The original intravascular ultrasound (IVUS) calcium score in percutaneous coronary intervention (PCI) applies only to lesions with a maximum calcium angle > 270°, distinguishing it from the optical coherence tomography (OCT) calcium score. We aimed to investigate a new IVUS-derived calcium score to predict stent underexpansion in moderately to severely calcified lesions. We retrospectively analyzed 238 IVUS-guided PCI cases with moderate to severe calcification visible on angiography, including 136 cases with IVUS-guided PCI as a derivation cohort and 102 cases with both IVUS- and OCT-guided PCI as a validation cohort, excluding cases in which atherectomy was used. In the derivation cohort, IVUS-derived maximum calcium angle showed significant area under the curve (AUC) to predict stent underexpansion (< 70%) at the maximum superficial calcium site (cutoff value: 228°, AUC: 0.72). A multivariable linear regression model showed that maximum calcium angle of 225° (regression coefficient: -11.69; p = 0.023) and the presence of calcified nodule (regression coefficient: -4.913; p = 0.004) were associated with stent expansion. A new IVUS calcium score (0-4 points) was defined as 3 points for maximum calcium angle > 225°, and 1 point for presence of a calcified nodule. A cutoff of ≥ 3 showed a good AUC (0.751) and an excellent negative predictive value (0.963) to predict stent underexpansion. In the validation cohort, the incidence of stent underexpansion was 0%, 0%, 8.6%, and 33.3% in patients with the new IVUS calcium score of 0, 1, 3, and 4, respectively (p = 0.004). The new IVUS-derived calcium score can effectively predict stent expansion in moderately to severely calcified lesions.
To evaluate the impact of Medicaid expansion (ME) and its timing on treatment patterns and survival in patients younger than 65 years with colorectal cancer and synchronous liver metastasis (CRLM). Management of CRLM requires multidisciplinary oncologic and surgical care. In 2010, the Affordable Care Act expanded Medicaid eligibility to adults earning ≤138% of the Federal Poverty Level. The effect of ME on outcomes in metastatic colorectal cancer requiring complex care remains incompletely defined. The SEER 2022 database was queried for patients <65 years old diagnosed with CRLM from 2010 to 2019. Patients with extrahepatic metastases or no follow-up were excluded. Event-study difference-in-differences analyses compared outcomes between expansion and nonexpansion states. Cox proportional hazards models clustered by state adjusted for demographic and socioeconomic factors evaluated 3-year all-cause and disease-specific mortality. Among 33,216 patients with CRLM, 13.4% underwent metastasectomy. In ME states, the 3-year disease-specific mortality rate decreased from 75% pre-expansion to 68% after 6+ years. Risk of 3-year disease-specific mortality in ME states compared with nonexpansion states was reduced beginning 2-3 years after expansion and persisted over time (HR range 0.90-0.95). Reduction in risk of disease-specific mortality was most pronounced among patients undergoing liver metastasectomy (HR range: 0.71-0.85). ME was not associated with increased likelihood of metastasectomy. ME was independently associated with improved survival among patients with CRLM, particularly those receiving surgical and systemic therapy. These data suggest ME may improve continuity of complex multidisciplinary oncologic care and access to systemic therapy.
Rings underpin pharmaceuticals, agrochemicals, and materials, driving renewed interest in skeletal ring expansion. Current skeletal ring expansion strategies mainly focus on single-atom insertion or rearrangement; reliable methods for multiple single-atom insertion and peripheral diversification of saturated small rings are lacking. Herein, we report a general and efficient photocatalytic system directly converting aminocyclopropanes to γ-lactams via sequential C-/N-single-atom [n + 2] ring-expansion and peripheral diversification. The system accomplishes both γ-lactam formation and subsequent diversification at the γ-position via six distinct bond-forming reactions across hundreds of synthetic examples under predictable reaction conditions. Experimental and computational studies converge on photoredox-mediated radical pathways.
