Medicine and Pharmacology

Abstract: The first detection of the Shamonda virus in Central Europe occurred in mid-June 2026. Direct detection of the virus in blood or cerebrospinal fluid from living horses has not yet been reliably achieved. Serological examinations could therefore be crucial for future diagnostics. This study aimed to determine whether clinically healthy horses develop antibodies against viruses of the simbu serogroup and at what point the first positive antibody titers can be detected. To this end, blood sera from eleven clinically healthy horses based in southern Germany were examined retrospectively at three different time points between June and September 2026. Serological testing was performed using the ID Screen® Schmallenberg virus Multi-species ELISA kit; Innovative Diagnostics, Grabels, France. The results showed that all horses were seronegative or doubtful (one horse) in June (time point 1) and seronegative in July 2026 (time point 2). All eleven horses tested positive for antibodies in August or September (time point 3). There was a significant increase in antibody titers between time point 1 and time point 3, as well as between time point 2 and time point 3. The study found that even clinically healthy horses had been exposed to the pathogen and developed antibodies. Therefore, a positive antibody titer is not necessarily associated with clinical disease.

Abstract: Background: Vertical craniofacial morphology represents a continuous spectrum from hypodivergent to hyperdivergent skeletal patterns. Although the intermaxillary angle between the palatal and mandibular planes is commonly used to categorize these patterns, vertical morphology reflects a broader combination of facial height, mandibular, cranial base, and dentoalveolar characteristics. Machine-learning approaches may capture complex and potentially nonlinear relationships among these features; however, their validity and clinical interpretability require rigorous prevention of target leakage and transparent interpretation of model predictions. Objectives: Here, we aimed to develop and internally validate an explainable multiclass machine-learning model for distinguishing deep-bite, healthy, and open-bite skeletal patterns in a German orthodontic cohort. A secondary objective was to identify the cephalometric features contributing to each class-specific prediction using the SHapley Additive exPlanations (SHAP). Materials and Methods: We analyzed pretreatment cephalometric records from 1,524 unique patients. We categorized the vertical skeletal pattern according to the NL/ML angle as deep bite (<18.0°), healthy (18.0°–28.0°), or open bite (>28.0°). Because NL/ML can be mathematically reconstructed from ML–NSL and NL/NSL, the outcome-defining angle and its direct components were excluded from the primary model to prevent target leakage. A leakage-resistant XGBoost model was developed using 19 demographic and cephalometric predictors. Performance was estimated using nested stratified cross-validation with five outer folds and five inner folds. Fifty randomly sampled hyperparameter combinations were evaluated within each outer training fold. Class-balanced observation weights were calculated exclusively from the training data. Confidence intervals were estimated from 2,000 bootstrap samples of the out-of-fold predictions. SHAP values were calculated only for observations held out from model training. Results: The cohort included 236 patients with a deep-bite pattern, 976 with a healthy pattern, and 312 with an open-bite pattern. The XGBoost model achieved an out-of-fold accuracy of 0.778 (95% CI, 0.758–0.798), balanced accuracy of 0.749 (95% CI, 0.722–0.774), macro-F1 score of 0.740 (95% CI, 0.715–0.763), and macro one-versus-rest area under the receiver operating characteristic curve of 0.893 (95% CI, 0.879–0.907). Sensitivity was 0.695 for the deep-bite pattern, 0.810 for the healthy pattern, and 0.740 for the open-bite pattern. The corresponding class-specific AUC values were 0.927, 0.827, and 0.926 for deep-bite, healthy, and open-bite patterns, respectively. No patient with a deep-bite pattern was directly classified as having an open-bite pattern, and no patient with an open-bite pattern was directly classified as having a deep-bite pattern. PFH/AFH was the most influential predictor for all three classes. Gonial angle and facial axis were the next most influential variables for the deep-bite and open-bite classes. A sensitivity model containing predictors that mathematically reconstructed NL/ML achieved an accuracy of 0.957, demonstrating the substantial inflation in apparent performance caused by target leakage. Conclusions: A leakage-resistant XGBoost model demonstrated moderate-to-good ability to distinguish three NL/ML-defined vertical skeletal patterns. PFH/AFH, gonial angle, and facial axis were the principal contributors to class-specific predictions. The findings also demonstrate that including mathematical components of the reference standard can produce misleadingly high estimates of model performance.

