Identification and Molecular Docking Analysis of Angiotensin-Converting Enzyme Inhibitors from Finger Millet (Eleusine coracana).

Hypertension remains a significant global health concern, contributing significantly to cardiovascular diseases and mortality rates. The inhibition of angiotensin-converting enzyme (ACE) plays a crucial role in alleviating high blood pressure. We investigated the potential of finger millets (Eleusine coracana) as a natural remedy for hypertension by isolating and characterizing its ACE-inhibitory compound. First, we evaluated the ACE-inhibitory activity of the finger millet ethanol extract and subsequently proceeded with solvent fractionation. Among the solvent fractions, the ethyl acetate fraction exhibited the highest ACE inhibitory activity and was further fractionated. Using preparative high-performance liquid chromatography, the ethyl acetate fraction was separated into four subfractions, with fraction 2 (F2) exhibiting the highest ACE inhibitory activity. Subsequent 1 H-nuclear magnetic resonance (NMR) and 13 C-NMR analyses confirmed that the isolated compound from F2 was catechin. Furthermore, molecular docking studies indicated that catechin has the potential to act as an ACE inhibitor. These findings suggest that finger millets, particularly as a source of catechin, have the potential to be used as a natural antihypertensive.

Evaluating the Efficiency of Black Soldier Fly (Hermetia illucens) Larvae in Converting Mackerel Head Waste into Valuable Resources.

The seafood processing industry generates significant waste, including mackerel heads (MH), constituting 20-32% of total waste. This study explored the potential of utilizing MH as a feed source for black soldier fly larvae (BSF larvae). BSF larvae are known for their ability to efficiently convert organic materials into nutrient-rich biomass. Five concentrations of MH (0, 10, 20, 30, 40, and 50% in chicken feed) were fed to BSF larvae for eight days. After harvesting, their growth, MH conversion efficiency, nutritional content, and heavy metals reduction potential were measured. BSF larvae showed optimal growth when fed with a feed containing 20% MH, resulting in a 14.36-fold increase in weight compared to the control group, as determined by the Fisher's Least Significant Difference Test. BSF larvae maintained a survival rate of 99.33%. With the lowest feed conversion ratio (FCR) of 2.09 at 20% MH, feed efficiency was improved by up to 65.15%, and feed reduction up to 73.53%. MH enhanced lipid and protein content in BSF larvae. Furthermore, BSF larvae in this study showed higher polyunsaturated fatty acids (PUFA), including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), as well as other amino acids which are required for breeding animals. The current study highlights the potential of MH as a feed source for BSF larvae, improving nutritional biomass. It also suggests BSF larvae as an eco-friendly option for handling seafood processing waste and as an alternative feed source for animals.

Comparison of Functional Outcomes after Anterior Cruciate Ligament Reconstruction with Meniscal Repair for Unstable versus Stable Meniscal Tears.

This study aimed to compare functional outcomes including knee muscle strength in the quadriceps and hamstrings, and proprioception, assessed through dynamic postural stability (overall stability index [OSI]) and self-reported outcomes in the operated and non-operated knees between anterior cruciate ligament reconstruction (ACLR) with meniscal repair for unstable (root and radial tears) and stable (longitudinal, horizontal, and bucket handle tears) meniscal tears. A total of 76 patients were randomly selected (41 with ACLR with meniscal repair for unstable meniscal tears and 35 with ACLR with meniscal repair for stable meniscal tears) at three different time points (preoperative, 6 months, and 12 months). Repeated measures analysis of variance was used to investigate the differences in outcomes for between-subject and within-subject factors. In the operated knees, there were no significant differences for functional outcomes between the two groups (all p > 0.05). In the non-operated knees, a significant difference was observed for the OSI between the two groups, which was significantly higher in ACLR with meniscal repair for unstable meniscal tears than for stable meniscal tears at 6 months (p < 0.001). Multiple linear regression analysis showed that age (p = 0.027), preoperative OSI in the operated knees (p = 0.005), and postoperative OSI in the operated knees at 6 months (p = 0.002) were significant and independent predictors for OSI in the non-operated knees at 6 months postoperatively. Therefore, while no differences were observed in functional outcomes between the two groups in the operated knees, dynamic postural stability was poorer at 6 months postoperatively in the non-operated knees of patients with ACLR with meniscal repair for unstable meniscal tears. Furthermore, a significant correlation was observed between preoperative/postoperative dynamic postural stability in the operated knees and postoperative dynamic postural stability in the non-operated knees. Hence, we recommend incorporating balance exercises for both knees in post-surgical rehabilitation, particularly for patients with unstable meniscal tears.

