Undifferentiated chest pain is a major driver of emergency department (ED) overcrowding and contributes to morbidity and mortality. Early risk stratification for major adverse cardiac events (MACE) allows for early discharge and ED decongestion. We developed a multimodal machine learning model integrating EHR data, laboratory results, demographic and comorbidity features and chest x-ray impressions to predict 30-day MACE in patients presenting to the ED with chest pain. Using 49,348 ED encounters from two healthcare systems, our model achieved a high area under the curve (AUC) of 82.0% at the development site and 74.6% at the external validation site. Predictions occurred within 6 h of ED arrival and demonstrated consistently high negative predictive values across time, supporting safe early-rule out. This model demonstrates the potential of integrating AI modeling to enhance early MACE risk stratification and improve ED overcrowding and efficiency.
China’s rapid renewable expansion coincides with deep structural reforms to its power markets. Over the past decade, reform has drawn on international market design experience while making substantial institutional progress since 2015. Unlike developed markets adapting established frameworks to accommodate renewables, China must address high-renewable integration alongside conventional market liberalisation challenges. High renewable penetration creates several shared analytical challenges, including revenue adequacy under near-zero marginal costs, intensified price volatility, limited participation by emerging flexible resources, incomplete markets for new system attributes, and ambiguous planning–market interactions. In China, responses to these challenges are shaped by two foundational drivers: (1) using the market as an instrument of government policy and (2) hierarchical prioritisation of end-user price stability and socio-political acceptability of reform over allocative efficiency. These drivers have produced a reform pathway characterised by strict price control, technology specific participation rules, and planning led adequacy coordination. Provincial pilots implement variants of this pathway iteratively, while international experience provides comparative reference points. The review concludes that power systems worldwide combine wholesale markets with broader planning and system operator governance, although the balance and institutional form differ substantially across jurisdictions. China’s reform occupies a distinct position on this continuum, warranting evaluation frameworks suited to layered market–administrative coordination and sector coupled net zero transitions. The principal implication is not that China will converge towards a single internationally recognised market template, but that reforms are likely to maintain structured divergence rooted in China’s political economy while remaining part of the broader shift towards hybrid governance everywhere.
Regulation of adipogenesis has classically been viewed through the lens of transcription initiation driven by lineage defining transcription factors. In this study, we uncover transcription elongation as a critical and previously underappreciated regulatory layer controlling adipocyte cell fate. We demonstrate that the elongation factors Spt4 and Spt6 are indispensable for adipogenic differentiation, as their depletion severely impairs adipogenic gene induction and perilipin expression. Spt4 and Spt6 directly regulate the genes coding for core adipogenic transcription factors, including Cebpa, Pparg, Krox20, and Stat3, by promoting RNA polymerase II (Pol II) progression through their gene bodies. In the absence of these factors, Pol II becomes stalled at the transcriptional start sites of these adipogenic genes. These data support a post transcription initiation requirement for Spt4 and Spt6 in productive elongation rather than promoter loading. Our findings identify transcription elongation control as a key determinant of adipogenic fate.
Emerging studies suggest that antibiotics can disrupt the gut microbiome and alter vaccine-induced immune responses. However, the specific consequences of early-life exposure on neonatal immune development remain poorly understood. Here, we examined how two antibiotics frequently used in perinatal care, broad-spectrum ampicillin (AMP) and the extended-spectrum combination amoxicillin/clavulanate (AMOX/CLAV), administered during gestation and lactation, influence neonatal gut microbiome composition, fecal metabolome profiles, and responses to the 20-valent pneumococcal conjugate vaccine (PCV20). Maternal treatment with AMOX/CLAV, but not AMP, significantly reduced PCV-specific IgG titers at 4 and 6 weeks post-prime immunization compared to untreated controls. Exclusive exposure to AMOX/CLAV also impaired neutrophil-mediated opsonophagocytic killing, indicating reduced antibody functionality. These effects were transient, with immune parameters normalizing by 8 weeks post-prime immunization. Metabolomic and microbiome profiling revealed that maternal AMP and AMOX/CLAV differentially perturbed specific metabolite classes, including bile acids, N-acyl lipids, and indole derivatives. Key commensal taxa, including Bacteroidales and Coriobacteriales were also impacted within the gut microbiota. Together, these findings reveal a previously underappreciated maternal-offspring route of antibiotic influence that is transiently associated with neonatal vaccine responsiveness and microbiome and metabolome alterations. These results highlight maternal antibiotic exposure as a possible modifiable factor shaping early-life immunity.
