Search Results (15,510)

Multiple myeloma (MM) is predominantly a disease of the elderly. In recent years, a surge of highly effective plasma cell therapies has revolutionized the care of elderly multiple myeloma (MM) patients, for whom frailty and age-related competing causes of mortality determine management. Traditionally, the treatment of newly diagnosed elderly patients has centered on doublet or triplet combinations composed of immunomodulators (IMIDs), proteasome inhibitors (PIs), anti-CD38 monoclonal antibodies (mAbs), and corticosteroids producing median progression-free survival (PFS) rates between 34 and 62 months. However, recently, a series of large phase III clinical trials examining quadruplet regimens of PIs, IMIDs, corticosteroids, and anti-CD38 mAbs have shown exceptional outcomes, with median PFS exceeding 60 months, albeit with higher rates of peripheral neuropathy (≥Grade 2: 27% vs. 10%) when PIs and IMIDs are combined, and infections (≥Grade 3: 40% vs. 29–41%) with the addition of anti-CD38mAbs. The development of T-cell redirecting therapies including T-cell engagers (TCEs) and CAR-T cells has further expanded the therapeutic arsenal. TCEs have shown exceptional activity in relapsed disease and are being explored in the newly diagnosed setting with promising early results. However, concerns remain regarding the logistical challenges of step-up dosing, which often necessitates inpatient admission, the infectious risks, and the financial burden associated with TCEs in elderly patients. CAR-T, the most potent commercially available therapy for MM, offers the potential of a ‘one and done’ approach. However, its application to elderly patients has been tempered by significant concerns of cytokine release syndrome, early and delayed neurological toxicity, and its overall tolerability in frail patients. Robust data in frail patients are still needed. How CAR-T and TCEs will be sequenced among the growing therapeutic armamentarium for elderly MM patients remains to be determined. This review explores the safety, efficacy, cost, and logistical barriers associated with the above treatments in elderly MM patients. Full article

Early blight, caused by the pathogen Alternaria solani, is a major fungal disease impacting potato production globally, with reported yield losses of up to 40% in susceptible varieties. As one of the most common diseases affecting potatoes, its incidence has been steadily increasing year after year. This study aimed to elucidate the molecular mechanisms underlying resistance to early blight by comparing gene expression profiles in resistant (B1) and susceptible (D30) potato seedlings. Transcriptome sequencing was conducted at three time points post-infection (3, 7, and 10 dpi) to identify differentially expressed genes (DEGs). Weighted Gene Co-expression Network Analysis (WGCNA) and pathway enrichment analyses were performed to explore resistance-associated pathways and hub genes. Over 11,537 DEGs were identified, with the highest number observed at 10 dpi. Genes such as LOC102603761 and LOC102573998 were significantly differentially expressed across multiple comparisons. In the resistant B1 variety, upregulated genes were enriched in plant–pathogen interaction, MAPK signaling, hormonal signaling, and secondary metabolite biosynthesis pathways, particularly flavonoid biosynthesis, which likely contributes to biochemical defense against A. solani. WGCNA identified 24 distinct modules, with hub transcription factors (e.g., WRKY33, MYB, and NAC) as key regulators of resistance. These findings highlight critical molecular pathways and candidate genes involved in early blight resistance, providing a foundation for further functional studies and breeding strategies to enhance potato resilience. Full article

Background: Severe damage to one side of the brain often leads to adverse consequences and can also cause widespread changes throughout the brain, especially in the contralateral area. Studying molecular changes in the contralateral cerebral hemisphere, especially with regard to genetic regulation, can help discover potential treatment strategies to promote recovery after severe brain trauma on one side. Methods: In our study, the right motor cortex was surgically removed to simulate severe unilateral brain injury, and changes in glial cells and synaptic structure in the contralateral cortex were subsequently assessed through immunohistological, morphological, and Western blot analyses. We conducted transcriptomic studies to explore changes in gene expression levels associated with the inflammatory response. Results: Seven days after corticotomy, levels of reactive astrocytes and hypertrophic microglia increased significantly in the experimental group, while synapsin-1 and PSD-95 levels in the contralateral motor cortex increased. These molecular changes are associated with structural changes, including destruction of dendritic structures and the encapsulation of astrocytes by synapses. Genome-wide transcriptome analysis showed a significant increase in gene pathways involved in inflammatory responses, synaptic activity, and nerve fiber regeneration in the contralateral cortex after corticorectomy. Key transcription factors such as NF-κB1, Rela, STAT3 and Jun were identified as potential regulators of these contralateral changes. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) confirmed that the mRNA expression levels of Cacna1c, Tgfb1 and Slc2a1 genes related to STAT3, JUN, and NF-κB regulation significantly increased in the contralateral cortex of the experimental group. Conclusions: After unilateral brain damage occurs, changes in the contralateral cerebral hemisphere are closely related to processes involving inflammation and synaptic function. Full article