Abstract: Calcium-activated chloride channels (CaCCs) are increasingly recognized as critical regulators of neuronal excitability, synaptic integration, sensory transduction, and ionic plasticity throughout the nervous system. Acting at the interface between intracellular calcium signaling and chloride homeostasis, CaCCs couple activity-dependent calcium elevations to dynamic changes in membrane excitability. Unlike canonical cationic conductances, the physiological effects of CaCC activation are not intrinsically excitatory or inhibitory but instead depend dynamically on intracellular chloride concentration and local chloride driving force. This state dependence allows CaCCs to function as chloride-sensitive calcium effectors whose polarity varies across neuronal populations, developmental stages, and pathological conditions. Recent advances in structural biology, electrophysiology, chloride imaging, and transcriptomics have substantially expanded current understanding of TMEM16/anoctamin channels, particularly TMEM16A and TMEM16B, revealing complex interactions among calcium binding, membrane voltage, phospholipid signaling, and ionic microdomains. In mature central neurons characterized by low intracellular chloride concentrations, CaCC activation frequently contributes to activity-dependent inhibitory feedback and dendritic stabilization. Conversely, in sensory neurons, immature circuits, and disease states associated with chloride accumulation, identical conductances may amplify depolarization and facilitate pathological hyperexcitability. This review summarizes the molecular organization, regional distribution, physiological functions, and pathological implications of neuronal CaCCs, with particular emphasis on how chloride homeostasis dynamically determines the functional polarity of calcium-dependent chloride signaling.

Abstract: Background. For more than two decades, opioid-involved overdose mortality in the United States followed a steep upward trajectory — from prescription opioids in the 1990s ("first wave") to heroin (~2010s), illicit fentanyl (~2013–2020), and a "fourth wave" combining fentanyl with stimulants (cocaine, methamphetamine). After peaking above 110,000 deaths in a rolling twelve-month window in 2023, mortality reversed: the Centers for Disease Control and Prevention (National Center for Health Statistics [NCHS], 2026) estimated 81,313 deaths in 2024 and 69,973 in 2025, a 14% decline and the third consecutive year of decrease. Methods. We conducted an analytic review integrating three bodies of evidence: (a) federal statistics and official reports (CDC/NCHS, DEA, DOJ, GAO, CBO, CRS); (b) peer-reviewed research, including the HEALing Communities Study cluster-randomized trial ("New England Journal of Medicine", 2024), a supply-shock analysis published in "Science" (January 2026), and systematic reviews of drug checking and supervised consumption (2022–2025); and (c) U.S. policy instruments issued between April 2025 and May 2026, including Executive Order 14321 (July 24, 2025) and two SAMHSA Dear Colleague letters (July 2025; April 24, 2026). Results. The dominant driver of the 2023–2025 decline appears to be a disruption of the global illicit fentanyl supply — a "supply shock" associated with precursor-chemical restrictions — rather than expansion of treatment or harm reduction (Caulkins et al., 2026). At the same time, U.S. federal policy moved away from harm reduction: the April 24, 2026 SAMHSA letter removes fentanyl and xylazine test strips, sterile water, saline, ascorbic acid, and overdose support hotlines from funding eligibility, while retaining naloxone, nalmefene, education, and HIV/hepatitis prevention services. "Conclusions. " The mortality decline is neither a "victory" of enforcement-centered policy nor a validation of harm reduction alone; it is a supply-side event whose durability is uncertain. In a market that is stabilizing in some respects while becoming pharmacologically more hazardous (xylazine, medetomidine, nitazenes), harm reduction instruments serve as an early-warning and shock-absorbing layer. U.S. policy should integrate — rather than dislodge — that layer, while restoring systematic surveillance of the illicit drug supply.

Abstract: Dental caries is a multifactorial disease mediated by a microbial biofilm, and it arises from the interaction of microbial metabolism, host defense mechanisms, salivary homeostasis and the mineral stability of enamel. Here we propose a multilevel molecular concept in which resistance to caries is defined by the capacity of the enamel–saliva–immunity–microbiome system to maintain mineral balance and to restore homeostasis after repeated acid loads. We identify seven interconnected functional nodes that determine the cariogenic activity of the biofilm: adhesion, synthesis of the extracellular matrix, acid production, acid tolerance, regulatory signaling, formation of alkaline metabolites, and interspecies metabolic cooperation. The key molecular mechanisms include the SpaP/PAc adhesins, the glucosyltransferases GtfB/GtfC/GtfD, phosphotransferase systems, lactate dehydrogenase, the F₁F₀-ATPase and the regulatory networks VicRK, LiaFSR, ComCDE/ComRS and CcpA. These processes are counteracted by salivary buffering systems, secretory IgA, antimicrobial proteins and microbial alkali-generating mechanisms, above all the arginine deiminase system and urease. We integrate molecular strategies directed at these vulnerabilities, including apigenin, tt-farnesol, epigallocatechin gallate, proanthocyanidins, structure-guided glucosyltransferase inhibitors, selective antimicrobial peptides (C16G2), arginine, fluoride and antigen-specific immunological approaches. We hypothesize that cariogenicity arises from a compensatory molecular network whose vulnerability depends on environmental conditions, metabolic redundancy and the spatial organization of the biofilm. Coordinated modulation of complementary targets may therefore suppress cariogenic functions more effectively than isolated blockade of single targets, while preserving the beneficial activity of the microbial community. The concept links molecular vulnerabilities with microbiome ecological resilience and enamel protection and yields experimentally testable predictions for multi-target caries prevention.

