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Background: The sophisticated behavioral and cognitive repertoires of non-human primates (NHPs) make them suitable subjects for studies involving cocaine self-administration (SA) schedules. However, ethical considerations, adherence to the 3Rs principle (replacement, reduction and refinement), and other factors make it challenging to obtain NHPs individuals for research. Consequently, there is a need for methods that can comprehensively analyze small datasets using artificial intelligence (AI)., New Methods: We employed AI to identify cocaine dependence patterns from collected data. First, we collected behavioral data from cocaine SA marmosets (Callithrix jacchus) to develop a dependence prediction model. SHapley Additive exPlanations (SHAP) values were used to demonstrate the importance of various variables. Additionally, we collected positron emission tomographic (PET) images showing dopamine transporter (DAT) binding potential and developed an algorithm for PET image segmentation., Results: The prediction model indicated that the Random Forest (RF) algorithm performed best, with an area under the curve (AUC) of 0.92. The top five variables influencing the model were identified using SHAP values. The PET image segmentation model achieved an accuracy of 0.97, a mean squared error of 0.02, an intersection over union (IoU) of 0.845, and a Dice coefficient of 0.913., Comparison With Existing Methods and Conclusion: Utilizing data from the marmoset SA experiment, we developed an ML-based dependence prediction model and analyzed variable importance rankings using SHAP. AI-based imaging segmentation methods offer a valuable tool for evaluating DAT availability in NHPs following chronic cocaine administration., 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 © 2024. Published by Elsevier B.V.)

Background: Although bispecific T-cell engager (BiTE) is a promising treatment for relapsed/refractory multiple myeloma (RRMM), it needs to be evaluated in a real-world setting., Objective: This study aimed to evaluate the efficacy and safety of BiTEs compared with a synthetic standard of care (SOC)., Study Design: From a multicenter registry database of 474 patients with RRMM who received third- or more advanced-line treatments between January 2021 and October 2023, 1:1 propensity score-matched BiTE cohort (n = 71) and SOC cohort (n = 71) were established. Matching was based on age, sex, number of prior therapies, international staging system at diagnosis, and baseline biochemical characteristics., Results: Compared with the matched SOC cohort, the matched BiTE cohort demonstrated a significant improvement in median progression-free survival (PFS, 19.2 vs 5.4 months, hazard ratio (HR) = 0.50 [95% CI, 0.33-0.78], p < 0.01). However, the overall survival (OS) was not significantly different between the two cohorts. Safety profiles showed that 37 (52%) patients in the matched BiTE cohort experienced cytokine release syndrome, mostly grade 1 (n = 29, 41%), with rare occurrences of neurotoxicity (n = 4, 5.6%). Infections were significantly more common in the matched BiTE cohort compared with the matched SOC cohort (81% vs. 49%, p < 0.01). Non-B-cell mutation antigen (BCMA)-targeted BiTEs improved 6-month OS rates compared with BCMA-targeted BiTEs in monotherapy (94% [95% CI, 84-100] vs. 65% [95% CI, 45-95], p = 0.04) and combination with daratumumab (100% [95% CI, 100-100] vs. 77% [95% CI, 57-100], p = 0.20). Non-BCMA-targeted BiTEs also provided benefit for 6-month PFS rate compared with the BCMA-targeted BiTE cohort in monotherapy (76% [95% CI, 59-100] vs. 50% [95% CI, 31-82], p = 0.11) and combination with daratumumab (100% [95% CI, 100-100] vs. 69% [95% CI, 48-99], p = 0.10). Quantitative bias and sensitivity analyses confirmed the robustness of these results., Conclusions: This real-world data-based study underscores the potential of BiTEs to significantly enhance survival outcomes in patients with heavily treated RRMM and manageable safety profiles. The difference in clinical outcomes by BiTE targets warrants further investigation in larger clinical trials (ClinicalTrials.gov identifier: NCT06205823)., Competing Interests: Conflict of interest disclosure The authors declare no competing financial interests., (Copyright © 2024. Published by Elsevier Inc.)

Carfilzomib, lenalidomide, and dexamethasone (KRd) combination therapy improves the survival of patients with relapsed and/or refractory multiple myeloma (RRMM). Nonetheless, evidence on the use of KRd in Asian populations remains scarce. Accordingly, this study aimed to investigate this regimen's efficacy in a large group of patients. This retrospective study included patients with RRMM who were treated with KRd at 21 centers between February 2018 and October 2020. Overall, 364 patients were included (median age, 63 years). The overall response rate was 90% in response-evaluable patients, including 69% who achieved a very good partial response or deeper responses. With a median follow-up duration of 34.8 months, the median progression-free survival (PFS) was 23.4 months and overall survival (OS) was 59.5 months. Among adverse factors affecting PFS, high-risk cytogenetics, extramedullary disease, and doubling of monoclonal protein within 2-3 months prior to start of KRd treatment significantly decreased PFS and OS in multivariate analyses. Patients who underwent post-KRd stem cell transplantation (i.e., delayed transplant) showed prolonged PFS and OS. Grade 3 or higher adverse events (AE) were observed in 56% of the patients, and non-fatal or fatal AE that resulted in discontinuation of KRd were reported in 7% and 2% of patients, respectively. Cardiovascular toxicity was comparable to that reported in the ASPIRE study. In summary, KRd was effective in a large, real-world cohort of patients with RRMM with long-term follow-up. These findings may further inform treatment choices in the treatment of patients with RRMM.

We evaluated the safety and efficacy of allogeneic, ex-vivo expanded, NK cells, MG4101, in patients with refractory or relapsed AML. The relationship between immunological characteristics and clinical responses was analyzed. Between April 2018 and February 2020, 11 patients (male:female = 5:6) were treated with MG4101. Of eight evaluable patients, two (25.0%) showed partial response and two (25.0%) showed stable disease. The median overall survival was 3.4 months (95% confidence interval [95% CI], 2.5-4.3 months), and the allogeneic hematopoietic stem cell transplantation (HSCT) censored duration of response was 2.9 months (95% CI, 1.5-4.4 months). Two patients underwent HSCT after MG4101 treatment. Except for one grade 3 infusion-related reaction, no serious adverse events were observed. The sum of activating KIRs in responders tended to be higher than that in non-responders. Analyses of NKRL and KIR highlighted the importance of immunological mechanisms in treating myeloid neoplasms.

