutic drug monitoring (TDM) but is infrequently used in routine care. This is due to the uncertainty of saliva-based TDM results to inform dosing. This study aimed to retrieve data on saliva-plasma concentration and subsequently determine the physicochemical properties that influence the excretion of drugs into saliva to increase the foundational knowledge underpinning saliva-based TDM. METHODS: Medline, Web of Science and Embase (1974-2023) were searched for human clinical studies, which determined drug pharmacokinetics in both saliva and plasma. Studies with at least ten subjects and five paired saliva-plasma concentrations per subject were included. For each study, the ratio of the area under the concentration-time curve between saliva and plasma was determined to assess excretion into saliva. Physicochemical properties of each drug (e.g. pKa, lipophilicity, molecular weight, polar surface area, rotatable bonds and fraction of drug unbound to plasma proteins) were obtained from PubChem and Drugbank. Drugs were categorised by their ionisability, after which saliva-to-plasma ratios were predicted with adjustment for protein binding and physiological pH via the Henderson-Hasselbalch equation. Spearman correlation analyses were performed for each drug category to identify factors predicting saliva excretion (α = 5%). Study quality was assessed by the risk of bias in non-randomised studies of interventions tool. RESULTS: Overall, 42 studies including 40 drugs (anti-psychotics, anti-microbials, immunosuppressants, anti-thrombotic, anti-cancer and cardiac drugs) were included. The median saliva-to-plasma ratios were similar for drugs in the amphoteric (0.59), basic (0.43) and acidic (0.41) groups and lowest for drugs in the neutral group (0.21). Higher excretion of acidic drugs (n = 5) into saliva was associated with lower ionisation and protein binding (correlation between predicted versus observed saliva-to-plasma ratios: R2 = 0.85, p = 0.02). For basic drugs (n = 21), pKa predicted saliva excretion (Spearman correlation coefficient: R = 0.53, p = 0.02). For amphoteric drugs (n = 10), hydrogen bond donor (R = - 0.76, p = 0.01) and polar surface area (R = - 0.69, p = 0.02) were predictors. For neutral drugs (n = 10), protein binding (R = 0.84, p = 0.004), lipophilicity (R = - 0.65, p = 0.04) and hydrogen bond donor count (R = - 0.68, p = 0.03) were predictors. Drugs considered potentially suitable for saliva-based TDM are phenytoin, tacrolimus, voriconazole and lamotrigine. The studies had a low-to-moderate risk of bias. CONCLUSIONS: Many commonly used drugs are excreted into saliva, which can be partly predicted by a drug's ionisation state, protein binding, lipophilicity, hydrogen bond donor count and polar surface area. The contribution of drug transporters and physiological factors to the excretion needs to be evaluated. Continued research on drugs potentially suitable for saliva-based TDM will aid in adopting this person-centred TDM approach to improve patient outcomes.

Optimizing Total Knee Arthroplasty Rehabilitation with Telehealth Physical Activity Behavior Change Intervention: A Randomized Clinical Trial.

OBJECTIVE: Conventional total knee arthroplasty (TKA) rehabilitation has little impact on sedentary lifestyles that have negative long-term health consequences. The purpose of this trial was to determine the effect of telehealth-based physical activity behavior change intervention on physical activity and functional outcomes following TKA. METHODS: This study was a 2-arm, parallel randomized controlled superiority trial at a regional Veterans Affairs medical center. The participants were 92 US military Veterans (mean age = 65.7 [SD =7.8] y) undergoing unilateral TKA. The Physical Activity Behavior Change (PABC) intervention included telehealth-based self-management training (ten 30-minute sessions) delivered over 12 weeks. The control intervention included telehealth-based health education sessions that matched PABC frequency and duration. Both groups participated in standardized conventional outpatient rehabilitation. Physical activity, measured as average daily step count, was the primary outcome. Secondary outcomes were Life-Space Assessment questionnaire, 30-Second Chair-Stand test, Timed Up-and-Go Test, Six-Minute Walk test, Western Ontario and McMaster Universities Osteoarthritis Index, and Veterans RAND 12-Item Health Survey. The Self Efficacy for Exercise scale and daily time spent in different postures (sitting/lying, standing, stepping) were exploratory variables. Outcomes were measured at baseline (before surgery), mid-intervention (8 weeks after surgery), after the intervention (14 weeks after surgery; primary endpoint), and follow-up (38 weeks after surgery). RESULTS: The PABC group had an estimated 931 (95% CI = 42-1819) more daily steps than the control group from baseline to 14 weeks, though a between-group effect was not sustained at 38 weeks. There were no group differences in secondary outcomes. Participants included only military veterans using Veteran's Health Administration services. The intervention targeted self-management and did not include peer support. CONCLUSIONS: The PABC intervention improved physical activity for Veterans recovering from unilateral TKA at 14 weeks after surgery, though the effect was not sustained at 38 weeks. Physical function improved with rehabilitation but was not different between groups, indicating that physical function was not a primary driver of physical activity behavior. IMPACT: Conventional TKA rehabilitation has a negligible effect on free-living physical activity, which is relevant to long-term health outcomes. This trial identified telehealth physical activity self-management as effective in addressing activity behaviors, separate from conventional rehabilitation strategies.

