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Heavy-duty diesel vehicles remain an important in-use source of atmospheric NOx, yet long-duration characterization of real-world emissions is constrained by the cost of Portable Emission Measurement Systems (PEMS) and by the irregular structure of Onboard Diagnostics (OBD) telematics. Using 13 months of 1 Hz telematics data from 502 China VI heavy-duty diesel vehicles, covering approximately 1.7 million trips, this study developed a Short-Trip Combination Method (STCM) to reconstruct a screening-oriented estimate of the 90th-percentile Moving Average Window (MAW) specific NOx emission indicator for hot-running operation. STCM segments thermally stabilized operation into short trips, classifies trips by driving mode, reconstructs regulation-constrained synthetic cycles through Monte Carlo resampling, and then calculates the MAW-based NOx indicator. The framework was benchmarked against 15 PEMS tests on four representative vehicles and further compared with a simple whole-trip averaging baseline. A 51-h evaluation window and 200 Monte Carlo iterations provided stable estimates. Median STCM estimates fell within the range of repeated PEMS measurements, with vehicle-level absolute errors of 0.11-0.182 g/kWh, whereas the supplementary baseline comparison showed lower agreement for whole-trip averaging. These results indicate that irregular long-duration OBD data can be converted into environmentally relevant hot-running NOx indicators that recover persistent elevated-emission behavior under real-world operation. Rather than replacing regulatory PEMS testing, the proposed framework provides a practical basis for continuous fleet-scale screening and prioritization of vehicles or operating periods requiring confirmatory inspection.
Background/purpose Breast cancer is among the most prevalent malignancies treated at the Liga Nacional Contra el Cáncer (LNCC) in Guatemala, representing a significant proportion of annual radiotherapy cases. Access to high-quality, standardized treatment planning in resource-constrained settings remains a critical challenge. This study evaluates the dosimetric performance of knowledge-based planning (KBP) models adapted from Washington University (WashU) in St. Louis for breast and chest wall radiotherapy at LNCC, validated against a retrospective 2025 clinical cohort, and benchmarked against the ASTRO 2026 Practical Radiation Oncology guidelines. Materials and methods A retrospective analysis of 84 treatment plans (40 left, 44 right) for whole-breast or chest-wall treatment with regional nodal involvement was performed. All patients were treated using volumetric modulated arc therapy (VMAT) under a moderate hypofractionation scheme (40.05 Gy in 15 fractions). KBP models were developed during 2022-2024 using Eclipse V18.0 (Varian Medical Systems, Palo Alto, CA) RapidPlanTM, originally built at Washington University, and augmented with 194 left-breast and 103 right-breast cases from LNCC. Model validity was confirmed with Varian's model analytics tool. Dosimetric metrics for the planning target volume (PTV) and organs at risk (OARs) were extracted using a custom ESAPI (the OWASP enterprise security application programming interface) application and compared against ASTRO 2026 Table 3 benchmarks, categorized as recommended (green), acceptable (yellow), or unacceptable (red). Results PTV coverage was adequate, with an average V95% of 97.3% ± 1.8%; V90% of 99.7% ± 0.4 (right), and average V95% of 96.6%±3.8%; V90% of 99.0%, ± 2.8% (left). Most plans met ASTRO's recommended range. The heart mean dose was well-controlled, with median values of 2.4 Gy (right) and 4.2 Gy (left). Ipsilateral lung V18Gy showed a median of 18.6% (right) and 17.7% (left), and V10Gy of 33.3% (right) and 31.6% (left), both within acceptable ranges. Spinal cord D0.035cc had a median of 8.3 Gy (right) and 10.1 Gy (left), well below neurological tolerance thresholds. Contralateral breast D10% had median doses of 2.6 Gy (right) and 2.9 Gy (left), with ranges of 1.7-3.1 Gy and 2.2-5.4 Gy, respectively. KBP model analytics validation confirmed institutional model statistics fell within acceptable quality benchmarks across all evaluated structures. Conclusion KBP models developed at a high-income institution and iteratively refined with local data can be successfully deployed for breast and chest wall radiotherapy in a resource-constrained low- and middle-income country (LMIC) setting, achieving dosimetric outcomes consistent with ASTRO 2026 guidelines. The temporal separation between model training (2022-2024) and retrospective validation (2025) further confirms the models' robustness and generalizability. This approach supports standardized, high-quality treatment planning at scale, contributing to more equitable access to radiotherapy for breast cancer patients.
