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Retinopathy of prematurity (ROP) is a disorder of neonatal retinal vascularization. The incidence is increasing in developing countries like India in view of the rising numbers of preterm deliveries and improved neonatal care. Traditional modalities of treatment included cryotherapy and laser therapy, which were laborious and required special training. Hence, research is on way to find novel treatment modalities directed at various levels of pathogenesis for this blinding disease. We reviewed the published and unpublished literature on newer methods of ROP management. The pathogenesis of ROP has been studied with respect to the mediators of angiogenesis. Anti vascular endothelial growth factor (Anti-VEGF) therapy has been extensively studied and the studies have demonstrated its promising role early stages of ROP. The role of Insulin like growth factor (IGF), Granulocyte colony stimulating factor (GCSF), and June kinases (JNK) inhibitors are being studied by various researchers across the world. Gene therapy holds promise in the reversal of ROP changes. [ABSTRACT FROM AUTHOR]

Background: Many patients with chronic hepatitis C have not responded to therapy with pegylated interferon plus ribavirin.Objective: To evaluate use of peginterferon-alpha2a plus ribavirin to re-treat nonresponders to peginterferon-alpha2b plus ribavirin.Design: Randomized, parallel-group trial conducted between September 2003 and February 2007. Patients and researchers were not blinded to intervention assignment. Random assignment was centralized, computer-generated, and stratified by geographic region, hepatitis C virus (HCV) genotype, and histologic diagnosis.Setting: 106 international centers.Patients: 950 nonresponders to 12 or more weeks of therapy with peginterferon-alpha2b plus ribavirin.Intervention: Peginterferon-alpha2a, 360 microg/wk, for 12 weeks, then 180 microg/wk to complete 72 weeks (group A) or 48 weeks (group B), or peginterferon-alpha2a, 180 microg/wk for 72 weeks (group C) or 48 weeks (group D). All patients received ribavirin, 1000 or 1200 mg/d.Measurements: Sustained virologic response (SVR), defined as undetectable (<50 IU/mL) HCV RNA levels 24 weeks after the end of treatment.Results: The SVR rates in groups A (n = 317), B (n = 156), C (n = 156), and D (n = 313) were 16%, 7%, 14%, and 9%, respectively (relative risk [RR] for group A vs. group D [the primary comparison], 1.80 [95% CI, 1.17 to 2.77]; P = 0.006). Extended treatment duration increased SVR rates (16% for 72 weeks [groups A and C] vs. 8% for 48 weeks [groups B and D]; RR, 2.00 [CI, 1.32 to 3.02]; P < 0.001). Complete viral suppression (HCV RNA level <50 IU/mL)at week 12 was achieved in 21% of patients in groups A and B and 13% of those in groups C and D. Rates of SVR were 49% (77 of 157 patients) and 4% (32 of 719 patients) among those with and without complete viral suppression at week 12, respectively.Limitation: Nonresponders to peginterferon-alpha2a plus ribavirin were not evaluated.Conclusion: Re-treating nonresponders to therapy with peginterferon-alpha2b plus ribavirin for 72 weeks significantly increases SVR rates compared with re-treating them for 48 weeks. The overall SVR rate was low, but patients who are most likely to respond to re-treatment can be identified at week 12.Primary Funding Source: Roche. [ABSTRACT FROM AUTHOR]

This study presents a sustainability assessment of geothermal heating and cooling system of three buildings at the University of Illinois at Chicago - Grant, Lincoln, and Douglas Halls based upon the triple bottom line sustainability framework and presents a comparison between geothermal and conventional heating and cooling systems. Life cycle assessment (LCA) was performed to evaluate and quantify the environmental impacts for both geothermal and conventional systems. Similarly, economic impacts were evaluated by making a comparison between direct and indirect costs of both systems. Indirect costs were calculated using Stepwise 2006 incorporated in monetized LCA and compared that cost with social cost of carbon. Social impacts were quantified using Social Sustainability Evaluation Matrix (SSEM) which covers four major dimensions of society: social-individual, socio-institutional, socio-economic, and socio-environmental. An overall sustainability index for geothermal system and conventional system was calculated by evaluating environmental, economic, and social impacts using Integrated Value Model for Sustainability Assessment (MIVES) methodology. The results show that the geothermal heating and cooling system is more sustainable and environmentally friendly than the conventional system.