Energetic Information from Information-Theoretic Approach in Density Functional Theory as Quantitative Measures of Physicochemical Properties.

The Hohenberg-Kohn theorem of density functional theory (DFT) stipulates that energy is a universal functional of electron density in the ground state, so energy can be thought of having encoded essential information for the density. Based on this, we recently proposed to quantify energetic information within the framework of information-theoretic approach (ITA) of DFT (J. Chem. Phys. 2022, 157, 101103). In this study, we systematically apply energetic information to a variety of chemical phenomena to validate the use of energetic information as quantitative measures of physicochemical properties. To that end, we employed six ITA quantities such as Shannon entropy and Fisher information for five energetic densities, yielding twenty-six viable energetic information quantities. Then, they are applied to correlate with physicochemical properties of molecular systems, including chemical bonding, conformational stability, intermolecular interactions, acidity, aromaticity, cooperativity, electrophilicity, nucleophilicity, and reactivity. Our results show that different quantities of energetic information often behave differently for different properties but a few of them, such as Shannon entropy of the total kinetic energy density and information gain of the Pauli energy density, stand out and strongly correlate with several properties across different categories of molecular systems. These results suggest that they can be employed as quantitative measures of physicochemical properties. This work not only enriches the body of our knowledge about the relationship between energy and information, but also provides scores of newly introduced explicit density functionals to quantify physicochemical properties, which can serve as robust features for building machine learning models in future studies.

Neuroinflammatory activation in sensory and motor regions of the cortex is related to sensorimotor function in individuals with low back pain maintained by nociplastic mechanisms: A preliminary proof-of-concept study.

BACKGROUND: Chronic pain involves communication between neural and immune systems. Recent data suggest localization of glial (brain immune cells) activation to the sensorimotor regions of the brain cortex (S1/M1) in chronic low back pain (LBP). As glia perform diverse functions that impact neural function, activation might contribute to sensorimotor changes, particularly in LBP maintained by increased nervous system sensitivity (i.e., nociplastic pain). This preliminary proof-of-concept study aimed to: (i) compare evidence of neuroinflammatory activation in S1/M1 between individuals with and without LBP (and between nociceptive and nociplastic LBP phenotypes), and (ii) evaluate relationships between neuroinflammatory activation and sensorimotor function. METHODS: Simultaneous PET-fMRI measured neuroinflammatory activation in functionally defined S1/M1 in pain-free individuals (n = 8) and individuals with chronic LBP (n = 9; nociceptive: n = 4, nociplastic: n = 5). Regions of S1/M1 related to the back were identified using fMRI during motor tasks and thermal stimuli. Sensorimotor measures included single and paired-pulse transcranial magnetic stimulation (TMS) and quantitative sensory testing (QST). Sleep, depression, disability and pain questionnaires were administered. RESULTS: Neuroinflammatory activation was greater in the lower back cortical representation of S1/M1 of the nociplastic LBP group than both nociceptive LBP and pain-free groups. Neuroinflammatory activation in S1/M1 was positively correlated with sensitivity to hot (r = 0.52) and cold (r = 0.55) pain stimuli, poor sleep, depression, disability and BMI, and negatively correlated with intracortical facilitation (r = -0.41). CONCLUSION: This preliminary proof-of-concept study suggests that neuroinflammation in back regions of S1/M1 in individuals with nociplastic LBP could plausibly explain some characteristic features of this LBP phenotype. SIGNIFICANCE STATEMENT: Neuroinflammatory activation localized to sensorimotor areas of the brain in individuals with nociplastic pain might contribute to changes in sensory and motor function and aspects of central sensitization. If cause-effect relationships are established in longitudinal studies, this may direct development of therapies that target neuroinflammatory activation.

