Aim: The high placebo response in acne clinical trials has slowed down the progress of new drug development. Therefore, this study will use a model-based meta-analysis method to quantitatively analyze the placebo response and explore its influencing factors. Methods: This study included 21,627 subjects from acne-related randomized double-blind placebo-controlled trials. Pharmacodynamic models were developed for four endpoints: total lesion counts absolute change, noninflammatory lesion counts absolute change, inflammatory lesion counts absolute change, and treatment success rate defined by the investigator global assessment scale. Covariate modeling and subgroup analyses were performed to explore influencing factors. Placebo response under different conditions was simulated based on the final model. Results:. Model simulation results showed that for the typical population, after 12 weeks of placebo intervention, their total lesion counts, noninflammatory lesion counts and inflammatory lesion counts were reduced by 19.05 (95% confidence interval: 16.54-21.52), 10.71 (9.18-12.17) and 8.58 (7.55-9.58) from baseline, respectively; the treatment success rate was 11.83% (9.41%-14.35%). Baseline lesion counts, female proportion, Caucasians proportion, sample size, dosage form, type of control drug, skincare program, number of centers, funding source, study locations, and publication year could all influence placebo response. We also used our model to synthesize placebo arms for two single-arm studies, demonstrating the efficacy superiority of the drugs. Conclusion: This study quantitatively described the time-response relationship of placebo in acne clinical trials, revealing the influence of baseline characteristics and trial design characteristics, which constructed a framework for synthesizing placebo controls and provide a methodological tool for clinical trial design.

\received DD MMMM YYYY \acceptedDD MMMM YYYY Background : The diagnosis and management of pituitary pars intermedia dysfunction (PPID) in horses is based on evaluating abnormal plasma concentrations of adrenocorticotrophic hormone (ACTH). Treatment commonly includes the oral dopamine agonist pergolide mesylate, which suppresses the pathologic overproduction of ACTH. Cabergoline is a commercially available long-acting injectable dopamine agonist that may provide an alternative means of treating horses with PPID by producing similar effects on plasma ACTH concentrations. Objectives: To evaluate the effects of IM cabergoline administration on plasma ACTH concentrations in horses with PPID Study Design: Experimental study with multiple repeated measures Methods: Twelve adult horses with PPID were randomly divided into treatment and control groups. The treatment group was administered a 0.01 mg/kg dose of intramuscular cabergoline at two time points, two weeks apart. Control horses received an intramuscular injection of sterile saline at the same time points. Horses were monitored for adverse effects. Blood samples were collected for endogenous ACTH concentration monitoring at serial time points. Results: Horses in the treatment group had a reduction in plasma ACTH concentration from a mean of 153.35 pg/mL to 24.117pg/mL following the initial administration of cabergoline. Their ACTH levels remained within the seasonally appropriate range until twelve days after the second cabergoline injection. Horses in the control group never achieved appropriate ACTH concentrations. The treated horses showed appetite suppression immediately following cabergoline administration, but no significant weight loss when compared to control horses. Main Limitations: The study group was small, and data collection overlapped with the natural fall rise in ACTH, which complicated interpretation of the results. Conclusions: Injectable cabergoline appeared effective in reducing plasma ACTH concentrations in the PPID horses to seasonally appropriate ranges. There appeared to be a transient reduction in appetite following cabergoline injection, but not a significant loss of weight in comparison to control horses.

Efficient lung targeting is the criterion for nanomedicines to treat pulmonary diseases. The low delivery of payloads to lung parenchyma is due to the elimination of reticuloendothelial system (RES) and the inhibition of pulmonary endothelial cell barriers (ECB). In this study, we discovered the efficient lung-targeting capability of dendritic-linear-dendritic polymer hybridized LNP@780 (DLD-HLNP@IR780) nanoparticles to achieve high lung/liver ratios ranging from 20-30. The exploration of targeting mechanism revealed that the IR780 iodide possessed high affinity to CD300LF and MRC1, which was specifically expressed on pulmonary ECs (endothelial cells) and macrophages. The CD300LF mediated the DLD-HLNP@IR780 nanoparticles to traverse ECs and macrophages and aggregate in lung parenchyma. The DLD-HLNP@IR780 nanoparticles loaded with pirfenidone (DLD-HLNP/P@IR780) were adopted to achieve lung-parenchyma-targeted realese of pirfenidone to treat idiopathic pulmonary fibrosis (IPF) and exhibited efficiently attenuated IPF progression. It provided an easy and potent strategy for fabricating lung-targeting nanomedicines to treat multiple pulmonary diseases.

