Intestinal ischemia is still one of the most complex pathological processes and characterized by high mortality and difficulties in early diagnosis. The article presents modern data on pathophysiological mechanisms of ischemia-induced intestinal wall damage. Etiological factors, molecular basis of ischemia-reperfusion injury, role of intestinal microbiota and innovative approaches to diagnosis and therapy are considered. Particular attention is paid to the paradoxical role of reperfusion. Indeed, the last one causes almost 70% of structural damages through activation of NADPH oxidase (NOX-4) and mitochondrial dysfunction. Metagenomic studies revealed a critical decrease in microbiota diversity (Shannon index 1.5-2.0) and butyrate deficiency. This directly correlates with violation of intestinal barrier function. In addition, the authors discuss clinical implications of new data, including probiotics and fecal microbiota transplantation. The article highlights the need for interdisciplinary approach involving microbiologists, clinicians and bioinformaticians to develop personalized strategies to reduce mortality and improve treatment outcomes.

Mitochondria serve as the primary cellular powerhouses, generating ATP through oxidative phosphorylation (OXPHOS) to sustain essential cellular processes. Beyond energy production, mitochondria function as critical regulators of metabolic homeostasis, intracellular signaling networks, and programmed cell death pathways. The mitochondrial genome comprises 37 genes encoding 13 OXPHOS subunits, 22 transfer RNAs, and 2 ribosomal RNAs, all transcribed and translated within the organelle. Mitochondrial DNA integrity becomes compromised through diverse pathological stimuli, including metabolic dysregulation, oxidative stress, and inflammatory cascades, contributing to disease pathogenesis across multiple organ systems. This review synthesizes current knowledge on the multifaceted roles of mtDNA in health and disease. We propose a framework of three interconnected mechanisms through which mtDNA exerts its effects: (1) retrograde signaling to the nucleus, reprogramming nuclear gene expression; (2) cytosolic and extracellular release of mtDNA as a damage-associated molecular pattern (DAMP), activating innate immune pathways like cGAS-STING and NLRP3; and (3) intrinsic epigenetic modifications that directly modulate mitochondrial gene expression. We critically evaluate the evidence linking mtDNA alterations to a spectrum of diseases, including cancer, cardiovascular and metabolic disorders, neurodegeneration, and psychiatric conditions. We conclude that a comprehensive understanding of mtDNA's multifaceted nature, moving beyond its perception as a mere DAMP, is essential for translating mitochondrial biology into effective clinical interventions.

Delayed endothelialization and inflammatory response are two major obstacles that hinder vascular healing by drug-eluting stents (DES). Here, we report a biomimetic nanozyme strategy to address this issue. We first design and anchor a robust glutathione peroxidase (GPx)-biomimetic nanozyme with diselenide-polyphenol networks on a stent. Then, a thrombin inhibitor, bivalirudin, is efficiently loaded onto the nanozyme utilizing its reversible interactions with polyphenol. The nanozymes exhibit potent GPx activity to controllably generate nitric oxide (NO) and on-demand elution of bivalirudin. The synergistic effects of NO and bivalirudin effectively inhibit thrombin activity, prevent platelet activation, and consequently suppress thrombosis as well as the inflammatory response associated with it. In vitro pathological model cell studies demonstrate that the nanozyme-engineered stents specifically inhibit smooth muscle cell (SMC) proliferation, regulate macrophage polarization, and promote the repair and proliferation of endothelial cells. Thus, it enables rapid endothelialization and vascular healing, preventing restenosis in rabbit and swine models.

Aloxistatin (E64d) is a membrane-permeable cysteine protease inhibitor prodrug that is converted by esterases to the active metabolite E64c (loxistatin). This first-in-human study evaluated the safety, tolerability and pharmacokinetics of single ascending doses of inhaled E64d in healthy volunteers.