Background: Attempts to successfully regenerate lost alveolar bone have always been a clinician′s dream. Angular defects, at least, have a fairer chance, but the same cannot be said about horizontal bone loss. The purpose of the present study was to evaluate the prevalence of horizontal alveolar bone loss and vertical bone defects in periodontal patients; and later, to correlate it with the treatment modalities available in the literature for horizontal and vertical bone defects. Materials and Methods: The study was conducted in two parts. Part I was the radiographic evaluation of 150 orthopantomographs (OPGs) (of patients diagnosed with chronic periodontitis and seeking periodontal care), which were digitized and read using the AutoCAD 2006 software. All the periodontitis-affected teeth were categorized as teeth with vertical defects (if the defect angle was ≤45° and defect depth was ≥3 mm) or as having horizontal bone loss. Part II of the study comprised search of the literature on treatment modalities for horizontal and vertical bone loss in four selected periodontal journals. Results: Out of the 150 OPGs studied, 54 (36%) OPGs showed one or more vertical defects. Totally, 3,371 teeth were studied, out of which horizontal bone loss was found in 3,107 (92.2%) teeth, and vertical defects were found only in 264 (7.8%) of the teeth, which was statistically significant (PConclusion: Horizontal bone loss is more prevalent than vertical bone loss but has been sidelined by researchers as very few papers have been published on the subject of regenerative treatment modalities for this type of bone loss. This study should be an impetus for greater attention to an otherwise ubiquitous periodontal challenge.

Background: The precise role of dentifrice in plaque removal has been debatable. While a considerable volume of literature attributes several beneficial properties and glorifies the role of dentifrice, a small body of researchers questions its efficacy. Lingering doubts are emerging about the plaque removal efficacy of toothpastes and probably a time has come to reassess its role in plaque removal. Aim: The present study is used to evaluate the plaque removal efficacy of dentifrice alone during the manual brushing of teeth. Materials and Methods: In a double blinded 2 Χ 2 crossover study design, 42 subjects had brushed randomly with or without dentifrice under supervision, with a standard dentifrice and toothbrush, after 48 hours of plaque accumulation, for two minutes. Results: Plaque reduction with dentifrice was 57.35% and without dentifrice was 66.19%. This 9% difference was statistically significant ( P ≤ 0.001). Conclusion: Dentifrice use does not enhance plaque removal when used in conjunction with a toothbrush, and instead, may marginally lessen the brushing effect. The role of a toothbrush appears to be more crucial in the maintenance of oral hygiene.

Background: Treatment with peginterferon alfa-2a alone produces significantly higher sustained virologic responses than treatment with interferon alfa-2a alone in patients with chronic hepatitis C virus (HCV) infection. We compared the efficacy and safety of peginterferon alfa-2a plus ribavirin, interferon alfa-2b plus ribavirin, and peginterferon alfa-2a alone in the initial treatment of chronic hepatitis C.Methods: A total of 1121 patients were randomly assigned to treatment and received at least one dose of study medication, consisting of 180 microg of peginterferon alfa-2a once weekly plus daily ribavirin (1000 or 1200 mg, depending on body weight), weekly peginterferon alfa-2a plus daily placebo, or 3 million units of interferon alfa-2b thrice weekly plus daily ribavirin for 48 weeks.Results: A significantly higher proportion of patients who received peginterferon alfa-2a plus ribavirin had a sustained virologic response (defined as the absence of detectable HCV RNA 24 weeks after cessation of therapy) than of patients who received interferon alfa-2b plus ribavirin (56 percent vs. 44 percent, P<0.001) or peginterferon alfa-2a alone (56 percent vs. 29 percent, P<0.001). The proportions of patients with HCV genotype 1 who had sustained virologic responses were 46 percent, 36 percent, and 21 percent, respectively, for the three regimens. Among patients with HCV genotype 1 and high base-line levels of HCV RNA, the proportions of those with sustained virologic responses were 41 percent, 33 percent, and 13 percent, respectively. The overall safety profiles of the three treatment regimens were similar; the incidence of influenza-like symptoms and depression was lower in the groups receiving peginterferon alfa-2a than in the group receiving interferon alfa-2b plus ribavirin.Conclusions: In patients with chronic hepatitis C, once-weekly peginterferon alfa-2a plus ribavirin was tolerated as well as interferon alfa-2b plus ribavirin and produced significant improvements in the rate of sustained virologic response, as compared with interferon alfa-2b plus ribavirin or peginterferon alfa-2a alone. [ABSTRACT FROM AUTHOR]

This study introduces a silver-catalyzed method for the efficient and regioselective synthesis of pyrano heterocycles, utilizing readily available alcohols and water as nucleophiles. The method demonstrates high efficiency, delivering excellent yields and selectivity, and is scalable to gram quantities while maintaining broad functional group tolerance. Notably, the synthesized pyrano[3,4- c ]quinolines were successfully transformed into diverse samoquasine A derivatives, underscoring the method's applicability in natural product synthesis. This work represents a significant advancement in pyrano heterocycle synthesis, offering a practical route to valuable compounds with potential applications in pharmaceutical and chemical research.