Abstract: Background: A dual-axis organization of non-alveolar macrophages—scar-associated SPP1+ and tissue-resident-like FOLR2+ populations—was recently delineated in idiopathic pulmonary fibrosis (IPF), but their functions and niches remain unresolved. Methods: We integrated full-transcriptome re-clustering of the GSE135893 myeloid compartment, independent replication (GSE136831), and GeoMx spatial profiling of bronchiolitis obliterans and fibrosing ILD lesions (GSE316672, GSE255174). Results: Two IPF-emergent entities were confirmed and first systematically quantified: SPP1+/TREM2+ scar-associated macrophages (97% IPF-derived; 4.0% to 30.7% of macrophages) and the FOLR2+/CD163+/SLC40A1+ iron-handling population (95% IPF; 11.9% to 19.0%). Both axes replicated in the Adams cohort (donor-level p = 1.2 × 10⁻⁵ and 8.2 × 10⁻¹¹). Spatial profiling revealed a core-and-ring architecture in BO lesions (SPP1+/TREM2+ luminal core; MCL1-high scavenger ring). Monocyte flux correlated with fibroblast apoptotic priming (rho = +0.54; nominal p = 0.045). No canonical M1/M2a enrichment was detected; the FOLR2+ efferocytosis arm was MERTK/GAS6-dominant across cohorts. Conclusion: The fibrotic lung’s dual-axis macrophage architecture is functionally attributed and spatially resolved, with implications for combination targeting.

Abstract: Background: Crimean-Congo hemorrhagic fever (CCHF) is a tick-borne disease endemic to in Africa, Asia, and Europe. This study examined the association between climate variables and CCHF in Iran, Iraq, Kazakhstan, and Russia from 2000 to 2022. Methods: CCHF case counts were collected from published, unpublished, and surveillance data sources. Cross-correlation analysis was used to evaluate the temporal effects of rainfall and temperature on CCHF incidence, applying generalized additive mixed models (GAMMs). The Akaike information criterion (AIC) was used to determine the most appropriate model. Kendall's W examined case peaks across countries and identified significant synchronicity among CCHF cases, temperature, and rainfall across countries (p< 0.05). Results: Synchronization analysis using GAMMs identified an optimal model describing the relationship between CCHF cases and annual rainfall and temperature, with temporal lags of five and the same year, respectively. Conclusions: Lower temperatures and increased rainfall were linked to a rise in CCHF cases, indicating that these climatic factors significantly influence tick population growth and activity. Additional environmental and ecological variables should be considered in future studies to develop a more comprehensive model.

Abstract: Fetal growth restriction (FGR) is a major obstetric complication associated with increased perinatal morbidity, mortality, and adverse long-term metabolic outcomes in adulthood. Placental dysfunction stands as the principal driver in a substantial proportion of cases, with accumulating evidence indicating that the disruption of placental redox homeostasis plays a central role in its pathophysiology. This review provides a comprehensive synthesis of redox dysregulation in FGR, extending beyond classical oxidative injury to incorporate emerging non-linear paradigms. Excessive production of reactive oxygen species (ROS), coupled with inadequate antioxidant defenses, promotes lipid, protein, and DNA damage, thereby impairing trophoblast function, vascular remodeling, cell survival, and nutrient transport. Crucially, this review integrates recent breakthroughs in the fields of iron-dependent ferroptosis, endoplasmic reticulum stress, and complex redox-epigenetic cross-talk mediated by non-coding RNAs ("redox-miRs"). Furthermore, we address the translational failure of conventional systemic antioxidant therapies, highlighting the newly recognized paradox of reductive stress, where over-supplementation disrupts essential ROS-dependent signaling cascades during early placentation. To resolve these diagnostic and therapeutic limitations, this work evaluates the clinical utility of multi-omics integration for mapping placental metabolic reprogramming and artificial intelligence (AI) machine learning models that combine maternal serum redox biomarkers with longitudinal fetal Doppler metrics for early risk stratification. Finally, we explore next-generation obstetric frontiers, including placenta-targeted nanomedicine for localized drug delivery, Placenta-on-a-Chip microfluidic and organoid screening platforms, and autologous mitochondrial transplantation aimed at rescuing syncytiotrophoblast bioenergetics. Overall, current evidence underscores placental redox dysregulation as an interconnected, systemic failure rather than an isolated molecular defect. Moving toward precision, redox-guided perinatal management requires longitudinal human studies and well-designed clinical trials to validate whether the targeted restoration of redox homeostasis can translate into improved maternal, fetal, and neonatal outcomes.

