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Microneedle technology has emerged as an advanced method for transdermal drug delivery, which focuses on diverse fabrication techniques to develop microneedles with various models and geometries. This study explores the application of Computer Numerical Control (CNC) milling technology to create microneedle master molds with extremely sharp tips. We examined the effects of two key machining parameters, feed rate and ramp angle, on the tip sharpness of the microneedles. Our results showed that increasing both the feed rate and ramp angle could significantly reduce machining time. However, a higher feed rate also led to larger tip diameters and notable tip defects. Conversely, changes in the ramp angle at a constant feed rate had minimal impact on tip size. We identified an optimal condition balancing cutting time and tip sharpness at a feed rate of 100 mm/min and a ramp angle of 1.5°. Additionally, we assessed the CNC's capability to produce needles with different tip angles. The findings confirm that needles with varying tip angles maintained tip diameters below 10 μm, with needles having a 50° tip angle exhibiting the sharpest tips at approximately 3.3 μm. Further compression, insertion and diffusion tests were conducted to evaluate the performance of needles with different geometries., Competing Interests: Declarations Consent for publication The authors declare that they have provided their consent for publishing this manuscript. Competing interests The authors report no conflicts of interest in this work., (© 2024. Controlled Release Society.)

This study explores the enhanced photocatalytic performance of ZnO nanorods (ZnO-R) for degrading the carbaryl pesticide (CB) in wastewater. For comparison, commercial ZnO (ZnO-C) was used to evaluate the differences in the photocatalytic decomposition of CB between ZnO-R and ZnO-C. The results regarding the material properties demonstrated that ZnO-R enhances CB removal performance due to its unique rod shape, which extends light absorption and improves electron-hole separation. The removal rates of the carbaryl pesticide from the aqueous solution using ZnO-R and ZnO-C were 98.2% and 87.3%, respectively. Besides, the presence of other pesticides had a more negative impact on the performance of CB than inorganic contaminants. The degradation rates of CB using ZnO-R in wastewater were 99.8%, 68.2%, and 21.7% under UV, solar, and visible light, respectively. In addition, the degradation mechanism of CB using ZnO-R under UV light was proposed based on the n-type photocatalysis process. This work provides a method for selecting a suitable type of ZnO photocatalyst to control pesticide residue pollutants that are commonly found in agricultural activities.

High spin polarization and low resistivity of Fe 3 O 4 at room temperature have been an appealing topic in spintronics with various promising applications. High-quality Fe 3 O 4 thin films are a must to achieve the goals. In this report, Fe 3 O 4 films on different substrates (SiO 2 /Si(100), MgO(100), and MgO/Ta/SiO 2 /Si(100)) were fabricated at room temperature with radio-frequency (RF) sputtering and annealed at 450 °C for 2 h. The morphological, structural, and magnetic properties of the deposited samples were characterized with atomic force microscopy, X-ray diffractometry, and vibrating sample magnetometry. The polycrystalline Fe 3 O 4 film grown on MgO/Ta/SiO 2 /Si(100) presented very interesting morphology and structure characteristics. More importantly, changes in grain size and structure due to the effect of the MgO/Ta buffering layers have a strong impact on saturation magnetization and coercivity of Fe 3 O 4 thin films compared to cases of no or just a single buffering layer., (Copyright © 2024, Ngo et al.)

The linear undecapeptide BP52 was previously reported to have antibacterial activity against phytopathogenic bacteria species. Due to the structural similarities to naturally occurring cationic helical antimicrobial peptides, it was speculated that this peptide could potentially target microbial pathogens and cancer cells found in mammals. Consequently, this study aims to further investigate the structural and biological properties of this peptide. Our findings indicate that BP52 exhibits strong antimicrobial and anticancer activity while displaying relatively low levels of hemolytic activity. Hence, this study suggests that BP52 could be a potential lead compound for drug discovery against infectious diseases and cancer. Besides, new insights into the relationships between the structure and the multifunctional properties of antimicrobial peptides were also explored., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Green silver nanoparticles (AgNPs) were synthesized using natural extracts as reducing agents and were firstly applied as co-catalysts in low-intensity-visible-light driven photocatalytic hydrogen production (PH2P), which a solution for green energy sources and independence from fossil fuels. The as-prepared AgNPs possessed size in a few tens nanometers and exhibited surface plasmon resonance (SPR) effects in the 310-560 nm region. Depositing AgNPs on g-C 3 N 4 nanosheets broadened the visible absorption range, reduced electron-hole recombination, and increased electronic communication at the interface. g-C 3 N 4 /Ag demonstrated high PH2P efficiency, stability over three consecutive cycles, and a rapidly rising photocurrent under low-intensity visible light irradiation, although these features were not observed in g-C 3 N 4 alone. The H 2 evolution of g-C 3 N 4 /Ag_CC (CC: Cinnamomum camphora ), g-C 3 N 4 /Ag_GT (GT: green tea), and g-C 3 N 4 /Ag_PP (PP: pomelo peels) reached 252.6, 125.3 and 92.0 μmol g -1 at 180 min at the first cycle, respectively. Among them, g-C 3 N 4 /Ag_CC showed the highest photocatalytic activity, which may be attributed to the superior morphology, optical properties of AgNPs_CC, and efficient electron transfer from g-C 3 N 4 to AgNPs_CC. The SPR effect and Schottky barriers formed at the interface could contribute to enhancing the overall efficiency of the heterojunction photocatalysts. The results highlighted a crucial advancement toward H 2 production under low-intensity visible-light irradiation., Competing Interests: The authors declare no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Pancreatic duct adenocarcinoma (PDAC) accounts for about 85-90% of all solid pancreatic tumors, which is well-known for poor prognosis and high morbidity. Despite the massive advent of chemotherapy and radiotherapy in recent years, surgical removal is still considered the cornerstone management option in this situation. Pancreaticoduodenectomy or Whipple procedure is generally contraindicated in metastasis or tumors that encase more than 50% of vessels. Vascular reconstruction is a state-of-the-art technique which requires the remarkable involvement of vascular experts in the setting of PDAC-invading vessels. In this article, we present an exceptional case of a 38-year-old male patient who underwent radical resection for advanced pancreatic cancer with superior mesenteric vein reconstruction by a great saphenous vein., (© 2024 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Objective: Indocyanine green has been used in the assessment of the gastric conduit perfusion in thoracoscopic esophagectomy to prevent malperfusion-associated anastomotic leak. This study aims to evaluate the initial results of investigating the gastric conduit perfusion with indocyanine green in the surgical treatment of esophageal cancer., Patients and Methods: This cross-sectional descriptive study was carried out on 54 esophageal cancer patients undergoing thoracoscopic esophagectomy and gastric conduit reconstruction. The blood flow in the gastric conduit was observed using an infrared camera and indocyanine green after completion of the conduit and after tunneling the conduit through the mediastinum to the neck., Results: The gastric conduit width and length were 5.2 ± 0.3 cm, and 31.5 ± 1.6 cm, respectively. The length of the gastric conduit from the junction between the right and left gastroepiploic to the point where the distal end of the gastric conduit still has a vascular pulse was 11.9 ± 4.3 cm. Seventeen patients (31.5%) had poor blood supply at the distal end of the gastric conduit, with indocyanine green appearance time ⩾ 60 s, in whom anastomotic leaks occurred in five patients (9.3%). The lack of connection between the right and left gastroepiploic vessels was associated with poor blood supply of the distal gastric conduit ( p  = 0.04). Multivariable logistic regression analysis showed association between the time of indocyanine green appearance at the distal gastric conduit and the risk of anastomotic leak (OR = 1.99, 95% CI = 1.10-3.60, p  = 0.02)., Conclusion: Investigation of gastric conduit perfusion using indocyanine green in gastric conduit reconstruction detected 31.5% of patients with poor blood supply at the distal end of the conduit, in whom 9.3% had anastomotic leak. The longer indocyanine green appearance time in the distal gastric conduit (segment BC), was associated with the higher rate of the anastomotic leak., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