Background: Clinical outcomes among older adults hospitalized with heart failure with preserved ejection fraction (HFpEF) in the setting of metabolically healthy obesity (MHO) remain insufficiently explored. This study aimed to evaluate whether MHO status is associated with different rates of major adverse cardiac and cerebrovascular events (MACCEs) during HFpEF-related hospitalizations compared to patients without MHO. Methods: Data from the 2019 National Inpatient Sample (NIS) database was analyzed using relevant ICD-10 codes to identify HFpEF admissions in older adults. Propensity score matching (1:1) was applied to generate balanced cohorts of patients with and without MHO. Multivariable adjustments were performed to assess primary outcomes, including MACCEs, all-cause mortality (ACM), acute myocardial infarction (AMI), dysrhythmia, cardiac arrest (CA), and stroke. Statistical significance was set at p < 0.05. Results: Each MHO cohort included 22,405 patients with a median age of 75 years. The MHO+ group demonstrated a significantly higher risk of dysrhythmia (OR 1.32, 95% CI 1.21–1.43, p < 0.001). Interestingly, an “obesity paradox” was observed, as the MHO+ cohort had lower odds of MACCEs (OR 0.70, 95% CI 0.61–0.81, p < 0.001), ACM (OR 0.66, 95% CI 0.54–0.82, p < 0.001), and AMI (OR 0.71, 95% CI 0.59–0.86, p = 0.001) compared to MHO−. No significant differences were found for CA or stroke between the groups. Conclusions: Although the MHO+ group had an elevated risk of dysrhythmia, they exhibited more favorable outcomes in terms of MACCEs, ACM, and AMI—supporting the concept of an “obesity paradox.” Further research is needed to better understand the role of MHO as a comorbid condition in patients with HFpEF. Full article

Phage therapy, long overshadowed by antibiotics in Western medicine, has a well-established history in some Eastern European countries and is now being revitalized as a promising strategy against antimicrobial resistance (AMR). This resurgence of phage therapy is driven by the urgent need for innovative countermeasures to AMR, which will cause an estimated 10 million deaths annually by 2050. However, the emergence of phage-resistant variants presents challenges similar to AMR, thus necessitating a deeper understanding of phage resistance mechanisms and control strategies. The highest priority must be to prevent the emergence of phage resistance. Although phage cocktails targeting multiple receptors have demonstrated a certain level of phage resistance suppression, they cannot completely suppress resistance in clinical settings. This highlights the need for strategies beyond simple resistance suppression. Notably, recent studies examining fitness trade-offs associated with phage resistance have opened new avenues in phage therapy that offer the potential of restoring antibiotic susceptibility and attenuating pathogen virulence despite phage resistance. Thus, controlling phage resistance may rely on both its suppression and strategic redirection. This review summarizes key concepts in the control of phage resistance and explores evolutionary engineering as a means of optimizing phage therapy, with a particular focus on Pseudomonas infections. Harnessing evolutionary dynamics by intentionally breaking the spontaneous evolutionary trajectories of target bacterial pathogens could potentially reshape bacterial adaptation by acquisition of phage resistance, unlocking potential in the application of phage therapy. Full article

