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Evidence on psychological, cognitive and functional outcomes of advanced diabetes technologies in older adults with long-standing type 1 diabetes (T1D) remains limited. We evaluated whether initiation of advanced hybrid closed-loop (AHCL) therapy was associated with changes in fear of hypoglycaemia, diabetes distress, psychological well-being, cognition, frailty-related measures and mobility-related function in adults aged ≥ 65 years with T1D. This prespecified, exploratory secondary analysis was conducted within a single-centre, open-label, randomised, controlled, parallel-group trial including adults aged ≥ 65 years with long-standing T1D. Participants were randomly assigned (1:1) to initiate AHCL therapy using the MiniMed 780G system or to continue standard diabetes treatment. The secondary outcomes included WHO-5, the 17-item Diabetes Distress Scale (DDS), Hypoglycemia Fear Survey-II (HFS-II), Montreal Cognitive Assessment, Digit Symbol Substitution Test, Fried frailty phenotype and performance-based functional measures. No formal sample-size calculation was performed for these secondary outcomes. Thirty-one participants were randomised and 29 completed 12 months of follow-up and were included in the treatment-effect analyses. In the baseline-adjusted primary analysis, AHCL therapy was associated with a lower HFS-II score than standard treatment (adjusted mean difference -18.9; 95% CI: -32.4 to -5.4; nominal p = 0.008), although this finding did not remain statistically significant after Holm correction (adjusted p = 0.104) or in an exploratory model additionally adjusted for sex (difference -13.6; 95% CI: -32.2 to 5.0; p = 0.145). Diabetes distress, psychological well-being, global cognition and processing speed did not differ between groups. In sex-adjusted sensitivity analyses, the between-group differences remained statistically significant for 6-min walk distance (92.6 m; 95% CI: 36.8 to 148.3; p = 0.002) and Timed Up and Go performance (-2.27 s; 95% CI: -4.28 to -0.27; p = 0.028), but not for gait speed (0.27 m/s; 95% CI: -0.05 to 0.59; p = 0.099). At 12 months, 12 of 14 AHCL participants were robust and 2 were pre-frail; in the control group, 11 of 15 were robust and 4 were pre-frail. No participant was classified as frail at follow-up. In this small, selected cohort, AHCL therapy was associated with a nominally lower fear-of-hypoglycaemia score and better performance on selected mobility-related tests over 12 months. The fear-of-hypoglycaemia finding did not remain statistically significant after correction for multiple comparisons or additional adjustment for sex. Six-minute walk distance and Timed Up and Go remained statistically significant in the exploratory sex-adjusted sensitivity analyses, whereas the gait-speed difference did not. No measurable between-group deterioration in global cognition or processing speed was observed. These exploratory findings require confirmation in larger studies with balanced representation by sex and direct measurement of physical activity. These findings also support a person-centred clinical message: older age alone should not be regarded as a barrier to AHCL when treatment is introduced with individualised education and appropriate ongoing support.

Transjugular intrahepatic portosystemic shunt (TIPS) is a well-established bridging therapy for the management of severe complications of portal hypertension. However, the impact of long-standing malpositioned TIPS on liver transplantation remains scarcely reported CASE REPORT: A 64-year-old male with alcoholic cirrhosis and refractory hepatic hydrothorax underwent TIPS placement with sustained clinical benefit for nearly 8 years. He later developed refractory ascites and recurrent hepatic encephalopathy and was listed for liver transplantation. He subsequently underwent the procedure using the piggyback technique, requiring venoplasty of the lateral wall of the inferior vena cava due to extensive pericaval fibrosis associated with a long-standing malpositioned TIPS, which was markedly protruded into the right atrium. Within 48 hours, the patient developed primary non-function and required emergent retransplantation. Intraoperatively, pressure measurements demonstrated a gradient between the infrahepatic and suprahepatic vena cava (16 and 9 mmHg, respectively), consistent with significant hepatic venous outflow obstruction. Extensive residual fibrosis near the suprahepatic inferior vena cava was also observed. The conventional technique with caval replacement was used, allowing resection of the stenotic suprahepatic inferior vena cava segment affected by fibrosis secondary to the malpositioned TIPS. At the end of the procedure, venous pressures were equalized between the suprahepatic and infra-renal inferior vena cava (10 mm Hg). The patient recovered uneventfully and is currently under outpatient follow-up. Long-term TIPS-related anatomical alterations, particularly in the setting of malposition, may increase surgical complexity during liver transplantation and require tailored operative strategies. Awareness of these challenges by the transplant team is essential to optimize outcomes in this unique patient population.