This study evaluated the antimicrobial activity, resistance development, and synergistic potential of cell-free supernatant (CFSs) derived from Levilactobacillus brevis (Lb-CFS) and Lactiplantibacillus plantarum (Lp-CFS) against Klebsiella pneumoniae. Both CFSs exhibited potent growth inhibition, with minimum inhibitory concentrations (MICs) of 128 μg/mL and 64 μg/mL for Lb-CFS and Lp-CFS, respectively, and demonstrated dose-dependent bactericidal activity, achieving complete bacterial eradication at minimum bactericidal concentrations (MBC) within 6 h. The CFSs suppressed the expression of virulence genes (galF, wzi, and manC) and biofilm formation in a dose-dependent manner. Synergistic interactions were observed when combining CFSs with antibiotics, resulting in 2- to fourfold reductions in antibiotic MICs and MBCs. Notably, adaptive evolution experiments revealed significantly slower resistance development in K. pneumoniae against CFSs (twofold MIC/MBC increase) compared to antibiotics (16- to 128-fold increase) after 21 days. Furthermore, CFS-adapted strains exhibited increased antibiotic susceptibility, while antibiotic-adapted strains displayed cross-resistance to multiple antibiotics. No cross-resistance occurred between Lb-CFS and Lp-CFS, suggesting distinct adaptive mechanisms. These findings highlight the potential of probiotic-derived CFSs as effective antimicrobials with a lower propensity for inducing rapid resistance compared to conventional antibiotics, suggesting their promise in combating multidrug-resistant infections., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The involvement of γδ TCR-bearing lymphocytes in immunological memory has gained increasing interest due to their functional duality between adaptive and innate immunity. γδ T effector memory (TEM) and central memory (TCM) subsets have been identified, but their respective roles in memory responses are poorly understood. In the present study, we used subsequent mouse cytomegalovirus (MCMV) infections of αβ T cell deficient mice in order to analyze the memory potential of γδ T cells. As for CMV-specific αβ T cells, MCMV induced the accumulation of cytolytic, KLRG1+CX3CR1+ γδ TEM that principally localized in infected organ vasculature. Typifying T cell memory, γδ T cell expansion in organs and blood was higher after secondary viral challenge than after primary infection. Viral control upon MCMV reinfection was prevented when masking γδ T-cell receptor, and was associated with a preferential amplification of private and unfocused TCR δ chain repertoire composed of a combination of clonotypes expanded post-primary infection and, more unexpectedly, of novel expanded clonotypes. Finally, long-term-primed γδ TCM cells, but not γδ TEM cells, protected T cell-deficient hosts against MCMV-induced death upon adoptive transfer, probably through their ability to survive and to generate TEM in the recipient host. This better survival potential of TCM cells was confirmed by a detailed scRNASeq analysis of the two γδ T cell memory subsets which also revealed their similarity to classically adaptive αβ CD8 T cells. Overall, our study uncovered memory properties of long-lived TCM γδ T cells that confer protection in a chronic infection, highlighting the interest of this T cell subset in vaccination approaches., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yared 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.)

Recently, the hazardous effects of antibiotic micropollutants on the environment and human health have become a major concern. To address this challenge, semiconductor-based photocatalysis has emerged as a promising solution for environmental remediation. Our study has developed Bi 2 WO 6 /g-C 3 N 4 (BWCN) photocatalyst with unique characteristics such as reactive surface sites, enhanced charge transfer efficiency, and accelerated separation of photogenerated electron-hole pairs. BWCN was utilized for the oxidation of tetracycline antibiotic (TCA) in different water sources. It displayed remarkable TCA removal efficiencies in the following order: surface water (99.8%) > sewage water (88.2%) > hospital water (80.7%). Further, reusability tests demonstrated sustained performance of BWCN after three cycles with removal efficiencies of 87.3, 71.2 and 65.9% in surface water, sewage, and hospital water, respectively. A proposed photocatalytic mechanism was delineated, focusing on the interaction between reactive radicals and TCA molecules. Besides, the transformation products generated during the photodegradation of TCA were determined, along with the discussion on the potential risk assessment of antibiotic pollutants. This study introduces an approach for utilizing BWCN photocatalyst, with promising applications in the treatment of TCA from various wastewater sources., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Gut microbiota impacts responses to immune checkpoint inhibitors (ICI). A high level of Faecalibacterium prausnitzii have been associated with a positive response to ICI in multiple cancer types. Here, based on fecal shotgun metagenomics data, we show in two independent cohorts of patients with non-small cell lung cancer and advanced melanoma that a high level of F. prausnitzii at baseline is positively associated with a better clinical response to ICI. In MCA205 tumor-bearing mice, administration of F. prausnitzii strain EXL01, already in clinical development for Inflammatory Bowel Disease, restores the anti-tumor response to ICI in the context of antibiotic-induced microbiota perturbation at clinical and tumor transcriptomics level. In vitro, EXL01 strain enhances T cell activation in the presence of ICI. Interestingly, oral administration of EXL01 strain did not induce any change in fecal microbiota diversity or composition, suggesting a direct effect on immune cells in the small intestine. F. prausnitzii strain EXL01 will be evaluated as an adjuvant to ICI in multiple cancers in the near future., Competing Interests: HS report lecture fee, board membership, or consultancy from Amgen, Fresenius, IPSEN, Actial, Astellas, Danone, THAC, Biose, BiomX, Eligo, Immusmol, Adare, Nestle, Ferring, MSD, Bledina, Pfizer, Biocodex, BMS, Bromatech, Gilead, Janssen, Mayoli, Roche, Sanofi, Servier, Takeda, Abbvie, has stocks from Enterome bioscience and is co-founder of Exeliom Biosciences. PL report lecture fee, board membership, or consultancy from Biose, Biostime, Boiron, Bonduelle, BMS, Bromatech, IPSEN, iTaK, Lallemand, Lesaffre, L’Oréal, Mayoli, Merck, Procter and Gamble, Second Genome, Therascience and URGO and is co-founder of Exeliom Biosciences. PR is an employee of Exeliom Biosciences. LD was supported by Philantropia Fondation. BR reports grants from Davoltera outside the submitted work, as well as consulting fees from BMS, AstraZeneca, Merck and Davolterra and he is the co-founder of Curebiota. ABC reports lecture fee, board membership, or consultancy from Amgen, Astra-Zeneca, Novartis, Merck KGaA, Pfizer, Roche, Janssen, Abbvie, Sanofi, Takeda, MSD, BMS, InhaTarget and Exeliom. The other authors declare that they have no competing interests., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background and Aims: Pre-clinical studies suggest that the simultaneous blockade of the α1b and 5HT2A receptors may be effective in reducing alcohol consumption. This study aimed to assess the efficacy and safety of prazosin (α1b blocker) and cyproheptadine (5HT2A blocker) combination in decreasing total alcohol consumption (TAC) in alcohol use disorder (AUD)., Design, Setting and Participants: This was a double-blind, parallel group, placebo-controlled, Phase 2, randomized clinical trial conducted in 32 addiction treatment centres in France. A total of 108 men and 46 women with severe AUD took part., Intervention: Participants were randomly assigned to one of the following 3-month treatments: (1) low-dose group (LDG) receiving 8 mg cyproheptadine and 5 mg prazosin extended-release (ER) formulation daily; (2) high-dose group (HDG) receiving 12 mg cyproheptadine and 10 mg prazosin ER daily; and (3) placebo group (PG) receiving placebo of cyproheptadine and prazosin ER. A total of 154 patients were randomized: 54 in the PG, 54 in the LDG and 46 in the HDG., Measurements: The primary outcome was TAC change from baseline to month 3., Findings: A significant main treatment effect in the change in TAC was found in the intent-to-treat population (P = 0.039). The HDG and LDG showed a benefit in the change in TAC from baseline to month 3 compared with PG: -23.6 g/day, P = 0.016, Cohen's d = -0.44; -18.4 g/day, P = 0.048 (Bonferroni correction P < 0.025), Cohen's d = -0.36. In a subgroup of very high-risk drinking-level participants (> 100 g/day of pure alcohol for men and > 60 g/day for women), the difference between the HDG and the PG in the primary outcome was -29.8 g/day (P = 0.031, Cohen's d = -0.51). The high and low doses were well-tolerated with a similar safety profile., Conclusions: A randomized controlled trial of treatment of severe alcohol use disorder with a cyproheptadine-prazosin combination for 3 months reduced drinking by more than 23 g per day compared with placebo. A higher dose combination was associated with a larger magnitude of drinking reduction than a lower dose combination while showing similar safety profile., (© 2024 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)