Background: The accuracy of current criteria for ruling out large oesophageal varices (LEV) and other endoscopic lesions of portal hypertension (PH) may be compromised by obesity and MASLD/MASH., Aims: In the US multicentre SHUNT-V study, we evaluated the disease severity index (DSI) for detecting LEV and other lesions of PH at endoscopy., Methods: Subjects were adults with compensated cirrhosis scheduled for endoscopy to screen for varices. DSI was calculated from clearances of labelled cholates after oral and intravenous administration. DSI ≤ 18.3 was evaluated as a cut-off for ruling out LEV with acceptance criteria of negative likelihood ratio < 0.52 and sensitivity > 85%., Results: SHUNT-V enrolled 306 subjects; 275 had both DSI and endoscopy, and 238 had Child-Pugh A cirrhosis (52.1% MASLD/MASH, 25.2% chronic hepatitis C and 15.6% alcoholic liver disease; 87% were overweight, 64% were obese and 54% had diabetes). AUROCs for DSI ranged from 0.81 to 0.82 for LEV and 0.79 to 0.80 for all significant PH lesions. DSI 18.3 had sensitivity 96.3%-100% for LEV and 97.3%-100% for all significant PH lesions. If DSI ≤ 18.3 were used as the sole determinant to defer EGD, 27%-35% of EGDs could have been avoided with 0%-3.7% of LEV and 0%-2.7% of all significant PH lesions missed., Conclusions: HepQuant DSI predicts the likelihood of LEV and significant PH lesions across a spectrum of patient characteristics and disease aetiologies. DSI, based on liver function and portal-systemic shunting, can aid in the decision to defer endoscopy for varices in patients with Child-Pugh A cirrhosis., Trial Registration: The SHUNT-V study was registered at ClinicalTrials.gov (NCT03583996)., (© 2024 The Author(s). Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background and Aims: Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis., Methods: Molecular (Prognostic Liver Secretome signature with alpha-fetoprotein) and clinical (aMAP score) variable-based scores were integrated to develop PAaM, which was subsequently validated in two phase 3 biomarker validation studies: the statewide Texas HCC Consortium (THCCC) and nationwide HCC Early Detection Strategy (HEDS) prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation (PRoBE) design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events., Results: Of 2,156 cirrhosis patients in THCCC, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared to low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios (sHRs) for incident HCC of 7.51 (95% confidence interval [CI], 4.42-12.8) and 4.20 (95%CI, 2.52-7.01), respectively. Of 1,328 cirrhosis patients in HEDS, PAaM identified 201 (15%) high-risk, 540 (41%) intermediate-risk, and 587 (44%) low-risk patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate risk groups were associated with sHRs for incident HCC of 6.54 (95%CI, 3.85-11.1) and 1.77 (95%CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease (MASLD) and cured hepatitis C infection., Conclusion: PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Acute liver failure (ALF) and acute-on-chronic liver (ACLF) are distinct phenotypes of liver failure and, thus, need to be compared and contrasted for appropriate management. There has been a significant improvement in the outcomes of these patients undergoing liver transplantation (LT). Survival post-LT for ALF and ACLF ranges between 90% and 95% and 80% and 90% at 1 year, futility criteria have been described in both ALF and ACLF where organ failures define survival. Plasma exchange and continuous renal replacement therapy may serve as bridging therapies. Identifying the futility of LT is as necessary as the utility of LT in patients with ALF and ACLF. The role of regenerative therapies such as granulocyte colony-stimulating factors in ACLF and hepatocyte and xenotransplantation in both conditions remains uncertain. Measures to increase the donor pool through increasing deceased donor transplants in Asian countries, living donations in Western countries, auxiliary liver transplants, and ABO-incompatible liver transplants are necessary to improve the survival of these patients. In this review, we discuss the similarities and differences in clinical characteristics and the timing and outcomes of LT for ALF and ACLF, briefly highlighting the role of bridging therapies and providing an overview of recent advances in the management of ALF and ACLF., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose: Exposomes are critical drivers of carcinogenesis. However, how they modulate tumor behavior remains unclear. Extensive clinical data link cigarette smoke as a key exposome that promotes aggressive tumors, higher rates of metastasis, reduced response to chemoradiotherapy, and suppressed anti-tumor immunity. We sought to determine whether smoke itself can modulate aggressive tumor behavior in head and neck squamous cell carcinoma (HNSCC) through reprogramming the cellular reductive state., Experimental Design: Using established human and murine HNSCC cell lines and syngeneic mouse models, we utilized conventional western blotting, steady state and flux metabolomics, RNA sequencing, quantitative proteomics and flow cytometry to analyze the impact of smoke exposure on HNSCC tumor biology., Results: Cigarette smoke persistently activated Nrf2 target genes essential for maintenance of the cellular reductive state and survival under conditions of increased oxidative stress in HNSCC regardless of HPV status. In contrast to e-cigarette vapor, conventional cigarette smoke mobilizes cellular metabolism toward oxidative stress adaptation, resulting in development of cross-resistance to cisplatin. In parallel, smoke exposure modulates both expression of PDL1 and the secretory phenotype of HNSCC cells through activation of NF-κB resulting in an altered tumor immune microenvironment (TIME) in syngeneic mouse models and altered PBMC differentiation that includes downregulated expression of antigen presentation and costimulatory genes in myeloid cells., Conclusion: Cigarette smoke exposome is a potent activator of the Nrf2 pathway and is a likely primary trigger for the tripartite phenotype of aggressive HNSCC consisting of: 1) reduced chemotherapy sensitivity, 2) enhanced metastatic potential and 3) suppressed anti-tumor immunity., Statement of Significance: The smoke exposome drives aggressive tumor behavior, treatment resistance and suppressed immunity through coordinated metabolic reprogramming. Successfully targeting this adaptation is critical to improving survival in smokers with head and neck cancer.