Tandem autologous stem cell transplantation can improve the prognosis of patients with multiple myeloma. However, the precise role of tandem transplantation remains debatable. We evaluated the clinical benefits of tandem transplantation retrospectively. Of the 655 included patients, 117 underwent tandem transplantation; the remaining were assigned to the control group. After a single transplantation, the tandem group achieved a complete remission (CR) rate of 24.8%, which increased to 46.2% after a second transplantation. The tandem group had a significantly longer median PFS than the control group in patients with International Staging System (ISS) III and high-risk cytogenetics (23.1 vs. 14.7 months, p = 0.007 for ISS III; 21.7 vs. 13.2 months, p = 0.042 for high-risk cytogenetics). The tandem group exhibited significantly superior PFS to the control group (20.3 vs. 12.6 months, p = 0.003) among patients who failed to achieve CR after a single transplantation. Tandem transplantation was associated with significantly improved PFS after adjusting for maintenance therapy in patients with ISS III, those with high-risk cytogenetics, and those who did not achieve CR after a single transplantation. Following propensity score matching, the tandem group exhibited significantly longer PFS than the control group (30.3 vs. 13.5 months, p = 0.028). Tandem transplantation should be considered in high-risk patients., (© 2024. The Author(s).)

The role of imatinib in PDGFRA/B-negative hypereosinophilic syndromes (HES) is controversial because of the heterogeneity of HES and the scarcity of prospective studies. We conducted a phase II clinical trial to evaluate the efficacy of imatinib in PDGFRA/B-negative HES. Thirty-two patients were treated with imatinib (100-400 mg daily), and the molecular basis of their response was identified using whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS). The haematological response rate was 46.9%, with a complete haematological response (CHR) rate of 18.8%. The median time to response was 1.5 months. Among the six patients who achieved CHR, five maintained it until the 24th cycle of imatinib and one lost response after 20 months. The median progression-free survival was 4.3 months. WES and WTS were conducted for 11 patients. The number of non-silent mutations did not differ between responders and non-responders. Nine differentially expressed genes, including SNORD15A, were downregulated in responders. STAT5B::RARA, PAK2::PIGX, and FIP1L1::CHIC2 fusions were identified in patients with sustained responses, and RNF130::BRAF and WNK1::KDM5A fusions were identified in non-responders. Imatinib, along with an appropriate biomarker, could be a promising option for PDGFRA/B-negative HES., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

The poultry red mite (PRM), Dermanyssus gallinae, significantly impacts the health of egg-laying hens. Mites feed on the blood of infested chickens and have a great economic impact on the poultry industry. Chemical treatment of mites raises concerns about their resistance to miticides and residues in eggs and poultry. Biocontrol using entomopathogenic fungi is expected to be a chemical-free strategy for reducing PRM infestations. Therefore, the present study aimed to investigate the effects of various entomopathogenic fungal species collected in South Korea on the inhibition of PRM. Seventeen strains of six fungal species collected from various sources were used to evaluate acaricidal activity against PRM. The results showed that 16/17 strains had acaricidal properties against PRM, of which strains of Metarhizium anisopliae had the highest acaricidal activity. Mites treated with M. anisopliae CBNU 4-2 showed 100 % mortality 5 d after inoculation, followed by M. flavoviride var. pemphigi. The M. flavoviride var. pemphigi CBNU 1-1-1 showed 97.78 % mortality after 10 d of exposure to fungi. The mortality rate of PRM treated with other strains slowly increased and reached its highest value on the 14th day of inoculation. The results of this study provide information on the acaricidal activity of different entomopathogenic fungi against PRM. This information is important for the selection of fungal species for developing biocontrol methods for PRM treatment. These strains could be used for further evaluation of PRM treatment on chicken farms, or in combination with other methods, to increase PRM treatment efficiency., Competing Interests: Declaration of Competing Interest The authors report there are no competing interests to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

A light-weight actuator developed in this work belongs to a class of soft robots, and in a sense, resembles an octopus. Its main function is in the attachment or detachment to a solid surface driven by an electro-thermopneumatic mechanism. In this study, a suction cup similar to that of an octopus is manufactured from an elastomer, which is actuated by an electro-thermopneumatic system, mimicking the movement of the octopus' acetabular muscle. Accordingly, the adhesion force generated by such an actuator is regulated by releasing the inner air or adjusting the cup's elasticity. This actuator is designed to be an assistive device that facilitates the individual's physical strength in case of conditions related to aging or cerebellar disease, or a person who lost limbs. In this study, the actuator capabilities are demonstrated in the form of a grip-assisting glove and prosthetic attacher. Moreover, the adhesion mechanism is quantified by numerical simulations and verified experimentally.

Extended-spectrum β -lactamase (ESBL)-producing Salmonella is emerging as a worldwide public health concern. In this study, we aimed to investigate the antimicrobial resistance profiles and molecular characteristics of ESBL-producing Salmonella enterica serovar Typhimurium ( S. Typhimurium). We obtained a total of 995 S. Typhimurium isolates from the feces and carcasses of pigs ( n = 678), chickens ( n = 202), and cattle ( n = 115) during 2010-2021 in Korea. We found that 35 S. Typhimurium isolates (3.5%) showed resistance to ceftiofur: pigs (51.4%, 18/35) and cattle (42.9%, 15/35). All of the ceftiofur-resistant S. Typhimurium isolates demonstrated multidrug resistance. Moreover, ceftiofur-resistant S. Typhimurium isolates displayed significantly higher rates of resistance to chloramphenicol and trimethoprim/sulfamethoxazole than ceftiofur-susceptible S. Typhimurium isolates ( p < 0.05). The ceftiofur-resistant S. Typhimurium isolates produced four different CTX-M-type β -lactamase, comprising bla CTX-M-55 in the majority (51.4%, 18/35), followed by bla CTX-M-65 (28.6%, 10/35), bla CTX-M-14 (17.1%, 6/35), and bla CTX-M-1 (2.9%, 1/35). Among the 35 ceftiofur-resistant S. Typhimurium isolates, 16 bla CTX-M-55 -positive isolates and one bla CTX-M-1 -positive isolate were transferred to recipient Escherichia coli RG488 by conjugation. The predominantly found transposable units were bla CTX-M-55 - orf477 (45.7%, 16/35), followed by bla CTX-M-65 -IS 903 (28.6%, 10/35) and bla CTX-M-14 -IS 903 (17.1%, 6/35). Ceftiofur-resistant S. Typhimurium represented 19 types, with types P1-19 (22.9%, 8/35) and P12-34 (22.9%, 8/35) making up the majority and being found in most farms nationwide. Sequence types (STs) were different by animal species: ST19 (48.6%, 17/35) and ST34 (42.9%, 15/35) were mostly found STs in pigs and cattle, respectively. These findings showed that food animals, especially pigs and cattle, act as reservoirs of bla CTX-M -harboring S. Typhimurium that can potentially be spread to humans.