Given uncertainty about whether later-life health at similar ages is improving over time, we examined trends across multiple health domains. We analysed data from community-dwelling adults aged 50 and older in the English Longitudinal Study of Ageing in 2004/05, 2012/13, and 2023/24 (main survey: N=8389, 8549, and 6090, respectively). Outcomes included self-rated health, limiting long-standing illness, pain, mobility limitations, cardiometabolic and chronic conditions, obesity, inflammation, mental health, quality of life and memory. Weighted pooled modified Poisson and linear regressions compared outcomes over time, overall, and by age group and education, with additional adjustment for sex and wealth. Adjusted estimates showed divergent trends. Fair/poor self-rated health increased from 27% to 34%, and any pain from 37% to 47%, whereas mobility impairments declined from 58% to 52%. Self-reported high cholesterol increased from 19% to 39%, while biomarker-defined high cholesterol declined from 78% to 54%; diabetes increased on both measures. Psychiatric problems increased from 6% to 10%, quality of life declined, and memory improved. However, trends differed by age and education, particularly for limiting long-standing illness, mobility limitations, cholesterol biomarkers, and mental health, indicating that aggregate trends masked unevenly distributed changes. Later-life health in England has not improved uniformly. Gains in functioning, biomarkers, and cognition coexist with rising pain and poorer mental health. Trends were also socially and age patterned, producing increasingly multidimensional and socially patterned health outcomes. Multidomain health monitoring is essential for interpreting population health trends and planning healthy ageing, prevention, long-term care, and work policies. What is already known on this topic: Previous studies have reported mixed trends in later-life health, often focusing on single health domains and giving limited attention to differences by age, education, or measurement method.What this study adds: Between 2004/05 and 2023/24, health at older ages in England changed in divergent rather than uniformly favourable directions, with improvements in mobility, selected biomarkers, and memory alongside worsening pain, diabetes, mental health, and quality of life. Trends also differed by age and education, and self-reported and biomarker-defined cardiometabolic measures sometimes moved in opposite directions.How this study might affect research, practice or policy: Monitoring and planning for ageing populations should use multidomain health measures and consider social inequalities rather than relying on population averages, chronological age, or single indicators alone.

Since the discovery of the Higgs boson, the long-standing task at hand in particle physics is the search for new physics beyond the Standard Model, which accounts for only about 5\% of the Universe.
 In light of this situation, the neutrino sector has drawn significant attention due to neutrino oscillations, which require physics beyond the Standard Model and have prompted a wide array of active and planned experimental programs.
 Notably, neutrino facilities offer substantial potential to search for new physics beyond neutrino oscillations, owing to their precision measurement capabilities, diverse experimental configurations, and various neutrino sources.
 This white paper summarizes the landscape of new physics that can be probed at current and future neutrino experiments, categorized into laboratory-produced and cosmogenic signals.
 We discuss recent experimental results interpreted through the lens of new physics, as well as detailed plans and projected sensitivities of next-generation facilities.
 This summary is based on presentations from the 4th Workshop on New Physics Opportunities in Neutrino Facilities (NPN 2024), held at IBS in Daejeon, Korea, on June 3-5, 2024.
 Particular emphasis is placed on accelerator-based neutrino experiments and a range of neutrino programs in East Asia. 
 We also outline key tasks necessary to realize the promising new physics opportunities ahead.&#xD.

