bluuebunny/crossref_metadata_2025 huggingface dataset:
Size selection of intrahepatic lesions for cryoablation contributes to abscopal effect and long-term survival in patients with liver metastatic melanoma receiving PD-1 blockade therapy
Authors: Shen Lujun , Tan Hongtong , Nie Juan , Jiang Yiquan , Nuerhashi Gulijiayina , Qi Han , Cao Fei , Wen Chunyong , Chen Shuanggang , Zhang Tianqi , Zheng Wei , Liu Peng , Liu Ying , Huang Tao , Li Dandan , Zhang Xiaoshi , Fan Weijun
Published: March 2024

Objectives

In this study, we aimed to examine parameters of cryoablation, tumor characteristics, and their correlations with distant tumor response and survival of liver metastatic melanoma patients receiving cryoablation and PD-1 blockade (cryo-PD-1) combination treatment.

Materials and methods

A retrospective study was conducted among 45 melanoma patients who received combined PD-1 blockade therapy and cryoablation for liver metastasis from 2018 to 2022. Cox regression was utilized to determine the associations between factors and overall survival (OS). Changes in cytokines and immune cell compositions in peripheral blood samples following the combined treatment were investigated, along with their correlations with treatment response.

Results

The mean cycle of cryo-PD-1 combination treatment was 2.2 (range, 1–6), and the 3-month overall response rate (RECIST 1.1 criteria) was 26.7%. Of the 21 patients who failed previous PD-1 blockade therapy after diagnosis of liver metastasis, 4 (19.0%) achieved response within 3 months since combination treatment. The diameter of ablated lesion  ≤ 30 mm, metastatic organs  ≤ 2, and pre-treatment LDH level  ≤ 300 U/L were independent prognostic factors for favorable OS. Further analysis showed patients with intrahepatic tumor size of 15–45 mm, and ablated lesion size of  ≤ 30 mm had significantly higher 3-month response rate (42.9% vs 12.5%; P = 0.022) and survival time (30.5 vs 14.2 months; P = 0.045) than their counterparts. The average increase in NLR among patients with ablated tumor size of  ≤ 3 cm and  > 3 cm were 3.59 ± 5.01 and 7.21 ± 12.57, respectively. The average increase in serum IL-6 levels among patients with ablated tumor size of  ≤ 3 cm and  > 3 cm were 8.62 ± 7.95 pg/ml and 15.40 ± 11.43 pg/ml, respectively.

Conclusion

Size selection of intrahepatic lesions for cryoablation is important in order to achieve abscopal effect and long-term survival among patients with liver metastatic melanoma receiving PD-1 blockade therapy.
Outcomes in biomarker-selected subgroups from the KESTREL study of durvalumab and tremelimumab in recurrent or metastatic head and neck squamous cell carcinoma
Authors: Seiwert Tanguy Y. , Wildsmith Sophie , Fayette Jérôme , Harrington Kevin , Gillison Maura , Ahn Myung-Ju , Takahashi Shunji , Weiss Jared , Machiels Jean-Pascal , Baxi Shrujal , Baker Valerie , Evans Brent , Morsli Nassim , Jill Walker  , Real Katia , L’Hernault Anne , Psyrri Amanda
Published: March 2024

Background

Selective biomarkers may improve outcomes in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitor therapy. We investigated three independent biomarkers for association with efficacy in the randomized, phase III KESTREL study (NCT02551159) of first-line durvalumab monotherapy or durvalumab plus tremelimumab versus the EXTREME regimen: programmed cell death ligand-1 (PD-L1) immunohistochemistry, blood tumor mutational burden (bTMB) via circulating tumor DNA, and neutrophil-to-lymphocyte ratio (NLR).

Methods

Tumor or blood samples from patients enrolled in the KESTREL study were analyzed for PD-L1, bTMB, and NLR. Associations with overall survival (OS) or objective response rates (ORRs) were evaluated based on prespecified cut-offs for PD-L1 (tumor cell [TC] ≥ 50%/immune cell ≥ 25% or TC ≥ 25%), bTMB (≥ 16 mutations [mut] per megabase [Mb]), and NLR (≤ 7). Ad hoc analyses of exploratory cut-offs were performed.

Results

Prespecified or exploratory cut-offs for PD-L1 did not enrich for ORR or OS for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME. In the bTMB ≥ 16 mut/Mb subgroup, OS hazard ratios (95% confidence interval) for durvalumab monotherapy and durvalumab plus tremelimumab versus EXTREME were 0.90 (0.48–1.72) and 0.69 (0.39–1.25), respectively. Complete response rates were 8.6% with durvalumab plus tremelimumab and 4.3% with EXTREME (≥ 16 mut/Mb subgroup). No improvement in OS was observed for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME at prespecified or exploratory NLR cut-offs.

Conclusions

bTMB demonstrated potential utility for selecting patients with R/M HNSCC who benefited from durvalumab with or without tremelimumab versus EXTREME.

Trial registration ClinicalTrials.gov identifier NCT02551159.
Integrating molecular subtype and CD8+ T cells infiltration to predict treatment response and survival in muscle-invasive bladder cancer
Authors: Li Bingyu , Jin Kaifeng , Liu Zhaopei , Su Xiaohe , Xu Ziyue , Liu Ge , Xu Jingtong , Liu Hailong , Chang Yuan , Wang Yiwei , Zhu Yu , Wang Zewei , Xu Le , Zhang Weijuan
Published: March 2024

Background

Luminal and Basal are the primary intrinsic subtypes of muscle-invasive bladder cancer (MIBC). The presence of CD8+ T cells infiltration holds significant immunological relevance, potentially influencing the efficacy of antitumor responses. This study aims to synergize the influence of molecular subtypes and CD8+ T cells infiltration in MIBC.