Background: Gram-positive bacteria are frequently resistant to empirical beta-lactams in febrile neutropenic patients with cancer. As microbiology and antibiotic susceptibility changes, we reevaluated the risk factors for resistant Gram-positive bacteremia in febrile neutropenic patients with cancer., Methods: Episodes of bacteremic febrile neutropenia in Seoul National University Hospital from July 2019 to June 2022 were reviewed. Resistant Gram-positive bacteria were defined as a pathogen susceptible only to glycopeptide or linezolid in vitro (e.g., methicillin-resistant staphylococci, penicillin-resistant viridans streptococci, and ampicillin-resistant enterococci). Episodes were compared to identify independent risk factors for resistant Gram-positive bacteremia., Results: Of 225 episodes, 78 (34.7%) involved resistant Gram-positive bacteremia. Multivariate analysis revealed that breakthrough bacteremia while being administered antibiotics (adjusted odds ratio [aOR], 6.794; 95% confidence interval [95% CI], 3.130-14.749; P < 0.001) and catheter-related infection (aOR 4.039, 95% CI 1.366-11.946; P = 0.012) were associated with resistant Gram-positive bacteremia. Chronic liver disease (aOR 0.231, 95% CI 0.059-0.905; P = 0.035) and hypotension at bacteremia (aOR 0.454, 95% CI 0.218-0.945; P = 0.035) were inversely associated with resistant Gram-positive bacteremia., Conclusions: Resistant Gram-positive bacteria should be considered in breakthrough bacteremia and catheter-related infection in febrile neutropenic patients with cancer., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background: Lysosomal dysfunction (LD) impacts cytokine regulation, inflammation, and immune responses, influencing the development and progression of cancer. Inflammation is implicated in the pathogenesis of myeloproliferative neoplasm (MPN). With a hypothesis that LD significantly contributes to MPN carcinogenesis by inducing abnormal inflammation, our objective was to elucidate the pathophysiological mechanisms of MPN arising from an LD background., Methods: Genotyping of the LD background was performed in a cohort of MPN patients (n = 190) and healthy controls (n = 461). Logistic regression modeling, utilizing genotype data, was employed to estimate the correlation between LD and MPN. Whole transcriptome sequencing (WTS) (LD carriers = 8, non-carriers = 6) and single-cell RNA sequencing data (LD carriers = 2, non-carriers = 2, healthy controls = 2) were generated and analyzed., Results: A higher variant frequency of LD was observed in MPN compared to healthy controls (healthy, 4.9%; MPN, 7.8%), with the highest frequency seen in polycythemia vera (PV) (odds ratio = 2.33, p = 0.03). WTS revealed that LD carriers exhibited upregulated inflammatory cytokine ligand-receptor genes, pathways, and network modules in MPNs compared to non-carriers. At the single-cell level, there was monocyte expansion and elevation of cytokine ligand-receptor interactions, inflammatory transcription factors, and network modules centered on monocytes. Notably, Oncostatin-M (OSM) consistently emerged as a candidate molecule involved in the pathogenesis of LD-related PV., Conclusions: In summary, an LD background is prevalent in MPN patients and leads to increased cytokine dysregulation and inflammation. OSM, as one of the potential molecules, plays a crucial role in PV pathogenesis by impairing lysosomal function., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Importance: Glutamic acid decarboxylase 67 (GAD67) is a gamma-aminobutyric acid (GABA) synthesis enzyme associated with the function of other neurotransmitter receptors, such as the N-methyl-D-aspartate (NMDA) receptor and cannabinoid receptor 1. However, the role of GAD67 in the development of different abused drug-induced reward behaviors remains unknown. In order to elucidate the mechanisms of substance use disorder, it is crucial to study changes in biomarkers within the brain's reward circuit induced by drug use., Objective: The study was designed to examine the effects of the downregulation of GAD67 expression in the dorsal striatum on reward behavior development., Methods: We evaluated the effects of GAD67 knockdown on depression-like behavior and anxiety using the forced swim test and elevated plus maze test in a mouse model. We further determined the effects of GAD67 knockdown on ketamine- and JWH-018-induced conditioned place preference (CPP)., Results: Knockdown of GAD67 in the dorsal striatum of mice increased depression-like behavior, but it decreased anxiety. Moreover, the CPP score on the NMDA receptor antagonist ketamine was increased by GAD67 knockdown, whereas the administration of JWH-018, a cannabinoid receptor agonist, did not affect the CPP score in the GAD67 knockdown mice group compared with the control group., Conclusions and Relevance: These results suggest that striatal GAD67 reduces GABAergic neuronal activity and may cause ketamine-induced NMDA receptor inhibition. Consequently, GAD67 downregulation induces vulnerability to the drug reward behavior of ketamine., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Korean Society of Veterinary Science.)