Background and Objectives: This study aimed to investigate the effect of zinc phosphate (ZnP) cement, glass ionomer cement (GIC), and nano-integrated bio-ceramic (NIB) cement on mineralization when placed in contact with bone tissue-forming cells. Materials and Methods: ZnP cement, GIC, and NIB cement were divided into direct and indirect groups. A total of 72 cement pellets (24 pellets of each test sample) of 3 × 1 mm (width × height) were prepared using polytetrafluoroethylene molds. A total of 3 sample groups were demarcated using 96- cell well culture plates. In the control group, 24 wells were filled with mineralized osteoblasts and 1 µL of gingival crevicular fluid (GCF). In test group 1, to show a direct effect, 36 samples were plated with mineralized osteoblasts and 1 µL GCF for 24 h; the cells were directly exposed to cement pellets. A total of 36 samples were immersed in GCF for 24 h; later the supernatant was transferred to the mineralized osteoblasts to demonstrate an indirect effect in test group 2. To assess the mineralization, osteoblasts were stained with alizarin red and later observed under an inverted phase-contrast microscope. Data were analyzed using the statistical package for social sciences. An independent t-test compared the direct and indirect effects of the ZnP cement, GIC, NIB cement, and control groups on the mineralization of osteoblasts derived from hDPCs. Results: A statistically significant difference was observed between the ZnP cement, GIC, and NIB cement groups ( p < 0.05). ZnP cement exhibited a moderate, NIB cement the least harmful effect, and GIC showed the most harmful effect on the mineralization of osteoblast cells. Conclusions: The biocompatibility of dental luting cements is an important aspect that clinicians should consider during their selection. Nano-integrated bio-ceramic cement showed the least negative effect on the mineralization of osteoblast cells which is beneficial for the cementation of cement-retained implant prostheses. However, further studies are needed to evaluate osteoblast and osteoclast activity in vivo.

Leprosy in children is considered as an indicator of active disease transmission in the community. We report about a seven-year-old male from Telangana, India, with anesthetic skin lesions and familial leprosy history. Clinical examination revealed multiple, dry, scaly, hypopigmented, well-defined, raised punched out anesthetic skin lesions all over the body with both ulnar nerves enlarged. On clinical and laboratory examination, the child was diagnosed with borderline-borderline (BB), multibacillary (MB) leprosy, and Type-1 reaction. The child received a weight-adjusted MB multidrug therapy regimen and corticosteroids for type-1 reactions. This case emphasizes the need for contact tracing and screening for early diagnosis of child leprosy to prevent complications like leprosy reactions which are the risk factors for disability., (Copyright© 2024 The Authors. Published by Tehran University of Medical Sciences.)