Methods

This study included 889 patients with MIBC from Zhongshan Hospital, The Cancer Genome Atlas, IMvigor210 and NCT03179943 cohorts. We classified the patients into four distinct groups, based on the interplay of molecular subtypes and CD8+ T cells and probed into the clinical implications of these subgroups in MIBC.

Results

Among patients with Luminal-CD8+Thigh tumors, the confluence of elevated tumor mutational burden and PD-L1 expression correlated with a heightened potential for positive responses to immunotherapy. In contrast, patients featured by Luminal-CD8+Tlow displayed a proclivity for deriving clinical advantages from innovative targeted interventions. The Basal-CD8+Tlow subgroup exhibited the least favorable three-year overall survival outcome, whereas their Basal-CD8+Thigh counterparts exhibited a heightened responsiveness to chemotherapy.

Conclusions

We emphasized the significant role of immune-molecular subtypes in shaping therapeutic approaches for MIBC. This insight establishes a foundation to refine the process of selecting subtype-specific treatments, thereby advancing personalized interventions for patients.
Mechanism exploration of Zoledronic acid combined with PD-1 in the treatment of hepatocellular carcinoma
Authors: Fan Xinru , Yan Zijun , Lin Yunkai , Wang Qing , Jiang Li , Yao Xiaomeng , Dong Liwei , Chen Lei , Zhao Tuan , Zhao Jieqiong , Hu Heping , Wang Hui
Published: March 2024

How to increase the response of immune checkpoint inhibitors (ICIs) is a challenge. In clinical, we found that Zoledronic acid (ZA) may increase the anti-tumor effect of immunotherapy for hepatocellular carcinoma (HCC). To explore the underlying mechanism, we established a mouse model of HCC by subcutaneously injecting Hepa1-6 cell line. The result showed that the tumor volume in the ZA plus anti-PD-1 monocloning antibody (anti-PD-1 mAb) treatment groups was significantly smaller than that of control group, and the onset time of tumor inhibition was even shorter than that of the anti-PD-1 mAb group. Using flow cytometry (FC) to detect the proportion of major immune cell subsets in tumor tissues of each group of mice, we found that the synergistic anti-tumor effect of ZA and anti-PD-1 mAb may be related to ZA-induced polarization of macrophages toward the M1 phenotype. Next, we performed bulk RNA sequencing on tumor samples from different groups to obtain differentially expressed genes (DEGs), which were then input DEGs into pathway enrichment analysis. Data indicated that ZA participated in the M1-type polarization via ferroptosis-related pathways. Our results revealed how ZA involves in the anti-tumor effect of PD-1 monoclonal antibody and provided a potential therapeutic candidate for patients with HCC.
Construction of an immune predictive model and identification of TRIP6 as a prognostic marker and therapeutic target of CRC by integration of single-cell and bulk RNA-seq data
Authors: Liu Wenjun , Luo Xitu , Zhang Zilang , Chen Yepeng , Dai Yongliang , Deng Jianzhong , Yang Chengyu , Liu Hao
Published: March 2024

Background

Investigations elucidating the complex immunological mechanisms involved in colorectal cancer (CRC) and accurately predicting patient outcomes via bulk RNA-Seq analysis have been notably limited. This study aimed to identify the immune status of CRC patients, construct a prognostic model, and identify prognostic signatures via bulk RNA sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq).

Methods

The scRNA-seq data of CRC were downloaded from Gene Expression Omnibus (GEO). The UCSC Xena database was used to obtain bulk RNA-seq data. Differentially expressed gene (DEG), functional enrichment, and random forest analyses were conducted in order to identify core genes associated with colorectal cancer (CRC) that were relevant to prognosis. A molecular immune prediction model was developed using logistic regression after screening features using the least absolute shrinkage and selection operator (LASSO). The differences in immune cell infiltration, mutation, chemotherapeutic drug sensitivity, cellular senescence, and communication between patients who were at high and low risk of CRC according to the predictive model were investigated. The prognostic genes that were closely associated with CRC were identified by random survival forest (RSF) analysis. The expression levels and clinical significance of the hub genes were analyzed in vitro. The LoVo cell line was employed to ascertain the biological role of thyroid hormone receptor-interacting protein 6 (TRIP6).

Results

A total of seven main cell subtypes were identified by scRNA-seq analysis. A molecular immune predictive model was constructed based on the risk scores. The risk score was significantly associated with OS, stage, mutation burden, immune cell infiltration, response to immunotherapy, key pathways, and cell–cell communication. The functions of the six hub genes were determined and further utilized to establish a regulatory network. Our findings unequivocally confirmed that TRIP6 upregulation was verified in the CRC samples. After knocking down TRIP6, cell proliferation, migration, and invasion of LoVo cells were inhibited, and apoptosis was promoted.