Background: Herbal medicine Ja-Geum-Jeong (JGJ) has been used for the treatment of detoxification in Eastern Asia. However, the mechanisms involved are not clearly defined. The purpose of the present study was to investigate if herb medication inhibits Methamphetamine (METH)'s reinforcing effect and also examined if a combination of herb medication and acupuncture produces a synergistic effect on METH., Methods: Male Sprague-Dawley rats were given acute METH intraperitoneally and the locomotor activity and ultrasonic vocalization (USV) calls were measured. Rats were administered JGJ orally and acupuncture was given at HT7 or SI5. Monosodium glutamate (MSG) and gamma-aminobutyric acid (GABA) agonists were injected into the Central amygdala (CeA) to investigate a possible neuroscientific mechanism. Tyrosine hydroxylase (TH) and fast scan cyclic voltammetry (FSCV) were measured to immunohistochemically and electrically confirm the behavioral data., Results: Locomotor activity and USV calls were increased by METH ( P < 0.05) and these increases were inhibited by JGJ ( P < 0.05). Also, JGJ had no effect on the normal group given saline, and acupuncture at SI5 acupoint, but not at HT7 acupoint, produced a synergistic effect when combined with JGJ ( P < 0.05). The JGJ's inhibition was blocked by the inactivation of CeA ( P < 0.05), and MSG mimicked JGJ ( P < 0.05). TH and FSCV measures showed the same pattern with the behavioral data ( P < 0.05)., Conclusion: Results of the present study suggest that JGJ had inhibitory effects on the METH which was mediated through the activation of CeA and that combination of acupuncture and herb produced synergistic effect., Competing Interests: The authors declare no competing interests., (© 2024 Korea Institute of Oriental Medicine. Published by Elsevier B.V.)

Background and Purpose: α-Pyrrolidinobutiothiophenone (α-PBT) is a chemical derivative of cathinone, a structural analogue of amphetamine. Until now, there have been a few previous neurochemical or neurobehavioural studies on the abuse potential of α-PBT., Experimental Approach: We examined the abuse potential of α-PBT by measuring psychomotor, rewarding, and reinforcing properties and methamphetamine-like discriminative stimulus effects in rodents using locomotor activity, conditioned place preference, self-administration, and drug discrimination studies. To clarify the underlying neuropharmacological mechanisms, we measured dopamine levels and neuronal activation in the dorsal striatum. In addition, we investigated the role of the dopamine D 1 receptor or D 2 receptors in α-PBT-induced hyperlocomotor activity, conditioned place preference, and the methamphetamine-like discriminative stimulus effect of α-PBT in rodents., Key Results: α-PBT promoted hyperlocomotor activity in mice. α-PBT induced drug-paired place preference in mice and supported self-administration in rats. In a drug discrimination experiment, α-PBT fully substituted for the discriminative stimulus effects of methamphetamine in rats. Furthermore, α-PBT increased dopamine levels and c-Fos expression in the dorsal striatum of mice, which was associated with these behaviours. Finally, pretreatment with the D 1 receptor antagonist SCH23390 or the D 2 receptors antagonist eticlopride significantly attenuated acute or repeated α-PBT-induced hyperlocomotor activity, place preference, and the methamphetamine-like discriminative stimulus effects in rodents., Conclusions and Implications: These findings suggest that α-PBT has abuse potential at the highest dose tested via enhanced dopaminergic transmission in the dorsal striatum of rodents. The results provide scientific evidence for the legal restrictions of the recreational use of α-PBT., (© 2024 British Pharmacological Society.)

Bortezomib-induced neuropathic pain (BINP) poses a challenge in multiple myeloma (MM) treatment. Genetic factors play a key role in BINP susceptibility, but research has predominantly focused on Caucasian populations. This research explored novel genetic risk loci and pathways associated with BINP development in Korean MM patients while evaluating the reproducibility of variants from Caucasians. Clinical data and buffy coat samples from 185 MM patients on bortezomib were collected. The cohort was split into discovery and validation cohorts through random stratification of clinical risk factors for BINP. Genome-wide association study was performed on the discovery cohort (n = 74) with Infinium Global Screening Array-24 v3.0 BeadChip (654,027 single nucleotide polymorphism [SNPs]). Relevant biological pathways were identified using the pathway scoring algorithm. The top 20 SNPs were validated in the validation cohort (n = 111). Previously reported SNPs were validated in the entire cohort (n = 185). Pathway analysis of the genome-wide association study results identified 31 relevant pathways, including immune systems and endosomal vacuolar pathways. Among the top 20 SNPs from the discovery cohort, 16 were replicated, which included intronic variants in ASIC2 and SMOC2, recently implicated in nociception, as well as intergenic variants or long noncoding RNAs. None of the 17 previously reported SNPs remained significant in our cohort (rs2274578, P = .085). This study represents the first investigation of novel genetic loci and biological pathways associated with BINP occurrence. Our findings, in conjunction with existing Caucasian studies, expand the understanding of personalized risk prediction and disease mechanisms. PERSPECTIVE: This article is the first to explore novel genetic loci and pathways linked to BINP in Korean MM patients, offering novel insights beyond the existing research focused on Caucasian populations into personalized risk assessment and therapeutic strategies of BINP., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