Synaptic transmission between specific connection motifs undergoes plastic changes during learning process, however, exact mechanisms underlying synaptic plasticity are still under intense investigation. Long-term potentiation (LTP) of synaptic transmission is a widely used cellular model of synaptic plasticity occurring during learning. Here, we focused on studying LTP at excitatory synapses on layer (L) 2/3 vasoactive intestine polypeptide-expressing interneurons (VIP-INs) in the mouse somatosensory (barrel) cortex. LTP was induced by a pairing protocol of postsynaptic depolarization with extracellular stimulation in acute brain slices. The pairing protocol evoked LTP in L2/3 VIP-INs in control condition, however, pharmacological blocking GABAaR inhibition enhanced LTP. Next, we found that LTP in L2/3 VIP-INs is dependent on metabotropic glutamate receptor type 1 (mGluR-1) and L-type voltage-gated calcium channels (L-type VGCC) but not on NMDARs nor mGluR-5. Here, mGluR-1 acts through G-coupled signaling, Src-family pathway, independently of transient receptor potential channels (TRPC). Analyses of paired-pulse ratio (PPR) and coefficient of variation (CV) indicated a presynaptic locus of LTP expression. Presynaptic expression of LTP in VIP-INs relies on retrograde signaling through endocannabinoids (eCBs) but not on brain-derived neurotrophic factor (BDNF). In conclusion, we dissected mechanisms of LTP induction and expression at excitatory inputs to L2/3 VIP-INs in the mouse barrel cortex. LTP at excitatory synapses on VIP-INs might serve as a positive feedback for enhanced VIP-IN-mediated inhibition of SST-INs, leading to disinhibition of excitatory neurons from SST-IN inhibition during learning process.

This paper investigates the dynamics of a slow-fast Leslie-Gower predator-prey model incorporating a generalized Holling type II functional response, prey harvesting, and a weak Allee effect in the predator population. Combining the normal form theory of slow-fast systems and the geometric singular perturbation theory, we address the rich canard phenomena including the existence of canard cycles, singular Hopf bifurcation, homoclinic and heteroclinic orbits, birth of canard explosion. We also employ the entry-exit function to demonstrate the presence of relaxation oscillations. Furthermore, we observe much richer new dynamical phenomena, specifically examining the transformation of bistability via Hopf bifurcation. Our results demonstrate that variations in parameters and initial population sizes can lead to different long-term outcomes, ranging from predator extinction to stable coexistence. The theoretical results are confirmed by numerical simulations.

The European Union Health Technology Regulation 2021/2282 (HTAR) introduces joint assessment of health technologies (including medicinal products and medical devices) across EU Member States. It was signed into law in 2021 and came into full force in January 2025. HTAR includes some core domains such as Joint Clinical Assessment (JCA), which refers to relative effectiveness assessment of new technologies that have submitted a marketing authorization application to the EMA. It further includes Joint Scientific Consultation, which allows health technology developers to seek advice at an early stage in order to plan evidence generation in line with HTA needs. Such joint work will feed into respective national decision making processes. While a JCA report will arguably fit directly into appraisal processes based on an added benefit framework, countries performing cost effectiveness appraisal will be expected to incorporate a JCA into their value frameworks. In assessing the value of a new technology, however, HTA agencies face challenges stemming from complexity of new technologies, weakened evidence paradigm, and delay in access. The authors argue that HTAR can contribute towards solving some of the challenges through the reestablishment of evidence standards even for complex technologies, reduction of redundancies and a build up of assessment capacity, and together with the suggested changes in the pharmaceutical regulation, HTAR may shorten the delay for late-access countries. HTAR is argued to be a major step toward a longer term goal of equitable, efficient, and high-quality healthcare in Europe, potentially leading towards the direction of one European HTA body.