Continuous TNF-α exposure in mammary epithelial cells promotes cancer phenotype acquisition via EGFR/TNFR2 activation.

Tumor necrosis factor alpha (TNF-α), an abundant inflammatory cytokine in the tumor microenvironment (TME), is linked to breast cancer growth and metastasis. In this study, we established MCF10A cell lines incubated with TNF-α to investigate the effects of continuous TNF-α exposure on the phenotypic change of normal mammary epithelial cells. The established MCF10A-LE cell line, through long-term exposure to TNF-α, displayed cancer-like features, including increased proliferation, migration, and sustained survival signaling even in the absence of TNF-α stimulation. Unlike the short-term exposed cell line MCF10A-SE, MCF10A-LE exhibited elevated levels of epidermal growth factor receptor (EGFR) and subsequent TNF receptor 2 (TNFR2), and silencing of EGFR or TNFR2 suppressed the cancer-like phenotype of MCF10A-LE. Notably, we demonstrated that the elevated levels of NAD(P)H oxidase 4 (NOX4) and the resulting increase in reactive oxygen species (ROS) were associated with EGFR/TNFR2 elevation in MCF10A-LE. Furthermore, mammosphere-forming capacity and the expression of cancer stem cell (CSC) markers increased in MCF10A-LE. Silencing of EGFR reversed these effects, indicating the acquisition of CSC-like properties via EGFR signaling. In conclusion, our results reveal that continuous TNF-α exposure activates the EGFR/TNFR2 signaling pathway via the NOX4/ROS axis, promoting neoplastic changes in mammary epithelial cells within the inflammatory TME.

Intratumor transforming growth factor-ß signaling with extracellular matrix-related gene regulation marks chemotherapy-resistant gastric cancer.

Drug-tolerant persister (DTP) cells remain following chemotherapy and can cause cancer relapse. However, it is unclear when acquired resistance to chemotherapy emerges. Here, we compared the gene expression profiles of gastric cancer patient-derived cells (GC PDCs) and their respective xenograft tumors with different sensitivities to 5-fluorouracil (5-FU) by using immunodeficient female BALB/c-nu mice. RNA sequencing analysis of 5-FU-treated PDCs demonstrated that DNA replication/cell cycle-related genes were transiently induced in the earlier phase of DTP cell emergence, while extracellular matrix (ECM)-related genes were sustainably upregulated during long-term cell survival in 5-FU-resistant residual tumors. NicheNet analysis, which uncovers cell-cell signal interactions, indicated the transforming growth factor-ß (TGF-ß) pathway as the upstream regulator in response to 5-FU treatment. This induced ECM-related gene expression in the 5-FU-resistant tumor model. In the 5-FU-resistant residual tumors, there was a marked upregulation of cancer cell-derived TGF-ß1 expression and increased phosphorylation of SMAD3, a downstream regulator of the TGF-ß receptor. By contrast, these responses were not observed in a 5-FU-sensitive tumor model. We further found that TGF-ß-related upregulation of ECM genes was preferentially observed in non-responders to chemotherapy with 5-FU and/or oxaliplatin among 22 patient-derived xenograft tumors. These observations suggest that chemotherapy-induced activation of the TGF-ß1/SMAD3/ECM-related gene axis is a potential biomarker for the emergence of drug resistance in GCs.

Essential Guidelines for Manufacturing and Application of Organoids.