The occurrence of extended-spectrum β-lactamase (ESBL)/AmpC β-lactamase-producing Salmonella conferring resistance to third-generation cephalosporin has emerged as a global public health concern. In this study, we aimed to investigate the prevalence and molecular characterization of third-generation cephalosporin-resistant Salmonella enterica serovar Infantis. In total, 409  S. Infatis isolates were collected from the feces and carcasses of healthy and diseased food animals, including chickens (n = 348), pigs (n = 48), cattle (n = 8), and ducks (n = 5) between 2010 and 2022 nationwide in South Korea. Among them, 61.9 % (253/409) of S. Infantis strains displayed resistance to ceftiofur, with the most resistant isolates obtained from chickens (98.4 %, 249/253). Moreover, S. Infantis isolates showed high resistance (47.7-67.2 %) to streptomycin, ampicillin, nalidixic acid, sulfisoxazole, chloramphenicol, tetracycline, and trimethoprim/sulfamethoxazole. Additionally, the multidrug resistance (MDR) was significantly greater in the ceftiofur-resistant isolates compared to the ceftiofur-susceptible isolates ( p  < 0.05). All the ceftiofur-resistant S. Infantis strains produced CTX-M/CMY-2 β-lactamase enzymes, with bla CTX-M-65 comprising the most (98.4 %, 249/253), followed by bla CTX-M-15 (1.2 %, 3/253), and bla CMY-2 (0.4 %, 1/253). The ceftiofur-resistant S. Infantis belonged to 37 different pulsotypes, with X1A1 (26.1 %, 66/253), X1A2 (20.9 %, 53/253), and X5A3 (9.1 %) being the most prevalent, representing a total of 56.1 % (142/253). Furthermore, the S. Infantis sequence type (ST)32 was the most common, accounting for 91.9 % (34/37) of the three distinct STs (ST32, ST16, and ST11) detected across farms located in various provinces nationwide. Most of the bla CMX-M-65 genes (77.5 %, 193/249), all of the bla CTX-M-15 genes (100 %, 3/3), and the bla CMY-2 gene (100 %, 1/1) were transferred to the recipient E. coli RG488 by conjugation. In addition, the majority of the transconjugants (98.9 %, 191/193) containing bla CTX-M-65 genes belong to the IncFIB replicon type, playing an important role in the quick and widespread dissemination of S. Infantis. Thus, ceftiofur-resistant S. Infantis carrying the β-lactamase genes in chickens has the potential to be transmitted to humans., Competing Interests: The authors declare that there are no competing interests., (© 2024 Published by Elsevier Ltd.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Mosunetuzumab is a CD20xCD3 T-cell-engaging bispecific antibody administered as an off-the-shelf, fixed-duration treatment in an outpatient setting. We report an updated analysis of the durability of response, by investigator assessment, after an overall median follow-up of 3.5 years in patients with relapsed/refractory indolent or aggressive B-cell non-Hodgkin lymphoma (iNHL/aNHL) from the dose-escalation stage of a phase I/II study of mosunetuzumab (ClinicalTrials.gov identifier: NCT02500407). Across dose levels, 65.7% of patients with iNHL and 36.4% with aNHL achieved a complete or partial response to mosunetuzumab. Median duration of response (DoR) in patients with iNHL for all responders was 23.2 months (95% CI, 13.8 to not estimable [NE]), but was not reached in complete responders (95% CI, 21.0 to NE). After a median time on study of 38.9 months, no relapses were observed beyond 26 months in complete responders. In patients with aNHL, median DoR for all responders was 7.8 months (95% CI, 4.6 to 22.8). Among 12 complete responders who progressed postmosunetuzumab treatment and were retreated with mosunetuzumab, 83.3% had an objective response and 58.3% achieved a second complete response. Our study reports the longest follow-up using bispecific antibodies in patients with B-cell non-Hodgkin lymphoma and demonstrates that mosunetuzumab can mediate durable remissions with time-limited treatment.

The outcomes of patients with myeloma after exposed to penta-classes are extremely poor. Selinexor is the first approved exportin inhibitor for those patients, but intractable toxicities may limit its use. This retrospective study evaluated the real-world efficacy and safety of selinexor plus dexamethasone (XD) and involved 48 patients with multiple myeloma, who were treated from November 2020 to October 2022. Their median age was 64 years, and the median number of prior lines of therapy was 6. The overall response rate was 25%, and the median progression-free survival (PFS) was 2.1 months (95% confidence interval (CI), 1.7-2.5). Patients on a reduced initial dose, delayed treatment, and dose reduction had better PFS. After XD treatment failure, 17 patients received subsequent therapy and had a median PFS of 2.4 months. The median overall survival was 4.6 months (95% CI, 2.3-6.9). Among the patients, 12 (25%) and 17 (35%) experienced dose reduction and delayed treatment, respectively. Our data show that the real-world efficacy of XD treatment in heavily pretreated patients was modest and that improving treatment adherence through reducing initial doses or delaying treatments may improve patient outcomes., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Osteolytic bone lesion is a major cause of lower quality of life and poor prognosis in patients with multiple myeloma (MM), but molecular pathogenesis of the osteolytic process in MM remains elusive. Fms-like tyrosine kinase 3 ligand (FLT3L) was reported to be elevated in bone marrow (BM) and blood of patients with advanced MM who often show osteolysis. Here, we investigated a functional link of FLT3L to osteolytic process in MM. We recruited 86, 306, and 52 patients with MM, acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL), respectively. FLT3L levels of patients with hematologic malignancies were measured in BM-derived plasma and found to be significantly higher in MM than in AML or ALL, which rarely show osteolysis. FLT3L levels were further elevated in MM patients with bone lesion compared with patients without bone lesion. In vitro cell-based assays showed that the administration of FLT3L to HEK293T, HeLa, and U2OS cells led to an increase in the DKK1 transcript level through STAT3 phosphorylation at tyrosine 705. WNT reporter assay showed that FLT3L treatment reduced WNT signaling and nuclear translocation of β-catenin. These results collectively show that the FLT3L-STAT3-DKK1 pathway inhibits WNT signaling-mediated bone formation in MM, which can cause osteolytic bone lesion. Finally, transcriptomic profiles revealed that FLT3L and DKK1 were predominantly elevated in the hyperdiploidy subtype of MM. Taken together, FLT3L can serve as a promising biomarker for predicting osteolytic bone lesion and also a potential therapeutic target to prohibit the progression of the osteolytic process in MM with hyperdiploidy.