Variable climate-change-driven range shifts will likely create novel species and population interactions. Most research has focused on how these interactions may impact expansion rates and adaptation of species on the move (range-shifters). However, slower-moving resident species could also respond to novel competitors, as seen in biological invasions. Whether resident adaptation can occur at initial, low-density phases of these range expansions remains unknown. Here, we simulate this scenario by constructing populations of eight duckweed genotypes (Lemna minor = resident) from various localities near and beyond the range edge of a potential range-shifting competitor, Spirodela polyrhiza, and introduce one genotype of S. polyrhiza at low density. After 14 weeks, we observed significant but subtle evidence for rapid evolution and phenotypic plasticity in the resident, including selection for resident genotypes with faster growth. These changes led to an increase in the production of dormant S. polyrhiza propagules (turions) when reintroduced to L. minor populations. However, whether turion production increases or decreases biotic resistance exerted by L. minor populations depends on the contribution of turion production to short- vs. long-term population growth in S. polyrhiza. Collectively, these results suggest that range-shifting species, even at low densities, may drive evolution, plasticity, and evolution of biotic resistance in resident competitors, but further study is needed to confirm the direction of change in biotic resistance as well as the existence and generality of these effects in a natural context.
Bone disease is well recognized in β-thalassemia, but bone microarchitecture in α-thalassemia remains poorly characterized. We prospectively studied 86 adults with thalassemia at a tertiary center in northeast Thailand: 16 with α-thalassemia and 70 with β-thalassemia. Lumbar spine (LS) and femoral neck bone mineral density (BMD) and trabecular bone score (TBS) were measured using the same DXA platform. A prespecified Marrow Expansion Phenotype Score (MEPS; 0-3), comprising thalassemic facies, scoliosis, and hepatomegaly, served as an exploratory marker of chronic ineffective erythropoiesis. Sequential linear regression assessed attenuation of genotype effects after adjustment for transfusion-dependent thalassemia status and MEPS. Compared with β-thalassemia, α-thalassemia was associated with higher LS BMD (0.822 ± 0.130 vs. 0.754 ± 0.117 g/cm²; p = 0.039), higher LS Z-score (-1.27 ± 0.65 vs. -1.99 ± 0.99; p = 0.009), and a trend toward higher TBS (1.318 ± 0.102 vs. 1.255 ± 0.128; p = 0.071). Low LS Z-score (<-2) was less frequent in α-thalassemia (12.5% vs. 45.7%; p = 0.021). Mean MEPS was lower (0.88 ± 0.62 vs. 1.84 ± 0.88; p < 0.001). Genotype associations with TBS, LS BMD, and LS Z-score persisted after adjustment for transfusion status but were attenuated and no longer significant after MEPS adjustment. Ferritin adjustment did not materially change the estimates but cannot exclude effects of total iron burden. Adults with α-thalassemia had better lumbar bone density and microarchitecture than those with β-thalassemia. Attenuation after MEPS adjustment is consistent with, but does not prove, a role for marrow-expansion phenotype. Formal mediation was not performed. Given the small α-thalassemia group, these findings are exploratory and require replication.
The Cardiovascular-Kidney-Metabolic (CKM) syndrome framework acknowledges metabolic dysfunction-associated steatotic liver disease (MASLD) as a major manifestation, yet hepatic involvement remains insufficiently incorporated into risk stratification. This review proposes the metabolic disorder-MASLD-cardiovascular disease-kidney disease (MMCK) syndrome as an operational extension that integrates hepatic fibrosis assessment into cardiometabolic-renal care. We conducted a comprehensive narrative review across PubMed/MEDLINE, Embase, Web of Science, Cochrane Library, and Scopus through March 2026. We synthesized evidence on pathophysiological crosstalk, proposed the Multi-Organ Risk Score (MORS)-enabled MMCK staging criteria (Stages 0-4), and developed stage-specific management algorithms. The MMCK framework introduces four key operational advances: (i) quantitative multi-organ risk stratification through the MORS (L + C + B + K, range 0-12) with mandatory FIB-4/VCTE-based hepatic fibrosis assessment as the L-Score; (ii) stage-specific therapeutic thresholds linked to objective clinical cutoffs; (iii) a structured multidisciplinary team governance model with MORS-based electronic health record triggers; and (iv) a three-tiered endpoint framework for quality improvement and prospective validation. Observational evidence indicates that incorporating MASLD fibrosis into cardiometabolic staging improves coronary artery disease risk prediction. The MMCK framework positions MASLD as a cardiovascular risk-modifying axis within established cardiometabolic-renal care. The MMCK syndrome operationalizes hepatic integration within established cardiometabolic-renal care by providing a quantitative, stage-specific framework for multi-organ risk assessment and management. Future research should prospectively validate MORS-based staging in diverse cohorts and evaluate whether MMCK-guided management improves clinical outcomes compared with CKM-guided care alone.