Introduction: Maternal disorders are the third leading cause of sepsis globally, accounting for 5.7 million (12%) cases in 2017. There are increasing concerns about the emergence of antimicrobial resistance (AMR) in bacteria commonly causing maternal sepsis. Our aim is to describe the protocol for a clinical and microbiology laboratory study to understand risk factors for and the bacterial etiology of maternal sepsis in a tertiary Obstetrics and Gynaecology Hospital., Methods: This case-control study aims to recruit 100 cases and 200 controls at Tu Du Hospital in Ho Chi Minh City, Vietnam, which had approximately 55,000 births in 2022. Women aged ≥ 18 years and ≥ 28 weeks gestation having a singleton birth will be eligible for inclusion as cases or controls, unless they have an uncomplicated localised or chronic infection, or an infection with SARS-CoV-2. Cases will include pregnant or recently pregnant women with sepsis recognised between the onset of labour and/or time of delivery/cessation of pregnancy for up to 42 days post-partum. Sepsis will be defined as suspected or confirmed infection with an obstetrically modified Sequential Organ Failure Assessment score of ≥ 2, treatment with intravenous antimicrobials and requested cultures of any bodily fluid. Controls will be matched by age, location, parity, mode of delivery and gestational age. Primary and secondary outcomes are risk factors associated with the development of maternal sepsis, the frequency of adverse outcomes due to maternal sepsis, bacterial etiology and AMR profiles of cases and controls., Discussion: This study will improve understanding of the epidemiology and clinical implications of maternal sepsis management including the presence of AMR in women giving birth in Vietnam. It will help us to determine whether women in this setting are receiving optimal care and to identify opportunities for improvement., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Thompson 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.)

This study investigates the removal of amoxicillin micropollutants (AM) from hospital wastewater using CoMoO 4 -modified graphitic carbon nitride (CMO/gCN). Consequently, CMO/gCN exhibits notable improvements in visible light absorption and electron-hole separation rates compared to unmodified gCN. Besides, CMO/gCN significantly enhances the removal efficiency of AM, attaining an impressive 96.5%, far surpassing the performance of gCN at 48.6%. Moreover, CMO/gCN showcases outstanding reusability, with AM degradation performance exceeding 70% even after undergoing six cycles of reuse. The removal mechanism of AM employing CMO/gCN involves various photoreactions of radicals (•OH, •O 2 - ) and amoxicillin molecules under light assistance. Furthermore, CMO/gCN demonstrates a noteworthy photodegradation efficiency of AM from hospital wastewater, reaching 92.8%, with a near-complete reduction in total organic carbon levels. Detailed discussions on the practical applications of the CMO/gCN photocatalyst for removal of micropollutants from hospital wastewater are provided. These findings underline the considerable potential of CMO/gCN for effectively removing various pollutants in environmental remediation strategies., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Background: The etiology of inflammatory bowel disease (IBD) is unclear but involves both genetics and environmental factors, including the gut microbiota. Indeed, exacerbated activation of the gastrointestinal immune system toward the gut microbiota occurs in genetically susceptible hosts and under the influence of the environment. For instance, a majority of IBD susceptibility loci lie within genes involved in immune responses, such as caspase recruitment domain member 9 (Card9). However, the relative impacts of genotype versus microbiota on colitis susceptibility in the context of CARD9 deficiency remain unknown., Results: Card9 gene directly contributes to recovery from dextran sodium sulfate (DSS)-induced colitis by inducing the colonic expression of the cytokine IL-22 and the antimicrobial peptides Reg3β and Reg3γ independently of the microbiota. On the other hand, Card9 is required for regulating the microbiota capacity to produce AhR ligands, which leads to the production of IL-22 in the colon, promoting recovery after colitis. In addition, cross-fostering experiments showed that 5 weeks after weaning, the microbiota transmitted from the nursing mother before weaning had a stronger impact on the tryptophan metabolism of the pups than the pups' own genotype., Conclusions: These results show the role of CARD9 and its effector IL-22 in mediating recovery from DSS-induced colitis in both microbiota-independent and microbiota-dependent manners. Card9 genotype modulates the microbiota metabolic capacity to produce AhR ligands, but this effect can be overridden by the implantation of a WT or "healthy" microbiota before weaning. It highlights the importance of the weaning reaction occurring between the immune system and microbiota for host metabolism and immune functions throughout life. A better understanding of the impact of genetics on microbiota metabolism is key to developing efficient therapeutic strategies for patients suffering from complex inflammatory disorders. Video Abstract., (© 2024. The Author(s).)

Kombucha, a fermented beverage, is gaining popularity due to its numerous beneficial health effects. Various substrates such as herbs, fruits, flowers, and vegetables, have been used for kombucha fermentation in order to enhance the flavor, aroma, and nutritional composition. This study aims to investigate the potential suitability of cascara as a novel ingredient for kombucha production. Our findings suggested that cascara is a suitable substrate for kombucha production. Fermentation elevated the total phenolic and flavonoid content in cascara, which enhanced the antioxidant, antibacterial, and prebiotic characteristics of the product. Furthermore, the accumulation of acetic acid-induced the pH lowering reached 2.7 after 14 days of fermentation, which achieved the microbiological safety of the product. Moreover, 14 days of fermentation resulted in a balanced amalgamation of acidity, sweetness, and fragrance according to sensory evaluation. Our findings not only highlight the potential of cascara kombucha as a novel substrate for kombucha production but also contribute to repurposing coffee by-products, promoting environmentally friendly and sustainable agricultural development.

The Eighth Asian National Control Laboratory (NCL) Network meeting, entitled "Biological Products Quality Control and Self-Sufficiency Strategy focusing on plasma-derived medicinal products (PDMPs)" was held in Seoul on 31 August 2023. The participants were NCL experts from Indonesia, Japan, Malaysia, the Philippines, Vietnam, and the Republic of Korea. Special lectures included the PDMPs self-sufficiency strategies of the World Health Organization (WHO) and Indonesian Food and Drug Authority, and a case study on Global Benchmarking Tool (GBT) assessment for vaccines by the Korea Ministry of Food and Drug Safety. The NCL delegates shared their current experiences with national lot releases and biological standardisation. The meeting contributed to a mutual understanding of the progress of the PDMPs self-sufficiency among Asian countries, the WHO's support strategies, and the NCL's plan for the preparation of the WHO GBT assessment. In the panel discussion, all participants agreed that building capacity in blood safety in the Asian region and harmonisation of relevant international regulatory requirements will support appropriate emergency preparedness, particularly source materials in the region, and will build the foundation for resolving the PDMPs supply insecurity that has worsened after the COVID-19 pandemic in some countries., (Copyright © 2024. Published by Elsevier Ltd.)

Background: The Coronavirus disease of 2019 (COVID-19) pandemic and the corresponding mitigation measures have had a discernible impact on drug utilization among outpatients. However, limited research exists on the prescription trends in the elderly population during the pandemic period in Viet Nam., Objectives: This study aims to analyze the effects of COVID-19 on outpatient drug utilization patterns at a national geriatric hospital in Ho Chi Minh City before and after the early onset of the pandemic., Methods: Data was collected from the prescriptions and administration claims, encompassing the period from January 2016 to December 2022. The dataset was divided into two periods: Period 1: January 2016 to December 2020 and Period 2: January 2021 to December 2022. The drug utilization was measured using DDD/1000P (defined daily doses-DDD per 1000 prescriptions) on a monthly basis. The analysis employed interrupted time series using Autoregressive Integrated Moving Average (ARIMA) to detect changes in drug use levels and rates., Results: A total of 1,060,507 and 644,944 outpatient prescriptions from Thong Nhat Hospital were included in Period 1 and Period 2, respectively. The median age of the patients were 58 in Period 1 and 67 years old in Period 2. The most common comorbidities were dyslipidemia, hypertension, and diabetes mellitus. In terms of medication utilization, cardiovascular drugs were the most frequently prescribed, followed by drugs active on the digestive and hormonal systems. The study observed significant surges in the number of prescriptions and the average number of drugs per prescription. However, there were no significant changes in the overall consumption of all drugs. Among the drug groups related to the cardiovascular system, three subgroups experienced a sudden and significant increase: cardiac therapy, beta-blocking agents, and antihypertensives, with increasing consumption levels of 1,177.73 [CI 95%: 79.29; 2,276.16], 73.32 [CI 95%: 28.18; 118.46], and 36.70 [CI 95%: 6.74; 66.66] DDD/1000P, respectively. On the other hand, there was a significant monthly decrease of -31.36 [CI 95%: -57.02; -5.70] DDD/1000P in the consumption of anti-inflammatory and antirheumatic products. Interestingly, there was a significant increase of 74.62 [CI 95%: -0.36; 149.60] DDD/1000P in the use of antigout preparations., Conclusion: COVID-19 resulted in a sudden, non-significant increase in overall drug consumption levels among outpatients. Notably, our findings highlight significant increases in the utilization of three drug groups related to the cardiovascular system, specifically cardiac therapy, beta-blocking agents, and antihypertensives. Intriguingly, there was a statistically significant increase in the consumption of antigout preparations, despite a decline in the monthly consumption rate of non-steroidal anti-flammatory drugs (NSAIDs). Further studies in the following years are necessary to provide a more comprehensive understanding of the impact of COVID-19 on outpatient drug utilization patterns., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Le-Dang 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.)