Drug-induced reproductive toxicity is a critical concern in drug safety evaluation, whereas conventional assessment methods are often constrained by high costs and long experimental cycles. In this study, a machine learning-based predictive model for reproductive toxicity was developed and integrated with data from the FDA Adverse Event Reporting System (FAERS), network toxicology analysis, molecular docking, and molecular dynamics simulation to systematically evaluate the post-marketing reproductive toxicity risk of drugs and explore their potential mechanisms. Among the evaluated machine learning algorithms, LightGBM demonstrated the best overall performance, achieving an F1-score of 0.854, a ROC-AUC of 0.933, a PR-AUC of 0.931, and an MCC of 0.705 on the independent test set, with robust generalization confirmed by ten-fold cross-validation. Among drugs approved between 2015 and 2024, 72 were predicted to have a high risk of reproductive toxicity. FAERS-based signal comparison showed that 55 of these drugs (76.39%) were associated with reproductive toxicity-related adverse event reports, indicating consistency between model predictions and FAERS-reported reproductive toxicity-related adverse events. Network toxicology analysis identified 12 key targets, including ESR1, IGF1, and AKT1, that may be involved in reproductive toxicity. Molecular docking showed that drugs with high predicted reproductive toxicity risk could bind effectively to multiple toxicity-related targets, while molecular dynamics simulations confirmed stable interactions between selected drugs and ESR1, mainly through hydrogen-bonding and hydrophobic interactions. Favorable binding free energies further supported their potential multi-target effects. Overall, this integrated strategy combining predictive modeling with FAERS-based signal comparison provides a useful framework for drug safety evaluation and mechanistic investigation of reproductive toxicity.
The shift toward plant- and fungal proteins is driven by environmental and public-health concerns, but wider adoption is constrained by poor sensory quality, limited techno-functionality, and variable nutritional performance. Fermentation has re-emerged as a versatile processing approach because it can improve flavor and texture while remaining compatible with clean-label food design. Yet the effects of fermentation designed for alternative proteins on host physiology remain largely unexplored. This chapter examines how fermentation modifies plant- and fungal-protein foods at multiple levels and how these changes may translate into health-relevant outcomes. After outlining the major chemical and physical transformations induced by fermentation, the chapter moves beyond the traditional focus on nutrients and bioactive metabolites to consider how fermentation-driven changes in flavor and food structure influence gastrointestinal signaling and digestion. Particular attention is given to how in situ production of exopolysaccharides (EPS) during fermentation reshapes matrix organization and governs the delivery of food components along the gastrointestinal tract, where they can be utilized by the host or serve as substrates for gut microbes in complex trophic chains. Accordingly, the gut microbiome provides a key interface for these processes by integrating both chemical and physical cues from foods after ingestion, while also mediating how these cues translate into physiological responses, thereby serving as a composite readout of food properties and host physiology. By highlighting what is known and where evidence is emerging, this chapter aims to support the future rational design of fermented plant- and fungal-protein foods for both product performance and health.
Human liver in vitro models are indispensable for toxicity studies requiring metabolic competence. However, widely used two-dimensional hepatocyte-derived cell lines exhibit limited drug-metabolizing capacity, whereas primary human hepatocytes are constrained by limited availability, donor variability, dedifferentiation, and poor long-term functional stability. Although three-dimensional liver models offer greater physiological relevance, many existing methods depend on exogenous extracellular matrix (ECM) scaffolds or specialized equipment, thereby limiting standardization, scalability, and broader implementation. Here, we developed a simple, scalable suspension culture method for generating human induced pluripotent stem cell (iPSC)-derived liver organoids (HLOs) without exogenous ECM scaffolds or specialized equipment. The resulting HLOs secreted albumin and exhibited hepatic gene expression profiles by RNA-seq analysis. Notably, cytochrome P450 3A4 activity was maintained more stably over an extended culture period than under the ECM-embedding condition. Immunostaining further confirmed the presence of hepatocyte-like populations together with CK19-positive epithelial structures exhibiting E-cadherin-positive cell-cell adhesion and ZO-1-positive tight junction-associated regions. These findings indicate that the HLOs recapitulate key structural and functional features of human liver tissue. Collectively, our results demonstrate that this simple suspension culture method provides a practical and accessible strategy for generating HLOs with sustained hepatic functionality. This platform should facilitate broader application of HLOs in drug screening, toxicity assessment, disease modeling, and other in vitro settings requiring reproducible and scalable human liver models.