Antimicrobial resistance represents a major global health challenge. In veterinary medicine, ceftiofur is widely used to treat bacterial infections, yet its efficacy has been increasingly compromised by the dissemination of extended-spectrum β-lactamase (ESBL) genes such as blaCTX-M. Although heteroresistance has been widely reported, its role in ceftiofur resistance, particularly in swine-derived Escherichia coli, remains poorly understood. Here, we identified four polyclonal ceftiofur heteroresistance (PCHR) E. coli isolates from swine, each comprising genetically distinct resistant and susceptible subpopulations. Whole-genome sequencing showed that all resistant subpopulations carried blaCTX-M genes, and conjugation assays demonstrated that blaCTX-M-carrying plasmids were transferable. Notably, in the resistant subpopulation EP91A, a chromosomal blaCTX-M-containing fragment was identified in the transconjugant plasmid pTEP91A-1, with sequence features consistent with a possible IS1380-associated recombination event. Under ceftiofur pressure, resistant subpopulations expanded in all four PCHR isolates, although the associated population-level processes differed among isolates, including plasmid-mediated transfer and differential expansion of preexisting resistant subpopulations. Under ceftiofur-free conditions, resistant subpopulations were maintained at different levels, with EP70A and EP91A reaching higher proportions and stabilizing at approximately 43%, suggesting clone-associated population dynamics under antibiotic-free conditions. Transcriptomic analysis further identified clone-associated transcriptional differences between EP91A and EP91B across pathways related to environmental sensing, metabolism, transport, and cellular processes, providing hypothesis-generating observations. Collectively, these findings suggest that PCHR in these selected swine-derived E. coli isolates is associated with genetic heterogeneity, transferable blaCTX-M-carrying plasmids, and distinct population dynamics, providing insights into ceftiofur resistance expansion and maintenance in heterogeneous bacterial populations.
Alcohol use is a leading cause of premature mortality in the US. Despite public health recommendations and insurance coverage mandates, alcohol screening and brief intervention (ASBI) in primary care remains underused. To estimate the population-level impact of expanded ASBI delivery on alcohol use and potential years of life lost (YLL) from major alcohol-related causes of death in US adults through 2030, by sex, race and ethnicity, and educational attainment as a proxy for socioeconomic status. This was a decision analytical study that used a dynamic individual-level microsimulation model of nationally representative of US adults (age ≥18 years) from 2000 to 2030 and considered sociodemographic variables, alcohol use, and mortality risks. Four expansion scenarios increasing the annual number of eligible individuals receiving ASBI from 2025 to 2030: scenario 1, expanding alcohol screening (AS) only; scenario 2, expanding brief intervention (BI) by 4 million; scenario 3, expanding BI by 8 million; and scenario 4, universal ASBI delivery. Scenarios were compared with a no-expansion counterfactual assuming historical trends. Prevalence of hazardous alcohol use (>20 or >40 g of alcohol per day for women and men) and YLL per 100 000 before age 75 years from 5 key alcohol-related causes of death (alcohol use disorder, liver disease and cirrhosis, motor vehicle injuries, other unintentional injuries, and suicide) in 2030. The analysis of the microsimulation model found that scenario 3 (additional 8 million BI) and scenario 4 (universal ASBI) had the strongest impact on alcohol use and mortality, and were projected to reduce annual alcohol-related YLL per 100 000 by -51.3 (95% credible interval [CrI], -73.2 to -32.8) and -68.9 (CrI, -102.2 to -44.8) among men, respectively, and -34.1 (CrI, -54.5 to -16.1) and -52.0 (CrI, -75.0 to -30.2) among women, respectively, by 2030. In scenario 4, the gap in YLL from causes associated with alcohol use between low and high education narrowed by -3.5% (-64.5 YLL per 100 000; 95% CrI, -106.3 to -35.9) among men and -4.9% (-31.4 YLL per 100 000; 95% CrI, -56.2 to -12.4) among women. In decision analytical model expanding ASBI delivery in primary care was projected to reduce premature mortality and may represent an important strategy for improving population health. Substantial expansion had measurable but modest potential to narrow socioeconomic inequalities in premature mortality from causes of death associated with alcohol use.