Conclusions

The molecular predictive model reliably distinguished the immune status of CRC patients. We further revealed that TRIP6 may act as an oncogene in CRC, making it a promising candidate for targeted therapy and as a prognostic marker for CRC.
Paracetamol transport by ZnO nanoparticle-doped polymer-containing membrane
Authors: Selimoglu Faysal , Akin Ilker , Ayhan Muhammed Emre
Published: March 2024

In this study, the transport performance of acetaminophen (paracetamol), which is most commonly prescribed and used for humans and animals and whose wastes are known to have toxic effects on the environment and some living organisms, was investigated using zinc oxide (ZnO)-reinforced polymer membranes. In this study, nanoparticle-containing polymer membranes were prepared from cellulose triacetate in dichloromethane and ZnO nanoparticles were synthesized to impart adsorption properties to the membrane in a single step, enabling adsorption and filtration to improve the removal of low molecular weight micropollutants that are poorly retained by conventional polymer membranes and by enabling re-release. Our membrane was prepared by phase inversion method by doping with cellulose triacetate (CTA) solution. Parameters such as carrier concentration, mixing rate, transport time, acceptor and feed phase concentrations were studied to determine the optimal conditions for the transport experiments of paracetamol (PARA). The presence of acid in the acceptor phase converted the hydrophilic part of paracetamol, which allowed the transport of PARA. The calculated flux values for different PARA concentrations ranged from (0.64) × 10−8 to (1.8) × 10−8 mol/(cm2s). Under optimal conditions, a transport efficiency of 84% was obtained for PARA with a CTA/ZnO polymer membrane. The obtained membranes can be used in wastewater treatment, recovery of pharmacological products from pharmaceutical industry waste, re-evaluation of hospital waste, etc.
Bioactive glass doped with zinc-based metal–organic frameworks (Zn/MOF) nanoparticles for antibiotic delivery applications
Authors: Ahmed Manar M. , Omar Areg E. , Zayed Heba S. , Moaness Mona
Published: March 2024

Zn-MOF/bioactive glass nanoparticles were successfully prepared using quick–alkali-modified sol–gel and tested for gentamicin drug delivery. Samples of 0 and 0.8 mol% Zn MOF contents (BG and BG/Zn MOF, respectively) were characterized using XRD, FTIR, TEM, and SEM/EDX. In addition, zeta characteristics and surface area parameters were also evaluated. Moreover, the cell viability of the prepared samples was tested against the osteosarcoma MG-63 cell line to evaluate the ability of prepared samples for bone regeneration. In addition, the antimicrobial activity of glass samples with and without antibiotics was determined against different microorganisms. Finally, the samples were loaded with gentamicin drug, and drug release profile and kinetics were studied too. XRD and FTIR results confirmed the physicochemical properties of the prepared samples. TEM results showed that particles were in the nano-sized range in both samples; however, the presence of Zn MOF increased the dispersity of particles. Both samples were bioactive, as indicated by hydroxyapatite formation on their surfaces. Cytotoxicity estimation of prepared materials exhibited their safe and nontoxic nature. BG/Zn MOF sample demonstrated prolonged drug release and excellent antimicrobial activity in comparison to BG alone. Therefore, the present study provides promising preliminary results regarding the usage of BG/Zn MOF nanoparticles loaded with gentamicin as an effective approach for bone regeneration.

Graphical Abstract
Risk of death, thrombotic and hemorrhagic events in anticoagulated patients with atrial fibrillation and systemic autoimmune diseases: an analysis from a global federated dataset
Authors: Bucci Tommaso , Cardamone Chiara , Triggiani Massimo , Ames Paul R. J. , Lip Gregory Y. H.
Published: March 2024

Background

Growing evidence showing that systemic autoimmune diseases (SADs) are associated with a high risk of atrial fibrillation (AF). However, the impact of SAD on the clinical course of AF patients is largely unknown.

Methods

Retrospective cohort study within a federated healthcare network (TriNetX). Using ICD codes, AF patients on anticoagulant therapy were categorized according to the presence of SAD (M32: Systemic Lupus Erythematosus (SLE); M33: Dermato-polymyositis (DMP); M34: Systemic Sclerosis (SSc); M35: Sjogren syndrome). The primary outcomes were the 5-year risks of (1) all-cause death, (2) thrombotic events (ischemic stroke, acute myocardial infarction, deep vein thrombosis, and pulmonary embolism), and (3) bleeding (intracranial (ICH) and gastrointestinal (GI)). Secondary outcomes were each component of the primary outcomes. Cox regression analysis after propensity score matching (PSM) was used to estimate hazard ratio (HR) and 95% confidence interval (95%CI).

Results

We identified 16,098 AF patients with SAD (68.2 ± 13.4 years; 71.0% female) and 828,772 AF controls (70.7 ± 12.9 years, 41.1% females). After PSM, AF patients with SAD were associated with a higher risk of all-cause death (HR 1.13, 95%CI 1.09–1.71), thrombotic events (HR 1.37, 95%CI 1.32–1.43), and hemorrhagic events (HR 1.41, 95%CI 1.33–1.50) compared to AF controls without SAD. The highest risk of all-cause death and GI bleeding was associated with SSc, while the highest risk of thrombotic events and ICH was associated with SLE.

Conclusion

AF patients with SAD are associated with a high risk of all-cause death, thrombotic, and hemorrhagic events. These patients merit careful follow-up and integrated care management to improve their prognosis.

Graphical Abstract
Diet quality in relation to kidney function and its potential interaction with genetic risk of kidney disease among Dutch post-myocardial infarction patients
Authors: van Westing Anniek C. , Heerkens Luc , Cruijsen Esther , Voortman Trudy , Geleijnse Johanna M.
Published: March 2024

Purpose

We examined the relation between diet quality, its components and kidney function decline in post-myocardial infarction (MI) patients, and we explored differences by genetic risk of chronic kidney disease (CKD).