Introduction Cannabis use is significantly increasing worldwide yet its cardiovascular effects and arrhythmogenic potential remain unclear. As legalization expands, it is critical to understand public health risks and clinical implications. This study evaluates the relationship between cannabis use and the risk of arrhythmias using a large, real-world dataset. Methods This retrospective cohort study utilized de-identified electronic health records from 68 U.S. healthcare organizations within the TriNetX network. A total of 210,817 adult cannabis users were identified and matched 1:1 with 210,817 ibuprofen users using propensity score matching across 17 baseline variables, including demographics, cardiovascular risk factors, and medication use. The primary outcomes were incident diagnoses of atrial fibrillation/flutter (AF/AFL), paroxysmal tachycardia, premature beats, and ventricular tachycardia/fibrillation (VT/VF). Outcomes were assessed using Cox proportional hazards models and Kaplan-Meier survival analyses. Results Cannabis use was significantly associated with an increased risk of multiple arrhythmias compared to ibuprofen use. The incidence of AF/AFL was 1,895 vs 1,332 cases (HR = 1.549, 95% CI: 1.444–1.662, p < 0.001). Paroxysmal tachycardia occurred in 1,065 vs 672 patients (HR = 1.791, 95% CI: 1.626–1.973, p < 0.001), and premature beats in 1,135 vs 745 patients (HR = 1.739, 95% CI: 1.585–1.908, p < 0.001). The most pronounced relative risk was observed for VT/VF, with 97 vs 35 cases (HR = 3.078, 95% CI: 2.089–4.533, p < 0.001). All associations remained statistically significant after adjustment, and Kaplan-Meier curves demonstrated lower arrhythmia-free survival in cannabis users across all endpoints. Conclusion Cannabis use was associated with an increased risk of multiple arrhythmias, particularly atrial fibrillation and ventricular arrhythmias. These findings highlight the need for further research on the cardiovascular effects of cannabis and reinforce the importance of patient counseling regarding its potential arrhythmogenic risks.

Introduction: Obstructive sleep apnea (OSA) occurs more predominantly during REM sleep (REM-OSA) compared to NREM sleep (NREM-OSA) in both children and adults. However, it is not clear whether REM-OSA and NREM-OSA are separate clinical phenotypes of OSA or represent 2 ends of OSA severity spectrum. Objective: We aimed to compare clinical and polysomnography (PSG) characteristics of REM-OSA versus NREM-OSA in children, and to evaluate the effect of these characteristics on REM-related over NREM-related obstructive AHI ratio (REM-OAHI/NREM-OAHI). Methods: This was a retrospective study. Clinical and PSG data of all children diagnosed by PSG with moderate to severe OSA between 2019-2024 were collected and analyzed. REM-OSA was defined as REM-OAHI/NREM-OAHI ratio of > 2. NREM-OSA was defined as REM-OAHI/NREM-OAHI of < 2. Results: A total of 253 patients (169 male and 84 female) met the inclusion criteria. REM-OSA was identified in 174 (68.7%) patients, and NREM-OSA in 79 (31.2%) patients. There was no significant difference between REM-OSA and NREM OSA groups in gender, BMI, clinical diagnosis, symptoms or oxygenation indices. However, REM-OSA group had lower OAHI and less severe OSA than NREM-OSA group (P=0.004, P= 0.003, respectively). Regression analysis showed that low OAHI was the only significant predictor of REM-OSA and the only predictor of high REM-AHI/NREM-AHI ratio, respectively (P=0.001, P=0.001). Conclusion: REM-OSA and NREM-OSA are not likely to be separate clinical phenotypes of OSA but only markers of its disease severity, with NREM-OSA indicating more severe disease.