Abstract: TRPM7 is a unique bifunctional protein that combines a divalent cation-permeable ion channel with a C-terminal serine/threonine kinase, enabling the integration of ionic, metabolic, mechanical, and redox signals into coordinated cellular responses. Beyond its established role in Mg²⁺ homeostasis, emerging evidence indicates that TRPM7 functions as a cellular state integrator that continuously monitors intracellular conditions and converts persistent environmental changes into adaptive structural, metabolic, and transcriptional programs. In this review, we examine the molecular architecture and regulatory mechanisms that underlie TRPM7 function, highlighting how channel activity, kinase-dependent and kinase-independent signaling, vesicular trafficking, and endolysosomal pathways cooperate to control cellular adaptation. We discuss recent models in which TRPM7 acts as a low-pass filter of metabolic fluctuations, regulates Mg²⁺ and Zn²⁺ availability, and coordinates mechanotransductive and stress-responsive remodeling. We further explore its roles in neuronal survival, cardiovascular homeostasis, immune regulation, fibrosis, and cancer progression, emphasizing how disruption of TRPM7-dependent state integration contributes to disease. Collectively, current evidence supports a unifying framework in which TRPM7 links bioenergetic status, ionic homeostasis, and environmental sensing to long-timescale phenotypic adaptation, establishing this chanzyme as a central regulator of cellular resilience and a promising therapeutic target in human disease.

Abstract: Background: Axial spondyloarthritis (axSpA) is characterized by coexisting bone loss and pathological new bone formation. Although alterations in circulating markers and osteoclastogenesis from peripheral blood monocytes (PBM) are documented in radiographic axSpA (r-axSpA), their status in non-radiographic axSpA (nr-axSpA) and association with bone loss remain unresolved. In this study, we evaluated serum markers of bone metabolism and inflammation, PBM osteoclastogenic capacity, and their association with bone mineral density across both axSpA phenotypes. Methods: In 81 axSpA patients, clinical characteristics and DEXA-based BMD were recorded. Serum TSH, PTH, 25(OH)D3, bCTX, PINP, osteocalcin, bALP, RANKL, OPG, CTSK, CRP, IL-6 and IL-17 were measured. PBM from a patient subset (N=26) were used for in vitro osteoclastogenesis assays. Results: In a multivariable model, femoral neck Z-scores were strongly negatively associated with serum OPG/RANKL ratio in males (48% OPG/RANKL increase per one-unit Z-score decrease, p< 0.01). Additionally, each one-unit decrease in femoral neck Z-score was associated with increased odds of r-axSpA (OR 1.96, p< 0.05), independently of OPG/RANKL. Though patients with r-axSpA had lower femoral neck Z-scores than nr-axSpA (mean −0.50 vs. 0.03, p< 0.05), their in vitro osteoclastogenesis did not differ significantly (median 21 vs. 40, p=NS). Instead, osteoclastogenesis associated with BMD, being lower in patients with reduced femoral neck BMD compared to normal BMD (mean 22 vs. 51, p< 0.05). Conclusions: This study highlights the femoral neck as a region of interest for studying bone loss in nr-axSpA and r-axSpA and supports a link between systemic bone loss, circulating OPG/RANKL levels, and precursor osteoclastogenic potential in axSpA.