Methods

We analysed 2169 patients from the Alpha Omega Cohort (aged 60–80 years, 81% male). Dietary intake was assessed at baseline (2002–2006) using a validated food-frequency questionnaire and diet quality was defined using the Dutch Healthy Diet Cardiovascular Disease (DHD-CVD) index. We calculated 40-months change in estimated glomerular filtration rate (eGFR, mL/min per 1.73m2). We constructed a weighted genetic risk score (GRS) for CKD using 88 single nucleotide polymorphisms previously linked to CKD. Betas with 95%-confidence intervals (CIs) were obtained using multivariable linear regression models for the association between DHD-CVD index and its components and eGFR change, by GRS.

Results

The average DHD-CVD index was 79 (SD 15) points and annual eGFR decline was 1.71 (SD 3.86) mL/min per 1.73 m2. The DHD-CVD index was not associated with annual eGFR change (per 1-SD increment in adherence score: -0.09 [95% CI -0.26,0.08]). Results for adherence to guidelines for red meat showed less annual eGFR decline (per 1-SD: 0.21 [0.04,0.38]), whereas more annual eGFR decline was found for legumes and dairy (per 1-SD: -0.20legumes [-0.37,-0.04] and − 0.18dairy [-0.34,-0.01]). Generally similar results were obtained in strata of GRS.

Conclusion

The DHD-CVD index for overall adherence to Dutch dietary guidelines for CVD patients was not associated with kidney function decline after MI, irrespective of genetic CKD risk. The preferred dietary pattern for CKD prevention in CVD patients warrants further research.
Pregnancy outcomes in patients complicated with pre-excitation syndrome
Authors: Wang Kana , Xin Junguo , Hu Qing , Wang Xiaodong , Yu Haiyan
Published: March 2024

Introduction

Pregnant women with pre-excitation syndrome are more likely to develop supraventricular tachycardia (SVT) during pregnancy and delivery, leading to an increased risk of adverse events.

Method

This was a retrospective study of 309 pregnancies in 280 women (29 women had two pregnancies in this series) with pre-excitation syndrome who delivered at West China Second University Hospital from June 2011 to October 2021. All the 309 pregnant women with pre-excitation syndrome were divided into SVT and non-SVT groups to analyze the cardiac and obstetric complications.

Results

Among the included pregnant women in the past 10 years, the prevalence of pre-excitation syndrome was 0.24% (309/127725). There were 309 cases with pre-excitation syndrome in all hospitalized pregnant women. Among them, 62 (20.1%, 62/309) had a history of SVT. In the 62 cases with SVT during pregnancy, 22 (35.5%) cases had a history of SVT. Gestational diabetes mellitus was associated with SVT during pregnancy. The cesarean section rate was 88.7% in the SVT group, which was significantly higher than that in the non-SVT group (64.8%) (P < 0.001). Cases with SVT during pregnancy had more cardiac and obstetric complications. Four fetal deaths were recorded in the SVT group. Additionally, 29 women experienced two pregnancies during the study period, among whom, five received radiofrequency ablation after the first delivery and obtained better outcomes in the second pregnancy.

Conclusion

The adverse outcomes such as cardiac complications, maternal and fetal complications (PROM, prematurity, SGA, fetal distress, etc.) in pregnant women with pre-excitation syndrome were closely related to SVT, with possible risk factors including history of SVT before pregnancy, cardiac function, heart organic abnormalities, and gestational diabetes mellitus.
Multicenter, randomized, double-blind, placebo-controlled phase 3 study of mogamulizumab with open-label extension study in a minimum number of patients with human T-cell leukemia virus type-1-associated myelopathy
Authors: Sato Tomoo , Nagai Masahiro , Watanabe Osamu , Misu Tatsuro , Takenouchi Norihiro , Ohkubo Ryuichi , Ishihara Satoshi , Tsuboi Yoshio , Katsuno Masahisa , Nakagawa Masanori , Matsushita Takuya , Aso Yasuhiro , Matsuura Eiji , Tokashiki Takashi , Mukaino Akihiro , Adachi Hiroaki , Nakanishi Kaoru , Yamaguchi Yusuke , Yamaguchi Saaya , Yamano Yoshihisa
Published: March 2024

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurodegenerative disease. This multicenter, randomized phase 3 study evaluated the efficacy and safety of 0.3 mg/kg intravenous mogamulizumab, a monoclonal antibody targeting-CC chemokine receptor 4, every 12 weeks in HAM/TSP patients. This study comprised a 24-week double-blind, placebo-controlled period, 24-week open-label period, and extension treatment period. The primary endpoint was the proportion of patients with a ≥ 1-grade improvement in the Osame motor disability score (OMDS). Secondary endpoints were changes in HTLV-1 proviral load, 10-m timed walk, cerebrospinal fluid (CSF) neopterin levels, and safety. The exploratory endpoint was CSF chemokine C-X-C motif ligand 10 (CXCL10) levels. Thirty-four and 33 patients were randomized to mogamulizumab and placebo arms, respectively. At the end of the double-blind period, no significant difference was found in the OMDS improvement rate or other secondary efficacy endpoints assessing motor activities. However, the mogamulizumab arm showed a significant decrease in HTLV-1 proviral load (− 59.39 ± 29.91% vs. placebo 2.32 ± 36.31%) and CSF neopterin (p < 0.001)/CXCL10 levels (p = 0.004). The baseline OMDS pattern and the 60–80% HTLV-1 proviral load reduction were sustained through the open-label and extension treatment periods. Although a higher incidence of rash (69.2%) was reported, the safety profile was similar compared with a previous phase 1/2a study. We found no significant difference in clinical benefit; however, mogamulizumab may provide long-term clinical benefit by preventing disease progression, as CSF neopterin/CXCL10 levels are associated with long-term prognosis in HAM/TSP.