Recently, the abuse of synthetic cathinones is increasing among young people. α-Pyrrolidinobutiothiophenone (α-PBT), a synthetic cathinone, is a designer drug that is freely traded online with no legal restrictions. Moreover, there is currently no scientific basis for legal regulation. Here, we examined the addictive properties of α-PBT using a drug discrimination (DD) task. We also investigated the role of α-PBT in brain stimulation reward (BSR) using an intracranial self-stimulation (ICSS) paradigm in rats. Initially, the rats were trained to discriminate between cocaine and saline. After the discrimination training criteria were met, we determined the dose-effect curves of cocaine and conducted generalization tests with α-PBT and α-pyrrolidinopentiothiophenone (α-PVT) using a cumulative dosing protocol. In a separate set of studies, we examined the dopaminergic mechanisms underlying the function of α-PBT as an interoceptive stimulus (17.8 mg/kg) by intraperitoneally injecting either the dopamine (DA) D1 antagonist SCH23390 (0.06 and 0.12 mg/kg) or the D2 antagonist eticlopride (0.05 and 0.1 mg/kg) 15 min before DD testing. Brain reward function was measured using an ICSS procedure to examine the effects of α-PBT on ICSS threshold under the frequency-rate procedure. Our results showed that α-PBT functioned as a discriminative cue similar to cocaine in rats. More importantly, SCH23390 abolished the effects of α-PBT as an interoceptive stimulus in a dose-dependent manner in rats trained to press a lever to receive cocaine. Similarly, eticlopride dose-dependently attenuated the effect of α-PBT used as a discriminative cue. Additionally, cumulative α-PBT administration dose-dependently lowered ICSS thresholds compared with those in saline-treated rats. Furthermore, α-PBT-induced potentiation of BSR was abolished by pretreatment with both SCH23390 and eticlopride. Taken together, our results suggest that α-PBT can function as a cocaine-like discriminative cue via the activation of D1 and D2 receptors. α-PBT also appears to influence BSR by reducing the brain reward threshold via changes in D1 and D2 receptors. The present study suggests that α-PBT could have addictive properties through DA D1 and D2 receptors and thus poses a threat to humans.

This study aimed to assess the efficacy of dual T-cell suppression using individually tailored doses of antithymocyte globulin (ATG) and attenuated dose of post-transplant cyclophosphamide (PTCy) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We conducted a retrospective analysis of 78 adults with acute leukemia or myelodysplastic syndrome who underwent haplo-HSCT using intravenous busulfan and fludarabine conditioning. Thirty-two patients received attenuated ATG/PTCy, while 46 patients received ATG (7.5 mg/kg) as GVHD prophylaxis. The 100-day cumulative incidence of grade III-IV (9.7% vs. 32.4%, P = 0.018) acute GVHD, as well as 2-year moderate-severe chronic GVHD (13.9% vs. 43.9%, P = 0.018) in the ATG/PTCy group were significantly lower than those in the ATG group. The 2-year overall survival was comparable between the two groups. However, 2-year GVHD-free, relapse-free survival in the ATG/PTCy group was significantly higher compared to that in the ATG group (38.9% vs. 21.7%, P = 0.021). Moreover, during post-engraftment period, the ATG/PTCy group exhibited lower incidences of life-threatening bacterial (12.5% vs. 37%, P = 0.033) and viral infection (0% vs. 17.4%, P = 0.035) than the ATG group. In conclusion, the combination of individually tailored ATG and low-dose PTCy appears to be a promising strategy in haplo-HSCT., (© 2024. The Author(s).)

Serious infection is common in patients with multiple myeloma due to immune deficiency from the underlying disease and/or its treatment. Immunoglobulin replacement is one approach to reduce infection risk in these patients. However, few real-world data exist on its use in patients with myeloma. We investigated immunoglobulin use in Australia, New Zealand and Asia-Pacific using registry data and explored its association with survival outcomes. A total of 2374 patients with a median follow-up time of 29.5 months (interquartile range 13.3-54.3 months) were included in the analysis - 1673 from Australia, 313 Korea, 281 New Zealand and 107 Singapore. Overall, 7.1% of participants received immunoglobulin replacement within 24 months of diagnosis. Patients who received immunoglobulin replacement were likely to be younger, had lower baseline IgG levels (excluding paraprotein), were more likely to have baseline hypogammaglobulinaemia, baseline severe hypogammaglobulinaemia and abnormal baseline fluorescent in-situ hybridisation status, receive first-line myeloma treatment with immunomodulatory drugs or anti-CD38 therapy and undergo upfront autologous stem cell transplant. In our patient cohort, the use of immunoglobulin was not associated with overall survival benefit at the time of last follow-up (adjusted hazard ratio 0.72, 95% CI 0.46-1.14, p  = 0.16). Understanding treatment approaches in clinical practice can help support future planning and provision of immunoglobulin resources., Competing Interests: This research project did not receive any specific grant from funding agencies in the public, commercial or not‐for‐profit sectors. However, the ANZ MRDR has received funding from Abbvie, Amgen, Antengene, Bristol‐Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi and Takeda. The APAC MRDR has received funding from Janssen Asia‐Pacific. Monash University has received funding from CSL Behring for other projects., (© 2024 The Author(s). eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Rationale & Objective: Atypical hemolytic uremic syndrome (aHUS) is a rare form of thrombotic microangiopathy (TMA) caused by complement dysregulation. Ravulizumab is a C5i approved for the treatment of aHUS. This analysis assessed long-term outcomes of ravulizumab in adults and pediatric patients with aHUS., Study Design: This analysis reports 2-year data from 2 phase 3, single-arm studies., Setting & Participants: One study included C5i-naïve adults (NCT02949128), and the other included 2 cohorts of pediatric patients (C5i-naïve and those who switched to ravulizumab from eculizumab [pediatric switch patients]; NCT03131219)., Exposure: Patients received intravenous ravulizumab every 4-8 weeks, with the dose depending on body weight., Outcomes: The primary endpoint in the studies of C5i-naïve patients was complete TMA response, which consisted of platelet count normalization, lactate dehydrogenase normalization, and ≥25% improvement in serum creatinine concentrations from baseline, at 2 consecutive assessments ≥4 weeks apart., Analytical Approach: All analyses used descriptive statistics. No formal statistical comparisons were performed., Results: In total, 86 and 92 patients were included in efficacy and safety analyses, respectively. Complete TMA response rates over 2 years were 61% and 90% in C5i-naïve adults and pediatric patients, respectively. The median increase in estimated glomerular filtration rate from baseline was maintained over 2 years in C5i-naïve adults (35 mL/min/1.73 m 2 ) and pediatric patients (82.5 mL/min/1.73 m 2 ). Most adverse events and serious adverse events occurred during the first 26 weeks. No meningococcal infections were reported. Improvement in the Functional Assessment of Chronic Illness Therapy - Fatigue score achieved by 26 weeks was maintained over 2 years., Limitations: Limitations were the small sample of pediatric switch patients and limited availability of genetic data., Conclusions: Long-term treatment with ravulizumab is well tolerated and associated with improved hematologic and renal parameters and quality of life in adults and pediatric patients with aHUS., (© 2024 The Authors.)