Motor neuron disease (MND) comprises several clinical phenotypes, with amyotrophic lateral sclerosis (ALS) being the most common. Despite the identification of over 40 ALS-associated genes, the pathogenesis remains complex and polygenic. This study evaluated the clinical phenotypes and prevalence of genetic causes in MND patients in Lithuania. We conducted a retrospective single-center study at a tertiary care clinic on patients with MND. Clinical and molecular genetic data were analyzed. The study included 53 patients with a mean age at symptom onset of 55 years. Most patients (43/53; 77.4%) were diagnosed with ALS, and the most common onset was spinal (39/53; 73.6%). The frequency of pathogenic or likely pathogenic genetic variants was 15.7% (8/51). C9orf72 hexanucleotide repeat expansion was detected in 5.9% (3/51) of patients. Next-generation sequencing was performed in 49 patients, of whom 5 (10.2%) had pathogenic or likely pathogenic variants, including pathogenic variants in the SOD1 and NEK1 genes and likely pathogenic variants in the FUS. The most common finding was C9orf72 hexanucleotide repeat expansion, followed by variants in SOD1 and FUS genes. The genetic spectrum was broadly similar to internationally recognized MND-associated genes, though formal comparisons were not performed due to the absence of a control group. These results emphasize the importance of systematic genetic testing in clinical practice and contribute to the limited data on the genetic spectrum of MND in the Baltic region.
Influenza A virus (IAV) infection induces complex antiviral immune responses, yet how innate sensing, host genetic susceptibility, and adaptive immune dysfunction converge remains incompletely understood. This study investigated peripheral immune remodeling during IAV infection, focusing on LAG-3-expressing CD8+ T cells and their transcriptional and genetic signatures. Single-cell and bulk transcriptomics, genetic analyses, Mendelian randomization, network modeling, and machine learning were integrated. Flow cytometry was used to validate LAG-3 expression and CD8+ T-cell dysfunction in healthy controls and children with IAV infection. IAV infection caused marked immune remodeling and expansion of LAG-3+ exhaustion-like CD8+ T cells spanning naïve, effector, and exhaustion-associated states. Interferon-stimulated genes dominated differential expression, co-expression modules, and pathway enrichment. Ten influenza-exhaustion signature genes were identified, with Mendelian randomization prioritizing IFI44, IFIT3, MX2, ZBP1, IFIT1, and HES4 as genetically associated with IAV susceptibility. Gene-based classifiers achieved AUCs up to 0.886 across three independent cohorts. Flow cytometry confirmed increased LAG-3 expression and reduced CD107a activity in pediatric IAV infection. IAV infection is characterized by an interferon-dominated program and expansion of dysfunctional LAG-3+ CD8+ T cells, highlighting candidate biomarkers for immune remodeling.
Cucumber fruits, with a relatively high rate of fruit expansion, are harvested at an early developmental stage once moderately expanded. Although DNA methylation regulating fruit ripening has been well studied, its function in organ development of cucumber remains unknown. In this study, the regulation and underlying mechanism of DNA methylation in cucumber fruit development were investigated. Chemical treatment with DNA methylation inhibitor 5-aza, together with whole genome bisulfite sequencing (WGBS), flow cytometry, small RNA sequencing, and functional validation via virus-induced gene silencing (VIGS), were comprehensively employed. Treating cucumber fruits with 5-aza at 0 or 4 days after anthesis (DAA) caused stage-dependent inhibition of fruit expansion, with stronger inhibition observed at 0 DAA. WGBS revealed that DNA methylation at CG and CHG contexts remained at high levels before 4 DAA, while mCG levels peaked at 20 DAA and mCHH levels increased throughout. Before 4 DAA, DNA methylation levels at CHG and CG contexts were higher in fruit than fruit neck, revealing spatiotemporal dynamics of DNA methylation during the development of cucumber fruit. These dynamics were functionally enriched in genes related to cell cycle transition, and this finding was further confirmed by impaired endoreduplication observed in 5-aza treated fruits when compared with control. In addition, CsRDR1a, an RNA-dependent RNA polymerase 1 homolog, displayed fruit stage-specific expression patterns, accompanied by significant accumulation of 19---23 nt small RNAs. Cross-tissue validation by silencing CsCMT3 or CsRDR1a showed reduced leaf size, inhibited endoreduplication, and increased expression of cell-cycle genes with decreased DNA methylation levels at their promoter regions, demonstrating that DNA methylation was essential for cell cycle transition during cucumber organ development. Our results unveil a dual mechanism in which DNA methylation and CsRDR1a-related small RNAs coordinately regulate cucumber organ development, highlighting the importance of epigenetic regulation in cucumber.