Clinical Trial Registration Number: NCT03191526 (registered date: 6-June-2017).
Early intensive versus escalation treatment in patients with relapsing–remitting multiple sclerosis in Austria
Authors: Guger Michael , Enzinger Christian , Leutmezer Fritz , Di Pauli Franziska , Kraus Jörg , Kalcher Stefan , Kvas Erich , Berger Thomas ,   Austrian MS Treatment Registry (AMSTR)
Published: March 2024

Objectives

To compare the effectiveness of early intensive treatment (EIT) versus escalation treatment (ESC) in a nationwide observational cohort of almost 1000 people with relapsing–remitting multiple sclerosis (RRMS).

Materials and methods

The EIT cohort started with alemtuzumab (AZM), cladribine (CLAD), fingolimod (FTY), natalizumab (NTZ), ocrelizumab (OCR), or ozanimod (OZA); whereas, the ESC cohort was escalated from dimethylfumarate (DMF) or teriflunomide (TERI) to AZM, CLAD, FTY, NTZ, OCR, or OZA within the Austrian MS Treatment Registry. Patients had to stay on therapy for at least 3 months and up to 16 years. The EIT cohort included 743 and the ESC cohort 227 RRMS patients. We used multinomial propensity scores for inverse probability weighting in generalized linear (GLM) and Cox proportional hazards models to correct for the bias of this non-randomized registry study.

Results

Estimated mean annualized relapse rates (ARR) were 0.09 for EIT and 0.4 for ESC patients. The incidence rate ratio (IRR) in the GLM model for relapses showed a decreased relapse probability of 78% for the EIT versus ESC cohort [IRR = 0.22, 95% CI (0.16–0.30), p < 0.001]. Analyzing the time to the first relapse by Cox regression, a hazard ratio (HR) of 0.17 [95% CI (0.13–0.22), p < 0.001] revealed a decreased risk of 83% for the EIT group. Regarding sustained Expanded Disability Status Scale (EDSS) progression for 12 weeks, a HR of 0.55 [95% CI (0.40–0.76), p < 0.001] showed a decreased probability of 45% for the EIT cohort.

Conclusions

ESC treatment after DMF and TERI revealed a higher relapse and EDSS progression probability compared to EIT in Austrian RRMS patients. Therefore, an early intensive treatment should be started in patients with an active or highly active disease course.
Long-term intraocular pressure-lowering efficacy and safety of ripasudil-brimonidine fixed-dose combination for glaucoma and ocular hypertension: a multicentre, open-label, phase 3 study
Authors: Tanihara Hidenobu , Yamamoto Tetsuya , Aihara Makoto , Koizumi Noriko , Fukushima Atsuki , Kawakita Koji , Kojima Satoshi , Nakamura Toka , Suganami Hideki ,   K-232 Clinical Study Group, Tagawa Yoshitsugu , Watanabe Hiroki , Shimizu Kiyoshi , Iwasaki Miki , Matsuzaki Sakae , Ueda Hiroko , Okayama Ryoko , Matsuoka Osamu , Hashida Setsuko , Kobayashi Sachi Amaki , Kiyosawa Motohiro , Asai Yuko , Nakajima Toru , Yoshimura Yuzuru , Sakai Takao , Nomura Ryoji , Inoue Satoshi , Hayashi Ken , Watanabe Junko , Kawabata Hidehito , Muramatsu Tomoyuki , Arai Mikki , Migita Masayoshi
Published: March 2024

Purpose

To evaluate the long-term efficacy and safety of ripasudil-brimonidine fixed-dose combination (RBFC), a new intraocular pressure (IOP)-lowering medication for glaucoma and ocular hypertension (OHT).

Methods

This prospective, multicentre (23 sites in Japan), open-label study enrolled patients with primary open-angle glaucoma (POAG), OHT or exfoliative glaucoma and assigned them to one of four combination therapy cohorts, based on previous treatment(s) received: prostaglandin (PG) analogue (Cohort 1); PG analogue and beta-adrenoceptor blocker (β-blocker) (Cohort 2); PG analogue, β-blocker and carbonic anhydrase inhibitor (Cohort 3); or other/no treatment (Cohort 4). After a ≥ 4-week screening period, eligible patients received twice-daily RBFC for 52 weeks in addition to the treatments they were already receiving. Efficacy was assessed by change in IOP from baseline through week 52. Adverse events and adverse drug reactions (ADRs) were monitored throughout.

Results

In total, 179 patients from Cohort 1 (n = 48), Cohort 2 (n = 44), Cohort 3 (n = 41) and Cohort 4 (n = 46) entered the RBFC treatment period. For all cohorts, mean IOP was significantly reduced at 11:00 (2 h after instillation of RBFC) through week 52 with the changes from baseline at week 52 of − 2.7 to − 4.1 mmHg across cohorts; all p < 0.001. Common ADRs were conjunctival hyperaemia (58%), allergic conjunctivitis (18%) and blepharitis (17%), most of which were mild in severity.

Conclusion

These data demonstrated the long-term efficacy and safety of RBFC, both alone and in combination with other anti-glaucoma agents. RBFC may offer a new treatment option for the long-term management of glaucoma and OHT.

Trial registration

Japan Registry of Clinical Trials Identifier: jRCT2080225063.