Abstract: Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease. Numerous studies have shown that the gut microbiota is closely related to the occurrence and development of Alzheimer's disease, suggesting that alterations in gut microbiota may represent a therapeutic strategy. However, the role and mechanisms of the gut microbiota in AD remain unclear, and standard research protocols for the gut microbiota are not uniform. The clinical safety and efficacy of oral capsule fecal microbiota transplantation, ( FMT) in patients with AD are not yet established, and related clinical studies are lacking. Objective: This study aimed to investigate the safety and effects of FMT capsule on cognitive im-pairment in patients with mild to moderate Alzheimer's disease and to explore the re-lationship between cognition and gut microbiota by evaluating changes in gut microbial gene expression after FMT. Methods: In this study, 18 patients with clinically and radiologically confirmed mild to moderate AD aged 60-80years old were enrolled in this prospective single-arm clinical observation study. All subjects received allograft FMT (intestinal bacteria capsules with strict do-norscreening and in line with international FMT donor standards) three times at 0, 30 and 60 days. Serum and fecal samples were collected at 0, 30, 60 and 90 days, and MoCA, MMSE scores, HAMD, HAMA, ADL and fecal metagenomics sequencing were evalu-ated.During FMT and follow-up, safety was assessed by recording adverse events (AEs), vital signs, and laboratory parameters. Results After the intervention of FMT capsule, various cognitive and behavioral scores in FMT1 and FMT2 groups were not significantly changed, MMSE and MoCA scores in FMT3 group were significantly higher than those in FMT0 group (P < 0.05), in addition, HAMD scores and HAMA scores in FMT3 group were significantly lower than those in FMT0 group (P < 0.05). Cognitive scores and depression scores improved compared with those before transplantation.Fecal microflora analysis showed that FMT intervention could increase α diversity and reshape the overall structure of intestinal flora in AD patients (β diversity analysis).The proportion of dominant bacteria at phyla level changed.Genus level microbial diversity improved;Dynamic up-regulation of target functional flora at species level; A total of 12 species were identified by LEfSe analysis.The adverse reactions were mainly gastrointestinal reactions, and no serious adverse events were observed. Conclusion: In this study, FMT capsules can alter the intestinal microbiome structure and achieve intestinal microbiome remodeling, which may be a potential mechanism for microbiome capsules to improve AD related phenotypes.It is well tolerated and safe in the treatment of patients with mild to moderate Alzheimer's disease.Despite the limited sample size and lack of control group, the results still provide clinical evidence for targeted inter-vention of the gut-brain axis in AD, but larger, randomized, double-blind place-bo-controlled trials are needed to further verify its efficacy and mechanism.

Abstract: Adoptive cell therapy (ACT) has transformed the treatment of hematological malignancies but largely fails against solid tumors; the biological basis of this divide has rarely been quantified across cancer types. We analyzed uniformly reprocessed RNA-seq data (Toil pipeline) from TCGA (9,359 tumors, 33 cancer types), TARGET (734 pediatric tumors), and GTEx (7,862 normal samples). A 132-gene panel yielded T/natural killer (NK) infiltration, functional, metabolic, and stromal scores, integrated into a composite Solid Tumor Immune Accessibility Score (STIAS); six public single-cell datasets provided cellular validation. Median T- and NK-cell infiltration was about 30% lower in solid than in hematological tumors—a gap reflecting tissue of origin rather than recruitment failure. Single-cell analysis revealed per-cell enrichment of exhausted T-cell programs in solid tumors (23.6% versus 8.9%) and NKG2A upregulation on colorectal-tumor NK cells, while the dominant cohort-level barriers were stromal (extracellular matrix 3.79-fold) and metabolic (IDO pathway 1.27-fold). STIAS classified 14.5% of solid tumors as hematological-like “Accessible” phenotypes—reproduced in the pediatric TARGET cohort and enriched for the C2 (IFN-γ–dominant) immune subtype (26.4% versus 3.5%)—with each 0.1-unit increase associating with 46% and 40% higher hazard of death and progression. A bidirectional target atlas validated epithelial antigens (MUC1, ERBB2, CLDN18, CEACAM5, FAP, CD73) at the protein level and mapped hematological off-tumor risks; hematological-lineage signals (CD38, BCMA) proved predominantly immune-infiltrate-derived. Stromal–metabolic barriers dominate the solid tumor–specific axes of ACT resistance; STIAS-guided stratification and microenvironment reprogramming may extend cellular immunotherapy to solid malignancies.