Recent advances in genetic engineering and in vivo reprogramming have opened transformative possibilities for controlling cell fate in tissue repair and regeneration. However, clinical translation remains constrained by the limited predictive value of animal models and traditional in vitro systems, which often fail to fully recapitulate human responses, including the physiological consequences of genetic manipulations. Emerging microphysiological systems, exemplified by three-dimensional organoids and organs-on-chips (OoCs) systems, help bridge this gap by recreating key aspects of human physiology while enabling precise bioengineering of the niche to modulate cell fate decisions and plasticity. Organoids derived from induced pluripotent stem cells, adult stem cells, primary tissues, or directly reprogrammed cells preserve the patient-specific genetic background, facilitating mechanistic studies of development and disease and the evaluation of gene correction and reprogramming strategies in a human-relevant context. Complementarily, OoC platforms provide regulated perfusion, tissue vascularization, mechanical forces, molecular gradients, and immune cell integration to promote tissue maturation, functional readouts, and quantitative assessment of therapeutic responses that are difficult to achieve in static cultures. In this review, we discuss how organoids and OoC-based platforms are being leveraged to study and enhance cell fate reprogramming, repair, and regeneration across multiple tissues. We highlight recent reports where these systems informed the design, optimization, and safety evaluation of gene and cell therapies. Finally, we outline current limitations, including scalability, standardization, and biomaterial constraints, and propose future directions for integrating organoids, OoC, and gene-modulation technologies to enable more predictive, personalized, and clinically translatable regenerative medicine.
The speed of insulin therapy remains fundamentally constrained by the self-association of insulin into hexamers. Here, a materials-based strategy is introduced to stabilize HALQ, a monomeric insulin analog, using a non-interacting inulin-derived excipient (BN-Inu). BN-Inu markedly mitigates aggregation and maintains HALQ stability for 96 h under stress and for at least 30 days at room temperature. In a porcine model of diabetes, monomeric HALQ exhibits significantly accelerated absorption and a shorter duration of action than the ultrarapid insulin aspart Fiasp. This "fast-on, fast-off" profile is consistent with faster clearance from the subcutaneous depot, more closely synchronizes with endogenous prandial insulin physiology. Addition of clinically used absorption enhancers further accelerates its pharmacokinetic profile, producing a faster time-to-peak and reduced exposure relative to ultrarapid insulin lispro Lyumjev in this animal model. Furthermore, translation to human physiology was evaluated through pharmacokinetic modeling, which predicts that HALQ could reduce time-to-peak from 60 to 39 min and shorten duration of action from 143 to 84 min in humans. These simulations suggest the potential utility of achieving a step-change in the speed of insulin therapy. These findings demonstrate that monomer-stabilizing excipients enable next-generation ultrafast insulin formulations with the potential to improve glycemic control in diabetes.
Lakes and reservoirs are estimated to be globally important sources of nitrous oxide (N2O) to the atmosphere but recent evidence of N2O uptake across a broad range of lakes have called the accuracy of emission estimates into question. Here, we use a new national-scale dataset of dissolved N2O concentration and a Bayesian hierarchical model to predict summertime N2O concentration and emission rates in 465,896 waterbodies in the conterminous U.S. (CONUS). We found that N2O undersaturation was pervasive throughout the CONUS during the summer of 2017, with an estimated 72.9% (95% credible interval: 68.9-76.6%) of lakes functioning as N2O sinks. The model predicts dissolved N2O concentrations reasonably well based partly on interactions between nitrate concentration, waterbody surface area, and water temperature. Despite working with the largest aquatic N2O dataset to date, our national-scale estimate of summertime N2O emissions from CONUS lakes is poorly constrained, with a 95% credible interval ranging from net uptake to net emission (-282 - 482 metric tons N2O summer-1). Pervasive N2O undersaturation in CONUS waterbodies during the summer highlights the need to revisit N2O models which presume surface waters are a N2O source.