Date of registration

17 February 2020.
MOTS-c regulates pancreatic alpha and beta cell functions in vitro
Authors: Bień Jakub , Pruszyńska-Oszmałek Ewa , Kołodziejski Paweł , Leciejewska Natalia , Szczepankiewicz Dawid , Sassek Maciej
Published: March 2024

The aim of this study is to determine the influence of the mitochondrial open-reading-frame of the twelve S rRNA-c (MOTS-c) peptide on pancreatic cell physiology. Moreover, in this study, we examined the changes in MOTS-c secretion and expression under different conditions. Our experiments were conducted using laboratory cell line cultures, specifically the INS-1E and αTC-1 cell lines, which represent β and α pancreatic cells, respectively. As the pancreas is an endocrine organ, we also tested its hormone regulation capabilities. Furthermore, we assessed the secretion of MOTS-c after incubating the cells with glucose and free fatty acids. Additionally, we examined key cell culture parameters such as cell viability, proliferation, and apoptosis. The results obtained from this study show that MOTS-c has a significant impact on the physiology of pancreatic cells. Specifically, it lowers insulin secretion and expression in INS-1E cells and enhances glucagon secretion and expression in αTC-1 cells. Furthermore, MOTS-c affects cell viability and apoptosis. Interestingly, insulin and glucagon affect the MOTS-c secretion as well as glucose and free fatty acids. These experiments clearly show that MOTS-c is an important regulator of pancreatic metabolism, and there are numerous properties of MOTS-c yet to be discovered.
Reliability and validity of the MX3 portable sweat sodium analyser during exercise in warm conditions
Authors: Brown Harry A. , Clark Brad , Périard Julien D.
Published: March 2024

Purpose

Accurately measuring sweat sodium concentration ([Na+]) in the field is advantageous for coaches, scientists, and dieticians looking to tailor hydration strategies. The MX3 hydration testing system is a new portable analyser that uses pre-calibrated biosensors to measure sweat [Na+]. This study aimed to assess the validity and reliability of the MX3 hydration testing system.

Methods

Thirty-one (11 females) recreationally active participants completed one experimental trial. During this trial, participants exercised at a self-selected pace for 45 min in a warm environment (31.5 ± 0.8 °C, 63.2 ± 1.3% relative humidity). Sweat samples were collected from three measurement sites using absorbent patches. The samples were then analysed for sweat [Na+] using both the MX3 hydration testing system and the Horiba LAQUAtwin-NA-11. The reliability of the MX3 hydration testing system was determined following two measurements of the same sweat sample.

Results

The mean difference between measurements was 0.1 mmoL·L−1 (95% limits of agreement (LoA): − 9.2, 9.4). The analyser demonstrated a coefficient of variation (CV) of 5.6% and the standard error of measurement was 3.3 mmoL·L−1. When compared to the Horiba LAQUAtwin-NA-11, there was a mean difference of − 1.7 mmoL·L−1 (95% LoA: − 0.25$${\overline{\text{X}}}$$

X
¯

, 0.25$${\overline{\text{X}}}$$

X
¯

) and the CV was 9.8%.

Conclusion

The MX3 hydration testing system demonstrated very good single-trial reliability, moderate agreement and a very good CV relative to the Horiba LAQUAtwin-Na-11. To further validate its performance, the MX3 hydration testing system should be compared with analytical techniques known for superior reliability and validity.
Educational programmes for paediatric healthcare professionals in patient- and family-centred care. A scoping review
Authors: Jeppesen Elisabeth , Schmidt Anne Aarslev , Skjødt Camilla Kriegbaum , Hybschmann Jane , Gjærde Line Klingen , Thestrup Jakob , Hansson Helena , Sørensen Jette Led
Published: March 2024

To identify and describe educational programmes in patient- and family-centred care for paediatric healthcare professionals. This scoping review was conducted and reported according to the JBI Manual for Evidence Synthesis and the PRISMA guideline. The databases searched included MEDLINE (PubMed), PsycINFO, CINAHL, Scopus, Cochrane, and Embase. Inclusion criteria were experimental, observational and qualitative studies about educational programmes on patient- and family-centred care for paediatric healthcare professionals. Exclusion criteria were reviews and non-peer-reviewed literature. Two reviewers independently screened and extracted the data using Covidence. Of the 13922 records identified, 49 articles met the inclusion criteria. There was a large variety of educational programmes, half of which were interdisciplinary, that mainly targeted nurses and doctors. The median number of participants was 51 (range 7 to 1411). The predominant target population was children with chronic disabilities and neonatal intensive care units, and only one programme specifically targeted adolescents. The median duration was one day (range 5 min to 3.5 years). Development of competencies was the most common objective. We identified 12 different educational content areas. Content mainly focused on communication and relational competencies, including partnership, which involved shared decision-making, mutual agenda setting, and negotiation of a plan. Many kinds of educational strategies were found but experiential learning through simulation and roleplay was used most.

   Conclusion: A large variety of educational programmes in paediatric patient- and family-centred care exist. Educational content mainly focused on communication and relational competencies. Experiential learning including roleplay and simulation was the most used educational strategy.

What is Known:• Delivery of patient- and family-centred care improves parental satisfaction of care but requires clinicians have a certain attitude towards involving the child and parents in a healthcare partnership as well as advanced triadic communication skills. Little is known about how this attitude, and more broadly, patient- and family-centred care, can be facilitated through education and training.