An organoid is a self-organized three-dimensional structure derived from stem cells that mimics the structure, cell composition, and functional characteristics of specific organs and tissues and is used for evaluating the safety and effectiveness of drugs and the toxicity of industrial chemicals. Organoid technology is a new methodology that could replace testing on animals testing and accelerate development of precision and regenerative medicine. However, large variations in production can occur between laboratories with low reproducibility of the production process and no internationally agreed standards for quality evaluation factors at endpoints. To overcome these barriers that hinder the regulatory acceptance and commercialization of organoids, Korea established the Organoid Standards Initiative in September 2023 with various stakeholders, including industry, academia, regulatory agencies, and standard development experts, through public and private partnerships. This developed general guidelines for organoid manufacturing and quality evaluation and for quality evaluation guidelines for organoid-specific manufacturing for the liver, intestines, and heart through extensive evidence analysis and consensus among experts. This report is based on the common standard guideline v1.0, which is a general organoid manufacturing and quality evaluation to promote the practical use of organoids. This guideline does not focus on specific organoids or specific contexts of use but provides guidance to organoid makers and users on materials, procedures, and essential quality assessment methods at end points that are essential for organoid production applicable at the current technology level.

The role of donor type and pre-transplant immunosuppression on outcomes of hematopoietic stem cell transplantation in children and young adults with severe aplastic anemia.

BACKGROUND: The goal of this study was to assess the effect of donor type and pre-transplant immunotherapy (IST) on outcomes of hematopoietic stem cell transplantation (HSCT) for children and young adults with severe aplastic anemia (SAA). METHODS: This retrospective, multi-center study included 52 SAA patients, treated in 5 pediatric transplant programs in Florida, who received HSCT between 2010 and 2020 as the first- or second-line treatment. RESULTS: The median age at HSCT for all 52 patients was 15 years (range 1-25). The 3-year overall survival (OS) by donor type were as follows: 95% [95% CI 85.4-99] for matched related donors (MRD) (N = 24), 84% [95% CI 63.5-99] for haploidentical (N = 13), and 71% [95% CI 36-99] for matched unrelated donors (MUD) (N = 7). The 3-year OS was 81% [95% CI 69.7-99] for all patients, 90.5% [95% CI 79.5-99] for non-IST patients (N = 27), and 70% [95% CI 51-99] for IST patients (N = 24) (log-rank p = .04). Survival of haploidentical HSCT (haplo-HSCT) recipients with post-transplant cyclophosphamide (PTCy) (N = 13) was excellent for both groups: 100% for non-IST patients (N = 3) and 80% for IST patients (N = 10). The 3-year OS for patients with previous IST by donor type in groups where >5 patients were available was 78.8% [95% CI 52.3-99] for haplo-HSCT (N = 10) and 66.7% [95% CI 28.7-99] for MUD (N = 6). Although it appears that patients receiving HSCT ≥6 months after the start of IST had worse survival, the number of patients in each category was small and log-rank was not significant(p = .65). CONCLUSIONS: Patients receiving MUD and haplo-HSCT with PTCy had similar outcomes, suggesting that haplo-HSCT with PTCy could be included in randomized trials of upfront IST versus alternative donor HSCT.

Addition of anterolateral ligament reconstruction to primary anterior cruciate ligament reconstruction could benefit recovery of functional outcomes.

This study aimed to compare functional outcomes sequentially up to 1 year after combined anterior cruciate ligament reconstruction (ACLR) and anterolateral ligament reconstruction (ALLR) and isolated ACLR. Fifty patients who underwent ACLR with versus without ALLR were analyzed at four different time points (preoperatively and 3, 6, and 12 months postoperatively). For the functional outcomes, muscle strength and acceleration time (AT) were measured using an isokinetic dynamometer. Proprioception was evaluated using joint position sense and dynamic postural stability. Patient-reported outcomes were measured using the Tampa Scale for Kinesiophobia (TSK-11) scores. Functional performance was assessed using single-leg hop distance (SLHD) and Limb Symmetry Index. In the operated knees, quadriceps (at 6 months postoperatively, p = 0.003) and hamstring (at 6 and 12 months postoperatively, p < 0.001) strength were significantly higher in the combined ACLR and ALLR group than the isolated ACLR group. The TSK-11 (at 6 and 12 months postoperatively, p < 0.001) was significantly lower in the combined ACLR and ALLR group than the isolated ACLR group. SLHD was significantly higher in the combined ACLR and ALLR group than the isolated ACLR group (at 6 months, p = 0.022 and at 12 months, p = 0.024). The addition of ALLR to primary ACLR yielded better muscle performance, fear of movement, and functional performance than isolated ACLR.

Main Group SnN4O Single Sites with Optimized Charge Distribution for Boosting the Oxygen Reduction Reaction.