In this randomized, double-blind, placebo-controlled phase 1 trial, 47 healthy male volunteers contributed 48 study participations across six dose cohorts. Thirty-six treatment assignments were to E64d and 12 to placebo. Study medication was administered by inhalation using a breath-triggered mesh nebulizer. Safety assessments included adverse events, pulmonary function, gas exchange, cardiovascular parameters, and laboratory variables. Plasma concentrations of E64d and E64c were characterized following inhalation.

No serious adverse events occurred, no adverse event was classified as severe and no participant discontinued because of an adverse event. Ten adverse events occurred following E64d and four following placebo; one mild event of mucosal dryness was considered treatment related. No clinically relevant changes were observed in pulmonary, cardiovascular, or laboratory safety assessments. E64d appeared rapidly and transiently in plasma, with a median T_max of 3 min. E64c showed sustained systemic exposure, with median T_max values of approximately 15-20 min and an elimination half-life of approximately 30-40 min across evaluable dose levels. Dose proportionality was not formally assessed.

Single ascending doses of inhaled E64d were generally well tolerated in healthy male volunteers. Inhalation resulted in rapid, transient systemic exposure to E64d followed by measurable formation of E64c. These findings provide a safety and pharmacokinetic basis for further investigation of inhaled aloxistatin.

Motor recovery after stroke is associated with changes in corticospinal integrity, intracortical excitability, and interhemispheric interactions. Transcranial magnetic stimulation (TMS) provides neurophysiological measures of these processes, but their relationship with motor recovery across randomized controlled trials remains uncertain. This systematic review synthesized evidence from randomized controlled trials investigating TMS-derived neurophysiological measures associated with motor recovery following TMS-based neuromodulation after stroke. PubMed/MEDLINE, Scopus, and Embase were searched for studies published between January 1, 2016, and July 10, 2026. Eligible trials enrolled adults with ischemic or hemorrhagic stroke, assessed at least one TMS-derived neurophysiological measure, and reported a motor or functional outcome. Study selection followed PRISMA 2020, risk of bias was assessed using Cochrane RoB 2, and certainty of evidence was evaluated using GRADE. Owing to methodological heterogeneity, findings were synthesized narratively. The search identified 1441 records; after removal of 519 duplicates, 922 records were screened, 55 full-text reports were assessed, and 16 randomized controlled trials were included. Motor evoked potential (MEP) amplitude, MEP status, and resting motor threshold were the most frequently reported measures. Several trials found that changes in corticospinal excitability accompanied improvements in upper-limb function, activities of daily living, gait, or balance. One trial found greater motor gains among participants with preserved baseline MEPs; however, the contemporary randomized-trial evidence is insufficient to establish MEP status as a predictor of differential response to neuromodulation. In contrast, short-interval intracortical inhibition, cortical silent period, and interhemispheric inhibition were assessed in very few trials, whereas intracortical facilitation was not directly evaluated in any eligible RCT. Most studies raised some risk-of-bias concerns, and one study had high overall risk. Certainty was moderate for clinical motor recovery, low for MEP- and motor-threshold-based measures, and very low for intracortical and interhemispheric measures. Overall, MEP-derived measures and resting motor threshold were the most frequently reported neurophysiological domains, whereas baseline MEP status was evaluated in only one stratified trial. Standardized TMS protocols are needed to clarify their monitoring, prognostic, and treatment-response value.

Primary aldosteronism (PA) involves excessive autonomous aldosterone (ALD) secretion by the adrenal cortex, leading to water and sodium retention and renin-angiotensin system inhibition, causing hypertension and K+ imbalance. Familial hyperaldosteronism type III (FH-III) is a rare subtype, characterized by hypokalemia with hypertension and adrenal hyperplasia. Eight associated pathogenic potassium inward rectifying channel protein subfamily J member 5 (KCNJ5) mutations have been reported. This study reports a Chinese family with FH-III associated with a rare KCNJ5 variant (c.536A>G, p.Asn179Ser), which has been previously reported in cardiac genetics databases (rs147070381). Our study expands its phenotypic spectrum to include familial aldosteronism.