Abstract: Introduction: Prediabetes represents an early stage of metabolic dysfunction characterised by insulin resistance and mild hyperglycaemia, yet its impact on female reproductive hormones remains poorly understood. Early hormonal disturbances may contribute to menstrual irregularities, impaired fertility, and progression to long-term reproductive dysfunction. This study investigated changes in reproductive hormone concentrations in females with prediabetes in their reproductive age in Durban, South Africa, with comparisons to non-diabetic and type 2 diabetic (T2DM) women. Methodology: A total of 135 females in their reproductive age were recruited and stratified into non-diabetic (n = 45), prediabetic (n = 45), and T2DM (n = 45) groups based on ADA diagnostic criteria. Blood samples were collected between days 2 and 5 of the menstrual cycle, and plasma levels of fasting glucose, HbA1c, insulin, estradiol, testosterone, progesterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were measured using ELISA assays. Data were analysed using one way ANOVA with a p < 0.05 considered as statistically significant. Results: Fasting glucose, HbA1c, and insulin increased progressively from the non-diabetic to the T2DM group (p < 0.0001), confirming worsening glycaemic control. Estradiol levels showed a significant decline across groups, with prediabetic women exhibiting significantly lower levels than controls but higher than T2DM (p < 0.0001). Testosterone significantly increased in prediabetes compared to non-diabetic women but significantly decreased in T2DM (p < 0.0001). Progesterone showed no significant differences between non-diabetic and prediabetic groups but declined slightly in T2DM. LH and FSH levels significantly increased from the non-diabetic, prediabetic to T2DM (p < 0.0001), suggesting early disruption of ovarian–pituitary feedback. Conclusion: The findings suggest that reproductive endocrine changes begin during the prediabetic stage, highlighting the importance of early metabolic screening to preserve reproductive health. Longitudinal studies are needed to clarify casual pathways and determine whether targeted metabolic interventions can restore hormonal balances and improve reproductive outcomes.

Abstract: Background/Objectives: Abdominal radical trachelectomy (ART) preserves fertility in early-stage cervical cancer, but little is known about its outcomes outside North America, Western Europe, and East Asia. We report complications, surgical margins, and disease-free survival (DFS) in the first ART cohort from Vietnam. Methods: In this single-center retrospective cohort study, 21 consecutive patients with FIGO 2018 stage IA1–IB1 cervical cancer (tumor ≤2 cm) underwent ART with fertility-preserving intent. Complications were graded by the Clavien–Dindo system and DFS was estimated by the Kaplan–Meier method. Given the small sample, exact 95% confidence intervals and the rule of three were used. Results: No intraoperative complication occurred (0/21; 95% CI 0.0–16.1%). Five patients (23.8%) had a complication within 30 days, mostly grade II, and two (9.5%) had a grade IIIb complication. The endocervical margin was positive in one patient (4.8%). Median follow-up was 39 months (IQR 19–73). No recurrence or death occurred, and DFS was 100% at 1, 3, and 5 years, although only 7/21 patients had reached 5 years. Conclusions: In this selected cohort, ART had acceptable early safety and no recurrences. With wide confidence intervals and immature 5-year data, the findings show feasibility but do not prove safety.

Abstract: Background/Objectives: Atrial fibrillation accounts for approximately 0.5–1% of emergency department visits. Contemporary ESC and ACC/AHA guidelines address acute pharmacological cardioversion, anticoagulation before cardioversion, and delayed “wait-and-see” strategies; however, real-world implementation of an early, specialist-guided pathway in the emergency department remains incompletely described. In the HEROMEDICUS study we implemented a protocol for acute management of patients presenting to the emergency department with atrial fibrillation as their main complaint. The present analysis reports the safety and efficacy of intravenous flecainide within that pathway. Methods: All patients who visited the emergency department from 8 September 2023 to 10 October 2025 with a primary diagnosis of atrial fibrillation, atrial flutter, or atrial tachycardia were screened. Patients with known heart failure (left ventricular ejection fraction < 40%), known coronary artery disease, symptoms of acute heart failure or acute coronary syndrome, or intraventricular conduction delay were excluded. Using tablet computers and an in-house application, on-duty cardiologists obtained contemporaneous electrophysiology consultation. In this institution, frontline emergency department care for arrhythmia presentations is provided by cardiologists rather than emergency-medicine physicians. Patients without prior oral loading with >300 mg propafenone or >200 mg flecainide were eligible for intravenous flecainide 2 mg/kg (maximum 150 mg) infused over 10 minutes. Follow-up at the outpatient atrial fibrillation clinic was scheduled through the application. Results: Of 277 patients screened (15 atrial tachycardia, 28 atrial flutter, 234 atrial fi-brillation - mean age 68.5±12.3 years, heart rates 122.9±25.1 bpm and CHA2DS2-VASc 2.3±1.5 points, 53% females), 85 fulfilled criteria for intravenous flecainide administration; of them, 83 had atrial fibrillation on both the triage and recruitment electrocardiograms and 2 had atrial flutter on the triage but atrial fibrillation on the recruitment electrocar-diogram – thus all patients receiving flecainide effectively had atrial fibrillation. A first-diagnosed episode was recorded in 130 patients. Sinus rhythm was restored with flecainide alone in 61/85 patients (71.8%; 95% CI 61.4–80.2%). Of the remaining 24 patients, 22 were subsequently electrically cardioverted in the emergency department and 2 failed both strategies and were discharged after rate control. Among the 26 successful pharmacological conversions with available timestamps, median time from start of in-fusion to sinus rhythm was 13 minutes. No patient developed ventricular proarrhythmia or atrial flutter with 1:1 atrioventricular conduction, at least during their stay in the emergency department. Also, no thromboembolic events occurred in the same period. None of the 85 flecainide-treated patients was admitted. Conclusions: Intravenous flecainide was safe and effective as the initial pharmacological option within the HEROMEDICUS emergency department pathway for selected patients with atrial fibrillation. Subsequent electrical cardioversion rescued most pharmacological failures. These findings apply to atrial fibrillation; they should not be extrapolated to atrial flutter or atrial tachycardia. In the absence of a control group, we report the observed absence of admissions following implementation of our protocol.