Transition metal single-atom catalysts (SACs) have been regarded as possible alternatives to platinum-based materials due to their satisfactory performance of the oxygen reduction reaction (ORR). By contrast, main-group metal elements are rarely studied due to their unfavorable surface and electronic states. Herein, a main-group Sn-based SAC with penta-coordinated and asymmetric first-shell ligands is reported as an efficient and robust ORR catalyst. The introduction of the vertical oxygen atom breaks the symmetric charge balance, modulating the binding strength to oxygen intermediates and decreasing the energy barrier for the ORR process. As expected, the prepared Sn SAC exhibits outstanding ORR activity with a high half-wave potential of 0.912 V (vs RHE) and an excellent mass activity of 13.1 A mgSn-1 at 0.850 V (vs RHE), which surpasses that of commercial Pt/C and most reported transition-metal-based SACs. Additionally, the reported Sn SAC shows excellent ORR stability due to the strong interaction between Sn sites and the carbon support with oxygen atom as the bridge. The excellent ORR performance of Sn SAC was also proven by both liquid- and solid-state zinc-air battery (ZAB) measurements, indicating its great potential in practical applications.

Peripapillary Versus Macular Thinning to Detect Progression According to Initial Visual Field Loss Location in Normal-Tension Glaucoma.

PURPOSE: To investigate the predictive capabilities of peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell-inner plexiform layer (mGCIPL) thinning to detect visual field (VF) progression in normal-tension glaucoma patients with an initial parafoveal scotoma (IPFS) or nasal step (INS). DESIGN: Retrospective cohort study. METHODS: 185 early-stage glaucoma eyes, followed for 10 years, were retrospectively stratified into IPFS and INS groups. Progressive pRNFL and mGCIPL thinning were assessed using spectral-domain optical coherence tomography and VF progression using both event- or trend-based analysis. Kaplan-Meier survival analysis compared VF survival in each VF phenotype with or without progressive pRNFL and mGCIPL thinning. Cox proportional regression analysis identified VF progression factors. RESULTS: VF progression was detected in 42 IPFS (n=86) and 47 INS (n=99) eyes. Among VF progressors, pRNFL thinning was significantly faster in INS group compared to IPFS group (P < 0.01), while mGCIPL thinning was similar (P = 0.16). At five years, eyes with progressive mGCIPL thinning showed significantly lower VF survival in both VF phenotypes (all P < 0.05). Progressive pRNFL thinning showed significantly lower VF survival only in INS eyes (P = 0.015). Cox multivariate regression revealed that mGCIPL thinning predicted subsequent VF progression in IPFS eyes, while mGCIPL and pRNFL thinning had significant associations with VF progression in INS eyes. CONCLUSIONS: mGCIPL outperforms pRNFL at early follow-up in detecting VF progression in IPFS eyes but not INS eyes. Appropriate selection of structural parameters (mGCIPL vs pRNFL) maximizes early VF progression detection according to initial VF defect location.

An updated analysis of safety climate and downstream outcomes in two convenience samples of U.S. fire departments (FOCUS 1.0 and 2.0 survey waves).