Timely diagnosis and referral of rheumatic and musculoskeletal diseases (RMDs) remain challenging in primary care, with substantial diagnostic delays and a high proportion of rheumatology referrals involving patients without inflammatory rheumatic disease. To examine the diagnostic trajectory of patients presenting with RMD-related complaints, we conducted a scoping review. We defined the diagnostic trajectory as the sequence of diagnostic considerations, investigations, management decisions, and referrals from first presentation to diagnosis or specialist referral. Across 47 included studies, early presentations were heterogeneous and non-specific, often leading to repeated consultations and diagnostic revisions. The underlying condition was frequently not suspected initially, requiring multiple visits before it was considered. General practitioners demonstrated reasonable knowledge of inflammatory features, but documentation of these features in routine electronic health records was often incomplete. Laboratory and imaging investigations were widely used and strongly influenced decision-making, functioning as objective gatekeeping tools for referral despite limited diagnostic yield. Marked variation was found between countries in referral patterns and investigations used, suggesting an important role for healthcare system structure in shaping diagnostic trajectories. The evidence base was constrained by predominantly narrow disease-specific populations and few studies capturing the full diagnostic pathway from primary care presentation to specialist diagnosis.Overall, our findings indicate that delayed diagnosis of RMDs reflects knowledge gaps, the ambiguity of early disease, and reliance on objective investigations. Efforts to improve clinical decision-making for early diagnosis and timely referral require consideration of the non-specific, early-stage nature of RMDs in primary care, longitudinal clinical information, and differences between healthcare systems.
Research on hair follicle neogenesis using cultured follicular cells remains constrained by the rapid cellular senescence of primary cells, including hair follicle keratinocytes (HFKs), significant inter-donor variability, and the progressive loss of hair-inductive potential (trichogenicity). To overcome these bottlenecks, we established immortalized human HFK lines via the co-transfection of SV40 large T antigen (SV40T) and human telomerase reverse transcriptase (hTERT). Among the generated clones, the Kyungpook National University Keratinocyte-8 (KNUK-8) line exhibited superior proliferative capacity and was selected for comprehensive characterization. Notably, although the karyotype underwent certain modifications during the immortalization process, KNUK-8 demonstrated no tumorigenic potential in vivo. Furthermore, KNUK-8 preserved its genetic identity with parental cells and maintained specific HFK marker expression. In chamber hair reconstitution assays, KNUK-8 combined with newborn mouse dermal cells generated robust and mature hair follicles comparable to primary HFKs for up to 12 weeks, whereas dermal cells or keratinocytes alone failed to induce neogenesis. Crucially, this trichogenic potential was reproducibly maintained even at extended passages (passages 35 and 45). To our knowledge, KNUK-8 represents the first immortalized human HFK line that reliably retains long-term trichogenic potential in vivo, offering a highly valuable standard resource for hair regeneration research.
Microplastics and antibiotics frequently co-occur in wastewater treatment systems, yet their combined effect on sulfur-driven bioprocesses and the subsequent post-stress recovery remains poorly resolved. In this study, the long-term response of a sulfate-reducing bacteria (SRB) sludge system treating sulfamethoxazole (SMX)-laden wastewater to polyethylene microplastics (PE MPs; 100 - 800 particles/L) was investigated by combining parallel continuous-flow reactors, batch physiological assays, and metagenomic analysis. PE MPs exerted a concentration-dependent but function-differentiated inhibition, in which SMX removal was more sensitive than chemical oxygen demand (COD) removal and sulfate reduction. At 800 particles/L, SMX removal declined from 37.1 ± 4.1% to 30.5 ± 5.2%, accompanied by elevated intracellular reactive oxygen species (ROS; 138.2 ± 4.0%), increased lactate dehydrogenase (LDH) leakage (122.0 ± 7.1% of the control), weakened antioxidant capacity, and a higher dead-cell fraction (29.7 ± 2.0%). Metagenomic analysis further revealed suppression of central carbon metabolism, dissimilatory sulfate reduction, lipid metabolism, and antioxidant defense, indicating that PE MPs disrupted redox homeostasis and thereby constrained energy supply, sulfur-related electron transfer, membrane maintenance, and stress-response capacity. Notably, after PE MPs withdrawal, SMX removal recovered to 37.8 ± 4.0%, and ROS declined to 107.8 ± 2.8% despite continued SMX loading, together with partial restoration of sulfur-related functional potential. These findings support a reversible, redox-mediated metabolic suppression model rather than irreversible functional collapse, providing an engineering basis for the stable application and functional resilience evaluation of sulfur-driven biotechnologies under fluctuating microplastic exposure, while highlighting the need for future enzyme-level verification of ROS-dependent causal mechanisms.