Hepatorenal syndrome-acute kidney injury (HRS-AKI) is associated with significant morbidity and mortality. While liver transplantation is the definitive treatment, continuous terlipressin infusion for HRS-AKI may provide benefit and, as such, was assessed in a population composed of candidates for liver transplant (LT). Fifty hospitalized LT-eligible patients with HRS-AKI received a single bolus followed by continuous terlipressin infusion. Acute-on-chronic liver failure grade 3, serum creatinine (SCr)>5.0 mg/dL, or Model for End-Stage Liver Disease (MELD) ≥35 were exclusions. Fifty hospitalized patients who received midodrine and octreotide or norepinephrine for HRS-AKI served as a historical comparator cohort. Complete response (CR) was defined as a ≥30% decrease in SCr with end-of-treatment (EOT) SCr≤1.5, partial response as a ≥30% decrease in SCr with EOT SCr>1.5, and nonresponse as a <30% decrease in SCr. CR rate was significantly higher in the terlipressin cohort compared to the historical cohort (64% vs. 16%, p <0.001). Survival, while numerically higher in those who received terlipressin, was statistically similar (D30: 94% vs. 82%, p =0.12; D90: 78% vs. 68%, p =0.37). Renal replacement therapy (RRT) was more common among terlipressin NR than CR and PR (70% vs. 3% vs. 13%, p < 0.001). EOT MELD and SCr were significantly lower within terlipressin cohort (MELD: 19 vs. 25, SCr: 1.4 vs. 2.1 mg/dL, p <0.001). Sixteen of 40 terlipressin-treated patients received LT-alone (terlipressin CR in 10/16). One patient on terlipressin had a hypoxic respiratory failure that responded to diuretics; one possibly had drug-related rash. With continuous terlipressin infusion, a CR rate of 64% was observed with a favorable safety profile. Terlipressin use was associated with lower EOT MELD and SCr than the historical midodrine and octreotide/norepinephrine cohort; LT-alone was accomplished in a high proportion of complete terlipressin responders., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Posttransplant diabetes mellitus (PTDM) is a prevalent complication of liver transplantation and is associated with cardiometabolic complications. We studied the consequences of genetic effects of liver donors and recipients on PTDM outcomes, focusing on the diverse genetic pathways related to insulin that play a role in the development of PTDM. One thousand one hundred fifteen liver transplant recipients without a pretransplant diagnosis of type 2 diabetes mellitus (T2D) and their paired donors recruited from 2 transplant centers had polygenic risk scores (PRS) for T2D, insulin secretion, and insulin sensitivity calculated. Among recipients in the highest T2D-PRS quintile, donor T2D-PRS did not contribute significantly to PTDM. However, in recipients with the lowest T2D genetic risk, donor livers with the highest T2D-PRS contributed to the development of PTDM (OR [95% CI] = 3.79 [1.10-13.1], P = .035). Recipient risk was linked to factors associated with insulin secretion (OR [95% CI] = 0.85 [0.74-0.98], P = .02), while donor livers contributed to PTDM via gene pathways involved in insulin sensitivity (OR [95% CI] = 0.86 [0.75-0.99], P = .03). Recipient and donor PRS independently and collectively serve as predictors of PTDM onset. The genetically influenced biological pathways in recipients primarily pertain to insulin secretion, whereas the genetic makeup of donors exerts an influence on insulin sensitivity., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2024 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Health system resilience is a prerequisite for effectively managing cataclysmic events adversely affecting health outcomes. The COVID-19 pandemic reasserted the importance of having resilient health systems and called for a relook at the existing framework that measures health system resilience. Mixed methods were used in this study. The review started with the measurement of health systems resilience and its context. Ebola epidemic triggered the importance, hence our search focused on published literature from 2014 to 2021. Based on the review, a semi-structured tool was developed for key in-depth interviews of seven experts from different countries. The frameworks focused on climate change, disaster management, health systems, city-specific resilience, and e-resilience were reviewed. In-depth interviews highlighted that resilient health systems need to engage the private sector, priority areas like leadership and governance, health resources, and a unified agenda for global collaboration. From experts' point of view, the inherent nature of health systems to respond to shock was clearly defined as the resilient health system. Health systems resilience definition needs to be defined, based on which assessment indicators will be identified. Indicators need to evolve continuously and be able to measure resilience at sub-national, national, regional, and global levels., Competing Interests: The authors have declared that no competing interest exist., (Copyright: © 2024 Dsouza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In tumors with WT p53, alternate mechanisms of p53 inactivation are reported. Here, we have identified a long noncoding RNA, PITAR ( p 53 I nactivating T RIM28 A ssociated R NA), as an inhibitor of p53. PITAR is an oncogenic Cancer/testis lncRNA and is highly expressed in glioblastoma (GBM) and glioma stem-like cells (GSC). We establish that TRIM28 mRNA, which encodes a p53-specific E3 ubiquitin ligase, is a direct target of PITAR. PITAR interaction with TRIM28 RNA stabilized TRIM28 mRNA, which resulted in increased TRIM28 protein levels and reduced p53 steady-state levels due to enhanced p53 ubiquitination. DNA damage activated PITAR , in addition to p53, in a p53-independent manner, thus creating an incoherent feedforward loop to inhibit the DNA damage response by p53. While PITAR silencing inhibited the growth of WT p53 containing GSCs in vitro and reduced glioma tumor growth in vivo, its overexpression enhanced the tumor growth in a TRIM28 -dependent manner and promoted resistance to Temozolomide. Thus, we establish an alternate way of p53 inactivation by PITAR , which maintains low p53 levels in normal cells and attenuates the DNA damage response by p53. Finally, we propose PITAR as a potential GBM therapeutic target., Competing Interests: SJ, MM, SM, BG, KP, LK, NJ, AC, VS, CK No competing interests declared, KS Reviewing editor, eLife, (© 2023, Jana et al.)