Background/Objectives: HIV testing is essential for early HIV diagnosis, timely treatment initiation, and HIV prevention. Despite Thailand's long-standing HIV prevention programs and universal access to HIV testing services, nationally representative evidence on lifetime HIV testing among Thai adults remains limited. This study aimed to estimate the prevalence of lifetime HIV testing and identify factors associated with lifetime HIV testing among Thai adults. Methods: This study was a secondary analysis of data from the 6th Thai National Health Examination Survey. A total of 11,843 Thai adults aged 20-59 years were included. Descriptive statistics were used to estimate the prevalence of lifetime HIV testing. Survey-weighted logistic regression analyses were performed to examine factors associated with lifetime HIV testing. Results: The overall prevalence of lifetime HIV testing was 41.9%, with a prevalence of 42.4% among males, and 41.4% among females. Individuals aged 30-39 years (AOR = 1.64, 95% CI: 1.43-1.87) and 40-49 years (AOR = 1.67, 95% CI: 1.41-1.99), those with secondary education (AOR = 1.64, 95% CI: 1.43-1.87) or certificate/higher education (AOR = 1.74, 95% CI: 1.48-2.05), those currently living with a partner (AOR = 1.60, 95% CI: 1.43-1.79), participants with higher monthly income (10,000-24,999 THB: AOR = 1.13, 95% CI: 1.01-1.27; ≥25,000 THB: AOR = 1.39, 95% CI: 1.13-1.70), residents in the Northern region (AOR = 1.74, 95% CI: 1.45-2.09), and those who had a relative or acquaintance living with HIV/AIDS (AOR = 1.46, 95% CI: 1.34-1.59) were more likely to have lifetime HIV testing. In contrast, Muslim participants (AOR = 0.72, 95% CI: 0.57-0.90), residents of rural areas (AOR = 0.88, 95% CI: 0.79-0.97), residents in the Central (AOR = 0.82, 95% CI: 0.69-0.98) and Southern regions (AOR = 0.83, 95% CI: 0.72-0.94), and those with higher HIV-related stigma (AOR = 0.91, 95% CI: 0.84-0.99) were less likely to have lifetime HIV testing. Conclusions: Lifetime HIV testing among Thai adults remained suboptimal, with geographic and sociodemographic disparities.

For decades, target-distractor similarity has been known to induce distinct visual search modes. A highly salient target can pop out, suggesting parallel processing of all items irrespective of set size. By contrast, high similarity among items requires item-by-item assessment, a characteristic of serial search. Despite this long-standing distinction, search modes remain poorly defined due to confounding of behavioural measures by differences in local contrasts and display density just as neural correlates are confounded by distinct displays used to prompt different search modes. Here, we biased search mode by manipulating target-distractor similarity in inducer trials, while embedded test trials afforded both modes, allowing us to isolate neural signatures of serial and parallel search under visually identical displays. Behavioral results from 24 participants (21 female, 3 male) confirmed successful induction of distinct search modes. EEG decoding reliably discriminated search modes and generalized across inducer and test trials. Attentional deployment toward the target differed across search modes, revealing topographical differences in target location representations. The representation of target location was associated with response times, indicating when subjects swapped search mode from parallel to serial if target was not detected quickly. Moreover, the representation of search target diverged between search modes: A temporally stable pattern emerged during serial search, suggesting the maintenance of conjunction item in working memory, whereas the representations were dynamic in parallel search, likely reflecting the relevant feature. These findings demonstrate that search history shapes search mode, giving rise to clearly distinct neural dynamics even under visually identical stimulation.Significance statement Serial and parallel search distinction is recognized half a century ago. However, search modes remain poorly defined. This is because visual displays used to prompt distinct search modes confound behavioural measures and neural correlates of search modes. Here, we biased search modes in subsequent blocks by manipulating target-distractor similarity in a set of inducer trials. Embedded among inducer trials, test trials afforded both search modes, allowing us to isolate neural signatures of serial and parallel search under visually identical displays. We used EEG decoding to distinguish neural correlates of search modes and their influence on the modulation of target location and the representation of the target itself.

Neuroborreliosis (NB) is a neurologic complication of Lyme disease that can cause sudden hearing loss, which can in some cases be bilateral. A 61-year-old woman consulted for bilateral sudden hearing loss with headache and earache, following an episode of fever. Interview found a skin lesion suggestive of migratory erythema, which had developed 3months previously after a walk in a German forest and had not initially been treated. Examination revealed severe sensorineural hearing loss and lymphocytic meningitis. Blood tests found long-standing IgM and IgG positive Borrelia burgdorferi infection with intrathecal synthesis of IgM and IgG antibodies. Corticosteroid treatment and ceftriaxone was initiated, and normalized hearing within 3weeks. Hearing impairment in NB may involve inflammatory, immunologic or cytotoxic mechanisms affecting hair cells. Early treatment with corticosteroids and targeted antibiotics should be prescribed when NB is suspected, to optimize the chances of recovery. In endemic geographic areas, signs of Lyme disease should be screened for in case of sudden hearing loss.