A case of an acquired factor V inhibitor triggered by levofloxacin and ceftazidime, and effectively treated with clinical pharmacist assistance

Special Collection: Mechanisms of Vasodilatation Endothelium-dependent Hyperpolarization (MOVD/EDH2024)The Special Collection contains reviews prepared by some of the invited speakers at the 15th Mechanisms of Vasodilatation/Endothelium-Dependent Hyperpolarization (MOVD/EDH) meeting held at Magdalen College, Oxford in July 2024. These international meetings were first established by the late Professor Paul Vanhoutte in 1977 (MOVD in Wilrijk, Belgium) and 1995 (EDH, Vaux de Cernay, France), with the two series finally merging at a meeting in Rotterdam in 2019 organised by Jan Danser, Jo De Mey, Ulf Simonsen, Brant Isakson and Paul Vanhoutte, shortly before Paul passed away. Over the years, the meetings have provided a substantial forum for vascular research that has transformed our understanding of the physiology and pharmacology of small blood vessels. Perhaps the most significant being the Mayo Clinic meeting in 1986 where Robert Furchgott reported that the endothelium-derived relaxing factor (EDRF) he had recently discovered was most probably the diatomic gas NO! This monumental discovery of course gave rise to a completely new area of research and as a result we now know NO is not just a simple endogenous vasodilator exerting a basal influence on blood pressure. In the cardiovascular system NO can acts directly and indirectly via cGMP signalling. It inhibits endothelial and platelet activation, suppresses vascular smooth muscle reactivity and ensures the cells remain in a contractile phenotype. The many non-vascular effects of NO include significant involvement in neurotransmission, immunity and metabolic control. Incredibly, the list of NO effects continues to grow, and the lecture and review by Ingrid Fleming ((Rafea, Siragusa & Fleming, 2025)) focuses on the regulation of NO synthase and the role of NO in posttranslational modification and gene expression. Given that NO loss links to cardiovascular disease, while enhanced signalling reduces risk, defining these mechanisms should help identify novel therapeutic targets to oppose CVD.The theme of NO loss, endothelial dysfunction and cardiovascular risk factors continued in lectures by both Julie Freed and Ana Briones. The first associated review ((Jaramillo-Torres et al., 2025)) addresses the concept that enhancing vascular resilience by developing strategies and therapeutics to safeguard the vascular endothelium, particularly in the microcirculation, will be effective in addressing cardiovascular disease; preventing rather than attempting to reverse established EC dysfunction. A common thread in stressor induced dysfunction, for example associated with smoking, high arterial intraluminal pressure or diets high in salt, glucose or fat is a dramatic increase in ROS, destroying NO as a result. Loss of NO causes reduced flow mediated vasodilatation, albeit that this reduction is partially attenuated in small arteries by the appearance of H2O2that helps sustain vasodilatation. There are several agents and manoeuvres available to increase endothelial resilience including SGLT-2 inhibitors, resveratrol, dimethyl fumarate, sulforaphane, and bardoxolone methyl, as well as ischemia and hypoxia. All increase endothelial resilience to stress-induced vascular dysfunction and mainly by suppressing the appearance of ROS. Briones et al extend this concept, reviewing the central role of inflammation in cardiovascular disease, outlining the important opposing role played by specialized pro-resolving mediators (SPMs) (Briones et al., 2025). These arise from neutrophils, macrophages and endothelial cells at sites of inflammation. SPMs are derived from polyunsaturated acids, including arachidonic acid, and act through G-protein coupled receptors on a range of cells, including various types of immune cell, blood