Background & Aims: Better surveillance tests for hepatocellular carcinoma (HCC) are needed. The GALAD score (gender, age, α-fetoprotein [AFP] L3, AFP, and des carboxyprothrombin) has been shown to have excellent sensitivity and specificity for HCC in phase 2 studies. We performed a phase 3 biomarker validation study to compare GALAD with AFP in detecting HCC., Methods: This is a prospective study of patients with cirrhosis enrolled at 7 centers. Surveillance for HCC was performed every 6 months at each site, and HCC diagnosis was confirmed per American Association for the Study of Liver Diseases guidelines. Blood for biomarker research was obtained at each follow-up visit and stored in a biorepository. Measurements of AFP, AFP-L3, and des-γ carboxyprothrombin) were performed in a FujiFilm laboratory by staff blinded to clinical data. The performance of GALAD in detecting HCC was retrospectively evaluated within 12 months before the clinical diagnosis. All analyses were conducted by an unblinded statistician in the EDRN data management and coordinating center., Results: A total of 1,558 patients with cirrhosis were enrolled and followed for a median of 2.2 years. A total of 109 patients developed HCC (76 very early or early stage), with an annual incident rate of 2.4%. The areas under the curve for AFP and GALAD within 12 months before HCC were 0.66 and 0.78 (P < .001), respectively. Using a cutoff for GALAD of -1.36, the specificity was 82%, and the sensitivity at 12 months before HCC diagnosis was 62%. For comparison, performance of AFP at 82% specificity showed 41% sensitivity at 12 months before HCC diagnosis (P = .001)., Conclusions: GALAD score, compared to AFP, improves the detection of HCC within 12 months before the actual diagnosis., (Copyright © 2024 AGA Institute. All rights reserved.)

Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy.

Maintaining genetic diversity in cultured shellfish can be challenging due to high variance in individual reproductive success, founder effects, and rapid genetic drift, but is important to retain adaptive potential and avoid inbreeding depression. To support broodstock management and selective breeding in cultured Pacific oysters (Crassostrea (Magallana) gigas), we developed an amplicon panel targeting 592 genomic regions and SNP variants with an average of 50 amplicons per chromosome. Target SNPs were selected based on elevated observed heterozygosity or differentiation in Pacific oyster populations in British Columbia, Canada. The use of the panel for parentage applications was evaluated using multiple generations of oysters from a breeding program on Vancouver Island, Canada (n = 181) and families selected for Ostreid herpesvirus-1 resistance from the Molluscan Broodstock Program in Oregon, USA (n = 136). Population characterization was evaluated using wild, naturalized, farmed, or hatchery oysters sampled throughout the Northern Hemisphere (n = 189). Technical replicates showed high genotype concordance (97.5%; n = 68 replicates). Parentage analysis found suspected pedigree and sample handling errors, demonstrating the panel's value for quality control in breeding programs. Suspected null alleles were identified and found to be largely population dependent, suggesting population-specific variation impacting target amplification. Null alleles were identified using existing data without the need for pedigree information, and once they were removed, assignment rates increased to 93.0 and 86.0% of possible assignments in the two breeding program datasets. A pipeline for analyzing the amplicon sequence data from sequencer output, amplitools, is also provided., Competing Interests: Conflicts of interest B.J.G.S. is affiliated with Sutherland Bioinformatics. The author has no competing financial interests to declare. Some authors affiliated with ThermoFisher Scientific have potential conflicts considering that the AgriSeq Targeted Genotyping by Sequencing solutions and associated Oligo panels that were designed and validated in the study are offered by ThermoFisher Scientific. However, the selection of markers, and data analysis was primarily conducted by other authors. The authors declare that the research was conducted in a scientific manner without any commercial considerations that could be construed as potential conflict of interest and further declare no other conflicts of interest. The other authors declare no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Genetics Society of America.)