Apicomplexans encode a single armadillo repeat-only (ARO) protein, exemplified by TgARO and PfARO, that anchors to the rhoptry envelope through N-terminal acylation and supports rhoptry positioning through interaction with an ARO-interacting protein (AIP). These AROs organize rhoptries but are not known to be secreted during invasion. Here, we show that Cryptosporidium parvum ARO (CpARO) localizes to the rhoptry envelope by immunofluorescence assay, ultrastructural expansion microscopy, and structured illumination microscopy. During sporozoite invasion, CpARO-positive rhoptry envelope structures shorten and condense into a discrete punctum after content discharge. Residual rhoptry membrane structures are subsequently detected between the host cell F-actin pad and parasite nucleus in developing trophozoites, consistent with a contribution to nascent feeder organelle formation. In contrast to TgARO and PfARO, CpARO is also detected in secreted fractions during excystation, gliding, invasion, and intracellular development, with no evidence of nuclear localization. Recombinant CpARO binds host cells with high affinity (Kd = 0.189 μM). Although C. parvum encodes an AIP homolog, this protein localizes to the sporozoite cytoplasm rather than to rhoptries; we therefore designate it AIP-like protein (CpAIP-L). Antibodies against both CpARO and CpAIP-L were detected in sera from C. parvum-infected mice. These findings reveal functional divergence of Cryptosporidium ARO-AIP-related proteins and identify CpARO as both a rhoptry envelope marker and a secreted host-interacting factor with potential roles in host interaction and virulence. CpARO localizes to the rhoptry envelope in Cryptosporidium parvum.CpARO-positive rhoptry remnants persist after invasion.Residual rhoptry membranes associate with the nascent feeder organelle.CpARO is also secreted and binds host cells.CpAIP-L diverges from canonical ARO–AIP system.
Robot-assisted surgery (RAS) may expand minimally invasive capacity, but its adoption in middle-income countries is shaped by constraints not captured by platform-level comparisons, including foreign-currency exposure, imported consumables and technical support, limited reimbursement, scarce simulators and proctors, and geographic concentration of specialized care. This narrative review examined literature on surgical innovation, health technology assessment, implementation, economics, training, governance and equity. A targeted PubMed/MEDLINE literature search last updated on 15 July 2026 was supplemented by reference chaining and searches of official institutional and professional sources; the Scale for the Assessment of Narrative Review Articles (SANRA) informed reporting transparency. The synthesis positions the proposed framework alongside existing consensus guidance, national governance models and disease-specific standardized outcome sets. It translates these sources into three linked components: responsible-adoption domains; a minimum institutional dataset covering clinical, technical, economic, training, access and governance variables; and a decision matrix for pilot adoption, expansion, correction, pause, restriction, reallocation or discontinuation. The framework treats RAS as a complex health-system intervention and links procedure-specific incremental value to the real local comparator, lifecycle costs, team competence, technical reliability, patient-centered consent and equity effects of centralization. It proposes locally prespecified review triggers rather than universal thresholds. This author-developed synthesis is not a validated instrument, consensus guideline, formal health technology assessment or cost-effectiveness model. Its next step is content review, feasibility piloting, structured consensus and multicenter evaluation. Used with local regulation and procedure-specific evidence, it could support transparent, accountable decisions about where RAS may be introduced, expanded, limited or stopped.