What is New:• This scoping review found a wide array of programmes.. Workshops with simulation or roleplay was the most frequent educational strategy. The programmes, which typically targeted nurses and doctors, chiefly focused on basic and advanced communication and relational competencies, including partnership, which involved shared decision-making and negotiation of plans.
Estimation of solar cell parameters through utilization of adaptive sine–cosine particle swarm optimization algorithm
Authors: Issa Mohamed , Helmi Ahmed M. , Ghetas Mohamed
Published: March 2024

Due to the growing demand for clean and sustainable energy sources, there has been an increasing interest in solar cells and photovoltaic panels. Nevertheless, determining the right design parameters to achieve the most efficient energy output that aligns with the energy system's needs can be quite challenging. This complexity arises from the intricate models and the inherent inaccuracies in the available information. To tackle this challenge, this paper introduces the adaptive sine–cosine particle swarm optimization algorithm (ASCA-PSO) as a method for estimating the parameters of solar cells and photovoltaic modules. The ASCA-PSO approach combines the strengths of the SCA and PSO algorithms in a two-tier process. In this process, SCA search agents explore the search space, while the PSO search agents leverage the outcomes derived from SCA exploration. This study evaluates the effectiveness of ASCA-PSO in accurately estimating the parameters of single- and double-diode models using data from two commercial solar cells. The findings are compared with those of cutting-edge methods. It is demonstrated that ASCA-PSO can identify global solutions for multifaceted and intricate objective functions. Furthermore, it proves to be a viable option for designing solar cells even in the presence of noise.
Depression, anxiety, and health-related quality of life in normal weight, overweight and obese individuals with diabetes: a representative study in Germany
Authors: Herhaus Benedict , Kruse Johannes , Hinz Andreas , Brähler Elmar , Petrowski Katja
Published: March 2024

Objective

Diabetes in the course of lifetime is related to a higher risk for mental disorders. The present study addresses the comparison of individuals with diabetes and non-diabetic individuals in depressive symptoms, generalized anxiety symptoms, and health-related quality of life. Furthermore, mediator effect of BMI and health-related quality of life (HRQOL) on the association between diabetes, depression, and generalized anxiety was analyzed.

Methods

In this cross-sectional study, the three questionnaires PHQ-9, GAD-7, EQ-5D-5L were measured in a representative sample of the German population (N = 2386). In addition, the presence of diabetes and BMI were assessed via self-report.

Results

There were higher values in depressive and anxiety symptoms as well as lower score in HRQOL in individuals with diabetes compared to non-diabetic individuals. Obese individuals with diabetes showed the highest rates in depressive symptoms and generalized anxiety as well as lowest score in HRQOL. With regard to the mediator analyses, association between diabetes, depressive symptoms, and anxiety symptoms is partially mediated by the BMI and fully mediated by the HRQOL.

Conclusions

In conclusion, individuals with diabetes have an increased risk in the development of depressive and anxiety symptoms as well as lower health-related quality of life. Future research and strategies in the public health policies among individuals with diabetes should take into account that the association between diabetes, depression, and anxiety is mediated by BMI and HRQOL.
Effect of sodium hypochlorite gel on bacteria associated with periodontal disease
Authors: Irani Delia , Jungbauer Gert , Sculean Anton , Eick Sigrun
Published: March 2024

Objectives

An adjunct in non-surgical periodontal therapy might be sodium hypochlorite (NaOCl)–based agents. The purpose of the present in vitro study was to get deeper knowledge on the influence of different parameters as time after mixing, pH, and chemical composition of an amino acid 0.475% NaOCl (AA-NaOCl) gel consisting of two components on its anti-biofilm activity.

Materials and methods

Six-species biofilms were cultured for 5 days, before AA-NaOCl gel was applied. In the different series, the influence of the time after mixing of the two components before application, of the concentration of NaOCl in the gel mixture, of the pH of the gel mixture, and of an exchange of the amino acid component by hyaluronic acid (HA), was analyzed.

Results

Mixing time point experiments showed that the AA-NaOCl gel is capable of statistically significantly reducing colony-forming unit (cfu) counts up to 30 min after mixing, but only up to 20 min after mixing the reduction was more than 2 log10 cfu. The pH experiments indicate that a reduced pH results in a reduced activity of the NaOCl formulation. NaOCl concentrations in the formulation in the range from 0.475 to 0.2% provide adequate activity on biofilms. A HA/NaOCl gel was equally active against the biofilm as the AA-NaOCl gel.

Conclusion

Mixing of the components should be made in a timeframe of 20 min before applications. An optimization of the composition of the NaOCl formulation might be possible and should be a topic in further in vitro studies.

Clinical relevance

The AA-NaOCl gel formulation can be mixed up to 20 min before application. Further, the study indicates that the composition of the NaOCl gel formulation can be optimized.
Cognitive flexibility in urban yellow mongooses, Cynictis penicillata
Authors: Müller Mijke , Pillay Neville
Published: March 2024

Cognitive flexibility enables animals to alter their behaviour and respond appropriately to environmental changes. Such flexibility is important in urban settings where environmental changes occur rapidly and continually. We studied whether free-living, urban-dwelling yellow mongooses, Cynictis penicillata, in South Africa, are cognitively flexible in reversal learning and attention task experiments (n = 10). Reversal learning was conducted using two puzzle boxes that were distinct visually and spatially, each containing a preferred or non-preferred food type. Once mongooses learned which box contained the preferred food type, the food types were reversed. The mongooses successfully unlearned their previously learned response in favour of learning a new response, possibly through a win-stay, lose-shift strategy. Attention task experiments were conducted using one puzzle box surrounded by zero, one, two or three objects, introducing various levels of distraction while solving the task. The mongooses were distracted by two and three distractions but were able to solve the task despite the distractions by splitting their attention between the puzzle box task and remaining vigilant. However, those exposed to human residents more often were more vigilant. We provide the first evidence of cognitive flexibility in urban yellow mongooses, which enables them to modify their behaviour to urban environments.
Do domestic budgerigars perceive predation risk?
Authors: Wang Chang , Zhao Xueqi , Tao Baodan , Peng Jiaqi , Wang Haitao , Yu Jiangping , Jin Longru
Published: March 2024