Photocatalytic synthesis of hydrogen peroxide (H2O2) offers a sustainable route toward green oxidation and environmental remediation, yet its efficiency is fundamentally constrained by rapid backward charge recombination, underscoring the synthetic challenge of creating molecular architectures capable of enforcing directional and recombination-suppressed charge transfer. Inspired by the stepwise electron transfer within the compartmentalized reaction centers of thylakoid membranes in natural photosynthesis, we design here biomimetic donor-acceptor 1-acceptor 2 (D-A1-A2) organic cages, where donors and acceptors are orderly positioned along an energy gradient to achieve a recombination-suppressed sequential charge transfer (RS-SCT) process, thereby promoting photocatalytic H2O2 production. Two single crystals of D-A1-A2 organic cages, BNC-O and BNC-S, are successfully constructed from in situ generated ditopic boronated monomers and C3-symmetric monomers via B-N dative bonds. Both cages show the RS-SCT process from electron-rich triphenylamines as the D through coordinated pyridines as A1 to more electron-deficient benzoxadiazoles or benzothiadiazoles as A2, which enable sequential charge migration and suppress backward charge recombination with prolonged excited-state lifetimes. As a result, the self-assembled two-dimensional crystalline cages featuring well-organized active sites exhibit significantly enhanced photocatalytic H2O2 production performance, achieving a rate of 4.15 mmol g-1 h-1 for crystalline BNC-O, which is markedly higher than those of the corresponding components lacking RS-SCT, including the individual D, A1, A2, and D-A systems. Furthermore, these D-A1-A2 organic cages are implemented in a photocatalytic microflow reactor for controllable in situ H2O2 generation under sunlight, which is further integrated into a cascade phenol-containing wastewater treatment system.
An augmented virtuality framework is presented in which the physical scene is admitted only through developer-defined geometric apertures, while all other pixels are rendered virtually. The scene initialises as a black field and uses surface-projected, overlay-style compositing so that the camera stream is visible only on circular or square meshes registered as projection surfaces. Tracking origin is configured to minimise unintended recentring, and the same method can operate either as a minimal black scene or within an optional three-dimensional environment. Main features of the framework are as follows: deterministic compositing that binds real imagery to user-defined meshes and prevents leakage outside apertures. stable alignment between virtual geometry and the physical workspace during head motion achieved through standard XR configuration. a flexible scene recipe that supports circular or square apertures and optional contextual environments without altering projection logic. The framework is intended for sensory and consumer studies that require real product interaction under controlled context and generalises to training, human factors, and rehabilitation scenarios requiring constrained visibility of the real world.
The benefit of long-term albumin (LTA) in improving survival and reducing complications in patients with cirrhosis and ascites is not consistently observed across studies, possibly reflecting differences in patient populations and treatment regimens. This study aimed to determine whether baseline serum albumin (SA) levels can predict which patients are most likely to benefit from LTA therapy. A post hoc analysis of the ANSWER trial was performed in 431 patients randomized to receive standard medical treatment (SMT) alone or SMT plus human albumin (SMT + HA). The interaction between baseline SA and LTA was investigated using competing-risk survival analysis. The primary endpoint was 18-month survival. Secondary endpoints included the incidence of cirrhosis-related complications and hospitalizations. A significant treatment-by-albumin non-linear interaction was found (p = 0.010), indicating heterogeneity of treatment effect across baseline SA levels with the upper bound of the region of statistically demonstrable benefit occurring at approximately 3.2 g/dL (sHR 0.53, 95% CI 0.28-0.99). In patients with SA ≤ 3.2 g/dL, 18-month survival was significantly higher in the SMT + HA group compared with SMT alone (HR 0.47, 95% CI 0.29-0.77; p = 0.0021). No significant survival difference could be demonstrated in patients with SA > 3.2 g/dL (HR 1.04, 95% CI 0.41-2.63; p = 0.93). Regardless of baseline SA levels, LTA was associated with improved ascites control and reduced rates of complications and hospitalizations. LTA provides survival and morbidity benefits in patients with mild-to-moderate hypoalbuminemia, whereas in patients with normal SA levels, its benefit appears mainly limited to morbidity reduction. Baseline SA may therefore help in prioritizing LTA therapy when resources are constrained.