BACKGROUND: The Fire service Organizational Culture of Safety (FOCUS) survey is an assessment tool comprised of psychometrically validated metrics of safety climate, safety behavior, and downstream outcomes (organizational and injury) that are specific to the U.S. fire and rescue service. METHODS: This analysis consists of a descriptive summary of two independent survey waves (FOCUS 1.0 and 2.0). The fire departments included in these survey waves were from convenience sampling (n1.0 = 275; n2.0 = 170). In addition to department level characteristics, we examined individual level characteristics for firefighters and EMS providers in participating departments (n1.0 = 22,719; n2.0 = 16,882). We conducted regression analyses to examine the associations between safety climate and safety behaviors, organizational outcomes, and safety outcomes. All analyses were stratified by organization type (career, volunteer). RESULTS: Our analysis indicated that a majority of respondents were males (90.7%FOCUS 1.0; 90.4%FOCUS 2.0), non-officers (68.4%FOCUS 1.0; 66.4%FOCUS 2.0), and non-Hispanic Whites (70.8%FOCUS 1.0; 69.5%FOCUS 2.0). For both samples there was a higher prevalence of injuries among individuals in career departments (nFOCUS 1.0 = 3778 [17.5%]; nFOCUS 2.0 = 3072 [18.7%]) than volunteer departments (nFOCUS 1.0 = 103 [8.8%]; nFOCUS 2.0 = 34 [7.4%]). We observed an approximate 10-point difference between the mean scores of Management Commitment to Safety for career and volunteer departments in both samples. We observed associations for two organizational outcomes, Safety Behavior and Job Satisfaction, with Management Commitment to Safety and Supervisor Support for Safety overall and when stratified by organization type. We observed a decrease in the odds of injuries associated with a one-unit increase in Management Commitment to Safety (OR1.0 overall: 0.98, 95% CI 0.97-0.99; OR2.0 volunteer: 0.90, 95% CI 0.85-0.95) and Supervisor Support for Safety (OR1.0 overall: 0.95, 95% CI 0.93-0.97; OR1.0 career: 0.95, 95% CI 0.92-0.98). CONCLUSIONS: From our current study, and a prior analysis of a geographically stratified random sample of U.S. fire departments, we identified that from all the organizational outcomes, job satisfaction was most consistently associated with FOCUS safety climate. Further, firefighters in our samples consistently rated Supervisor Support for Safety higher than Management Commitment to Safety. Future interventions should support fire departments in improving their departmental Management Commitment to Safety and maintaining their Supervisor for Safety.

Guidelines for Packaging, Transport, and Storage of Source Cells for Organoids.

This paper presents guidelines for the systematic management of packaging, storage, transportation, and traceability of source cells used for organoid research. Given the important role of source cells in organoid studies, it is important to ensure the preservation of their quality and integrity throughout transportation and distribution processes. The proposed guidelines, therefore, call for a cohesive strategy through these stages to minimize the risks of contamination, deterioration, and loss-threats that significantly compromise the safety, efficacy, and efficiency of source cells. Central to these guidelines is the quality control measures that include roles and responsibilities across the entire supply chain, with recommendations specific to packaging materials, transportation facilities, and storage management. Furthermore, the need for an integrated management system is emphasized, spanning from source cell collection to the final application. This system is crucial for maintaining the traceability and accountability of source cells, facilitating the sharing, distribution, and utilization on a global scale, and supporting to advance organoid research and development.

TASL mediates keratinocyte differentiation by regulating intracellular calcium levels and lysosomal function.

Maintaining epidermal homeostasis relies on a tightly organized process of proliferation and differentiation of keratinocytes. While past studies have primarily focused on calcium regulation in keratinocyte differentiation, recent research has shed light on the crucial role of lysosome dysfunction in this process. TLR adaptor interacting with SLC15A4 on the lysosome (TASL) plays a role in regulating pH within the endo-lysosome. However, the specific role of TASL in keratinocyte differentiation and its potential impact on proliferation remains elusive. In our study, we discovered that TASL deficiency hinders the proliferation and migration of keratinocytes by inducing G1/S cell cycle arrest. Also, TASL deficiency disrupts proper differentiation process in TASL knockout human keratinocyte cell line (HaCaT) by affecting lysosomal function. Additionally, our research into calcium-induced differentiation showed that TASL deficiency affects calcium modulation, which is essential for keratinocyte regulation. These findings unveil a novel role of TASL in the proliferation and differentiation of keratinocytes, providing new insights into the intricate regulatory mechanisms of keratinocyte biology.

Safety of deer antler extract in children: A 12-week randomized controlled clinical trial.

BACKGROUND: Deer antlers have been used as strong tonifying medicine in Asian countries, especially for the growth and development of children in pediatrics of Korean medicine. The safety of deer antler in adults cannot be applied directly to children because of their physiological characteristics. To accumulate reliable data on the safety of deer antler in pediatric populations, well-designed clinical studies are required. METHODS: This research is a 12-week, randomized, double-blind, placebo-controlled clinical trial evaluating the safety of deer antler extract (DAE) in children. The DAE group received an intervention containing 1586 mg of DAE, whereas the control group received a placebo for 12 weeks. The safety was assessed by monitoring adverse drug reactions (ADRs) and laboratory test results. RESULTS: One hundred participants were included in the safety analysis. Three and 2 participants in the DAE and control groups, respectively, reported ADRs. There was no significant difference in incidence between the 2 groups. ADRs are categorized into gastrointestinal and skin-related symptoms. No serious ADR was observed throughout the study. The laboratory test results were within or outside the normal range at clinically insignificant levels. CONCLUSION: The research discovered that the DAE is safe in terms of ADRs and laboratory parameters under the conditions studied. Further studies are required to accumulate safety data about DAE dosage adjustment and potential interactions with other medicines.