Background: Ethical and professional pharmacy practice is fundamental to supporting patient safety and trust. Despite advances in Good Pharmacy Practice (GPP), evidence from developing systems indicates gaps in ethical performance. This study aimed to assess the ethical dimensions of community pharmacists' practice in Jordan from the public's perspective, focusing on counseling quality, privacy, autonomy, and fairness. Methods: A cross-sectional survey was conducted among 710 community pharmacy clients across Jordan using a validated questionnaire measured five ethical domains and an attitude scale. Composite scores for patient satisfaction, ethical conduct, and pharmacist attitude were calculated. Descriptive statistics and logistic regression were used to identify demographic predictors. Results: Participants were predominantly female (57.9%) and from central Jordan (69.6%). Mean domain scores were: history-taking (51.3 ± 34.3), counseling (60.3 ± 29.6), privacy (67.8 ± 26.1), autonomy (60.2 ± 36.6), and justice (86.5 ± 24.0). Counseling was strongest for medication use and timing but weakest for safety aspects-adverse effects (41.4%), storage (40.1%), and drug interactions (31.7%). Justice and professionalism received the highest perception scores, while privacy and autonomy received moderate ratings. Gender (female) and south region predicted higher satisfaction and ethical perception (p < 0.05). Conclusion: Community pharmacists in Jordan were perceived as demonstrating strong fairness and professionalism, but gaps remain in safety-oriented counseling and privacy assurance. These findings highlight areas where communication practices, privacy infrastructure, and ethics-oriented training may warrant further attention. Strengthening these areas could contribute to supporting patient trust and the ethical quality of community pharmacy services.
Purpose of Review: Concurrent HIV and hepatitis B virus (HBV) affect an estimated 4-5 million people worldwide and remain a major driver of liver-related morbidity and mortality, even among individuals receiving tenofovir-containing antiretroviral therapy (ART). Both viruses establish long-lived reservoirs that are not eliminated by current antiviral therapies. This review summarizes current mechanistic and clinical frameworks for understanding concurrent HIV and HBV, highlights the interplay between their viral reservoirs, and discusses the implications of these interactions for cure strategies. Recent Findings: The liver functions as a multicellular reservoir. HBV persists within hepatocytes as nuclear covalently closed circular DNA (cccDNA) and integrated viral sequences. HIV persists as integrated provirus in tissue-resident CD4⁺ T cells and liver macrophages, with evidence supporting viral transfer or cell-to-cell spread involving stellate cells and hepatocytes. Concurrent HIV and HBV accelerate fibrosis and immune dysfunction through shared pathogenic pathways, including epigenetic silencing, cytokine- and checkpoint-mediated T-cell exhaustion, metabolic stress, and inflammation driven by the gut-liver axis. HBV-associated liver injury promotes recruitment of HIV target cells, while HIV-associated immune dysregulation impairs HBV control. Despite these interlinked biological mechanisms, individuals living with HIV and HBV are frequently excluded from clinical trials, slowing therapeutic progress and exacerbating health inequities. Summary: Concurrent HIV and HBV represent a synergistic disease model that demands integrated therapeutic approaches and inclusive research frameworks. Priority needs include robust tissue-based reservoir measurements, validated biomarkers that distinguish latent from transcriptionally active viral states, combination strategies incorporating antiviral, antifibrotic, and immunomodulatory agents, and community-engaged clinical trial designs that are inclusive of individuals living with HIV and HBV and safe in the context of HBV. Advancing these areas will be essential to achieving durable remission-and ultimately functional cure-for both viruses.
This study presents a centrifuge modeling investigation of the seismic performance of shallow, rocking-dominated foundations supported by soil-cement columns intended to limit detrimental settlement and rotation, while preserving the beneficial energy dissipation afforded by a rocking foundation. The footings investigated in this study are modeled after shallow foundations supporting a two-span highway bridge, which served as the archetypal bridge in previous centrifuge studies. While earlier studies proved that rocking foundations in sand exhibit good re-centering while dissipating energy, this study aims to broaden the use cases for the rocking foundation concept for heavily loaded foundations in dry sand that may be prone to excessive settlement by incorporating ground improvement in the form of soil-cement columns with different configurations. A baseline case was developed for a rocking footing without ground improvement by subjecting the soil-foundation system to shaking at a level that caused excessive settlement (more than 5% of its length in this study) and permanent rotation. Foundation performance in the baseline case and rocking footings with ground improvement was assessed based on settlement accumulation rate with increasing cumulative rotation demand, and a correlation diagram relating re-centering and energy dissipation. Test results demonstrate that footings without ground improvement dissipate the most energy but experience excessive settlement. In contrast, paired soil-cement columns at either end of the footing's length preserved adequate energy dissipation and re-centering, while minimizing settlement to an acceptable limit.