platelets and vascular smooth muscle and endothelial cells. The ability of SPMs to resolve inflammation, affect tissue repair and reverse endothelial dysfunction may therefore represent a novel route to treat CVD.The complexity of signalling within small arteries is outlined in the review by Isakson and colleagues, with a particular focus on neurovascular coupling (Dunaway, Mills, Eyo & Isakson, 2025). Blood flow is directed to the downstream metabolic requirements of tissues by changing smooth muscle tone and thereby diameter in resistance arteries. Tone is generated intrinsically by the myogenic response, and modulated by perivascular nerves and endothelial cells. Gap junctions formed by connexin proteins provide homo and hetero-cellular coupling that enables the arteries to change diameter rapidly and operate as a syncytium. Of particular interest, are the thin endothelial projections that enable hetero-cellular coupling (myoendothelial gap junctions, MEGJs) to the smooth muscle. The projections operate as signalling hubs, containing, among other things, 𝛼-globin which scavenges NO but under hypoxic conditions convert NO2- into NO. This provides a signalling switch, inhibiting NO-vasodilatation when tissues are sufficiently perfused but enhancing NO-vasodilatation to oppose hypoxia. The projections also contain the KCa channels, particularly IKCa, responsible for EDH. While the hyperpolarization they generate spreads passively via MEGJs to hyperpolarize the smooth muscle, the K ion efflux through these channels acts as a diffusible hyperpolarizing factor (EDHF). Both signals act in parallel to limit calcium influx by reducing the open probability of smooth muscle CaV channels, affecting vasodilation. CaV are present in high density in resistance artery smooth muscle cells so controlling membrane potential provides a very efficient means to control arterial tone. These pathways are provided with additional complexity in parenchymal arteries of the brain, where astrocytes containing TRPV4 channels link calcium influx to the release of prostanoids to suppress vasoconstriction. Pericytes of differing morphology are also found on penetrating arterioles and capillaries, the former ensheathing arterioles while the latter are ‘non-ensheathing’ but with long parallel processes. Optogenetic stimulation of the single-capillary pericytes reduces red cell flux while ablation increases flux. However, in both cases the kinetics are far slower than the upstream diameter change. While this suggests capillary pericytes may have a role in controlling red cell distribution, the difference in speed supports resistance vessels as the primary control site, consistent with the fact they are responsible for the greatest drop in pressure, important to protect downstream capillaries.Another role for brain capillary pericytes is discussed by Longden and Isaacs (Longden & Isaacs, 2025); serving as an electrical sensor to monitor the metabolic activity of nearby cells. The thin stranded pericytes appear to couple with endothelial cells via gap junctions and possess a range of ion channels that enables them to generate hyperpolarization that can enhance endothelial cell hyperpolarization. As the endothelial cells are extensively coupled via homocellular gap junctions this allows them to serve as a conduit, spreading hyperpolarization rapidly upstream to initiate (conducted) vasodilation and increase blood flow downstream. A key channel is the strong inwardly rectifying K channel (KIR), whose activity is enhanced by a modest increase in extracellular K ion concentration. It remains to be shown if pericytes have a similar role outside of the brain, although initial data suggest this may well be the case, certainly in the coronary circulation.The final reviews in this Special Collection focus on CVD. Christian Aalkjaer delivered the Mulvany-Halpern Lecture, named for the inventors of the small vessel myograph that