The latitudinal diversity gradient (LDG) is observed across various biological groups, but its causes remain debated. Here, using Escherichia coli as a model system, we experimentally tested whether spatial-scale evolutionary bias (SSEB)-the tendency for species to evolve adaptively toward areas with higher fitness gains-exists and whether it may contribute to the LDG. We conducted competition and experimental evolution assays between high-fitness-gain and low-fitness-gain populations. Our results show three key findings: (i) high-fitness-gain populations exhibit significantly faster spatial expansion than low-fitness-gain populations; (ii) under gene flow, high-fitness-gain populations tend to competitively exclude low-fitness-gain populations, whereas the reverse effect is minimal; and (iii) experimental populations are more likely to evolve and spread toward regions with higher fitness gains than toward regions with lower gains. These empirical findings collectively demonstrate the occurrence of SSEB. Given that climatic conditions become increasingly favorable from the poles to the equator, a latitudinal fitness gradient is expected for many taxa. Under such a gradient, SSEB would drive biased adaptation toward lower latitudes, either by suppressing adaptation of low-latitude species to higher latitudes or by promoting evolutionary migration from high to low latitudes. Thus, SSEB may provide a novel evolutionary mechanism contributing to the LDG.
Coronary microvascular dysfunction (CMD) represents a key pathological mechanism in patients with ischemia and non-obstructive coronary artery disease (INOCA). Structural and functional abnormalities of the left heart are associated with poor prognosis. The aim of this study was to evaluate the imaging features of early left-heart remodeling associated with CMD in patients with INOCA, including structural and functional changes. A total of 74 patients underwent coronary computed tomography angiography (CCTA) and invasive physiological assessment. They were classified into two groups: the CMD group (index of microcirculatory resistance (IMR) >25 or coronary flow reserve (CFR) <2.0, n = 36) and the control group (n = 38). Structural parameters included left ventricular mass (LVM), left ventricular mid-diastolic volume (LVMDV), left ventricular mid-systolic volume (LVMSV), left atrial mid-diastolic volume (LAMDV), and left atrial mid-systolic volume (LAMSV), all of which were indexed to body surface area (LVMi, LVMDVi, LVMSVi, LAMDVi, and LAMSVi, respectively). The concentricity index (CI) and left ventricular mid-diastolic wall thickness (LVMDWT) were also evaluated. Functional parameters included LAMDV, LAMSV, the diastolic expansion (DE) index, and left ventricular ejection fraction (LVEF). The CMD group showed significantly higher values for LVMi, LVMDVi, LVMSV, LVMSVi, LAMDV, LAMDVi, LAMSV, and LAMSVi than the control group (p = 0.023, 0.018, 0.025, 0.017, 0.003, 0.002, <0.001, <0.001, respectively). No significant differences were found in the absolute values of LVM, LVMDV, CI, LVMDWT, DE, or LVEF (p = 0.113, 0.080, 0.868, 0.879, 0.406, 0.289, respectively). Multivariable logistic regression analysis revealed that higher LAMSVi (adjusted odds ratio (OR) [AOR] = 1.129, 95% confidence interval (CI) 1.052-1.211, p < 0.001), LAMDVi (AOR = 1.133, 95% CI 1.048-1.225, p = 0.002), LVMi (AOR = 1.072, 95% CI 1.020-1.127, p = 0.006), LVMDVi (AOR = 1.069, 95% CI 1.015-1.126, p = 0.012), and LVMSVi (AOR = 1.084, 95% CI 1.007-1.168, p = 0.032) were independently associated with CMD status in adjusted logistic regression models. These principal multivariable associations remained significant after correction for false discovery rate (all Q <0.05). CMD was associated with adverse left-heart remodeling, as manifested by myocardial hypertrophy, eccentric left ventricular remodeling, atrial dilation, and indices suggestive of early diastolic alterations.