DNA mismatch repair (MMR) corrects DNA replication errors, some forms of chemical damage to DNA bases, and acts in processes such as heteroduplex rejection, triplet repeat expansion, antibody maturation and cytotoxicity of alkylating agents. During MMR, the newly synthesized DNA strand containing the error must be removed and resynthesized to prevent mutations. In bacteria, this strand is displaced by the UvrD DNA helicase. In eukaryotes, this strand is excised by redundant pathways. In the first excision pathway identified, Saccharomyces cerevisiae Msh2-Msh6 (or Msh2-Msh3) and/or Mlh1-Pms1 (human MLH1-PMS2) recruit Exo1 to 5' nicks, and 5'-to-3' excision by Exo1 excises the daughter strand containing the mispair to generate a single-stranded gap. The Mlh1-Pms1 endonuclease also mediates excision through extensive nicking of the daughter strand to generate single-stranded gaps. In coupled strand-displacement synthesis coordinated by Msh2-Msh6 (or Msh2-Msh3), DNA polymerase delta and Rad27 (human FEN1)-mediated 5' flap cleavage excise the mispair and resynthesize the daughter strand. Resynthesis in the Exo1- and Mlh1-Pms1-mediated pathways can be performed by both DNA polymerase delta and epsilon, and in all excision pathways the nicked product can be sealed by DNA ligase. Genetic analysis in S. cerevisiae suggests that these three pathways correspond to all or at least the major excision pathways; however, other factors such as Fan1, Artemis, Mre11, Dna2, Fun30, and the RSC complex have been implicated in eukaryotic MMR but are less well understood. The roles of excision and its redundant pathways have also been less well characterized for other processes involving MMR proteins.
Recent DIII-D tokamak experiments have demonstrated the integration of intrinsic low-collisionality grassy edge-localized mode (ELM) regime with high-performance hybrid core scenario, possibly offering a core-edge compatible solution for ITER and future fusion reactors. This regime features grassy ELMs (with ELM energy loss over pedestal stored energy <2%) at ITER-relevant pedestal top collisionality ( νe∗ ∼ 0.1), ITER similar shape, while maintaining high core confinement ( H98y2 ∼ 1.5) in non-inductive hybrid scenarios. A small ELM-focused database is constructed to investigate the parametric dependence of the small/grassy ELM regimes. Access and sustainment of this regime appear to be favored by high poloidal beta ( βp > 1.5), higher ratio of separatrix-to-pedestal density ( ne,sep/ne,ped > 0.4) and low pedestal top collisionality ( νe,ped∗ = 0.1–0.4). In this scenario, the pedestal width exceeds the prediction from EPED–KBM scaling, consistent with the expectation of a turbulence-limited pedestal. Linear modeling using ELITE indicates that this grassy ELM regime is along the peeling boundary. Relative to a large-ELM phase, the grassy-ELM phase exhibits a broader inner-target heat-flux width and a substantially reduced ELM-induced transient heat-flux increment. These results motivate further evaluation of low-collisionality grassy ELMs as a potentially reactor-relevant operating regime, while full-duration sustainment and compatibility with divertor detachment remain unresolved.
Purpose of ReviewTailoring treatment strategies to the biological features of invasive disease and the individual needs and preference of each patient has transformed the way we manage breast cancer. This article calls for a similar shift in the management paradigm of ductal carcinoma in situ (DCIS) from a uniform treatment model toward a risk-stratified stepwise approach that aligns with the heterogeneous nature of the disease to avoid overtreatment.Recent FindingsMost DCIS lesions are hormone receptor positive, and only a subset have a risk for progression to invasive cancer. Early results from observational and clinical studies indicate that active surveillance is a safe and feasible alternative to upfront surgical treatment for low-risk DCIS. Ongoing clinical trials like RECAST will further inform and refine strategies for optimal management of this condition.SummaryThe integration of risk-adapted management strategies, endocrine risk-reducing interventions, and advanced imaging modalities into active surveillance protocols hold significant potential to reduce overtreatment and personalize care for patients with DCIS. Early data from clinical trials support the notion that providing a period of active surveillance is safe and offers a critical assessment window during which DCIS treatment can be individualized. Strengthening the evidence base to support the adoption of active surveillance as an initial approach in the management of DCIS is an important clinical priority.