The antibiotic oxytetracycline (OCA) exhibits high insolubility in the natural environment, posing a significant challenge for its removal. This study synthesized a porous structure and a high-surface-area carbon fiber, incorporating zinc oxide (ZnO/CFB) for the effective removal of OCA in wastewater. The material characterization revealed exceptional optical and photochemical properties of ZnO/CFB, featuring a reduced band gap energy of 2.7 eV. ZnO/CFB exhibited robust performance in the photodegradation of OCA in wastewater, achieving an impressive removal efficiency of 86.7%. Remarkably, the reduction of total organic carbon (TOC) reached an outstanding 97.5%. LC-MS analysis confirmed the complete oxidation of OCA and its intermediates, transforming them into inorganic substances within 60 min. This study introduces an efficient strategy for eliminating antibiotic pollutants from wastewater, highlighting the potential of ZnO/CFB as an effective and stable photocatalyst for environmental remediation.

Kombucha is a widely consumed fermented tea beverage with diverse health benefits. In a previous study, we demonstrated that the use of cascara as a substrate results in a special kombucha beverage with high bioactivity. Traditional kombucha fermentation using a symbiotic culture of bacteria and yeast (SCOBY) can lead to inconsistent product quality because of the lack of control over microbial composition. We successfully isolated and identified yeast and bacteria, including Saccharomyces cerevisiae , Komagataeibacter rhaeticus , and Lactobacillus brevis that are appropriate starter cultures for cascara kombucha fermentation. We also demonstrated that a supplementation with lactic acid bacteria (LAB) and a mixture of S. cerevisiae and K. rhaeticus resulted in higher total polyphenol and flavonoid content of cascara kombucha compared with the traditionally fermented product using SCOBY as the inoculum. The free radical scavenging activity, inhibitory effects on α-amylase, tyrosinase activity, and antibacterial properties of cascara kombucha were also enhanced as a result of LAB supplement. These findings provide valuable insights into the controlled microbiological composition required for the fermentation of cascara kombucha, thereby ensuring consistent quality and enhanced bioactivity of the product. Further, the use of cascara as a substrate for kombucha production not only offers various health benefits and biological effects, but also repurposes by-products from the coffee industry, which contributes to sustainable development and is eco-friendly., Competing Interests: AUTHOR DISCLOSURE STATEMENT The authors declare no conflict of interest., (© 2023 The Korean Society of Food Science and Nutrition.)

Background: The use of 3D-printed Patient-Specific Instruments (PSI) has been investigated to enhance the postoperative functional results in total hip arthroplasty (THA) and has been recognized as an innovative approach for the optimal alignment of hip implant components. Point-of-care production is gradually becoming the norm for PSI manufacturing. The purpose of this article is to assess the accuracy and safety of PSI for total hip arthroplasty performed at the point-of-care in Vietnam., Methods: 34 THA cases were assessed in this prospective study. A template for the size and orientation of the implant and the design of the PSI was generated using data from preoperative 3D computed tomography (CT) scanning of the lower limb. The principal surgeon determined the implants' position and PSI design directly using the software. The PSI is then produced using a 3D-compatible resin printer in our manufacturing hospital. The PSI, consisting of an acetabulum and a femoral component placed press-fit on the bony surface, guided surgeons to precisely ream the acetabulum and cut the femoral neck according to the pre-planned plane. Postoperative CT scanning was obtained and superimposed onto the 3D model of the implant to evaluate the accuracy of the procedure by comparing the orientation values of the cup and the alignment of the stem between the planned and the actual results. Intra- and postoperative clinical parameters of surgery, including surgical time, intra-operative blood loss, complications, and the first ambulation, were also recorded to evaluate the safety of the surgery., Results: The preparation for PSI required an average of 3 days. 94% of cup size and 91% of stem size were correctly selected. The mean values of postoperative inclination and anteversion were 44.2° ± 4.1° and 19.2° ± 5.6°, respectively. 64.7% of cases deviated from planned within the ± 5 0 range and 94.1% within the ± 10° range. There was no significant statistical difference between the planned and the achieved values of stem anteversion, osteotomy height, and leg length discrepancy (p > 0.05). The average surgical time was 82.5° ± 10.8 min, and the intraoperative blood loss was estimated at 317.7° ± 57.6 ml. 64.7% of patients could walk on the day of surgery. There were no complications reported., Conclusions: The point-of-care manufactured PSI is a useful solution for improving the accuracy of total hip arthroplasty surgery, especially in restoring implant orientation and reducing leg length discrepancy. However, long-term clinical follow-up evaluation is needed to confirm the efficacy and safety of this approach., (© 2023. The Author(s).)

With the acceleration of global industrialization, organic pollutants have become a threat to ecological safety and human health. This work prepared TiO 2 /rice husk biochar (TiO 2 /BC) for removal of bisphenol A (BA) micropollutant in wastewater. Experiment results revealed a low BA removal efficiency by TiO 2 /BC was observed at 34.5% under the dark environment. However, the removal rate of BA by UV light-assisted TiO 2 /BC significantly increased to 97.6% in 1 h. The results also demonstrated that the removal performance of BA using TiO 2 /BC was 2.1times higher than that of commercial TiO 2 (46.4%). Besides, the removal efficiency of BA by reused TiO 2 /BC after eight cycles slightly decreased by 12.8%, demonstrating the excellent properties of the prepared composite. TiO 2 /BC also exhibited high removal efficiency of BA (over 89%) from the synthetic wastewater sample, indicating the potential utilization of composite for removing BA in wastewater. This work provides a new way to turn biomass waste into useful material and effective method to remove micropollutant BA., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

In this work, magnesium oxide nanoparticles supported biochar derived from tea wastes (MgO@TBC) was prepared as an effective adsorbent for removing hazardous o-chlorophenol (o-CP) from industrial wastewater. The surface area, porous structure, surface functional groups and surface charge of tea waste biochar (TBC) significantly enhanced after the modification process. The best uptake performance of o-CP was found at pH = 6.5 and 0.1 g of MgO@TBC adsorbent. According to the adsorption isotherm, the adsorption of o-CP onto MgO@TBC followed the Langmuir model with a maximum uptake capacity of 128.7 mg/g, which was 26.5% higher than TBC (94.6 mg/g). MgO@TBC could be reused for eight cycles with a high o-CP uptake performance (over 60%). Besides, it also exhibited good removal performance of o-CP from industrial wastewater with a removal rate of 81.7%. The adsorption behaviors of o-CP onto MgO@TBC are discussed based on the experimental results. This work may provide information to prepare an effective adsorbent for removing hazardous organic contaminants in wastewater., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Optimizing CD34 recovery while minimizing harm to hematopoietic progenitor cell donors by apheresis (HPC(A) donors) is critical to the success of allogeneic hematopoietic cell transplantation. We examined the efficacy and safety of starting allogeneic HPC(A) donors at a collect pump rate (CPR) of 2 mL/min on the Spectra Optia regardless of the inlet flow rate and/or pre-apheresis white blood cell (WBC) count (high CPR group)., Study Design and Methods: A single-center retrospective study was performed on allogeneic adult donors from 10/2020 to 12/2022. From 10/2020 to 6/19/2022, all donors had CPR of ~1 mL/min (historical group). High CPR group started 6/20/2022., Results: During the study period, 412 donors were in historical group versus 196 (32.2%) in high CPR group. Median CD34 collection efficiency (CE) was higher and more consistent in high CPR group (55.1% vs. 53% in historical group, p < .0001) and remained significant in multivariate analysis. Although product volume was higher in high CPR group, WBC, hematocrit, and platelet concentrations were significantly lower. No difference in engraftment outcomes in patients receiving products from two groups was observed. Moreover, no differences occurred in a significant peri-procedural adverse event or percent decrease in platelets (6.87% decrease in platelets per 100 × 10 6 CD34 cells collected versus 6.66% in historical group, p = .89). Furthermore, high CPR group had ~26 min less in collection time for every 100 × 10 6 CD34 cells collected, resulting in less positive fluid balances., Conclusions: Starting allogeneic HPC(A) donor collection at a CPR of 2 mL/min is safe and effective., (© 2023 AABB.)