The management of early colorectal cancer (CRC) is increasingly debated among gastroenterologists and colorectal surgeons, driven by advances in endoscopic resection that enable curative organ-preserving treatment. Conventional endoscopic mucosal resection (EMR) remains the first-line small-to-moderate sized superficial lesions, although its application is limited for larger or fibrotic polyps, because of piecemeal resection and higher recurrence rates. Modified EMR techniques, including anchoring, precutting, and underwater EMR, are widely available and achieve superior technical outcomes without compromising safety, thus broadening the indications for endoscopic resection of low-risk neoplastic lesions. Endoscopic submucosal dissection (ESD) allows en bloc resection regardless of lesion size, and provides accurate histopathological evaluation even when curative criteria are not met, though its use is constrained by its technical complexity and limited availability. For rectal lesions exhibiting features suggestive of deep submucosal invasion, endoscopic intermuscular dissection may serve as an effective endoscopic therapeutic option, as it extends the resection plane into the intermuscular space, achieving clear vertical margins while facilitating organ preservation. Endoscopic full-thickness resection, alone or combined with EMR/ESD, addresses non-lifting, fibrotic or anatomically challenging lesions throughout the colon. Together, these modalities have reshaped the therapeutic landscape of endoscopy, allowing curative and organ-sparing management of early CRCs. This review summarizes organ-preserving endoscopic approaches for early CRC, and proposes a practical algorithm for technique selection while identifying key evidence gaps and future directions.
Antegrade continence enema (ACE) appendicostomy is widely used in children with complex colorectal and neurogenic bowel conditions, yet data from resource-constrained settings remain limited. We aimed to describe the experience of a single-center pediatric cohort in a low-middle-income country (LMIC). A retrospective review of all ACE procedures performed between 2012 and 2026 was conducted. Demographics, diagnoses, indications, complications, surgeries, and functional outcomes (assessed with Milan Bowel Function Questionnaire) were collected from clinical and operative records. Descriptive statistics were applied. Forty-five children (80% male) underwent ACE procedures, with a median age of 8.3 years. Most had appendicostomy; two required cecostomy intraoperatively. The most common diagnosis was anorectal malformation (n = 33, 73.3%), followed by neurogenic bowel (n = 7, 15.5%). Eight patients (17.7%) underwent a concomitant Mitrofanoff procedure. The main complication was skin-level stricture (n = 17, 37.8%), representing the only indication for surgical revision (n = 15, 33.3%), with a median time to revision of 5.5 months. Nearly all patients achieved clinical success, with high satisfaction reported on the questionnaire. ACE appendicostomy is an effective and satisfactory option in LMICs, with outcomes comparable to high-income settings, supported by careful patient selection and ongoing quality improvement efforts.
Poultry meat and egg quality result from complex interactions among host genetics, metabolism, nutrition, microbiome ecology, physiology, management practices, and environmental conditions. These multidimensional interactions limit the predictive capacity of conventional phenotype-based approaches and increasingly necessitate systems-level frameworks capable of capturing biological complexity. Recent advances in multi-omics technologies have transformed poultry quality research by enabling integrated analyses of genomic, transcriptomic, proteomic, metabolomic, lipidomic, epigenomic, and microbiome datasets. These approaches have substantially enhanced understanding of the molecular, cellular, physiological, and ecological networks associated with product quality, production efficiency, physiological resilience, and environmental adaptation. Integrated multi-omics analyses, particularly when combined with artificial intelligence and machine-learning approaches, have the potential to identify biologically interpretable biomarkers, candidate mechanistic pathways, and predictive signatures associated with meat and egg quality traits; however, most proposed signatures remain at early stages of validation and require rigorous external testing before commercial deployment. This review synthesizes current advances in omics-driven poultry research and critically evaluates emerging applications in precision nutrition, breeding, health monitoring, environmental adaptation, and sustainable production systems. To provide a unifying biological framework, we propose the Adaptive Systems Theory of Poultry Quality (ASTPQ), which conceptualizes poultry quality as an emergent adaptive phenotype arising from coordinated interactions among mitochondrial function, redox homeostasis, immune competence, metabolic flexibility, physiological resilience, endocrine-immune regulation, and host-microbiome dynamics. Within this conceptual framework, adaptive-system capacity is proposed as the principal integrative mechanism linking molecular regulation with phenotypic quality outcomes across diverse production environments. Despite substantial advances, commercial implementation remains constrained by biological heterogeneity, methodological variability, limited external validation, computational complexity, challenges in data integration, infrastructure requirements, and economic barriers. Current evidence suggests that predictive performance depends less on increasing molecular dimensionality than on developing biologically interpretable, externally validated, economically feasible, and operationally scalable systems. Future progress will likely require integrated precision-production frameworks that combine molecular biomarkers, physiological monitoring, environmental sensing, microbiome-informed interventions, explainable artificial intelligence, and rigorous large-scale field validation to support sustainable, resilient, and commercially applicable poultry production systems.