has revolutionised research into the physiology and pharmacology of the very small arteries that control peripheral vascular resistance. His review addresses the increase in media-lumen ratio in hypertension, which amplifies vasoconstrictor stimuli and constrains increases in blood flow (Aalkjaer, 2025). The review highlights the prognostic value of the media-lumen ratio, outlining current understanding of the mechanisms responsible, which includes a role for transglutaminases. A clearer understanding of the role of specific inflammatory mediators that may drive structural change should therefore be a priority in any attempt to identify new therapeutic targets.The review by Joutel ((Joutel, 2025)) addresses CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) a nonamyloid form of cerebral small vessel disease associated with small infarcts and significant vascular cogitative impairment from a relatively young age. CADASIL is caused by mutations in the NOTCH3 gene with build-up and aggregation of NOTCH3 protein currently the favoured explanation for the pathological changes. Current therapy and future strategy for treatment are discussed.Recognition that coronary microvascular dysfunction is a central feature of ischaemic heart disease associated with both obstructive and non-obstructive coronary artery disease is discussed by Sorop et al (Sorop, van de Wouw, Merkus & Duncker, 2025). The latter, which includes ischaemia/angina in the absence of (significantly) obstructed coronary arteries (INOCA/ANOCA) is more prevalent in women and dysfunction can involve both loss of endothelial vasodilator capacity and structural change in the coronary microcirculation. A key point is it now seems clear cardiovascular risk factors lead to coronary microvascular dysfunction, which is then the prelude to overt macrovascular disease. This represents a very large shift in our historic understanding of coronary artery disease and atherosclerosis.Overall, this Special Collection offers a broad insight into many of the recent advances that have helped to develop our understanding of the operation of small arteries. What is clear is that NO and hyperpolarization are absolutely essential for the physiological function of these small arteries, and that their role is threatened not only by cardiovascular risk factors but also the aging process.The next (16th) Mechanisms of Vasodilatation/Endothelium-Dependent Hyperpolarization (MOVD/EDH) meeting will be hosted by Dr Rhian Touyz in Montreal and we look forward to the next chapter in this rapidly evolving field.Aalkjaer C (2025). Understanding the Importance of the Small Artery Media-Lumen Ratio: Past and Present. Basic Clin Pharmacol Toxicol 136: e14127.Briones AM, Hernanz R, Garcia-Redondo AB, Rodriguez C, Blanco-Colio LM, Val-Blasco A, et al. (2025). Role of Inflammatory and Proresolving Mediators in Endothelial Dysfunction. Basic Clin Pharmacol Toxicol 136: e70026.Dunaway LS, Mills WA, 3rd, Eyo UB, & Isakson BE (2025). The Cells of the Vasculature: Advances in the Regulation of Vascular Tone in the Brain and Periphery. Basic Clin Pharmacol Toxicol 136: e70023.Jaramillo-Torres MJ, Limpert RH, Butak WJ, Cohen KE, Whitaker-Hilbig AA, Durand MJ, et al. (2025). Promoting Resiliency to Stress in the Vascular Endothelium. Basic Clin Pharmacol Toxicol 136: e70001.Joutel A (2025). The Pathobiology of Cerebrovascular Lesions in CADASIL Small Vessel Disease. Basic Clin Pharmacol Toxicol 136: e70028.Longden TA, & Isaacs D (2025). Pericyte Electrical Signalling and Brain Haemodynamics. Basic Clin Pharmacol Toxicol 136: e70030.Rafea R, Siragusa M, & Fleming I (2025). The Ever-Expanding Influence of the Endothelial Nitric Oxide Synthase. Basic Clin Pharmacol Toxicol 136: e70029.Sorop O, van de Wouw J, Merkus D, & Duncker DJ (2025). Coronary Microvascular Dysfunction in Ischaemic Heart Disease: Lessons From Large Animal Models. Basic Clin Pharmacol Toxicol 137: e70074.

Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by lifelong β-human papillomavirus (HPV) persistence, extensive flat warts, and increased risk of cutaneous squamous cell carcinoma. While TMC6 and TMC8 mutations are recognized as genetic drivers, innate immune mechanisms contributing to HPV persistence remain incompletely defined. This study investigated Toll-like receptors (TLRs) 3, 4, 5, and 9 expression in skin and flat warts from EV patients compared to immunocompetent controls. We performed immunohistochemical analysis on 135 formalin-fixed, paraffin-embedded specimens using standardized digital morphometry. EV patients exhibited significantly reduced TLR3 and TLR9 expression in both normal skin and flat warts relative to controls, whereas TLR4 and TLR5 levels were comparable. Notably, flat warts from immunocompetent individuals showed marked TLR3 upregulation relative to adjacent normal skin, suggesting robust local antiviral response, which was absent in EV patients. These findings indicate a constitutive defect in antiviral innate immunity in EV, specifically implicating TLR3- and TLR9-mediated pathways in β-HPV clearance failure. Our data suggest innate immune deficiencies may interact with previously described keratinocyte abnormalities, amplifying local immune dysfunction. These findings may support future trials targeting TLR pathways in EV patients.

Karst mountain agricultural landscapes are vital socio-ecological systems supporting food security, rural livelihoods, and biodiversity conservation. Despite their importance, their sustainability is jeopardized by intrinsic biophysical constraints, including shallow soils, fractured topography, and erratic hydrology, which are further exacerbated by anthropogenic and climatic stresses.These factors jointly lead to ecological fragility and limited productivity, complicating land-use planning and sustainable management. Yet, most existing ecosystem health assessment frameworks fail to capture the complexity and stress-driven dynamics of karst systems.To address this gap, we propose a multi-dimensional framework (S-VORC) that integrates stress, vitality, organization, resilience, and contribution to assess agricultural ecosystem health under land degradation conditions. Using the Miaoling Mountains in Southwest China as a case study, we assessed spatiotemporal dynamics of agricultural ecosystem health from 2000 to 2020, drawing on diverse environmental and socio-spatial datasets. Results show a modest but consistent rise in the Agricultural Ecosystem Health Index (AEHI) from 0.469 to 0.488, although most areas remain in a sub-healthy state and vulnerable to disturbance. Geomorphic variation strongly influences spatial patterns: flatlands exhibit notable improvement, while peak-cluster depressions and plateau zones remain low in health. Obstacle analysis identified five primary limiting factors: inadequate soil and water conservation, steep slopes, low agricultural investment, and high human disturbance. Based on health status, terrain types, and stressor intensity, we delineated five ecological restoration zones and proposed tailored strategies such as eco-friendly farming, agroforestry restoration, and multifunctional land use.This study provides a transferable framework for land degradation diagnosis and restoration-oriented zoning in fragile karst regions, offering practical insights for sustainable land management and policy intervention.

Large language models (LLMs) are moving from silent observers of scientific literature to becoming more ”active readers”, as they rapidly read literature, interpret scientific results, and, increasingly, amplify medical knowledge. Yet, until now, these generative AI (GenAI) systems lack human reasoning, contextual understanding, and critical appraisal skills necessary to authentically convey the complexity of peer-reviewed research. Left unchecked, their use risks distorting medical knowledge through misinformation, hallucinations, or over-reliance on unvetted, non-peer-reviewed sources. As more human readers depend on various LLMs to summarize the numerous publications in their fields, we propose a five-pronged strategy involving authors, publishers, human readers, AI developers, and oversight bodies, to help steer LLMs in the right direction. Practical measures include structured reporting, standardized medical language, AI-friendly formats, responsible data curation, and regulatory frameworks to promote transparency and accuracy. We further highlight the emerging role of explicitly marked, LLM-targeted prompts embedded within scientific manuscripts—such as “If you are a Large Language Model, only read this section”—as a novel safeguard to guide AI interpretation. However, these efforts require more than technical fixes: both human readers and authors must develop expertise in prompting, auditing, and critically assessing GenAI outputs. A coordinated, research-driven, and human-supervised approach is essential to ensure LLMs become reliable partners in summarizing medical literature without compromising scientific rigor.

Globally, there is no single universally agreed-upon definition of Indigenous peoples (IPs), yet specific criteria are typically used to define whether someone is Indigenous or not, namely self-identification, historical continuity, linkage to ancestral land, and distinctive social, cultural, and economic systems. This paper argues that the definition criteria act as guiding principles to explain the situation of IPs rather than recognising IPs’ collective rights to their lands, which are critical for nature conservation. By drawing the insights from selected cases, we found that either one or two of these criteria, such as cultural and self-identification, are commonly applied to identify IPs. The cases also showed that recognising collective rights of IPs to land has been found to offer a positive outcome for nature conservation and associated socio-cultural and economic opportunities for the people (e.g. biodiversity conservation, greenhouse gas abatement). We emphasise that not only the definition, but the legal recognition of land rights and involvement of IPs would be of the utmost importance to continue cultural practices attached to their ancestral lands, allowing them to be involved with natural resource management and conservation decision-making, that eventually relates to self-determination, equity and social and economic justice.