Introduction: Patients with hematologic malignancies (HMs) often face challenges in accessing palliative care (PC) and receiving quality end-of-life (EOL) care. We examined factors associated with referrals to tertiary PC and the effects of tertiary PC on EOL care in patients with HMs., Method: We included patients with HMs who were admitted to a university-affiliated hospital and died during hospitalization between January 2018 and December 2021. We investigated the receipt of PC consultations, patient characteristics, and EOL care indicators., Results: Overall, 487 patients were included in the analysis, with 156 (32%) undergoing PC consultation. Sex, residence, disease status, and admission purpose were factors associated with the likelihood of PC consultation, and there has been an increasing trend in the frequency of consultations in recent cases. A higher proportion of patients who received PC completed advance statements and life-sustaining treatment documents. Patients who received PC had lower rates of aggressive EOL care, including chemotherapy and intensive care unit admission, than those who did not receive PC. Notably, PC reduced the number of blood transfusions., Conclusion: Tertiary PC aims to reduce aggressive EOL care through patient-centered goal-of-care discussions. Therefore, there is an imperative need for concerted efforts toward seamless integration of PC., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Respiratory viral infection increases host susceptibility to secondary bacterial infections, yet the precise dynamics within airway epithelia remain elusive. Here, we elucidate the pivotal role of CD47 in the airway epithelium during bacterial super-infection. We demonstrated that upon influenza virus infection, CD47 expression was upregulated and localized on the apical surface of ciliated cells within primary human nasal or bronchial epithelial cells. This induced CD47 exposure provided attachment sites for Staphylococcus aureus, thereby compromising the epithelial barrier integrity. Through bacterial adhesion assays and in vitro pull-down assays, we identified fibronectin-binding proteins (FnBP) of S. aureus as a key component that binds to CD47. Furthermore, we found that ciliated cell-specific CD47 deficiency or neutralizing antibody-mediated CD47 inactivation enhanced in vivo survival rates. These findings suggest that interfering with the interaction between airway epithelial CD47 and pathogenic bacterial FnBP holds promise for alleviating the adverse effects of super-infection., (© 2024. The Author(s).)

The chronic use of the novel synthetic cathinone mexedrone, like other psychoactive drugs, can be considered addictive, with a high potential for abuse and the ability to cause psychological dependence in certain users. However, little is known about the neurobehavioral effects of mexedrone in association with its potential for abuse. We investigated the abuse potential for mexedrone abuse through multiple behavioral tests. In addition, serotonin transporter (SERT) levels were measured in the synaptosome of the dorsal striatum, and serotonin (5-HT) levels were measured in the dorsal striatum of acute mexedreone (50 mg/kg)-treated mice. To clarify the neuropharmacological mechanisms underlying the locomotor response of mexedrone, the 5-HT2A receptor antagonist M100907 (0.5 or 1.0 mg/kg) was administered prior to the acute injection of mexedrone in the locomotor activity experiment in mice. Mexedrone (10-50 mg/kg) produced a significant place preference in mice and mexedrone (0.1-0.5 mg/kg/infusion) maintained self-administration behavior in rats in a dose-dependent manner. In the drug discrimination experiment, mexedrone (5.6-32 mg/kg) was fully substituted for the discriminative stimulus effects of cocaine in rats. Mexedrone increased locomotor activity, and these effects were reversed by pretreatment with M100907. Acute mexedrone significantly increased c-Fos expression in the dorsal striatum and decreased SERT levels in the synaptosome of the dorsal striatum of mice, resulting in an elevation of 5-HT levels. Taken together, our results provide the possibility that mexedrone has abuse potential, which might be mediated, at least in part, by the activation of the serotonergic system in the dorsal striatum., Competing Interests: Declaration of competing interest The authors declare no competing interests related to the present study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

In this study, we identified a new strain of the genus Neocypholaelaps from the beehives of Apis mellifera colonies in the Republic of Korea (ROK). The Neocypholaelap sp. KOR23 mites were collected from the hives of honeybee apiaries in Wonju, Gangwon-do, in May 2023. Morphological and molecular analyses based on 18S and 28S rRNA gene regions conclusively identified that these mites belong to the genus Neocypholaelaps, closely resembling Neocypholaelaps sp. APGD-2010 that was first isolated from the United States. The presence of 9 of 25 honeybee pathogens in these mite samples suggests that Neocypholaelaps sp. KOR23 mite may act as an intermediate vector and carrier of honeybee diseases. The identification of various honeybee pathogens within this mite highlights their significance in disease transmission among honeybee colonies. This comprehensive study provides valuable insights into the taxonomy and implications of these mites for bee health management and pathogen dissemination., Competing Interests: No authors have competing interests, (Copyright: © 2024 Nguyen 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.)