The current limitation of ancient DNA data from Vietnam led to the controversy surrounding the prehistory of people in this region. The combination of high heat and humidity damaged ancient bones that challenged the study of human evolution, especially when using DNA as study materials. So far, only 4 k years of history have been recorded despite the 65 k years of history of anatomically modern human occupations in Vietnam. Here we report, to our knowledge, the oldest mitogenomes of two hunter-gatherers from Vietnam. We extracted DNA from the femurs of two individuals aged 6.2 k cal BP from the Con Co Ngua (CCN) site in Thanh Hoa, Vietnam. This archeological site is the largest cemetery of the hunter-gatherer population in Southeast Asia (SEA) that was discovered, but their genetics have not been explored until the present. We indicated that the CCN haplotype belongs to a rare haplogroup that was not detected in any present-day Vietnamese individuals. Further matrilineal analysis on CCN mitogenomes showed a close relationship with ancient farmers and present-day populations in SEA. The mitogenomes of hunter-gatherers from Vietnam debate the "two layers" model of peopling history in SEA and provide an alternative solution for studying challenging ancient human samples from Vietnam., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Titanium oxide-based photocatalysts (TOBPs) have been widely utilized as potential materials for numerous applications, such as wastewater treatment, water-splitting reactions, carbon dioxide (CO 2 ) reduction and photosynthesis. However, the large bandgap of intrinsic TiO 2 limits their absorption toward visible light, which is the central part of the solar spectrum, resulting in low photocatalytic activities under sunlight. To overcome this obstacle, several strategies, such as doping with either metal or non-metal elements or combining with other compounds, are efficient ways to reduce the bandgap of TiO 2 , leading to effectively extending their absorption toward the visible region and increasing their catalytic performance. In this review, we discussed the application of TOBPs for the photodegradation of hazardous organic pollutants in wastewater to produce quality reused water. The synthesis of TiO 2 and the enhancement of photocatalytic activities of TOBPs by different techniques with detailed information were provided. Application of TOBPs for decomposing hazardous organic pollutants such as dyes, phenolic compounds and pharmaceuticals under optimum conditions have been listed. Also, the photodegradation mechanisms of hazardous organic compounds have been investigated. This work also brings ideas for future perspectives and research plan to inhibit the disadvantages and expand the application of TOBPs to remove toxic organic pollutants., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The natural antimicrobial peptide Polybia-MP1 is a promising candidate for developing new treatment therapy for infection and cancer. It showed broad-spectrum antimicrobial and anticancer activity with high safety on healthy cells. However, previous sequence modification usually resulted in at least one of two consequences: a notable increase in hemolytic activity or a considerable decrease in activity against Gram-negative bacteria and cancer cells. Herein, a new approach was applied by replacing the amino acid Glutamine at position 12 with Lysine and generating the MP1-Q12K analog. Our preliminary data suggested an enhancement in antibacterial and antifungal activity, whereas the anticancer and hemolytic activity of the two peptides were comparable. Moreover, MP1-Q12K was found to be less self-assembly than Polybia-MP1, which further supports the enhancement of antimicrobial properties. Hence, this study provides new information regarding the structure-activity relationships of Polybia-MP1 and support for the development of potent, selective antimicrobial peptides., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

One of the major challenges on the way to low-cost, simple, and effective cancer treatments is the lack of smart anticancer drug delivery materials with the requisite of site-specific and microenvironment-responsive properties. This work reports the development of plasma-engineered smart drug nanocarriers (SDNCs) containing chitosan and nitrogen-doped graphene quantum dots (NGQDs) for drug delivery in a pH-responsive manner. Through a customized microplasma processing, a highly cross-linked SDNC with only 4.5% of NGQD ratio can exhibit enhanced toughness up to threefold higher than the control chitosan group, avoiding the commonly used high temperatures and toxic chemical cross-linking agents. The SDNCs demonstrate improved loading capability for doxorubicin (DOX) via π-π interactions and stable solid-state photoluminescence to monitor the DOX loading and release through the Förster resonance energy transfer (FRET) mechanism. Moreover, the DOX loaded SDNC exhibits anticancer effects against cancer cells during cytotoxicity tests at minimum concentration. Cellular uptake studies confirm that the DOX loaded SDNC can be successfully internalized into the nucleus after 12 h incubation period. This work provides new insights into the development of smart, environmental-friendly, and biocompatible nanographene hydrogels for the next-generation biomedical applications., (© 2023 Wiley-VCH GmbH.)

Most lactobacilli produce extracellular polysaccharides that are considered to contribute to the probiotic effect of many strains. Lacticaseibacillus rhamnosus CNCM I-3690 is an anti-inflammatory strain able to counterbalance gut barrier dysfunction. In this study ten spontaneous variants of CNCM I-3690 with different EPS-production were generated and characterized by their ropy phenotype, the quantification of the secreted EPS and genetic analysis. Amongst them, two were further analysed in vitro and in vivo: an EPS over-producer (7292) and a low-producer derivative of 7292 (7358, with similar EPS levels than the wild type (WT) strain). Our results showed that 7292 does not have anti-inflammatory profile in vitro, and lost the capacity to adhere to the colonic epithelial cells as well as the protective effect on the permeability. Finally, 7292 lost the protective effects of the WT strain in a murine model of gut dysfunction. Notably, strain 7292 was unable to stimulate goblet cell mucus production and colonic IL-10 production, all key features for the beneficial effect of the WT strain. Furthermore, transcriptome analysis of colonic samples from 7292-treated mice showed a down-regulation of anti-inflammatory genes. Altogether, our results point out that the increase of EPS production in CNCM I-3690 impairs its protective effects and highlight the importance of the correct EPS synthesis for the beneficial effects of this strain., (© 2023. The Author(s).)

The American Society for Apheresis (ASFA) Journal of Clinical Apheresis (JCA) Special Issue Writing Committee is charged with reviewing, updating, and categorizing indications for the evidence-based use of therapeutic apheresis (TA) in human disease. In the Ninth Edition, the JCA Special Issue Writing Committee has incorporated systematic review and evidence-based approaches in the grading of evidence and categorization of apheresis indications to make recommendations on the use of apheresis in a wide variety of diseases and conditions. This edition has largely maintained the general layout and concept of a fact sheet introduced in the Fourth Edition (2007). Each fact sheet succinctly summarizes the evidence for the use of TA in a specific disease or medical condition. The Ninth Edition of the JCA Special Issue comprises 91 fact sheets and 166 graded and categorized indications. This includes seven new fact sheets, nine new indications on existing fact sheets, and eight changes in the category for existing indications. The Ninth Edition of the JCA Special Issue seeks to continue to serve as a key resource that guides the utilization of TA in the treatment of human disease., (© 2023 Wiley Periodicals LLC.)

Solid dispersions are typically binary systems with a hydrophilic matrix polymer and a lipophilic active substance. During formulation, the drug undergoes a crystalline to amorphous phase transition, which leads to a supersaturated solution providing enhanced bioavailability. The interaction of the active substance and the polymer is unique and influences the level of supersaturation. We aimed to investigate the relationship between low molecular weight polyethylene glycol derivates PEG 1000, 1500, and 2000 and ketoprofen regarding the effect of molecular weight. The physicochemical properties of solid dispersions prepared with hot melt homogenization and their respective physical mixtures were investigated with Fourier transform infrared spectroscopy, powder X-ray diffraction and scanning electron microscopy techniques. A phase solubility study was carried out in hydrochloric acid media which showed no difference between the three polymers, but the dissolution curves differed considerably. PEG 1000 had higher percentage of released drug than PEG 1500 and 2000, which had similar results. These results indicate that when multiple low molecular weight PEGs are suitable as matrix polymers of solid dispersions, the molecular weight has only limited impact on physicochemical characteristics and interactions and further investigation is needed to select the most applicable candidate.