Abstract: Background: Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease in which apoptosis-resistant fibroblasts drive progressive scarring. Fibrotic mesenchymal cells are functionally “primed for death”, but the transcriptional architecture of apoptotic priming in the human IPF fibroblast lineage—and its dominant anti-apoptotic dependency—remains undefined. Methods: We reanalyzed the 114,396-cell GSE135893 atlas [1], scoring 2,653 fibroblast-lineage cells for pre-specified pro- and anti-apoptotic BCL-2-family modules and a composite Apoptosis Index, with donor-level replication in GSE136831 [2] and cell-level confirmation in two further cohorts. Results: In IPF fibroblasts, the anti-apoptotic (cell-level p = 3.0 × 10⁻²¹; d = 0.66) and caspase modules were elevated and the Apoptosis Index shifted toward survival, with MCL1 the dominant anti-apoptotic transcript (log2FC = +1.84; 91.3% versus 63.0% of cells)—an elevation driven substantially by disease-emergent subtype composition (93.5–100% detection, near-absent in control); depth-matched within-state difference attenuates (65.6% versus 62.1%, ns). Cell-level p-values are descriptive; donor-level analyses are the primary inference. The double-high “primed” fraction was elevated in IPF (25.6% versus 11.6%; cell-level p = 2.6 × 10⁻⁴; nominal at donor level, p = 0.023), concentrated in disease-emergent subsets; threshold-sensitivity and module-arm decoupling showed it is driven by the anti-apoptotic arm alone: the fibroblast pool is survival-protected, not genuinely primed, while pro-apoptotic loading emerged only upon myofibroblast differentiation (p = 1.1 × 10⁻⁸)—a two-stage architecture: protected fibroblasts give rise to primed, death-leaning myofibroblasts. Module-level elevations were donor-level null (p = 0.30–0.43); the supported findings are the donor-level primed-pool expansion (Habermann nominal p = 0.023; GSE136831 nominal p = 0.0068) and the compositional MCL1 elevation, with cell-level confirmation in two further cohorts. Conclusions: Apoptotic priming along the IPF fibroblast–myofibroblast lineage is a two-stage program dissected at single-cell resolution, nominating MCL-1 as an antifibrotic target warranting protein-level and pharmacological validation.

Abstract: Single-cell atlases have resolved the fibroblast compartment of idiopathic pulmonary fibrosis (IPF) into discrete subtypes [1], but subtype-resolved secretory output and surface-marker logic for prospective isolation remain incompletely defined. We re-analyzed the Habermann et al. single-cell atlas of fibrotic lung (GSE135893; 114,396 cells, including 3,605 fibroblast-lineage cells, of which 2,653 IPF/control cells entered the main contrasts) [1], quantifying detection rates and mean expression of 72 secreted genes and 16 candidate surface markers across four curated subtypes, validated by full-transcriptome re-clustering. Inflammatory chemokine production was concentrated in HAS1-high fibroblasts (CXCL2 in 70.4% of cells, CXCL8 in 46.9%), whereas PLIN2+ fibroblasts carried an angiogenic bias (VEGFA 65.6%). CSF1 was silenced upon myofibroblast differentiation irrespective of diagnosis (fibroblasts 34.2–48.6% versus myofibroblasts 8.7–14.8%), a differentiation-linked rather than disease-specific switch, and the interferon-γ–inducible chemokines CXCL9, CXCL10 and CXCL11 were detected in only 0.0–2.6% of cells across subtypes (maximum 2.6% = CXCL9, 5/196 control myofibroblasts). A CD34-low/PDPN-high/CD73-high/FAP+ panel resolved all four subtypes at the marginal transcript level (pending joint, antibody-level validation), whereas CD90 lost discriminatory value in disease. CD10 (MME) marked a control-enriched, putatively resolving myofibroblast state that contracted from 23.0% to 5.4% in IPF; its interleukin-4 induction was tested across cohorts and remains unresolved. Key findings replicated in two independent cohorts (GSE136831; GSE122960) and were spatially corroborated by GeoMx profiling (GSE255174), while CSF1 and compartment-level chemokine effects varied across cohorts. Fibroblast subsets thus carry distinct, isolable secretory identities in IPF, providing a transcriptome-resolved resource for protein-level and spatial validation of fibroblast functions in fibrotic lung.