Floods pose a growing threat globally, causing tragic loss of life, billions in economic damage annually, and disproportionately affecting socio-economically vulnerable populations. This paper aims to improve flood-risk communication for community leaders by exploring the application of artificial intelligence. We categorize U.S. flood information sources, review communication modalities and channels, synthesize the literature on community leaders’ roles in risk communication, and analyze existing technological tools. Our analysis reveals three key challenges: the fragmentation of flood information, information overload that impedes decision-making, and the absence of a unified communication platform to address these issues. We find that AI techniques can organize data and significantly enhance communication effectiveness, particularly when delivered through infographics and social media channels. Based on these findings, we propose FLAI (Flood Language AI), an AI-driven flood communication platform that unifies fragmented flood data sources. FLAI employs knowledge graphs to structure fragmented data sources and utilizes a retrieval-augmented generation (RAG) framework to enable large language models (LLMs) to produce contextualized narratives, including infographics, maps, and cost–benefit analyses. Beyond flood management, FLAI’s framework demonstrates how AI can transform public service data management and institutional AI readiness. By centralizing and organizing information, FLAI can significantly reduce the cognitive burden on community leaders, helping them communicate timely, actionable insights to save lives and build flood resilience. Full article

Diabetic retinopathy (DR) is a progressive, multifactorial complication of diabetes and one of the major global causes of visual impairment. Its pathogenesis involves chronic hyperglycaemia-induced oxidative stress, inflammation, mitochondrial dysfunction, neurodegeneration, and pathological angiogenesis, as well as emerging systemic contributors such as gut microbiota dysregulation. While current treatments, including anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroids, and laser photocoagulation, have shown clinical efficacy, they are largely limited to advanced stages of DR, require repeated invasive procedures, and do not adequately address early neurovascular and metabolic abnormalities. Resveratrol (RSV), a naturally occurring polyphenol, has emerged as a promising candidate due to its potent antioxidant, anti-inflammatory, neuroprotective, and anti-angiogenic properties. This review provides a comprehensive analysis of the molecular mechanisms by which RSV exerts protective effects in DR, including modulation of oxidative stress pathways, suppression of inflammatory cytokines, enhancement of mitochondrial function, promotion of autophagy, and inhibition of pathological neovascularisation. Despite its promising pharmacological profile, the clinical application of RSV is limited by poor aqueous solubility, rapid systemic metabolism, and low ocular bioavailability. Various routes of administration, including intravitreal injection, topical instillation, and oral and sublingual delivery, have been investigated to enhance its therapeutic potential. Recent advances in drug delivery systems, including nanoformulations, liposomal carriers, and sustained-release intravitreal implants, offer potential strategies to address these challenges. This review also explores RSV’s role in combination therapies, its potential as a disease-modifying agent in early-stage DR, and the relevance of personalised medicine approaches guided by metabolic and genetic factors. Overall, the review highlights the therapeutic potential and the key translational challenges in positioning RSV as a multi-targeted treatment strategy for DR. Full article

Background: Congenital diarrhea is persistent diarrhea that manifests during the neonatal period. Mutations in DGAT1, which is crucial for triglyceride synthesis and lipid absorption in the small intestine, are causal factors for congenital diarrhea. In this study, we aimed to determine the value of tissue RNA sequencing (RNA-seq) for assisting with the clinical diagnosis of some genetic variants of uncertain significance. Methods: We clinically evaluated a patient with watery diarrhea, vomiting, severe malnutrition, and total parenteral nutrition dependence. Possible pathogenic variants were detected using whole-exome sequencing (WES). RNA-seq was utilized to explore the transcriptional alterations in DGAT1 variants identified by WES with unknown clinical significance, according to the American College of Medical Genetics guidelines. Systemic examinations, including endoscopic and histopathological examinations of the intestinal mucosa, were conducted to rule out other potential diagnoses. Results: We successfully diagnosed a patient with congenital diarrhea and protein-losing enteropathy caused by a DGAT1 mutation and reviewed the literature of 19 cases of children with DGAT defects. The missense mutation c.620A>G, p.Lys207Arg located in exon 15, and the intronic mutation c.1249-6T>G in DGAT1 were identified by WES. RNA-seq revealed two aberrant splicing events in the DGAT1 gene of the patient’s small intestinal tissue. Both variants lead to loss-of-function consequences and are classified as pathogenic variants of congenital diarrhea. Conclusions: Rare DGAT1 variants were identified as pathogenic evidence of congenital diarrhea, and the detection of tissue-specific mRNA splicing and transcriptional effects can provide auxiliary evidence. Full article