T-cell receptors (TCRs) are formed by stochastic gene rearrangements, theoretically generating >10 19 sequences. They are selected during thymopoiesis, which releases a repertoire of about 10 8 unique TCRs per individual. How evolution shaped a process that produces TCRs that can effectively handle a countless and evolving set of infectious agents is a central question of immunology. The paradigm is that a diverse enough repertoire of TCRs should always provide a proper, though rare, specificity for any given need. Expansion of such rare T cells would provide enough fighters for an effective immune response and enough antigen-experienced cells for memory. We show here that human thymopoiesis releases a large population of clustered CD8 + T cells harboring α/β paired TCRs that (i) have high generation probabilities and (ii) a preferential usage of some V and J genes, (iii) which CDR3 are shared between individuals, and (iv) can each bind and be activated by multiple unrelated viral peptides, notably from EBV, CMV, and influenza. These polyspecific T cells may represent a first line of defense that is mobilized in response to infections before a more specific response subsequently ensures viral elimination. Our results support an evolutionary selection of polyspecific α/β TCRs for broad antiviral responses and heterologous immunity., Competing Interests: VQ Valentin Quiniou is affiliated with Parean biotechnologies. The author has no financial interests to declare, PB, VM, PS, HV, ZZ, FM, NC, MB, BC, HV, MS, AS, BB, RM, EM, DK No competing interests declared, HP Hang-Phuong Pham is affiliated with ILTOO pharma and Parean biotechnologies. The author hasno financial interests to declare, (© 2023, Quiniou et al.)

In this report, red-emitting alumina nanophosphors doped with Mn 4+ and Mg 2+ (Al 2 O 3 :Mn 4+ , Mg 2+ ) are synthesized by a hydrothermal method using a Pluronic surfactant. The prepared samples are ceramic-sintered at various temperatures. X-ray diffraction shows that Al 2 O 3 :Mn 4+ , Mg 2+ annealed at 500 °C exhibits a cubic γ-Al 2 O 3 phase with the space group Fd 3 m -227. The tetragonal δ-Al 2 O 3 and rhombohedral α-Al 2 O 3 phase is obtained at 1000 and 1300 °C, respectively. Cube-like nanoparticles in a size of ∼40 nm are observed for the alumina heated at 500-1000 °C. The size and red-emitting intensity of the phosphors remarkably increased with annealed temperature ∼1300 °C. Emission spectra of the phosphors show strong peaks at 678 and 692 nm due to 2 E g → 4 A 2 transitions of the Mn 4+ ion, under a light excitation of 460 nm. A strong zero-phonon line (ZPL) emission is observed in the luminescence spectra of δ-Al 2 O 3 :Mn 4+ , Mg 2+ at 298 K, whereas a weak one is observed in those of α- and γ-Al 2 O 3 :Mn 4+ , Mg 2+ . The alumina phosphors exhibited an excellent waterproof ability during 60 days in water and good thermal stability in the range of 77-573 K. A warm-white light-emitting diode (WLED) fabricated using In x Ga 1- x N nanowire chips with Al 2 O 3 :Mn 4+ , Mg 2+ red-emitting nanophosphors presents a high color rendering index of ∼95.1 and a low correlated color temperature of ∼4998 K. Moreover, the current-voltage characteristic of the nanowire LEDs could be improved using Al 2 O 3 :Mn 4+ , Mg 2+ nanophosphors which is attributed to the increased heat dissipation in the nanowire LEDs., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

BACKGROUND: Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia (AIHA). Information regarding the impact of CAD from the patient and health care system perspective is limited. OBJECTIVE: To understand longitudinal trends in outcomes in patients with CAD, including anemia severity, hemolytic status, administration of CAD-related therapies, and health care resource utilization (HCRU). METHODS: This retrospective, observational cohort study used data from the US Optum Electronic Health Record database. Included patients were aged 18 years and older at the index date (first CAD mention in physician"s notes), had 1 or more medical encounters with an AIHA-related diagnosis code during the study period, and had 3 or more CAD mentions during the patient identification period (January 2008 to March 2019). The baseline period was the 12 months preceding the index date. Anemia severity (severe, hemoglobin < 8.0 g/dL; moderate, 8.0-10.0 g/dL; mild, 10.1-11.9 g/dL; no anemia, ≥ 12.0 g/dL) and hemolytic status (elevated lactate dehydrogenase [LDH; > 250 μ/L] and/or elevated bilirubin [> 1.2 mg/dL]) were assessed at baseline and 6-monthly followup intervals. Use of CAD-related therapies, blood transfusions, and all-cause HCRU were analyzed every 6 months; results were stratified by anemia severity. RESULTS: The analysis included 610 adults with CAD (median [interquartile range; IQR] age 72.0 [61.0-78.0] years; 65.4% female). Median (IQR) duration of follow-up was 42.8 (22.8-68.4) months. The proportion of patients with moderate/severe anemia was 51.0% at baseline, 57.7% over 12 months' follow-up, and 66.6% over full follow-up. During the full follow-up period, approximately 50% of patients had elevated bilirubin and LDH levels. Corticosteroids were the most frequently used medication (65.6% of patients) over full follow-up. Mean (SD) number of blood transfusions per patient was 3.26 (9.21) over 12 months and 5.47 (17.11) over the full follow-up. At full follow-up, 68.7% of patients with severe anemia received a transfusion vs 12.6% and 0.0% with moderate or mild anemia, respectively. At 12 months, 34.1%, 97.7%, and 29.3% of patients had 1 or more hospitalizations, outpatient services, or emergency department visits (full follow-up: 52.5%, 99.0%, and 53.9%), respectively. Across all time periods, HCRU was greater in patients with severe anemia vs mild or moderate anemia. CONCLUSIONS: CAD imposed a substantial long-term burden on patients and health care systems, and despite the use of several therapies, hemolysis and anemia still occurred. The use of CAD-related therapies and HCRU was generally greater with greater anemia severity. These results suggest a lack of effective treatment options available for patients with CAD at the time of this analysis. DISCLOSURES: This study was sponsored by Sanofi. Dr Wilson, Dr Joly, Mr Carita, and Ms Miles are employees and stockholders of Sanofi. Dr Adeyemi was an employee and may have held stocks at Sanofi at the time of the study. Ms Miles and Ms Kuang were employees of Aetion Inc at the time of this study; Aetion Inc is a software company that received funding from Sanofi for the current study. Dr Pham is a consultant for Sanofi and Argenx.

Objectives: A regulatory T cell (Treg) insufficiency due to shortage of interleukin-2 (IL-2) is central to the pathophysiology of systemic lupus erythematosus (SLE). We performed a multicentre, double-blinded, randomised, placebo-controlled phase II proof-of-concept trial to evaluate the efficacy of low-dose IL-2 therapy in patients with SLE having moderate-to-severe disease activity while receiving standard treatment., Methods: We randomly assigned 100 patients in a 1:1 ratio to receive either 1.5 million IU/day of subcutaneous IL-2 (ILT-101) or placebo for 5 days followed by weekly injections for 12 weeks. Clinical efficacy was assessed at week 12 in a predefined hierarchical analysis of (1) the SLE responder index-4 (SRI-4) response as a primary end point, and of (2) relative and (3) absolute changes in the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index scores as key secondary end points., Results: The primary end point was not met in the intention-to-treat population (ILT-101: 68%, placebo: 58%; p=0.3439), due to a 100% SRI-4 response rate in the placebo group from the two sites from Bulgaria. A post hoc per-protocol analysis on a prespecified population that excluded patients from these two sites (n=53) showed a statistically significant difference for the SRI-4 response rate (ILT-101: 83.3%; placebo: 51.7%; p=0.0168), and for the two key secondary end points, accompanied by differences in several secondary exploratory end points. ILT-101 was well tolerated and there was no generation of antidrug antibodies., Conclusions: The post hoc hierarchical analysis of the primary and key secondary end points in a per-protocol population, complemented by the exploratory analyses of multiple other secondary end points, support that low-dose IL-2 is beneficial in active SLE., Trial Registration Number: NCT02955615., Competing Interests: Competing interests: PC, MR and DK are inventors for patents related to the therapeutic use of IL-2, which belongs to their academic institutions and have been licensed to ILTOO Pharma in which they hold interests. HPP, JG, DL and TV are employees of ILTOO Pharma., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: CD70 is a costimulatory molecule known to activate CD27-expressing T cells. CD27-CD70 interaction leads to the release of soluble CD27 (sCD27). Clear-cell renal cell carcinoma (ccRCC) expresses the highest levels of CD70 among all solid tumors; however, the clinical consequences of CD70 expression remain unclear., Experimental Design: Tumor tissue from 25 patients with ccRCC was assessed for the expression of CD27 and CD70 in situ using multiplex immunofluorescence. CD27+ T-cell phenotypes in tumors were analyzed by flow cytometry and their gene expression profile were analyzed by single-cell RNA sequencing then confirmed with public data. Baseline sCD27 was measured in 81 patients with renal cell carcinoma (RCC) treated with immunotherapy (35 for training cohort and 46 for validation cohort)., Results: In the tumor microenvironment, CD27+ T cells interacted with CD70-expressing tumor cells. Compared with CD27- T cells, CD27+ T cells exhibited an apoptotic and dysfunctional signature. In patients with RCC, the intratumoral CD27-CD70 interaction was significantly correlated with the plasma sCD27 concentration. High sCD27 levels predicted poor overall survival in patients with RCC treated with anti-programmed cell death protein 1 in both the training and validation cohorts but not in patients treated with antiangiogenic therapy., Conclusions: In conclusion, we demonstrated that sCD27, a surrogate marker of T-cell dysfunction, is a predictive biomarker of resistance to immunotherapy in RCC. Given the frequent expression of CD70 and CD27 in solid tumors, our findings may be extended to other tumors., (©2022 American Association for Cancer Research.)