Predation risk may affect the foraging behavior of birds. However, there has been little research on the ability of domestic birds to perceive predation risk and thus adjust their feeding behavior. In this study, we tested whether domestic budgerigars (Melopsittacus undulatus) perceived predation risk after the presentation of specimens and sounds of sparrowhawks (Accipiter nisus), domestic cats (Felis catus), and humans, and whether this in turn influenced their feeding behavior. When exposed to visual or acoustic stimuli, budgerigars showed significantly longer latency to feed under sparrowhawk, domestic cat, and human treatments than with controls. Budgerigars responded more strongly to acoustic stimuli than visual stimuli, and they showed the longest latency to feed and the least number of feeding times in response to sparrowhawk calls. Moreover, budgerigars showed shorter latency to feed and greater numbers of feeding times in response to human voices than to sparrowhawk or domestic cat calls. Our results suggest that domestic budgerigars may identify predation risk through visual or acoustic signals and adjust their feeding behavior accordingly.
A first exploratory comparison of the behaviour of wolves (Canis lupus) and wolf-dog hybrids in captivity
Authors: Amici Federica , Meacci Simone , Caray Emmeline , Oña Linda , Liebal Katja , Ciucci Paolo
Published: March 2024

Extensive introgression of genes from domesticated taxa may be a serious threat for the genomic integrity and adaptability of wild populations. Grey wolves (Canis lupus) are especially vulnerable to this phenomenon, but there are no studies yet assessing the potential behavioural effects of dog-introgression in wolves. In this study, we conducted a first systematic comparison of admixed (N = 11) and non-admixed (N = 14) wolves in captivity, focusing on their reaction to unfamiliar humans and novel objects, and the cohesiveness of their social groups. When exposed to unfamiliar humans in the experimental task, wolves were more vigilant, fearful and aggressive than admixed wolves, and less likely to approach humans, but also more likely to spend time in human proximity. When exposed to novel objects, wolves were more aggressive than admixed wolves, less likely to spend time in object proximity, and more likely to interact with objects, but also less vigilant and as fearful as admixed wolves. Finally, social networks were more cohesive in wolves than in admixed wolves. Although caution is needed when comparing groups of captive individuals with different life experiences, our study suggests that dog admixture may lead to important behavioural changes in wolves, with possible implications for conservation strategies.
Choosing the best way: how wild common marmosets travel to efficiently exploit resources
Authors: Xavier Dêverton Plácido , Abreu Filipa , Souto Antonio , Schiel Nicola
Published: March 2024

While foraging, animals have to find potential food sites, remember these sites, and plan the best navigation route. To deal with problems associated with foraging for multiple and patchy resources, primates may employ heuristic strategies to improve foraging success. Until now, no study has attempted to investigate experimentally the use of such strategies by a primate in a context involving foraging in large-scale space. Thus, we carried out an experimental field study that aimed to test if wild common marmosets (Callithrix jacchus) employ heuristic strategies to efficiently navigate through multiple feeding sites distributed in a large-scale space. In our experiment, we arranged four feeding platforms in a trapezoid configuration with up to 60 possible routes and observe marmosets’ decisions under two experimental conditions. In experimental condition I, all platforms contained the same amount of food; in experimental condition II, the platforms had different amounts of food. According to the number and arrangement of the platforms, we tested two heuristic strategies: the Nearest Neighbor Rule and the Gravity Rule. Our results revealed that wild common marmosets prefer to use routes consistent with a heuristic strategy more than expected by chance, regardless of food distribution. The findings also demonstrate that common marmosets seem to integrate different factors such as distance and quantity of food across multiple sites distributed over a large-scale space, employing a combination of heuristic strategies to select the most efficient routes available. In summary, our findings confirm our expectations and provide important insights into the spatial cognition of these small neotropical primates.
Atypical and delayed spinal cord MRI features of COVID-19-associated myelopathies: a report of four cases and literature review
Authors: Wang Jie , Zhang Huijun , Lin Jingya , Yang Lingli , Zhao Lipeng , Du Ailian
Published: March 2024

We reported four patients with coronavirus disease 2019 (COVID-19)–associated myelopathies, highlighting the delayed and atypical spinal cord magnetic resonance imaging (MRI) features and the literature review. All four patients were males, aged 37 to 72 years old. The latencies from COVID-19 to the onset of myelitis were 5, 15, 30, and 80 days. The initial symptoms were numbness and weakness of lower limbs in three cases, and back pain with weakness of lower limbs in one case. The peak symptoms included paraplegia, sphincter dysfunction, sensory disturbance level, and spastic gait. The EDSS scores were 7.5, 9.0, 9.0, and 7.5, respectively. Magnetic resonance imaging (MRI) showed delayed atypical spinal cord lesions at onset, i.e., two cases without lesions, one with linear spinal meningeal enhancement, and one with punctate lesions on T2-weighted imaging (T2WI). During the follow-up period, punctate, linear, and cloudy lesions in the lateral and posterior funiculus were seen on T2WI in the peak stage. The prominent features of spinal cord lesions were linear spinal meningeal enhancement, the mismatch of deteriorated clinical symptoms, and inapparent MRI findings. All four patients were left with an obvious disability, with two patients completely bedridden and two who could stand with support. This report highlights the recognition of COVID-19-associated myelopathy even months after initial infection, especially in patients with delayed and atypical spinal cord findings on MRI.