Nosocomial infections caused by ESKAPE pathogens represent a significant burden to global health. These pathogens may exhibit multidrug resistance (MDR) mechanisms, of which mechanisms such as efflux pumps and biofilm formation are gaining significant importance. Multidrug resistance mechanisms in ESKAPE pathogens have led to an increase in the effective costs in health care and a higher risk of mortality in hospitalized patients. These pathogens utilize antimicrobial efflux pump mechanisms and bacterial biofilm-forming capabilities to escape the bactericidal action of antimicrobials. ESKAPE bacteria forming colonies demonstrate increased expression of efflux pump-encoding genes. Efflux pumps not only expel antimicrobial agents but also contribute to biofilm formation by bacteria through (1) transport of molecules and transcription factors involved in biofilm quorum sensing, (2) bacterial fimbriae structure transport for biofilm adhesion to surfaces, and (3) regulation of a transmembrane gradient to survive the difficult conditions of biofilm microenvironments. The synergistic role of these mechanisms complicates treatment outcomes. Given the mechanistic link between biofilms and efflux pumps, therapeutic strategies should focus on targeting anti-biofilm mechanisms alongside efflux pump inactivation with efflux pump inhibitors. This review explores the molecular interplay between efflux pumps and biofilm formation, emphasizing potential therapeutic strategies such as efflux pump inhibitors (EPIs) and biofilm-targeting agents. Full article

Colorectal cancer (CRC) is not only the third most common cancer worldwide, with 1.1 million new cases per year; it is also the second leading cause of cancer death. However, mortality has decreased since 2012 due to early detection programs and better therapeutic approaches. While many patients are diagnosed at an early stage, there is up to 50% relapse after optimal initial treatment. Therefore, it is crucial to explore the mechanism underlying the development of recurrences and metastasis. It is known that tumors release dormant cells that escape chemotherapy and nest in a target organ without proliferating. Under certain circumstances that are not yet entirely clear, they can be activated and metastasize. Therefore, the objective of this work is to explore the detailed mechanisms of dormancy, including early detection of recurrence and therapeutic approaches for the treatment of CRC. The specific objectives are to determine biomarkers that may be useful in identifying dormant cells to detect minimal residual disease (MRD) after surgery and predicting disease progression, as well as evaluating biomarkers that are susceptible to therapeutic intervention. Full article

Though the pursuit of sustainable desalination processes with high water recovery has intensified the research interest in membrane distillation (MD), the influence of module connection configuration on performance stability remains poorly explored. The current study provided a comprehensive multiparameter assessment of hollow fibre membrane modules connected in parallel and series in direct contact membrane distillation (DCMD) for the first time. The configurations were evaluated under varying process parameters such as temperature (50–70 °C), flow rates (22.1–32.3 mL·s⁻¹), magnesium concentration as scalant (1.0–4.0 g·L⁻¹), and flow direction (co-current and counter-current), assessing their influence on temperature gradients (∆T), flux and pH stability, salt rejection, and crystallisation. Interestingly, the parallel module configuration maintained high operational stability with uniform flux and temperature differences (∆T) even at high recovery factors (>75%). On one hand, the serial configuration experienced fluctuating ∆T caused by thermal and concentration polarisation, causing an early crystallisation (abrupt drop in feed conductivity). Intensified polarisation effects with accelerated crystallisation increased the membrane risk of wetting, particularly at high recovery factors. Despite these changes, the salt rejection remained relatively high (99.9%) for both configurations across all tested conditions. The findings revealed that acidification trends caused by MgSO₄ were configuration-dependent, where the parallel setup-controlled rate of pH collapse. This study presented a novel framework connecting membrane module architecture to mass and heat transfer phenomena, providing a transformative DCMD module configuration design in water desalination. These findings not only provide the critical knowledge gaps in DCMD module configurations but also inform optimisation of MD water desalination to achieve high recovery and stable operation conditions under realistic brine composition. Full article