Cardiovascular disease (CVD) and cardiometabolic risk (CMR) are highly prevalent globally. The interplay between CVD/CMR and COVID-19 morbidity and mortality has been intensely studied over the last three years and has yielded some important discoveries and warnings for public health. Despite many advances in cardiovascular medicine, CVD continues to be the global leading cause of death. Much of this disease burden results from high CMR imposed by behaviors centered around poor nutrition related to lifestyle choices and systemic constraints. Increased CVD/CMR contributed to the COVID-19 pandemic's unprecedented wave of disability and death, and the current state of cardiovascular health been equated to a "Population Code Blue." There is an urgent and unmet need to reorient our priorities towards health promotion and disease prevention. This manuscript will review how nutrition and lifestyle affect outcomes in COVID-19 and how some interventions and healthy lifestyle choices can markedly reduce disease burden, morbidity, and mortality., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024 The Author(s).)

Colorectal cancer (CRC) is the main driver of fatality and the 3rd most often determined malignancy. Despite advances in detection and therapy, colorectal cancer (CRC) endures as the largest driver of cancer-related morbidity, and mortality. Modern habits and dietary negligence might be one of the reasons that have enhanced cancer prevalence. Thus, changes in Dietary habits will have a better impact, and help in finding a better cure for CRC. Initially, CRC was explored as a genetic event and currently, the research is focused on the epigenetic modifications of chromatin and microRNA (miRNA) in CRC cells. Natural products such as Curcumin, Resveratrol, Flavonoids, and Ellagitannins are been explored as compounds from the perspective of genetic, epigenetic, and miRNA modifications which will have future therapeutic aspects. Also, the extracts of these key players and their analogs will intervene the signaling pathway activation that involves in cancer propagation, apoptosis, cell cycle arrest, and epigenetic and miRNA modifications. Modulations of these miRNAs, and modification globally might have impact on CRC progression, and cancer tumor cell sensitivity., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Humans have profoundly altered phosphorus (P) cycling across scales. Agriculturally driven changes (e.g., excessive P-fertilization and manure addition), in particular, have resulted in pronounced P accumulations in soils, often known as "soil legacy P." These legacy P reserves serve as persistent and long-term nonpoint sources, inducing downstream eutrophication and ecosystem services degradation. While there is considerable scientific and policy interest in legacy P, its fine-scale spatial heterogeneity, underlying drivers, and scales of variance remain unclear. Here we present an extensive field sampling (150-m interval grid) and analysis of 1438 surface soils (0-15 cm) in 2020 for two typical subtropical grassland types managed for livestock production: Intensively managed (IM) and Semi-natural (SN) pastures. We ask the following questions: (1) What is the spatial variability, and are there hotspots of soil legacy P? (2) Does soil legacy P vary primarily within pastures, among pastures, or between pasture types? (3) How does soil legacy P relate to pasture management intensity, soil and geographic characteristics? and (4) What is the relationship between soil legacy P and aboveground plant tissue P concentration? Our results showed that three measurements of soil legacy P (total P, Mehlich-1, and Mehlich-3 extractable P representing labile P pools) varied substantially across the landscape. Spatial autoregressive models revealed that soil organic matter, pH, available Fe and Al, elevation, and pasture management intensity were crucial predictors for spatial patterns of soil P, although models were more reliable for predicting total P (68.9%) than labile P. Our analysis further demonstrated that total variance in soil legacy P was greater in IM than SN pastures, and intensified pasture management rescaled spatial patterns of soil legacy P. In particular, after controlling for sample size, soil P was extremely variable at small scales, with variance diminished as spatial scale increased. Our results suggest that broad pasture- or farm-level best management practices may be limited and less efficient, especially for more IM pastures. Rather, management to curtail soil legacy P and mitigate P loading and losses should be implemented at fine scales designed to target spatially distinct P hotspots across the landscape., (© 2024 The Ecological Society of America.)

Studies on the bioactive phytochemicals found in traditional medicinal plants are growing. This study focuses on Rauvolfia tetraphylla L. and its unique bioactive chemical composition. Previous research has demonstrated the plant's antimicrobial properties due to this composition. In this study, however, we also aim to investigate the antiviral properties of the plant. Rauvolfia tetraphylla L. has long been used for medicinal purposes. It is primarily located in Mexico, Central America, the West Indies, and northern South America. Along with checking out its in-silico SARS-CoV-2 activity, current work also evaluates the leaf extracts qualitative phytochemical, antioxidant, and cytotoxicity properties. While several conventional procedures were employed in the bio active compounds and phytochemical study that identified multiple phytochemicals, compounds derived from plants will be the most effective substitution with unfavorable side effects. The focus of this work is on in silico analysis, which determines the experimental plants activity against SARS-CoV-2 using molecular docking and pharmacokinetic analysis. We identified 20 phytochemical compounds from the GC-MS data of the plant, out of these 12 compounds failed to meet ADMET properties and the remaining 8 compounds passed TOPKAT Ames Mutagenicity. These compounds were docked against one important protein 3CLpro (PDB ID: 7DPV) that is implicated in the development of SARS-CoV-2. Docking studies have demonstrated binding results with maximum score and three compounds showed promising results. The results of this study highlighted the potential efficacy of (E,E,E,E,E,E)-()-2,6,10,15,19,23-hexamethyltetracosa-1,6,10,14,18,22-hexaen-3-ol, α-Tocospiro A, and α-Tocopherol. Furthermore, a thorough examination of the in-silico data indicates that the leaf has the potential to be a powerful source of medication and an efficient therapy in the future., Competing Interests: Compliance with Ethical Standards Conflict of Interest The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