Enterococcal bloodstream infections (BSI) are associated with high morbidity and limited treatment options, particularly in resource-limited settings where access to standard agents may be constrained. Comparative effectiveness data directly informing the choice among available agents for both vancomycin-resistant (VRE) and ampicillin-resistant, vancomycin-susceptible (VSE) enterococcal bacteremia are specifically lacking in such settings, where regimen selection is frequently dictated by drug availability and cost rather than guideline preference. We conducted a retrospective cohort study across three hospitals of a single university health system (Dr. Ziauddin University, Karachi, Pakistan) including hospitalized adults (≥ 18 years) with clinically significant enterococcal bacteremia (a positive blood culture together with clinical evidence of infection, as adjudicated by the treating physician) between January 1, 2010, and May 31, 2025. Only the first episode per patient was analyzed. VRE and VSE cohorts were compared for baseline characteristics and empiric therapy. Definitive monotherapy-receipt of a single study agent active against the isolate, assigned within the prespecified 48- to 72-h window after index blood culture (time-zero), by which time organism identification and susceptibility results were generally available-was assessed within the VRE and VSE cohorts. Because discharge alive is a competing event for in-hospital death, cumulative incidence functions (CIF) with Gray's test and an adjusted Fine-Gray competing-risks model (adjusted for age, Charlson Comorbidity Index, qPitt score, septic shock, and definitive antibiotic exposure (vancomycin, teicoplanin, daptomycin, tigecycline)) were used. Of 925 screened patients, 501 met inclusion criteria (VSE n = 404; VRE n = 97). VRE bacteremia presented with greater acute severity (higher APACHE II) and was more frequently catheter-associated, while VSE more often had urinary and intra-abdominal sources (all p < 0.001). In definitive monotherapy analyses among VRE (n = 67; tigecycline excluded, as it was used only as salvage therapy), 28-day mortality was numerically higher with teicoplanin (66.7%) but did not differ significantly across linezolid, teicoplanin, and daptomycin; CIF analysis similarly showed no difference in cumulative incidence of in-hospital death (Gray's p = 0.246). Tigecycline, used only as salvage therapy, was associated with higher 28-day mortality (80.0% vs 47.8%; p = 0.003; Supplementary Table S1). In VSE monotherapy (n = 404), teicoplanin exposure was associated with higher ICU admission and higher 28-day mortality, and CIF curves differed across vancomycin, teicoplanin, and linezolid (Gray's p < 0.001); however, the linezolid-exposed group had sparse/zero events for several endpoints, suggesting confounding by indication. In the adjusted Fine-Gray model, higher qPitt score was independently associated with mortality (sHR 2.21, 95% CI 1.62-3.01; p < 0.001). Tigecycline (sHR 4.00, 95% CI 2.11-7.60; p < 0.001) and daptomycin exposure (sHR 3.11, 95% CI 1.37-7.07; p = 0.007) were associated with higher subdistribution hazard of death, whereas vancomycin exposure was associated with lower hazard (sHR 0.36, 95% CI 0.20-0.67; p = 0.001). In this multi-hospital, single-system cohort, VRE bacteremia was more severe and more often catheter-associated than VSE. When accounting for discharge as a competing event, mortality differences across definitive monotherapy groups were not significant in VRE, while VSE comparisons were influenced by treatment selection and sparse outcome counts in some groups. Severity (qPitt score) was a key independent predictor of mortality, and observed antibiotic-mortality associations should be interpreted cautiously given confounding by indication.