Tuberculosis (TB) remains a leading cause of death in Bangladesh, disproportionately affecting low socio-economic status (SES) populations. This review, guided by the WHO Social Determinants of Health framework and Rockefeller-Lancet Planetary Health Report, examined how social, economic, and ecological factors link SES to TB burden. The first literature search identified 28 articles focused on SES-TB relationships in Bangladesh. A second search through snowballing and conceptual mapping yielded 55 more papers of diverse source types and disciplines. Low-SES groups face elevated TB risk due to smoking, biomass fuel use, malnutrition, limited education, stigma, financial barriers, and hazardous housing or workplaces. These factors delay care-seeking, worsen outcomes, and fuel transmission, especially among women. High-SES groups more often face comorbidities like diabetes, which increase TB risk. Broader contextual drivers include urbanisation, weak labour protections, cultural norms, and poor governance. Recommendations include housing and labour reform, gender parity in education, and integrating private providers into TB programmes. These align with the WHO End TB Strategy, UN SDGs and Planetary Health Quadruple Aims, which expand the traditional Triple Aim for health system design by integrating environmental sustainability alongside improved patient outcomes, population health, and cost efficiency. Future research should explore trust in frontline workers, reasons for consulting informal carers, links between makeshift housing and TB, and integrating ecological determinants into existing frameworks. Full article

Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries. Predicting its progression is crucial for preventing late-stage AMD, as it is an irreversible retinal disease. Both genetic factors and retinal images are instrumental in diagnosing and predicting AMD progression. Previous studies have explored automated diagnosis using single fundus images and genetic variants, but they often fail to utilize the valuable longitudinal data from multiple visits. Longitudinal retinal images offer a dynamic view of disease progression, yet standard Long Short-Term Memory (LSTM) models assume consistent time intervals between training and testing, limiting their effectiveness in real-world settings. To address this limitation, we propose time-varied Long Short-Term Memory (TV-LSTM), which accommodates irregular time intervals in longitudinal data. Our innovative approach enables the integration of both longitudinal fundus images and AMD-associated genetic variants for more precise progression prediction. Our TV-LSTM model achieved an AUC-ROC of 0.9479 and an AUC-PR of 0.8591 for predicting late AMD within two years, using data from four visits with varying time intervals. Full article

This review explores sexual aggression in broiler breeder males, aiming to synthesize existing scientific evidence regarding its causes, behavioral manifestations, and consequences, while addressing the genetic, neuroendocrine, and environmental mechanisms involved. Through an extensive analysis of scientific literature, the paper highlights that intensive genetic selection aimed at enhancing growth and productivity has resulted in unintended behavioral dysfunctions. These include the reduction or absence of courtship behavior, the occurrence of forced copulations, and a notable increase in injury rates among hens. Reproductive challenges observed in meat-type breeder flocks, in contrast to those in layer lines, appear to stem from selection practices that have overlooked traits related to mating behavior. Environmental and managerial conditions, including photoperiod manipulation, stocking density, nutritional imbalances, and the use of mixed-sex rearing systems, are also identified as contributing factors to the expression of sexual aggression. Furthermore, recent genetic findings indicate a potential link between inherited neurobehavioral factors and aggressive behavior, with the SORCS2 gene emerging as a relevant candidate. Based on these insights, the review emphasizes the importance of considering behavioral parameters in breeding programs in order to reconcile productivity objectives with animal welfare standards. Future research may benefit from a more integrative approach that combines behavioral, physiological, and genomic data to better understand and address the multifactorial nature of sexual aggression in poultry systems. Full article

Plaque erosion (PE) is now recognized as a common and clinically significant cause of acute coronary syndromes (ACSs), accounting for up to 40% of cases. Unlike plaque rupture (PR), PE involves superficial endothelial loss over an intact fibrous cap and occurs in a low-inflammatory setting, typically affecting younger patients, women, and smokers with fewer traditional risk factors. The growing recognition of PE has been driven by high-resolution intracoronary imaging, particularly optical coherence tomography (OCT), which enables in vivo differentiation from PR. Identifying PE with OCT has opened the door to personalized treatment strategies, as explored in recent trials evaluating the safety of deferring stent implantation in selected cases in favor of intensive medical therapy. Given its unexpectedly high prevalence, PE is now recognized as a common pathophysiological mechanism in ACS, rather than a rare exception. This growing awareness underscores the importance of its accurate identification through OCT in clinical practice. Early recognition and a deeper understanding of PE are essential steps toward the implementation of precision medicine, allowing clinicians to move beyond “one-size-fits-all” models toward “mechanism-based” therapeutic strategies. This narrative review aims to offer an integrated overview of PE, tracing its epidemiology, elucidating the molecular and pathophysiological mechanisms involved, outlining its clinical presentations, and placing particular emphasis on diagnostic strategies with OCT, while also discussing emerging therapeutic approaches and future directions for personalized cardiovascular care. Full article