The Efficacy and Tolerability of Irbesartan/Amlodipine Combination Therapy in Patients With Essential Hypertension Whose Blood Pressure Were not Controlled by Irbesartan Monotherapy.

PURPOSE: This study aimed to evaluate the efficacy and tolerability of irbesartan (IRB) and amlodipine (AML) combination therapy in patients with essential hypertension whose blood pressure (BP) was not controlled by IRB monotherapy. METHODS: Two multicenter, randomized, double-blind, placebo-controlled, phase III studies were conducted in Korea (the I-DUO 301 study and the I-DUO 302 study). After a 4-week run-in period with either 150 mg IRB (I-DUO 301 study) or 300 mg IRB (I-DUO 302 study), patients with uncontrolled BP (ie, mean sitting systolic BP [MSSBP] ≥140 mmHg to <180 mmHg and mean sitting diastolic BP <110 mmHg) were randomized to the placebo, AML 5 mg, or AML 10 mg group. A total of 428 participants were enrolled in the 2 I-DUO studies. In the I-DUO 301 study, 271 participants were randomized in a 1:1:1 ratio to receive either IRB/AML 150/5 mg, IRB/AML 150/10 mg, or IRB 150 mg/placebo. In the I-DUO 302 study, 157 participants were randomized in a 1:1 ratio to receive IRB/AML 300/5 mg or IRB 300 mg/placebo. The primary endpoint was the change in MSSBP from baseline to week 8. Tolerability was assessed according to the development of treatment-emergent adverse events (TEAEs) and clinically significant changes in physical examination, laboratory tests, pulse, and 12-lead electrocardiography. FINDINGS: In I-DUO 301, the mean (SD) changes of MSSBP at week 8 from baseline were -14.78 (12.35) mmHg, -21.47 (12.78) mmHg, and -8.61 (12.19) mmHg in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively. In I-DUO 302, the mean (SD) changes of MSSBP at week 8 from baseline were -13.30 (12.47) mmHg and -7.19 (15.37) mmHg in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively. In both studies, all combination groups showed a significantly higher reduction in MSSBP than the IRB monotherapy groups (P < 0.001 for both). TEAEs occurred in 10.00%, 10.99%, and 12.22% of participants in the IRB/AML 150/5 mg, IRB/AML 150/10 mg, and IRB 150 mg/placebo groups, respectively, in I-DUO 301 and in 6.33% and 10.67% of participants in the IRB/AML 300/5 mg and IRB 300 mg/placebo groups, respectively, in I-DUO 302, with no significant between-group differences. Overall, there was one serious adverse event throughout I-DUO study. IMPLICATIONS: The combination of IRB and AML has superior antihypertensive effects compared with IRB alone over an 8-week treatment period, with placebo-like tolerability. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05476354 (I-DUO 301), NCT05475665 (I-DUO 302).

Comparison of Helicobacter pylori eradication rates between 7 and 14 days of tailored therapy according to clarithromycin resistance test: A randomized, multicenter, non-inferiority study.