The (un)folding rates of natural proteins determine their native stability and functional homeostasis, making them important targets for protein engineering and design. From a prediction standpoint, the rates have been a long-standing puzzle. We have known for decades that folding rates empirically correlate with properties of the native three dimensional (3D) structures and that both, folding and unfolding rates, scale with protein size. Whereas such rate correlations are too rough for being of practical use, no significant progress in prediction accuracy has occurred since then, despite many efforts even including machine learning approaches. Here, we retake on this challenge by expanding the simple one-dimensional free energy surface (1D-FES) model that originally led to demonstrate the size scaling of both rates, and a curated database with rates for 75 single-domain proteins. We define the weighted sequence order (WSO) as a novel parameter that allows incorporating structural information into the 1D-FES model explicitly. Via the WSO, we examine the role of global structural properties such as fold topology and core packing in defining the (un)folding rates within the context of a physics-based model of protein folding. After introducing fold topology and packing at a coarse-grained level, the model uses three floating parameters to predict the folding and unfolding rates within 6.5- and 10-fold, respectively, resulting in ±6.5 kJ/mol accuracy in native stability, equivalent to the typical perturbation induced by one single-point mutation. The net improvement over the 2-parameter size-only prediction is of 2.5-fold. These new rate predictions are significantly closer to the threshold of usefulness for engineering and design. More importantly, this WSO-modified 1D-FES model can now directly accommodate atomistic, high-resolution, force-fields to further optimize the rate predictions, and/or to use rate information as a testbed for force-field refinement. Finally, the WSO-1D-FES model could also serve as foundation for developing more complex models capable of dealing with multi-domain proteins as well as with the evolutionary information cryptically encoded in natural protein sequences.

Most conventional alkene synthesis reactions (e.g., elimination et al.) inherently favor the formation of thermodynamically more stable E-isomers, posing a long-standing challenge for direct access to Z-alkenes. Here, we report the reprogramming of a thiamine diphosphate (ThDP)-dependent enzyme to catalyze a formal dehalogenative elimination that overrides this intrinsic thermodynamic bias, enabling the direct and selective synthesis of Z-α,β-unsaturated carboxylic acids. In contrast to classical approaches that rely on substrate control, directing groups, or complex ligand architectures, our strategy harnesses the enzyme's confined active site to achieve kinetic control exclusively via noncovalent interactions─representing a fundamentally distinct and more sustainable approach to stereochemical programming. This transformation diverts the enzyme from its native function in C-C bond formation by channeling the Breslow intermediate toward a homoenolate-mediated pathway, wherein specific noncovalent interactions stabilize the syn-periplanar geometry required for Z-selective dehalogenative elimination. Through rational active-site engineering, the stereochemical trajectory can be inverted to furnish the complementary E-isomer, enabling stereodivergent synthesis from a common scaffold. This work establishes a biocatalytic platform that addresses a critical gap in Z-alkene synthesis, expands the catalytic repertoire of ThDP-dependent enzymes, and provides a sustainable alternative to conventional methodologies.

Overutilization of the emergency department (ED) is costly and often reflects unmet needs and suboptimal care, raising concerns when patients rely on the ED persistently over many years. Long-term ED use trajectories for patients with substance-related disorders (SRDs) have never been investigated. This study aimed to identify ED use trajectories over a 10-year period and examine associations with patients' sociodemographic and clinical characteristics, quality-of-care indicators, and subsequent adverse outcomes. A cohort of 9642 patients with long-standing SRDs was examined using Québec (Canada) medical records (1996-2022). Group-Based Trajectory Modeling identified 10-year ED use trajectories. Multinomial logistic regression assessed associations between trajectories and covariates, while Cox models examined links to subsequent adverse outcomes (suicidal behavior, hospitalization, death). Four ED use trajectories were identified: Trajectory 1 ("Low ED users," 50% of cohort), Trajectory 2 ("Increasing ED users," 20%), Trajectory 3 ("Sinusoidal ED users," 20%), and Trajectory 4 ("Very frequent ED users," 10%). Half of the cohort showed frequent ED use (≥3 visits/year), including 10% who were very frequent users (≥8 visits/year), underscoring substantial unmet needs. ED use frequency was strongly linked to social and health conditions-most favorable in Trajectory 1, who were mostly men, and markedly worse in Trajectories 4, 2, and 3. Adverse outcomes were also strongly associated with poorer social and health conditions and lower treatment motivation, even though Trajectories 4, 2, and 3 received more healthcare services. Findings indicate that the healthcare system is not adequately structured to meet the needs of patients with severe multimorbidity involving SRDs, mental disorders, chronic physical illnesses, and social instability, contributing to care quality insufficiently meeting the complex needs of Trajectories 2-4. Tailored interventions may be warranted, including Integrated Treatment for Dual Disorders and Assertive Community Treatment for Trajectories 2 and 4, and Intensive Case Management, Recovery Management Checkups, or mobile health technologies for Trajectory 3. Across Trajectories 2-4, enhanced motivational interventions, social support, reduced stigma, optimized medication management, peer-helper programs, and stronger ED-outpatient collaboration remain essential. Improving services for patients with frequent ED use-particularly those in Trajectory 4 with recurrent very frequent use-should be prioritized to reduce costs, optimize service use, and support recovery.