A middle-aged female presented with recurrent hypokalemia unresponsive to oral potassium supplementation. She and her family underwent comprehensive clinical examination, biochemical testing, imaging studies, and whole-exome sequencing.

She exhibited recurrent hypokalemia without hypertension, with fluctuating ALD, which were controlled with spironolactone. The proband, along with her sister and mother, were found to carry a heterozygous KCNJ5 variant (exon 2: c.536A>G, p.Asn179Ser).

FH-III symptoms vary widely, making diagnosis challenging in patients who solely present with recurrent hypokalemia. Early gene sequencing facilitates accurate diagnosis to guide appropriate treatment.

Prenatal testosterone (T) excess programs sex-specific cardiovascular dysfunction in sheep offspring. Given the close reciprocal relationship between the cardiopulmonary system, we hypothesized that prenatal T excess would also adversely program the offspring's pulmonary system in a sex-specific manner from fetal life into adulthood. Pregnant ewes received intramuscular injections of T propionate (100 mg) or a vehicle control (C) twice weekly from gestational days (GD) 30-90 (term 147 days). Offspring lungs were collected at GD120 (n=6-7 per group), and at 24 months of age (n=4-6 per group) for histological and molecular analyses. Data were analyzed using two-way ANOVA (fetal) and/or sex-specific stratified t-tests for adults and Cohen's effect size analyses. Prenatal T significantly increased fetal lung collagen deposition in males. Prenatal T treatment had a significant overall treatment main effect on fetal lung apoptosis and the ratio of small to total blood vessels. Some adverse effects of prenatal T excess persisted into adulthood, including a significant increase in lung collagen in both sexes. Fetal lung transcriptome revealed differential enrichment of pathways involved in regulation of hormone biosynthetic process, and neuron apoptotic process in T- treated males, whereas pathways related to bicarbonate transport and regulation of muscle cell differentiation were enriched in T- treated females. Overall, early- to mid-gestational T excess adversely reprograms the offspring's lungs in a sex-specific manner, from fetal life extending into adulthood.

Fetal intrahepatic portosystemic shunt may complicate fetal growth assessment, particularly when maternal and umbilical cord abnormalities coexist. We report a pregnancy first evaluated at our center at 26 + 3 weeks for suspected severe early-onset fetal growth restriction, with estimated fetal weight below the 1st percentile and abdominal circumference below the 3rd percentile. Prenatal ultrasound and fetal magnetic resonance imaging findings were consistent with fetal intrahepatic portosystemic shunt. Subsequent serial assessments showed improved fetal biometry. Routine umbilical artery and ductus venosus assessments were not clearly abnormal, whereas middle cerebral artery pulsatility index decreased in late gestation. A focal hypercoiled cord segment showed a higher umbilical artery systolic-to-diastolic ratio than routine sampling. Delivery at 35 + 2 weeks was indicated by severe preeclampsia and a positive oxytocin challenge test. The neonate was appropriate for gestational age, with postnatal ultrasound confirmation of persistent shunting and mild hyperammonemia.

Self-directed digital mental health programs can increase access to evidence-based interventions for child anxiety. However, there has been little comprehensive investigation of real-world dissemination, especially using implementation science approaches.

This study aimed to describe and comprehensively assess the implementation of the BRAVE Self-Help program for child and adolescent anxiety in Australia over a 10-year period, including implementation strategies during establishment and sustainability phases and implementation-effectiveness outcomes.

This study was a large, open implementation-effectiveness trial involving Australian child and adolescent participants in the BRAVE Self-Help Program, conducted between January 1, 2015, and December 31, 2024. Implementation strategies were reported descriptively across program establishment and sustainability phases. Implementation and effectiveness outcomes were reported across 10 years, in line with the implementation outcomes framework (IOF) and taxonomy of implementation outcomes for digital interventions. Metrics included adoption, penetration, appropriateness, fidelity, feasibility, acceptability, and effectiveness.