Background: The Coronavirus Disease 2019 (COVID-19) pandemic in early 2020 has resulted in an unprecedented level of uncertainty and challenge for the stem cell donor registries. To address these challenges, rapid strategies were implemented by the National Marrow Donor Registry (NMDP) and its network partners. Herein, we aim to report the impact of the COVID-19 pandemic on the collection, utilization of grafts, and short-term outcomes of patients who received stem cell products from COVID-19-positive donors., Methods: NMDP data during the early phase (1 March 2020 through 1 May 2020) of the pandemic were compared to the later phase (1 March 2021 through 1 May 2021). Odds ratios were calculated to determine the impact of the pandemic on graft sources requested by transplant centers (TCs). The Kruskal-Wallis test was used to test the effect of the pandemic on the disease indication, volume of searches, and number of products not infused., Results: Although there was an initial decline in overall donor searches during the early phase of the pandemic, these numbers increased reaching pre-pandemic levels during the later phase. Urgent malignant diseases remained the most common indication for transplant in 2021. The pandemic necessitated cryopreservation of stem cell products due to transportation restrictions as well as clinical uncertainties in managing the virus. Cryopreserved grafts remained the most common requested grafts throughout the pandemic. In the later phase of the pandemic, the total numbers of requests for fresh grafts increased, mostly due to the increase in requests for fresh bone marrow (BM) grafts. As the pandemic continued, TCs became more accepting of cryopreservation, resulting in a reduction in the number of products not infused. Lastly, no short-term deleterious outcomes were noted among the patients who had stem cell products infused from a SARS-CoV-2-positive donor., Conclusion: Throughout the pandemic, the NMDP and TCs worked tirelessly to ensure that patients would receive lifesaving grafts when needed. The data reported here, although limited by small numbers, illustrate that transplantation from donors with COVID-19 is feasible and safe., Competing Interests: JNe, JNo, JB, EN, JO, MC, HP, JA, JM, SD and HS are employees of the National Marrow Donor Program. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Farhadfar, Newman, Novakovich, Barten, Ndifon, Oakes, Cody, Pham, Auletta, Miller, Devine and Stefanski.)

Von Willebrand factor (VWF) level and/or function is altered in von Willebrand disease (VWD), the most common heritable bleeding disorder worldwide. Laboratory assessment of VWF is continually evolving. Historically, the primary method for the assessment of VWF platelet-binding activity was the ristocetin cofactor assay (VWF:RCo). Contemporary alternative measures of VWF platelet-binding activity include VWF:GPIbR (recombinant; using ristocetin), VWF:GPIbM (recombinant; gain-of-function mutant), and monoclonal antibody. Recently, the American Society of Hematology, International Society on Thrombosis and Haemostasis, National Hemophilia Foundation, and World Federation of Hemophilia collaboration issued guidelines recommending the use of newer assays of VWF platelet-binding activity (VWF: GPIbM, VWF: GPIbR) over VWF:RCo, given known limitations of the VWF:RCo assay. Despite this recommendation, the newer VWF:GPIbM and VWF:GPIbR assays are not United States Food and Drug Administration cleared, limiting their availability in the United States. We sought to assess assay utilization trends, agreement of VWF testing methods, and imprecision of VWF testing (based on assigned sample type) from the College of American Pathologists Proficiency Testing Surveys. The analysis confirms that, while VWF antigen testing has low imprecision, the various VWF activity assays have significant interassay variability, with VWF:RCo showing greater imprecision than the newer GPIb-binding assays. The overall trends in assay utilization reflect the barriers to complete compliance with modern VWD diagnostic guidelines in North America., Competing Interests: None declared., (Thieme. All rights reserved.)

In the gut ecosystem, microorganisms regulate group behaviour and interplay with the host via a molecular system called quorum sensing (QS). The QS molecule 3-oxo-C12:2-HSL, first identified in human gut microbiota, exerts anti-inflammatory effects and could play a role in inflammatory bowel diseases where dysbiosis has been described. Our aim was to identify which signalling pathways are involved in this effect. We observed that 3-oxo-C12:2-HSL decreases expression of pro-inflammatory cytokines such as Interleukine-1β (- 35%) and Tumor Necrosis Factor-α (TNFα) (- 40%) by stimulated immune RAW264.7 cells and decreased TNF secretion by stimulated PBMC in a dose-dependent manner, between 25 to 100 µM. Transcriptomic analysis of RAW264.7 cells exposed to 3-oxo-C12:2-HSL, in a pro-inflammatory context, highlighted JAK-STAT, NF-κB and TFN signalling pathways and we confirmed that 3-oxo-C12:2-HSL inhibited JAK1 and STAT1 phosphorylation. We also showed through a screening assay that 3-oxo-C12:2-HSL interacted with several human bitter taste receptors. Its anti-inflammatory effect involved TAS2R38 as shown by pharmacologic inhibition and led to an increase in intracellular calcium levels. We thus unravelled the involvement of several cellular pathways in the anti-inflammatory effects exerted by the QS molecule 3-oxo-C12:2-HSL., (© 2022. The Author(s).)

Upon infection, B lymphocytes develop clonal responses. In teleost fish, which lack lymph nodes, the kinetics and location of B cell responses remain poorly characterized. Fish pronephros is the site of B cell differentiation and the main niche for persistence of plasma cells. In this study, we undertook the analysis of the rainbow trout IgHμ repertoire in this critical tissue for humoral adaptive immunity after primary immunization and boost with a rhabdovirus, the viral hemorrhagic septicemia virus (VHSV). We used a barcoded 5' RACE-cDNA sequencing approach to characterize modifications of the IgHμ repertoire, including VH usage in expressed V(D)J rearrangements, clonal diversity, and clonotype sharing between individual fish and treatments. In the pronephros, our approach quantified the clonotype frequency across the whole IgH repertoire (i.e., with all VH), measuring the frequency of Ag-responding clonotypes. Viral infection led to extensive modifications of the pronephros B cell repertoire, implicating several VH subgroups after primary infection. In contrast, only modest changes in repertoire persisted 5 mo later, including VHSV-specific public expansions. The IgM public response implicating IgHV1-18 and JH5, previously described in spleen, was confirmed in pronephros in all infected fish, strongly correlated to the response. However, the distribution of top clonotypes showed that pronephros and spleen B cells constitute distinct compartments with different IgH repertoires. Unexpectedly, after boost, the frequency of anti-VHSV clonotypes decreased both in pronephros and spleen, raising questions about B cell circulation. A better monitoring of B cell response kinetics in lymphoid tissues will be an essential step to understand B memory and plasmocyte formation mechanisms in fish., (Copyright © 2022 by The American Association of Immunologists, Inc.)