Bladder cancer is a long-standing clinical issue, with frequent recurrence and continuously disappointing results in patients, so that therapeutic development is primarily reliant on delineating the original molecular defects. Increasing interest has turned to the Kinesin Superfamily Proteins (KIFs), basic molecular motors that move along microtubule rails, and are now emerging as important key oncogenic derivers in bladder cancer pathogenesis. This review synthesizes available evidence indicating that several KIFs, specifically KIF4A, KIF14, KIF20A, and KIFC1, function as key oncogenic regulators and represent important prognostic biomarkers and therapeutic targets in bladder cancer. When KIF expression or activity is disrupted, it provides mechanical and signaling support for all the cancer hallmarks, facilitating cellular proliferation, invasion, metastasis, and resistance to highly effective cell death. Its oncogenic activity is generally facilitated by the activation of principal signaling pathways. A remarkable proportion of certain KIF isoforms are commonly overexpressed in cancer, and the scale of such overexpression increases with the severity of adverse clinical predictors, such as increasing disease stage, and patient survival worsens. This nuanced molecular image renders KIFs so highly promising targets for therapeutic intervention and prognostic stratification, and initial exploration of kinesin inhibitors is encouraging to abate chemoresistance, aside from optimizing the efficacy of current immunotherapies. Uncovering modalities that exploit the aggressive bladder cancer cell dependence on KIF motor activity is a highly promising path to clinical application.

In East Asia, incense burning for religious and ceremonial purposes is a long-standing cultural practice. However, incense combustion generates particulate matter and toxic pollutants that may adversely affect maternal and fetal health. Associations between maternal incense exposure and pre-eclampsia, adverse neurodevelopmental outcomes, and impaired fetal growth are noted. Evidence regarding the association between household incense burning and small for gestational age (SGA), particularly according to gestational-age strata, remains limited. We analyzed data from 18,666 mother-infant pairs enrolled in the Taiwan Birth Cohort Study with follow-up at 6 months postpartum. Household incense-burning exposure during pregnancy was categorized as none, occasional, or daily. Multivariable logistic regression models were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for SGA, stratified by term and preterm births. Multiple sensitivity analyses were conducted to assess the robustness of the findings, including adjustments for additional indoor environmental factors, maternal medical history, gestational complications, gestational weight gain, and evaluation of interactions with secondhand-smoke exposure. Overall, 583 (8.1%) SGA infants were identified in the non-exposure group (n = 7242), 415 (9.4%) in the occasional-exposure group (n = 4413), and 700 (10.0%) in the daily exposure group (n = 7011). Among term infants, household incense burning was significantly associated with SGA, with aORs of 1.16 (95%CI: 1.00-1.33) for occasional exposure and 1.25 (95%CI: 1.10-1.41) for daily exposure, demonstrating a dose-response relationship. Similar, but nonsignificant, patterns were observed among preterm infants. No significant association was found between household incense burning and preterm birth. In this large population-based cohort, maternal exposure to household incense burning during pregnancy was associated with increased risk of delivering an SGA infant, particularly among term births. The risk was higher for daily than for occasional exposure. These findings highlight the potential public health implications of household incense use during pregnancy.