Over the 10-year period, the BRAVE Self-Help program had 53,726 users, including 28,700 children (mean age 9.36, SD 1.40 years) and 25,026 adolescents (mean age 14.15, SD 1.62 years). Data revealed a wide variety of user characteristics in terms of age, gender, geographical location, baseline severity, and referral sources (community, health, and education settings). Improvement in anxiety symptoms from first to last interaction with the program was observed for participants in general, particularly among those with elevated anxiety at program registration (P<.001; Cohen d=0.54). Of all users completing the registration assessment, 38.72% (20,026/51,721) completed 3 or more of the 10 sessions, with consistent moderate to high satisfaction rates across all sessions.

This study demonstrated that a self-help digital program for child and adolescent anxiety can be successfully disseminated nationally, and that it is feasible, acceptable, and effective for many young people. During a span of 10 years, the BRAVE Self-Help program for child and adolescent anxiety offered evidence-based support to more than 50,000 families. Notably, although progress through sessions was low for some young people, significant improvements could be made in as few as 3 sessions, and decisions to stop treatment occurred for many reasons, including treatment success.

Young people exposed to adverse childhood experiences (ACEs) are at risk of poor mental and physical health across the life course, yet many struggle to access timely help. Serious games offer an engaging, scalable, and stigma-reducing support, but few are co-designed with young people who have lived experience of ACEs, and methodological accounts of how participatory design is operationalized alongside software delivery are scarce.

We aimed to (1) develop and apply a novel methodological framework integrating experience-based co-design (EBCD) with agile game development to co-design a serious game with young people affected by ACEs, (2) describe the co-designed game prototype and the design decisions shaped by youth participation, and (3) examine the ethical and safeguarding considerations arising from co-designing digital mental health interventions with trauma-exposed young people.

We conducted a participatory co-design study comprising 12 workshops across 8 iterative co-design sprints, involving 18 diverse young people (aged 12-24 years) with lived experience of ACEs, 5 professional stakeholders, and a multidisciplinary game development team. Young people were recruited across England through partner youth organizations and regional Young People's Advisory Groups. Co-design ran from June 2022 to April 2024 in hybrid and online formats. Baseline characteristics include demographics, and mental health and well-being measures. EBCD activities were mapped onto agile practices (sprint planning, sprint reviews, and retrospectives); all feedback was logged in a "you said, we did" form. Analyses were descriptive, and reporting followed the GRIPP2-LF (Guidance for Reporting Involvement of Patients and the Public, long-form) checklist.

The resulting prototype, ACE of Hearts, comprised a central "cozy den" hub and 4 mini-games addressing bereavement and caregiving, trauma and disability, gender dysphoria, and poverty. Youth feedback directly shaped 47 documented feedback and design decisions. Co-design participants (14 of 18 participants) were diverse in gender (8/14, 57% men or boys; 3/14, 21% women or girls; 1/14, 7% nonbinary; 2/14, 14% another identity; and 3/14, 21% transgender), ethnicity (5/14, 36% from minoritized ethnic backgrounds), sexuality (6/14, 43% bisexual or pansexual), and neurodivergence (7/14, 50% autistic), with elevated levels of depression (mean Patient Health Questionnaire 9-item scale 8.8, SD 4.5) and anxiety (mean Generalized Anxiety Disorder 7-item scale 8.4, SD 3.9). Mean posttraumatic stress symptom severity (Children's Revised Impact of Event Scale, 8-item; n=13) was 22.5 (SD 7.7). Design innovations included metaphoric storytelling, integration of narrative exposure therapy principles into gameplay, and an embedded ethics framework addressing representation, agency, and emotional safety.

Integrating EBCD with agile development is a feasible and transparent method for coproducing trauma-informed serious games with young people who have lived experience of ACEs. The approach is transferable to other participatory digital-health projects involving vulnerable populations. Future work would evaluate acceptability, feasibility, and clinical outcomes.