Background: Identifying differentially expressed genes between experimental conditions is still the gold-standard approach to interpret transcriptomic profiles. Alternative approaches based on diversity measures have been proposed to complement the interpretation of such datasets but are only used marginally., Methods: Here, we reinvestigated diversity measures, which are commonly used in ecology, to characterize mice pregnancy microenvironments based on a public transcriptome dataset. Mainly, we evaluated the Tsallis entropy function to explore the potential of a collection of diversity measures for capturing relevant molecular event information., Results: We demonstrate that the Tsallis entropy function provides additional information compared to the traditional diversity indices, such as the Shannon and Simpson indices. Depending on the relative importance given to the most abundant transcripts based on the Tsallis entropy function parameter, our approach allows appreciating the impact of biological stimulus on the inter-individual variability of groups of samples. Moreover, we propose a strategy for reducing the complexity of transcriptome datasets using a maximation of the beta diversity., Conclusions: We highlight that a diversity-based analysis is suitable for capturing complex molecular events occurring during physiological events. Therefore, we recommend their use through the Tsallis entropy function to analyze transcriptomics data in addition to differential expression analyses., Competing Interests: The authors do not declare any conflict of interest.

Background: Prostate cancer (PC) responds to androgen deprivation therapy (ADT) usually in a transient fashion, progressing from hormone-sensitive PC (HSPC) to castration-resistant PC (CRPC). We investigated a mouse model of PC as well as specimens from PC patients to unravel an unsuspected contribution of thymus-derived T lymphocytes and the intestinal microbiota in the efficacy of ADT., Methods: Preclinical experiments were performed in PC-bearing mice, immunocompetent or immunodeficient. In parallel, we prospectively included 65 HSPC and CRPC patients (Oncobiotic trial) to analyze their feces and blood specimens., Results: In PC-bearing mice, ADT increased thymic cellularity and output. PC implanted in T lymphocyte-depleted or athymic mice responded less efficiently to ADT than in immunocompetent mice. Moreover, depletion of the intestinal microbiota by oral antibiotics reduced the efficacy of ADT. PC reduced the relative abundance of Akkermansia muciniphila in the gut, and this effect was reversed by ADT. Moreover, cohousing of PC-bearing mice with tumor-free mice or oral gavage with Akkermansia improved the efficacy of ADT. This appears to be applicable to PC patients because long-term ADT resulted in an increase of thymic output, as demonstrated by an increase in circulating recent thymic emigrant cells (sjTRECs). Moreover, as compared with HSPC controls, CRPC patients demonstrated a shift in their intestinal microbiota that significantly correlated with sjTRECs. While feces from healthy volunteers restored ADT efficacy, feces from PC patients failed to do so., Conclusions: These findings suggest the potential clinical utility of reversing intestinal dysbiosis and repairing acquired immune defects in PC patients., Competing Interests: Competing interests: LZ and GK are scientific cofounders of everImmune, a company that develops bacteria for the treatment of cancer. GK is a scientific cofounder of Samsara Therapeutics and Therafast Bio. Acknowledgments: LZ laboratory was supported by the Germano-French ANR Ileobiome—19-CE15-0029-01 and H2020 ONCOBIOME N°825410, RHU Torino Lumière ANR-16-RHUS-0008; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE). GK is supported by Agence Nationale de la Recherche (ANR)—Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Association 'Ruban Rose'; Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); Gustave Roussy Odyssea, the European Union Horizon 2020 Projects Oncobiome and Crimson; Fondation Carrefour; Institut National du Cancer (INCa); Inserm (HTE); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); the Leducq Foundation; the and SIRIC Cancer Research and Personalized Medicine (CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. AMT and EC are supported by the French Government’s Investissement d’Avenir Program, Laboratoire d’Excellence 'Milieu Intérieur' Grant ANR-10-LABX-69-01. INSERM U.1160 is a member of OPALE Carnot Institute, The Organization for Partnerships in Leukemia. MG-H and DGM are supported by the grant funding NIH/NCI P01 CA250927., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Tenosynovial giant cell tumor (TSGCT) is a slow-growing soft tissue tumor that develops from the synovial tissue of tendon sheaths, joints, or bursae. In the knee, this type of tumor is uncommon. Giant cell tumors of the cruciate ligaments' tendon sheath are far more infrequent. Only 16 localized TSGCTs of the cruciate ligaments have been recorded in the literature to our knowledge, with 9 involving the anterior cruciate ligament (ACL) and 7 involving the posterior cruciate ligament (PCL)., Case Presentation: We present a rare case of localized TSGCT arising from the PCL's femoral insertion in a 44-year-old male, as well as a literature review on localized TSGCT of cruciate ligaments in the knee. The diagnosis of tumor's presence was made using MRI while the definitive diagnosis was obtained through intraoperative evaluation and postoperative pathology., Conclusion: Arthroscopic tumor resection was an effective and safe treatment option based on the available data., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Context.—: Assessing direct oral anticoagulant (DOAC) drug levels by reliable laboratory assays is necessary in a number of clinical scenarios., Objective.—: To evaluate the performance of DOAC-specific assays for various concentrations of dabigatran and rivaroxaban, assess the interlaboratory variability in measurement of these DOACs, and investigate the responsiveness of the routine clotting assays to various concentrations of these oral anticoagulants., Design.—: College of American Pathologists proficiency testing survey data from 2013 to 2016 were summarized and analyzed., Results.—: For dabigatran, the interlaboratory coefficient of variation (CV) of ecarin chromogenic assay was broad (ranging from 7.5% to 29.1%, 6.3% to 15.5%, and 6.8% to 9.0% for 100-ng/mL, 200-ng/mL, and 400-ng/mL targeted drug concentrations, respectively). The CV for diluted thrombin time for dabigatran was better overall (ranging from 11.6% to 17.2%, 9.3% to 12.3, and 7.1% to 11.2% for 100 ng/mL, 200 ng/mL, and 400 ng/mL, respectively). The rivaroxaban-calibrated anti-Xa assay CVs also showed variability (ranging from 11.5% to 22.2%, 7.2% to 10.9%, and 6.4% to 8.1% for 50-ng/mL, 200-ng/mL, and 400-ng/mL targeted drug concentrations, respectively). The prothrombin time (PT) and activated partial thromboplastin time (aPTT) showed variable dose- and reagent-dependent responsiveness to DOACs: PT was more responsive to rivaroxaban and aPTT to dabigatran. The undiluted thrombin time showed maximum prolongation across all 3 dabigatran concentrations, making it too sensitive for drug-level monitoring, but supporting its use as a qualitative screening assay., Conclusions.—: DOAC-specific assays performed reasonably well. While PT and aPTT cannot be used safely to determine DOAC degree of anticoagulation, a normal thrombin time excludes the presence of dabigatran.

The coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become a global health concern. The development of vaccines with high immunogenicity and safety is crucial for controlling the global COVID-19 pandemic and preventing further illness and fatalities. Here, we report the development of a SARS-CoV-2 vaccine candidate, Nanocovax, based on recombinant protein production of the extracellular (soluble) portion of the spike (S) protein of SARS-CoV-2. The results showed that Nanocovax induced high levels of S protein-specific IgG and neutralizing antibodies in three animal models: BALB/c mouse, Syrian hamster, and a non-human primate ( Macaca leonina ). In addition, a viral challenge study using the hamster model showed that Nanocovax protected the upper respiratory tract from SARS-CoV-2 infection. Nanocovax did not induce any adverse effects in mice ( Mus musculus var. albino) and rats ( Rattus norvegicus ). These preclinical results indicate that Nanocovax is safe and effective., Competing Interests: All authors except TTL, DCV and LKHN were employed by Nanogen Pharmaceutical Biotechnology Joint Stock Company (JSC). The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tran, May, Ung, Nguyen, Nguyen, Dinh, Doan, Tran, Khong, Nguyen, Hua, Nguyen, Ha, Phan, Nguyen, Bui, Tu, Nguyen, Le, Dong, Huynh, Ho, Le, Truong, Pham, Luong, Y, Cao, Nguyen, Le, Vuong, Nguyen and Do.)

Neutrophils are an integral component of the innate immune system and key regulators of cell-mediated defense against bacterial and fungal pathogens. The potential of granulocyte transfusions has been investigated to temporarily replenish innate immune function to prevent and/or treat infections in patients with severe neutropenia or neutrophil dysfunction. However, evidence has been largely theoretical, experimental, and/or inconclusive. Clinical efficacy has yet to be confirmed by large-scale randomized controlled clinical trials. Performing such trials has been hampered by low granulocyte collection yield and poor patient accrual. We provide a practical summary of the current literature surrounding the practice of granulocyte transfusion., Competing Interests: Disclosure H.P. Pham is a consultant for Sanofi and a speaker for Alexion. All other authors declared no conflict of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)