Eisenmenger syndrome (ES) represents the end stage of uncorrected congenital heart defects with long-standing left-to-right shunts that evolve into irreversible pulmonary vascular remodelling and pulmonary arterial hypertension. This report highlights the complex cardio-oncological management of a patient with ES and chronic thromboembolic pulmonary hypertension (CTEPH), who developed endometrial carcinoma complicated by life-threatening uterine bleeding. A 66-year-old woman with an uncorrected ostium secundum atrial septal defect complicated by Eisenmenger physiology and CTEPH presented with vaginal bleeding. She was diagnosed with endometrioid adenocarcinoma. Due to prohibitive surgical risk, radiotherapy was selected as the primary treatment; however, bleeding persisted despite completion of 28 sessions. Interruption of warfarin therapy was contraindicated, given her high thrombotic risk. Following multidisciplinary team deliberation, uterine artery embolization (UAE) was performed successfully, achieving haemorrhage control without major haemodynamic instability. This minimally invasive intervention proved life-saving in a patient for whom both surgical and medical alternatives carried unacceptable risk. The case exemplifies the intricate balance between anticoagulation and haemorrhagic control in ES complicated by malignancy. Severe hypoxaemia and haemostatic abnormalities inherent to ES amplify both bleeding and thrombotic risks, complicating oncological management. Tumour hypoxia secondary to chronic cyanosis may contribute to radioresistance and poor response to local therapy. The successful use of UAE underscores the vital role of a multidisciplinary cardio-gynaecology-oncology team in navigating life-threatening clinical conflicts and tailoring individualized strategies when conventional guidelines offer limited direction.

To examine all-cause and cause-specific mortality by age group in Switzerland during and after the COVID-19 pandemic, in order to determine whether pre-pandemic trends recovered in 2023-24. Standardised mortality rates since COVID-19 were compared with those expected by continuing trends estimated over the pre-pandemic years 2000-19 by log-linear Poisson models, resulting in estimates of all-age and age-specific excess death and mortality for 2020-24. Mortality trends for the leading causes of death were analysed by age group using Joinpoint regression models.  In 2024, all-cause mortality in Switzerland showed a complete return to pre-pandemic trends. However, marked differences between age groups were observed. While mortality among people aged 85 and over was significantly lower than trend in 2024 (-5.4% for men and -3.5% for women), people aged 65 to 84 were still struggling to recover the pre-pandemic trend this year (+4.2% for men and +3.5% for women). Mortality in the 15-44 age group began to stagnate a few years before the pandemic and remained significantly above trend in recent years, with excess mortality being systematically outside the 95% prediction intervals, reaching +33.6% for men and +20.4% for women in 2024. At the same time, accidents and suicides, among the leading causes of death in this age group, appear to have stopped declining, with a stabilisation in the suicide trend since 2014 among men (p = 0.005) and 2013 among women (p = 0.001), and in the accident trend since 2019 among men (p = 0.031). A slowdown in the decline of cardiovascular and respiratory mortality has been observed in the 65-84 age group. The long-standing decline in mortality has stalled in recent years in Switzerland among young adults and, to a lesser extent, among young retirees, due to stagnation or slowdown of several major causes of death in these age groups. These phenomena, in addition to their importance for considering appropriate preventive interventions, also raise questions about the future of mortality and longevity in Switzerland and, more generally, in Western societies, and must be taken into account when developing realistic life expectancy and demographic scenarios. These are essential for decision-making in the areas of insurance, retirement planning and healthcare cost management.

Irritable bowel syndrome (IBS) and metabolic dysfunction-associated steatotic liver disease (MASLD) are two of the most common gastroenterological conditions worldwide. Traditionally viewed as unrelated, with one serving a canonical functional role and the other a purely metabolic function, these two processes have recently been linked by compelling evidence, challenging their traditional segregation and pointing to a significant, biologically relevant association. This review aims to evaluate the current evidence for a potential causal contribution of IBS to hepatic steatosis, critically examining the proposed pathophysiological mechanisms via the gut-liver axis while acknowledging that the available data are primarily observational. Notably, epidemiological studies demonstrate a 1.4-2.0-fold increased association between IBS and MASLD, independent of obesity and metabolic syndrome, though causality remains to be established. The primary mechanism is increased intestinal permeability ("leaky gut") leading to endotoxemia, activation of hepatic toll-like receptor 4 (TLR4) receptors, and subsequent de novo lipogenesis. The relationship is bidirectional, with steatosis also worsening gut barrier function. Therefore, we highlight emerging evidence suggesting that irritable bowel syndrome, particularly the diarrhea-predominant subtype (IBS-D), may contribute to hepatic steatosis through plausible biological mechanisms, though direct causal evidence in humans remains limited. Accordingly, routine screening for metabolic dysfunction-associated steatotic liver disease (MASLD) may be warranted in patients with long-standing IBS-D.