Odd-Even Alkyl Chain Effects on the Structure and Charge Carrier Transport of Two-Dimensional Sn-Based Perovskite Semiconductors.

Oscillations in the chemical or physical properties of materials, composed of an odd or even number of connected repeating methylene units, are a well-known phenomenon in organic chemistry and materials science. So far, such behavior has not been reported for the important class of materials, perovskite semiconductors. This work reports a distinct odd-even oscillation of the molecular structure and charge carrier transport properties of phenylalkylammonium two-dimensional (2D) Sn-based perovskites in which the alkyl chains in the phenylalkylammonium cations contain varying odd and even carbon numbers. Density functional theory calculations and grazing-incidence wide-angle X-ray scattering characterization reveal that perovskites with organic ligands containing an alkyl chain with an odd number of carbon atoms display a disordered crystal lattice and tilted inorganic octahedra accompanied by reduced mobilities. In contrast, perovskites with cations of an even number of carbon atoms in the alkyl chain form more ordered crystal structures, resulting in improved charge carrier mobilities. Our findings disclose the importance of minor changes in the molecular conformation of organic cations have an effect on morphology, photophysical properties, and charge carrier transport of 2D layered perovskites, showcasing alkyl chain engineering of organic cations to control key properties, of layered perovskite semiconductors.

An evaluation of the behavioural inhibition system and behavioural activation system (BIS-BAS) model of pain in athletes.

This study examined coping and pain responses using a behavioural inhibition (BIS) - behavioural activation (BAS) framework in 489 student athletes (M(age) = 20, SD = 4; 69% female). Two samples of athletes (226 pain-free athletes and 232 athletes with current pain) completed surveys assessing BIS- and BAS-related cognitions, emotions, and behaviours. Distinct groupings of BAS-related variables were identified in both samples, evidenced by significant positive correlations within BAS-related variables (positive affect, pain openness, approach thoughts and behaviours). Most BIS-related variables (depression, anxiety, harm beliefs, pain catastrophizing and avoidance behaviours) were also correlated in the sample of athletes with pain; however, this was not observed in pain-free athletes. In athletes with pain, BIS-related variables were significantly associated with pain variables, with this association stronger than that found for BAS-related variables. Regression analyses highlighted the pivotal role of pain catastrophizing as a predictor of pain unpleasantness and intensity. Findings shed light on the factors shaping athletes' coping, pain perception and decisions as to whether to pause or push through. Future investigations to explore these dynamics in more depth may aid in the development of targeted interventions that enhance athletes' ability to cope and to manage pain more effectively.

Symptom subtype progression in obstructive sleep apnea over 5 years.

STUDY OBJECTIVES: There is limited knowledge regarding the progression or consistency of symptoms in OSA over time. Our objective was to examine the changes in symptom subtypes and identify predictors over a span of 5 years. METHODS: Data of 2,643 participants of the Sleep Heart Health Study with complete baseline and 5-year follow-up visits were analyzed. Latent Class Analysis on 14 symptoms at baseline and follow-up determined symptom subtypes. Individuals without OSA (AHI<5) were incorporated as a known class at each time point. Multinomial logistic regression assessed the effect of age, sex, body mass index (BMI) and AHI on specific class transitions. RESULTS: The sample consisted of 1,408 women (53.8%) and mean (SD) age 62.4 (10.5) years. We identified four OSA symptom subtypes at both baseline and follow-up visits: minimally symptomatic, disturbed sleep, moderately sleepy, and excessively sleepy. Nearly half (44.2%) of the sample transitioned to a different subtype; transitions to moderately sleepy were the most common (77% of all transitions). A five-year older age was associated with a 50% increase in odds to transit from excessively sleepy to moderately sleepy [OR (95% CI: 1.52 (1.17, 1.97)]. Women had 1.97 times higher odds (95% CI: 1.21, 3.18) to transition from moderately sleepy to minimal symptoms. A 5-unit increase in BMI was associated with 2.39 greater odds (95% CI: 1.30, 4.40) to transition from minimal symptoms to excessively sleepy. Changes in AHI did not significantly predict any transitions. CONCLUSIONS: The symptoms of OSA may fluctuate or remain stable over time. Knowledge of symptom progression in OSA may support clinicians with treatment decisions.