Venetoclax-azacitidine is approved for treatment of patients with newly diagnosed acute myeloid leukemia (AML) ineligible for intensive chemotherapy based on the interim overall survival (OS) analysis of the VIALE-A study (NCT02993523). Here, long-term follow-up is presented to address survival benefit and long-term outcomes with venetoclax-azacitidine. Patients with newly diagnosed AML who were ineligible for intensive chemotherapy were randomized 2:1 to receive venetoclax-azacitidine or placebo-azacitidine. OS was the primary endpoint; complete remission with/without blood count recovery (CR/CRi) was a key secondary endpoint. This final analysis was conducted when 100% of the predefined 360 OS events occurred. In VIALE-A, 431 patients were enrolled to venetoclax-azacitidine (n = 286) or placebo-azacitidine (n = 145). At 43.2 months median follow-up, median OS was 14.7 months (95% confidence interval [CI], 12.1-18.7) with venetoclax-azacitidine, and 9.6 months (95% CI, 7.4-12.7) with placebo-azacitidine (hazard ratio, 0.58 [95% CI, 0.47-0.72], p < .001); the estimated 24-month OS rate was 37.5% and 16.9%, respectively. Median OS for patients with IDH1/2 mutations and those with measurable residual disease responses was reached in this final analysis. CR/CRi rate was similar to interim analysis. Any-grade hematologic and gastrointestinal adverse events were most common in venetoclax-azacitidine and placebo-azacitidine arms, including thrombocytopenia (47% and 42%) and neutropenia (43% and 29%). No new safety signals were identified. Long-term efficacy and safety confirm venetoclax-azacitidine is an improvement in standard-of-care for patients with AML who are not eligible for intensive chemotherapy because of advanced age or comorbidities., (© 2024 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Background: Acute myeloid leukemia (AML) is characterized by clonal heterogeneity, leading to frequent relapses and drug resistance despite intensive clinical therapy. Although AML's clonal architecture has been addressed in many studies, practical monitoring of dynamic changes in those subclones during relapse and treatment is still understudied., Method: Fifteen longitudinal bone marrow (BM) samples were collected from three relapsed and refractory (R/R) AML patients. Using droplet digital polymerase chain reaction (ddPCR), the frequencies of patient's leukemic variants were assessed in seven cell populations that were isolated from each BM sample based on cellular phenotypes. By quantifying mutant clones at the diagnosis, remission, and relapse stages, the distribution of AML subclones was sequentially monitored., Results: Minimal residual (MR) leukemic subclones exhibit heterogeneous distribution among BM cell populations, including mature leukocyte populations. During AML progression, these subclones undergo active phenotypic transitions and repopulate into distinct cell population regardless of normal hematopoiesis hierarchic order. Of these, MR subclones in progenitor populations of patient BM predominantly carry MR leukemic properties, leading to more robust expansion and stubborn persistence than those in mature populations. Moreover, a minor subset of MR leukemic subclones could be sustained at an extremely low frequency without clonal expansion during relapse., Conclusions: In this study, we observed treatment persistent MR leukemic subclones and their phenotypic changes during the treatment process of R/R AML patients. This underscores the importance of preemptive inhibition of clonal promiscuity in R/R AML, proposing a practical method for monitoring AML MR subclones., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Large granular lymphocytic (LGL) leukemia is a clonal lymphoproliferative disorder of LGLs derived from cytotoxic T lymphocytes or natural killer cells. However, the clinical features and treatment responses are still not fully understood because of the rarity of the disease. To describe and assess a cohort of patients with T-cell large granular lymphocytic leukemia (T-LGLL). Single-center, retrospective, observational study. We retrospectively collected the clinical data of patients diagnosed with T-LGLL at Seoul National University Hospital since 2006. We included 67 patients in this study. The median age at diagnosis was 60 years. Additionally, 37 patients (55%) were symptomatic, and 25 (37%) had splenomegaly; 54 patients (81%) required treatment. Cyclophosphamide (n = 35), methotrexate (n = 25), and cyclosporin A (n = 19) were used most frequently for treatment, and their overall response rates were similar: cyclophosphamide (77%), methotrexate (64%), and cyclosporin A (63%). Splenomegaly was associated with an increased response rate to first-line therapy and a decreased complete response rate. Thrombocytopenia was associated with decreased response rates to cyclophosphamide, methotrexate, cyclosporin A, and steroids. In contrast, a high LGL number (> 2000/µL) in the peripheral blood smear was associated with increased response rates to cyclophosphamide, methotrexate, cyclosporin A, and steroids. This study describes the clinical features and treatment outcomes of patients with T-LGLL, providing valuable information for clinical decision-making regarding T-LGLL treatment., (© 2023. The Author(s).)

Purpose: Despite the recent success of Bruton's tyrosine kinase (BTK) inhibitors for the treatment of Waldenstrom macroglobulinemia (WM), their indefinite treatment duration ultimately tantamount to substantial financial and emotional burden. On the other hand, fixed duration of proteasome inhibitors (PI) have shown rapid and reasonable response in WM treatment. Despite the well-known synergism between PI and immunomodulatory drugs (IMiD), there is no trials evaluating such combination in WM., Materials and Methods: Based on above, we designed this phase II study to investigate the efficacy and safety of 6 cycles of 28-day bortezomib-thalidomide-dexamethasone (VTD) regimen for treatment-naïve WM., Results: A total of 15 patients were enrolled: major response rate was 64.3%, and overall response rate was 78.6%. During the median follow-up of 41 months, median progression-free survival (PFS) was 13 months and overall survival 40 months. For responders, median duration of response was 13 months and median PFS 19 months. The most common adverse event (AE) of any grade was constipation (57.1%). The most common grade ≥ 3 AE was anemia (21.4%)., Conclusion: All in all, we hereby provide proof-of-concept that PI + IMiD may be an attractive backbone for fixed duration treatment. It should be noted that granting the same level of access to newer drugs globally is virtually impossible. Thus efforts to develop regimens using readily available drugs to yield similar or adequate treatment outcomes should not be disregarded. In this sense, we believe our study holds its place for its novelty and eloquently addresses achieving the daunting societal quest of health equity.

Potential synergism between Bruton's tyrosine kinase (BTK) inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab (R2A) in patients with aggressive relapsed/refractory aggressive (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint of this study is objective response rate (ORR), and the secondary endpoints are complete remission (CR) rate, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). A total of 66 patients are enrolled mostly with diffuse large B-cell lymphoma. The ORR is 54.5% and CR rate is 31.8% meeting the primary end point. The median DoR is 12.9 months, and 1-year PFS and OS rate is 33.1% and 67.5% respectively. Adverse events (AE) are manageable with the most frequent AE being neutropenia (31.8%). Patients with MYD88 mutations, subtypes known for NF-κB activation, and high BTK expression by immunohistochemistry respond well. Overall, these results show a significant efficacy of the R2A regimen in patients with aggressive R/R B-cell NHL, with exploratory biomarkers suggesting potential associations with response. (ClinicalTrials.gov 51 identifier: NCT04094142)., (© 2024. The Author(s).)