Stable oral delivery of macromolecules, which easily lose conformation and activity, is far more carrier-demanding than small molecules and a long-standing food science challenge. This study developed a cellulose-based IUSRHP to address this issue. Tests under separate independent conditions showed IUSRHP stayed stable in simulated gastric fluid (pH 3.0) for over 3&#xa0;h, and achieved unidirectional load release in simulated intestinal fluid (pH 7.2). Its loading capacity (96, 125, 200&#xa0;mg/piece at 10%, 30%, 50% sodium carboxymethylcellulose (NaCMC)) and thermal stability (glass transition temperature (Tg) from 219&#xa0;&#xb0;C to 302&#xa0;&#xb0;C) rose with NaCMC content. In the gastrointestinal tract, water permeated the pH-responsive layer, swelling the patch into a 3D hydrogel for unidirectional release of proteins (isoelectric point&#x2009;<&#x2009;7.2) (release rate tunable via protein negative charge). IUSRHP enhances local effective loads concentration, stability and bioavailability, key for stable oral delivery of food nutrient macromolecules or pharmaceutical active proteins. The online version contains supplementary material available at 10.1007/s10068-026-02194-w.

Proteolysis-targeting chimeras (PROTACs) offer a powerful strategy for targeted protein degradation but suffer from poor solubility, bioavailability, and in vivo distribution due to their "beyond rule-of-five" physicochemical properties, severely limiting clinical translation. Here, we transform these intrinsic drug-likeness liabilities into a driving force for molecular self-assembly by developing a carrier-free nanoplatform in which PROTACs spontaneously co-assemble with cyanine dyes, including IR783 and the clinically approved indocyanine green (ICG). This strategy generates stable supramolecular assemblies with ultra-high PROTAC loading (up to 70&#x202f;wt%) without the need for exogenous carriers, while imparting intrinsic NIR fluorescence for real-time, non-invasive in vivo tracking. The assemblies undergo stimuli-responsive disassembly upon ultrasound or X-ray irradiation, enabling spatiotemporally controlled PROTAC release within tumors. Incorporation of diselenide-bridged cyanine derivatives further confers radiosensitization capability, allowing synergistic combination with radiotherapy. In vivo studies demonstrate efficient tumor accumulation, robust target protein degradation, and potent antitumor efficacy. Collectively, this work establishes a versatile supramolecular strategy that directly addresses the long-standing delivery challenges of PROTACs and advances precise, controllable oncological therapy.

Magnesium-based materials remain among the most intensively studied solid-state hydrogen storage systems because they combine high theoretical hydrogen capacity, elemental abundance, and comparatively low cost. Yet their practical performance is still constrained by sluggish sorption kinetics, difficult hydrogen release, surface passivation, and transport instability under repeated cycling. This perspective argues that these long-standing limitations are most coherently understood not as isolated thermodynamic or kinetic problems, but as a multiscale hydrogen transport-network problem. In this view, hydrogen storage performance depends on whether hydrogen can be admitted, transferred, redistributed, and released through a sufficiently continuous and durable sequence of interfaces, phases, defects, and microstructural pathways. The discussion therefore moves from activated interfaces, which govern hydrogen entry, to phase-network engineering, in which alloying reorganizes internal transport connectivity, and then to hierarchical architectures, where porous hosts, scaffolded secondary phases, and multicomponent microstructures amplify transport efficiency across scales. The perspective further emphasizes that these material-internal transport advantages become meaningful only when they remain compatible with heat and mass transfer at the level of a working storage body and device. Possible descriptors, including active-interface density, connected phase fraction, effective diffusion length, pathway tortuosity, apparent network efficiency, and rate retention during cycling, are further discussed to make this framework more operational. On this basis, the article proposes that future progress in Mg-based hydrogen storage will depend less on isolated optimization of additives or descriptors and more on the deliberate design of connected hydrogen transport networks from the atomic and interfacial scales to the system scale.