High Initial Heart Rate Score is an Independent Predictor of New Atrial High-Rate Episodes in Pacemaker Patients with Sinus Node Dysfunction.

BACKGROUND: Heart Rate Score (HRSc), the percent of atrial depolarizations in the largest paced/sensed 10-bpm histogram bin recorded in cardiac devices, is associated with several adverse outcomes but it remains uncertain if HRSc independently predicts atrial high-rate episodes (AHREs) in patients with sinus node dysfunction (SND) undergoing pacemaker (PM) implantation. OBJECTIVE: To determine if initial HRSc post-PM implant predicts new-onset AHREs in patients with SND. METHODS: Patients had Boston Scientific PMs implanted for SND from 2012-2021 at Cleveland Clinic, University of Occupational and Environmental Health, Japan, Kyushu Rosai Hospital, and JCHO Kyushu Hospital. Patients were excluded if they had atrial fibrillation before PM implant or AHREs within 3-months post-implant. Subsequent AHREs post-implant were evaluated and correlated with HRSc. RESULTS: Over 48.9 (IQR 25.7-50.4) months, 130 consecutive PM patients (76±10 years, 40% male) had a median initial HRSc of 74(57-86)%. AHREs defined by >1%, >6h/day burden, and ATR events>24h developed in 27/130(21%), 15/130(12%), and 9/130(7%), respectively. For each definition, patients with HRSc≥80% had higher occurrence of AHREs than those with HRSc<80% (both p=0.008, log-rank test). After adjusting for age, race, comorbidities, left ventricular ejection fraction, left atrial diameter, and cumulative %RA/RV pacing, initial HRSc ≥80% (HR:3.33, 95% CI:1.35-8.18; P=0.009) and male sex (HR:2.59, 95% CI:1.06-6.33; P=0.04) independently predicted AHREs. CONCLUSION: HRSc≥80% is associated with new-onset, device-determined AHREs for patients undergoing PM implant for SND. HRSc may have prognostic and therapeutic implications.

Incidence of Antibiotic Exposure for Suspected and Proven Neonatal Early-Onset Sepsis between 2019 and 2021: A Retrospective, Multicentre Study.

Management of suspected early-onset sepsis (EOS) is undergoing continuous evolution aiming to limit antibiotic overtreatment, yet current data on the level of overtreatment are only available for a select number of countries. This study aimed to determine antibiotic initiation and continuation rates for suspected EOS, along with the incidence of culture-proven EOS in The Netherlands. In this retrospective study from 2019 to 2021, data were collected from 15 Dutch hospitals, comprising 13 regional hospitals equipped with Level I-II facilities and 2 academic hospitals equipped with Level IV facilities. Data included birth rates, number of neonates started on antibiotics for suspected EOS, number of neonates that continued treatment beyond 48 h and number of neonates with culture-proven EOS. Additionally, blood culture results were documented. Data were analysed both collectively and separately for regional and academic hospitals. A total of 103,492 live-born neonates were included. In 4755 neonates (4.6%, 95% CI 4.5-4.7), antibiotic therapy was started for suspected EOS, and in 2399 neonates (2.3%, 95% CI 2.2-2.4), antibiotic treatment was continued beyond 48 h. Incidence of culture-proven EOS was 1.1 cases per 1000 live births (0.11%, 95% CI 0.09-0.14). Overall, for each culture-proven EOS case, 40.6 neonates were started on antibiotics and in 21.7 neonates therapy was continued. Large variations in treatment rates were observed across all hospitals, with the number of neonates initiated and continued on antibiotics per culture-proven EOS case varying from 4 to 90 and from 4 to 56, respectively. The high number of antibiotic prescriptions compared to the EOS incidence and wide variety in clinical practice among hospitals in The Netherlands underscore both the need and potential for a novel approach to the management of neonates with suspected EOS.

GLUT2 regulation of p38 MAPK isoform protein expression and p38 phosphorylation in male versus female rat hypothalamic primary astrocyte Cultures.