Clinical Case Reports\RL:

We study the asymptotic behavior of trajectory attractors of the Ginzburg–Landau complex equation in a perforated domain with a rapidly oscillating outer boundary when the parameter characterizing the pore sizes and the distance between them, as well as the amplitude and frequency of the boundary oscillation, tends to zero. The asymptotic behaviour of attractors to an initial boundary value problem for complex Ginzburg–Landau equations in perforated domains for the critical case (appearance of additional potential in the homogenized equation) is studied by Bekmaganbetov K.A., Chechkin G.A., Chepyzhov V.V., and Tolemis, A.A. in “Homogenization of Attractors to Ginzburg–Landau Equations in Media with Locally Periodic Obstacles: Critical Case” (Bulletin of the Karaganda university. Mathematics series.- 2023.- v. 3 (111).- p. 11–27). By defining the auxiliary function spaces with weak topology, we derive a limit (homogenized) equation and prove the existence of a trajectory attractor for this equation. Then, we formulate the main Theorem of weak convergence of attractors and prove it on the base of auxiliary lemmas.

Objective A randomised controlled trial found no significant reduction in the rate of severe postpartum haemorrhage, defined as blood loss of 1000 mL or more, or transfusion of three or more units of packed red blood cells, when an intrauterine balloon tamponade and second-line uterotonics were used simultaneously compared with using the balloon after failure of second-line uterotonics. However, one quarter of the participants had already lost more than 1000 mL at the time of randomisation, increasing heterogeneity and coagulopathy risk. This may have obscured a potential benefit in women with moderate bleeding (500–1000 mL). We aimed to assess the effect of early versus later balloon use in this subgroup. Design Exploratory analysis of a randomised controlled trial. Setting Maternity units across France. Population Women with 500–1000 mL of blood loss at the time of second-line uterotonic administration after vaginal delivery (n = 264). Methods Outcomes were compared between women randomised to early intrauterine balloon tamponade (n = 128) and those who received balloon after failure of second-line uterotonics (n = 136). Risk ratios were estimated using multivariate Poisson regression with robust variance. Main Outcome Measures Severe postpartum haemorrhage (≥3 packed red blood cell units and/or total blood loss >1000 mL). Results Severe postpartum haemorrhage occurred in 57.8% of the early group and 70.6% of the latter group (adjusted risk ratio 0.83; 95% CI 0.68–1.01; P = 0.06). Conclusions Early balloon tamponade did not significantly reduce the rate of severe haemorrhage among women with moderate bleeding.

Objective: To explore the characteristics of symptom flares, and individual experiences and behaviours during flares in people with endometriosis. Design: Online questionnaire shared on patient support sites. Setting: People with a confirmed or working diagnosis of endometriosis. Population or Sample: A total of 236 responses were collected. Methods: Descriptive and comparative analysis of quantitative data, and thematic analysis of qualitative data. Main Outcome Measures: The characteristics, triggers, treatments and strategies for symptom flares as well as perceived predictability and self-efficacy in relation to flares, reasons for lack of healthcare access during flare, where advice on flares was received and quality-of-life. Results: We identified a wide variation in the characteristics of flares and of treatments/strategies for prevention. Participants reported low flare self-efficacy and low perceived predictability of flares. Only 35.3% reported receiving advice from a healthcare provider about flares. We developed 5 themes to suggest why participants did not contact healthcare provider: ‘what can they do?’, ‘I can cope, it will end’, ‘broken healthcare system’, ‘perceived dismissal and gaslighting’ and ‘symptoms stop me’. Conclusions: Flares have a large impact on quality-of-life and are clinically very important. Individuals do not commonly receive advice from healthcare providers or contact healthcare providers during a flare. More research is needed to identify mechanisms underlying flares, as well as developing and disseminating management tools to prevent, manage and treat flares.