Biofilm-associated diseases like peri-implant mucositis (PIM) and peri-implantitis (PI) are significant clinical challenges affecting millions of dental implant patients globally. Although studies have described the role of microbial, host, or environmental factors in disease development, their complex interplay, particularly during dysbiosis, remains poorly understood. This cross-sectional study characterized the microbiome composition and metatranscriptomes of 125 peri-implant biofilms from 48 individuals, uncovering molecular signatures linked to peri-implant health (PIH), PIM, and PI. Distinct variations were observed in biofilm amount, microbial composition and activity, phage populations, and host response. Biofilms were categorized into four community types (CTs) based on the bacterial transcriptional activity: one linked to PIH, one to PI, and two to PIM. PIH and PIM were primarily characterized by aerotolerant taxa with increased anabolic processes, while PI was dominated by obligate anaerobes with complex biofilm morphology. PIM samples, relative to PIH, were characterized by biofilm expansion with minimal functional changes, except for the Neisseria-rich PIM subtype showing higher pyruvate and lipoic acid metabolism. The phagome mirrored the bacterial compositional variations across disease states. Furthermore, human transcriptome responses varied, indicating increased keratinization in PIH, enhanced expression of ribosome components in PIM, and inflammatory signaling and hypoxia in PI. Additionally, we identified complex species-enzyme, phage-bacterium, and host-microbe associations within the peri-implant ecosystem. Our integrative multi-omics approach provides a comprehensive view of microbial, biochemical, host, and ecological factors associated with dysbiosis, offering novel insights into peri-implant disease dynamics. Peri-implant mucositis and peri-implantitis are highly prevalent inflammatory conditions that compromise the long-term survival and success of dental implants, yet their underlying biological mechanisms are largely unresolved. The full-length 16S rRNA gene amplicon sequencing (full-16S) allows for high-resolution taxonomic profiling of peri-implant biofilms, thereby advancing our understanding of microbial composition across health and peri-implant diseases. The integration of metatranscriptomics, furthermore, captures actively transcribed genes within the biofilm and offers direct insights into microbial community functions and the broader molecular context of peri-implant dysbiosis. DNA- and RNA-derived abundances were strongly correlated, with only a few microbial classes showing moderate diagnosis-related differences after DNA-based normalization of transcriptional activity. In this study, we integrated full-16S with metatranscriptomic profiling to simultaneously assess microbial taxonomy, functional activity, phage dynamics, and host gene expression in peri-implant biofilms. Importantly, we provide a systems-level view and report previously undescribed associations between different molecular signatures in the peri-implant ecosystem.
The COVID-19 pandemic catalyzed unprecedented global expansion of telehealth services, with utilization increasing exponentially from pre-pandemic baselines. While digital health technologies promise to democratize healthcare access, they have simultaneously created and amplified new forms of healthcare disparity. This review distinguishes between health equity - the absence of avoidable, unjust differences in health outcomes across population groups, and health equality- the provision of identical services regardless of differing needs. These concepts, while related, require distinct policy responses. Our aim was to synthesize global evidence on equity challenges in telehealth implementation, identify key barriers to equitable access, and analyze strategies for promoting inclusive digital health delivery, with Israel examined as an in-depth case study illustrating broader themes. A narrative review methodology was employed, searching PubMed/MEDLINE and Google Scholar (January 2020-June 2025) using Boolean search strings combining telehealth-related terms with equity, access, and barrier keywords. Initial searches yielded 847 articles; 623 underwent title/abstract screening after deduplication; 156 met criteria for full-text review; 49 high-quality studies formed the final evidence base. Israel was integrated as an in-depth case study within this global synthesis. Significant telehealth utilization disparities persist globally across age, race/ethnicity, geography, and language groups. Technology access alone is insufficient to ensure equity: cultural barriers, digital literacy gaps, provider readiness, and systemic policy failures produce compound digital disadvantage. Israel's experience demonstrates that even in technologically advanced universal-coverage systems, Arab-Jewish and center-periphery disparities persist despite high smartphone ownership and internet access. Achieving telehealth equity requires multi-layered interventions addressing digital divides, cultural and linguistic barriers, and systemic inequalities. Success depends on equity-first design, multi-modal service delivery, provider training encompassing all available modalities, infrastructure investment, and continuous monitoring of disparate impacts.