BACKGROUND: Recently, a simple tailored therapy based on clarithromycin resistance has been implemented as Helicobacter pylori (H. pylori) eradication therapy. Nonetheless, despite the tailored therapy and frequent adverse events, studies on treatment period are lacking. This study aimed to compare the H. pylori eradication rates of 7-day and 14-day tailored therapy regimens according to clarithromycin resistance. MATERIALS AND METHODS: This multicenter, prospective, randomized, noninferiority trial enrolled H. pylori-positive patients who were randomly assigned to 7-day and 14-day regimen groups, depending on the presence or absence of clarithromycin resistance by 23S rRNA gene point mutations. Standard triple therapy (STT) (20 mg rabeprazole, 1 g amoxicillin, and 500 mg clarithromycin twice daily) or bismuth quadruple therapy (BQT) (20 mg rabeprazole twice daily, 500 mg metronidazole thrice daily, 120 mg bismuth four times daily, and 500 mg tetracycline four times daily) was assigned by clarithromycin resistance. Eradication rates and adverse events were evaluated. RESULTS: A total of 314 and 278 patients were included in the intention-to-treat (ITT) and per-protocol (PP) analyses, respectively; however, 31 patients were lost to follow-up, whereas five patients violated the protocol. Both the 7-day and 14-day regimens showed similar eradication rates in the ITT (7-day vs. 14-day: 78.3% vs. 78.3%, p > 0.99) and PP (87.9% vs. 89.1%, p = 0.851) analyses. Non-inferiority was confirmed (p < 0.025). A subgroup analysis according to clarithromycin resistance (clarithromycin resistance rate: 28.7%) revealed no significant difference in eradication rates between the 7-day and 14-day STT (90.0% vs. 90.1%, p > 0.99) and BQT (82.5% vs. 86.5%, p = 0.757). Furthermore, adverse events did not significantly differ between the two groups. CONCLUSIONS: The 7-day triple and quadruple therapy according to clarithromycin resistance showed similar eradication rates, as compared to the 14-day therapy.

Reversibility of Cognitive Deficits and Functional Connectivity With Transfusion in Children With Sickle Cell Disease.

BACKGROUND AND OBJECTIVES: People with sickle cell disease (SCD) are at risk of cognitive dysfunction independent of stroke. Diminished functional connectivity in select large-scale networks and white matter integrity reflect the neurologic consequences of SCD. Because chronic transfusion therapy is neuroprotective in preventing stroke and strengthening executive function abilities in people with SCD, we hypothesized that red blood cell (RBC) transfusion facilitates the acute reversal of disruptions in functional connectivity while white matter integrity remains unaffected. METHODS: Children with SCD receiving chronic transfusion therapy underwent a brain MRI measuring white matter integrity with diffusion tensor imaging and resting-state functional connectivity within 3 days before and after transfusion of RBCs. Cognitive assessments with the NIH Toolbox were acquired after transfusion and then immediately before the following transfusion cycle. RESULTS: Sixteen children with a median age of 12.5 years were included. Global assessments of functional connectivity using homotopy (p = 0.234) or modularity (p = 0.796) did not differ with transfusion. Functional connectivity within the frontoparietal network significantly strengthened after transfusion (median intranetwork Z-score 0.21 [0.17-0.30] before transfusion, 0.29 [0.20-0.36] after transfusion, p < 0.001), while there was not a significant change seen within the sensory motor, visual, auditory, default mode, dorsal attention, or cingulo-opercular networks. Corresponding to the change within the frontoparietal network, there was a significant improvement in executive function abilities after transfusion (median executive function composite score 87.7 [81.3-90.7] before transfusion, 90.3 [84.3-93.7] after transfusion, p = 0.021). Participants with stronger connectivity in the frontoparietal network before transfusion had a significantly greater improvement in the executive function composite score with transfusion (r = 0.565, 95% CI 0.020-0.851, p = 0.044). While functional connectivity and executive abilities strengthened with transfusion, there was not a significant change in white matter integrity as assessed by fractional anisotropy and mean diffusivity within 16 white matter tracts or globally with tract-based spatial statistics. DISCUSSION: Strengthening of functional connectivity with concomitant improvement in executive function abilities with transfusion suggests that functional connectivity MRI could be used as a biomarker for acutely reversible neurocognitive injury as novel therapeutics are developed for people with SCD.

Clinical outcomes of transarterial chemoembolization in Child-Turcotte Pugh class A patients with a single small (≤3 cm) hepatocellular carcinoma.