Abstract: Deep learning systems have matched dermatologists on curated skin cancer image sets for almost a decade, but evidence from patient care has accumulated slowly and unevenly. This systematic review mapped where that evidence now sits along the translational continuum. A reproducible PubMed search run in August 2026 identified 656 records; after single-screener selection against pre-specified criteria and full-text assessment of 39 reports, 29 clinical-stage studies (prospective, controlled, or real-world evaluations of AI for cutaneous malignancy in patients) were included and staged as prospective standalone accuracy (n = 19), prospective clinician-with-AI use (n = 5), controlled evaluation (n = 1), or real-world deployment (n = 4). Risk of bias, appraised with QUADAS-2, ROBINS-I, or JBI tools, was high or serious in 24 studies, most often because of partial verification and preselected lesion spectra, and the certainty of every principal finding was low or very low (GRADE). No included study was a randomised trial with patient outcomes, and none reported stage at diagnosis, mortality, or overdiagnosis. Across modalities, sensitivity held up in prospective use, commonly above 90% at the pre-set operating point, while specificity fell to between 9% and 85% and was frequently lower than that of the clinicians it was compared against. Performance moved with acquisition hardware, lesion spectrum, and skin type, and one market-approved dermoscopic classifier reached areas under the curve of 0.54 to 0.62 in two Australian primary care studies. One product family progressed from prospective accuracy to national-pathway deployment under a conditional health technology recommendation, with human second reading overturning a large share of automated discharges. We argue that the reported specificity loss reflects safety-first operating points, spectrum preselection, and the choice of comparator rather than model failure alone, and propose readiness criteria linking each translational stage to the evidence needed before autonomous or primary-care use. The review followed PRISMA 2020, was not registered, and received no external funding.

Abstract: For a century, the study of human body weight regulation has been dominated by the Energy Balance Model (EBM) and challenged by the Carbohydrate-Insulin Model (CIM). Both frameworks, however, rely on the indirect conversion of mass to energy, introducing propagated uncertainties and theoretical stalemates. The Eagle Project proposes a paradigm shift: direct mass accounting. By conducting feeding experiments in state-of-the-art whole-room metabolic chambers capable of continuous measurement for up to seven days, we will quantify every gram of mass entering and leaving the human body (food, beverages, O₂, CO₂, urine, feces, sweat). This extended duration eliminates the need for mathematical extrapolations. Furthermore, the project will integrate comprehensive, high-frequency blood sampling to map the full endocrine and metabolic response against physical mass fluxes. Committed to radical transparency, all raw data will be published in near real-time via preprints, free of paywalls and embargoes. The Eagle Project is not merely an experiment – it is a global, collaborative effort to resolve the metabolic stalemate and establish a new, physically rigorous foundation for nutritional science.

Abstract: Neuromodulation techniques, such as repetitive transcranial magnetic stimulation (rTMS), have demonstrated efficacy across several neuropsychiatric disorders, yet identifying symptom-specific and biologically informed stimulation targets remains a major challenge. Lesion network mapping (LNM) addresses this problem by treating focal brain lesions as natural perturbations and mapping anatomically heterogeneous lesion locations onto normative connectomes to identify convergent symptom-relevant circuits. Since its introduction in 2015, LNM has generated candidate neuromodulation targets across diverse neurological and psychiatric conditions, with several studies showing overlap between lesion-derived networks, independent neuroimaging findings, and therapeutic neuromodulation targets. However, these observations do not establish whether the identified networks connected to lesion sites are causally responsible for symptom expression or how they should be therapeutically modulated. Because LNM relies on correlation-based connectivity measures, it cannot determine which circuit components or pathways causally mediate the relevant symptom, or whether candidate neuromodulation targets should be activated or inhibited. We therefore propose a translational framework in which LNM-derived circuit hypotheses are examined through cross-species anatomical and functional mapping, region-, cell-, and projection-specific perturbation in animal models, and concurrent behavioral and whole-brain functional readouts, before clinical evaluation. This framework positions LNM as a tool for identifying candidate circuits that are first tested in animal models for causal relevance and perturbation direction, and then evaluated clinically for therapeutic relevance.