The chimeric antigen receptor (CAR) T cell therapy targeting cluster of differentiation 19 (CD19)-positive malignancies has shown considerable efficacy in clinical settings. However, the potential genotoxicity of viral-based CAR-T therapy, their considerable manufacturing cycle and high costs, prompts questions about its safety and leads to limitations in clinical application. Aiming to explore a safe, efficient, and low-cost mRNA-based CAR-T therapy, we characterize a nonviral, mRNA-based approach utilizing a current good manufacturing practice (cGMP)-compatible electroporation (EP) platform to generate anti-CD19, anti-CD22, and tandem anti-CD19/CD22 CAR-T products with a turn-around time of less than 48 h. The protocol yields a more than 90% cellular viability with a CAR expression of exceeding 60% within the 24 h of transfection. The mRNA-based CAR-T products have a significantly enhanced T cell activation profile with CD69 upregulation, production of tumor necrosis factor-alpha (TNF-α), interleukin-2 (IL-2), and Granzyme B, and higher Ki67 expression level. Robust in vitro tumor neutralization by the mRNA-based CAR-T was observed compared to control. Interestingly, we have observed that the short-term cell cryopreservation after EP resulted in a 50% reduction of cellular expansion. However, the cryopreservation and thaw did not have an observed negative impact on the in vitro tumor neutralization. Lastly, we have evaluated the metabolic activity of the mRNA-based CAR-T products, which has a clearly inducible and significant increase in basal respiration (by 60%) and a 2-fold spare respiratory capacity (SRC) upon exposure with the antigen positive target cells. We believe this approach holds promise as a viable alternative that addresses the limitations of current CAR-T therapies, offering a potential solution for future nonviral CAR-T clinical application.
Spontaneous intracerebral hemorrhage (ICH) is associated with high risks of mortality and disability, yet early and accurate outcome prediction remains challenging. This study systematically evaluated the performance of machine learning (ML) models in predicting key adverse outcomes (hematoma expansion [HE], poor functional outcome, mortality) in ICH, aiming to provide consolidated evidence for future research and clinical translation. We systematically searched PubMed, Embase, Web of Science, and Cochrane Library up to September 2025. Studies developing and validating ML models for predicting HE, poor functional outcome (modified Rankin Scale 3-6), or mortality in adults with spontaneous ICH were included. Pooled concordance index (C-index), sensitivity, and specificity were calculated using a random-effects or bivariate model. Eighty-three studies (involving at least 136,840 patients) were included. Meta-analysis of model performance, derived predominantly from internal validation set, demonstrated that models integrating both clinical and radiomics features achieved the highest discriminative performance across key prognostic prediction tasks: predicting HE (pooled C-index 0.822, 95% confidence interval [CI] 0.789-0.855), poor functional outcome (C-index 0.850, 95% CI 0.830-0.869), and mortality (C-index 0.860, 95% CI 0.809-0.911). These findings should be interpreted with caution, as true external validation remains sparse. Logistic regression exhibited performance comparable to more complex ML algorithms. ML models, particularly integrated clinical-radiomics models, demonstrate strong performance for the prediction of outcomes in ICH. They hold significant potential to enhance risk stratification and guide personalized management, pending further validation in diverse cohorts.
Diabetic retinopathy (DR) is a leading cause of preventable blindness worldwide, affecting approximately 93 million people globally. Accurate automated grading is critical for large-scale public health screening, yet existing deep learning methods face challenges related to structure-coupled sparse evidence and domain shift across imaging conditions. We propose VesselMetaKAN, a two-stage framework integrating explicit vessel guidance with meta-learning. Stage 1 employs GMF-SwinUnet for topology-aware vessel segmentation using Frangi-guided attention fusion, reliability gating, and clDice loss. Stage 2 employs KAN-MAML, combining Kolmogorov-Arnold networks with radial basis function expansions as an interpretable decision head and Reptile-style meta-learning over augmentation-defined tasks. Vessel probability maps from Stage 1 guide Stage 2 classification through vessel-gated feature fusion. On APTOS 2019, VesselMetaKAN achieved 74.9 ± 0.4% accuracy, 58.7 ± 0.6% macro-F1, and 0.838 ± 0.005 QWK over five runs. The best single run reached 75.44% accuracy, 59.44% macro-F1, and 0.843 QWK, outperforming EfficientNet-B4 on the principal grading metrics with paired bootstrap significance (p < 0.05). Ablation studies confirmed the synergistic contributions of vessel guidance, KAN-based interpretability, and meta-learning. VesselMetaKAN provides a principled, structure-aware, and interpretable solution for robust DR grading in public health screening programs.