BACKGROUND AND AIM: Transarterial chemoembolization (TACE) is one of the standard modalities used to treat unresectable hepatocellular carcinoma (HCC), but the effectiveness of TACE for treating patients with a solitary small (≤3 cm) HCC and well-preserved liver function has not been definitively established. This study aimed to determine the therapeutic impact of TACE in patients with these characteristics. METHODS: This multicenter (four university hospitals) retrospective cohort study analyzed the medical records of 250 patients with a solitary small (≤3 cm) HCC and Child-Turcotte-Pugh (CTP) class A liver function diagnosed over 10 years. Posttreatment outcomes, including overall survival (OS), recurrence-free survival (RFS), and adverse events, were assessed following TACE therapy. RESULTS: One hundred and thirty-eight of the 250 patients (55.2%) treated with TACE achieved complete remission (CR). Overall median OS was 77.7 months, and median OS was significantly longer in the CR group than in the non-CR group (89.1 vs. 58.8 months, P = 0.001). Median RFS was 19.1 months in the CR group. Subgroup analysis identified hypertension, an elevated serum albumin level, and achieving CR as significant positive predictors of OS, whereas diabetes, hepatitis c virus infection, and tumor size (>2 cm) were poor prognostic factors of OS. CONCLUSIONS: The study demonstrates the effectiveness of TACE as a viable alternative for treating solitary small (≤3 cm) HCC in CTP class A patients.

Efficacy and Safety of Surgical Resection in Elderly Patients with Hepatocellular Carcinoma: A Systematic Review and Meta-Analysis.

Background/Aims: : With increased life expectancy, the management of elderly hepatocellular carcinoma (HCC) patients became a crucial issue, yet it is still challenging due to comorbidities and high surgical risks. While surgical resection is considered as primary treatment for eligible HCC patients, systematic evidence on its outcomes in elderly patients remains scarce. In this review, we aimed to analyze the efficacy and safety outcomes of surgical resection in elderly HCC patients. Methods: : The studies included in this meta-analysis were selected from Ovid-MEDLINE, Ovid-Embase, CENTRAL, KoreaMed, KMbase, and KISS databases following a predefined protocol. Efficacy outcomes included overall survival and disease-free survival, while the safety outcomes included postoperative mortality and complications. Results: : Patients in the elderly group (≥65 years) who underwent surgery exhibited non-inferior overall survival (hazard ratio [HR], 1.26; 95% confidence interval [CI], 0.92 to 1.74) and disease-free survival (HR, 1.03; 95% CI, 0.99 to 1.08) compared to the non-elderly group. Overall postoperative mortality exhibited no statistical difference (odds ratio [OR], 1.07; 95% CI, 0.87 to 1.31), but 30-day, 90-day, and in-hospital mortality were higher in the elderly group. The incidence of overall complications was higher in the elderly group (OR, 1.44; 95% CI, 1.22 to 1.69). Sensitivity analysis for the super elderly group (≥80 years) showed significantly higher in-hospital mortality compared to the non-super elderly group (OR, 2.51; 95% CI, 1.16 to 5.45). Conclusions: : The efficacy outcome of surgical resection in the elderly HCC patients was not worse than that in the non-elderly HCC patients, while in-hospital mortality and complications rates were higher. Therefore, surgical resection should be purposefully considered in the elderly population, with careful candidate selection.

Age-Related Decrease in Pellino-1 Expression Contributes to Osteoclast-Mediated Bone Loss.

Aging-related bone loss is driven by various biological factors, such as imbalanced bone metabolism from decreased osteoblast and increased osteoclast activities. Various transcriptional and post-transcriptional factors increase osteoclast activity with aging; however, studies regarding the post-translational regulators of osteoclast activity are still limited. The ubiquitin E3 ligase Pellino-1 is a well-known post-translational regulator of inflammation. However, how Pellino-1 expression regulation affects osteoclast differentiation remains unclear. This study determined that Pellino-1 levels are reduced in bone marrow monocytes (BMMs) from 40-week-old mice compared to 4-week-old mice. Interestingly, conditional Knockout (cKO) of Pellino-1 in 6-week-old mice resulted in decreased bone mass, reduced body size, and lower weight than in Pellino-1 floxed mice; however, these differences are not observed in 20-week-old mice. The increased number of tartrate-resistant acid phosphatase (TRAP)-positive cells and serum levels of C-terminal telopeptides of type I collagen, a marker of bone resorption, in 6-week-old Pellino-1 cKO mice implied a connection between Pellino-1 and the osteoclast population. Enhanced TRAP activity and upregulation of osteoclast genes in BMMs from the cKO mice indicate that Pellino-1 deletion affects osteoclast differentiation, leading to decreased bone mass and heightened osteoclast activity. Thus, targeting Pellino-1 could be a potential gene therapy for managing and preventing osteoporosis.