HIV-1 envelope glycoproteins (Envs) of most primary HIV-1 strains exist in closed conformation and infrequently sample open states, limiting access to internal epitopes. Thus, immunogen design aims to mimic the closed Env conformation as preferred target for eliciting broadly neutralizing antibodies (bnAbs). Here we identify incompletely closed Env conformations of 6 out of 13 transmitted/founder (T/F) strains that are sensitive to antibodies that recognize internal epitopes typically exposed on open Envs. A 3.6 Å cryo-electron microscopy structure of unliganded, incompletely closed T/F Envs (1059-SOSIP) reveals protomer motion that increased sampling of states with incompletely closed trimer apex. We reconstruct de novo the post-transmission evolutionary pathway of a second T/F. Evolved viruses exhibit increased Env resistance to cold, soluble CD4 and 19b, all of which correlate with closing of the adapted Env trimer. Lastly, we show that the ultra-broad N6 bnAb efficiently recognizes different Env conformations and exhibits improved antiviral breadth against VRC01-resistant Envs isolated during the first-in-humans antibody-mediated-prevention trial., (© 2024. The Author(s).)

Background & Aims: Chronic hepatitis C-related decompensated cirrhosis is associated with lower sustained virologic response (SVR)-12 rates and variable regression of disease severity after direct-acting antiviral agents. We assessed rates of SVR-12, recompensation (Baveno VII criteria), and survival in such patients., Methods: Between July 2018 and July 2023, patients with decompensated chronic hepatitis C-related cirrhosis after direct-acting antiviral agents treatment were evaluated for SVR-12 and then had 6-monthly follow-up., Results: Of 6516 patients with cirrhosis, 1152 with decompensated cirrhosis (age 53.2 ± 11.5 years; 63% men; Model for End-stage Liver Disease-Sodium [MELD-Na]: 16.5 ± 4.6; 87% genotype 3) were enrolled. SVR-12 was 81.8% after 1 course; ultimately SVR was 90.8% after additional treatment. Decompensation events included ascites (1098; 95.3%), hepatic encephalopathy (191; 16.6%), and variceal bleeding (284; 24.7%). Ascites resolved in 86% (diuretic withdrawal achieved in 24% patients). Recompensation occurred in 284 (24.7%) at a median time of 16.5 (interquartile range, 14.5-20.5) months. On multivariable Cox proportional hazards analysis, low bilirubin (adjusted hazard ratio [aHR], 0.6; 95% confidence interval [CI], 0.5-0.8; P < 0.001), international normalized ratio (aHR, 0.2; 95% CI, 0.1-0.3; P < 0.001), absence of large esophageal varices (aHR, 0.4; 95% CI, 0.2-0.9; P = 0.048), or gastric varices (aHR, 0.5; 95% CI, 0.3-0.7; P = 0.022) predicted recompensation. Portal hypertension progressed in 158 (13.7%) patients, with rebleed in 4%. Prior decompensation with variceal bleeding (aHR, 1.6; 95% CI, 1.2-2.8; P = 0.042), and presence of large varices (aHR, 2.9; 95% CI, 1.3-6.5; P < 0.001) were associated with portal hypertension progression. Further decompensation was seen in 221 (19%); 145 patients died and 6 underwent liver transplantation. A decrease in MELDNa of ≥3 was seen in 409 (35.5%) and a final MELDNa score of <10 was seen in 335 (29%), but 2.9% developed hepatocellular carcinoma despite SVR-12., Conclusions: SVR-12 in hepatitis C virus-related decompensated cirrhosis in a predominant genotype 3 population led to recompensation in 24.7% of patients over a follow-up of 4 years in a public health setting. Despite SVR-12, new hepatic decompensation evolved in 19% and hepatocellular carcinoma developed in 2.9% of patients. (ClinicalTrials.gov, Number: NCT03488485)., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)