Recent studies documented regulation of hypothalamic astrocyte mitogen-activated protein kinase (MAPK) pathways, including p38, by the plasma membrane glucose carrier/sensor glucose transporter-2 (GLUT2). Sex-specific GLUT2 control of p38 phosphorylation was observed, but effects on individual p38 family protein profiles were not investigated. Current research employed an established primary astrocyte culture model, gene knockdown tools, and selective primary antisera against p38-alpha, p38-beta, p38-gamma, and p38-delta isoforms to investigate whether GLUT2 governs expression of one or more of these variants in a glucose-dependent manner. Data show that GLUT2 inhibits baseline expression of each p38 protein in male cultures, yet stimulates p38-delta profiles without affecting other p38 proteins in female. Glucose starvation caused selective up-regulation of p38-delta profiles in male versus p38-alpha and -gamma proteins in female; these positive responses were amplified by GLUT2 siRNA pretreatment. GLUT2 opposes or enhances basal p38 phosphorylation in male versus female, respectively. GLUT2 siRNA pretreatment did not affect glucoprivic patterns of phospho-p38 protein expression in either sex. Outcomes document co-expression of the four principal p38 MAPK family proteins in hypothalamic astrocytes, and implicate GLUT2 in regulation of all (male) versus one (female) variant(s). Glucoprivation up-regulated expression of distinctive p38 isoforms in each sex; these stimulatory responses are evidently blunted by GLUT2. Glucoprivic-associated loss of GLUT2 gene silencing effects on p38 phosphorylation infers either that glucose status determines whether this sensor controls phosphorylation, or that decrements in screened glucose in each instance are of sufficient magnitude to abolish GLUT2 regulation of that function.

Improved long-term outcome of children with congenital diarrhea followed by an intestinal rehabilitation program.

BACKGROUND: Long-term outcomes of congenital diarrheas and enteropathies (CODE) are poorly described. We evaluated the morbidity and mortality of children with CODE followed by an intestinal rehabilitation program (IRP) compared to children with short bowel syndrome (SBS). METHODS: Matched case-control study of children with intestinal failure (IF) due to CODE (diagnosed between 2006 and 2020; N = 15) and SBS (N = 42), matched 1:3, based on age at diagnosis and duration of parenteral nutrition (PN). Nutritional status, growth, and IF-related complications were compared. Survival and enteral autonomy were compared to a nonmatched SBS cohort (N = 177). RESULTS: Fifteen CODE patients (five males, median age 3.2 years) were followed for a median of 2.9 years. Eleven children were alive at the end of the follow-up, and two achieved enteral autonomy. The CODE group had higher median PN fluid and calorie requirements than their matched SBS controls at the end of the follow-up (83 vs. 45 mL/kg/day, p = 0.01; 54 vs. 30.5 kcal/kg/day, p < 0.01), but had similar rates of growth parameters, intestinal failure associated liver disease (IFALD), central venous catheter (CVC) complications and nephrocalcinosis. Kaplan-Meier (KM) analyses of 10-year survival and enteral autonomy were significantly lower in CODE patients compared to the nonmatched SBS population (60% vs. 89% and 30% vs. 87%, respectively; log-rank p < 0.008). CONCLUSIONS: Despite higher PN needs in CODE, rates of IF complications were similar to matched children with SBS. Enteral autonomy and survival rates were lower in CODE patients. Treatment by IRP can mitigate IF-related complications and improve CODE patient's outcome.

Unsupervised Segmentation of 3D Microvascular Photoacoustic Images Using Deep Generative Learning.

Mesoscopic photoacoustic imaging (PAI) enables label-free visualization of vascular networks in tissues with high contrast and resolution. Segmenting these networks from 3D PAI data and interpreting their physiological and pathological significance is crucial yet challenging due to the time-consuming and error-prone nature of current methods. Deep learning offers a potential solution; however, supervised analysis frameworks typically require human-annotated ground-truth labels. To address this, an unsupervised image-to-image translation deep learning model is introduced, the Vessel Segmentation Generative Adversarial Network (VAN-GAN). VAN-GAN integrates synthetic blood vessel networks that closely resemble real-life anatomy into its training process and learns to replicate the underlying physics of the PAI system in order to learn how to segment vasculature from 3D photoacoustic images. Applied to a diverse range of in silico, in vitro, and in vivo data, including patient-derived breast cancer xenograft models and 3D clinical angiograms, VAN-GAN demonstrates its capability to facilitate accurate and unbiased segmentation of 3D vascular networks. By leveraging synthetic data, VAN-GAN reduces the reliance on manual labeling, thus lowering the barrier to entry for high-quality blood vessel segmentation (F1 score: VAN-GAN vs. U-Net = 0.84 vs. 0.87) and enhancing preclinical and clinical research into vascular structure and function.