bluuebunny/crossref_metadata_2025 huggingface dataset:
Bioequivalence of a new coated 15 mg primaquine formulation for malaria elimination
Authors: Nguyen Ngoc Pouplin Julie , Kaendiao Thoopmanee , Rahimi Bilal Ahmad , Soni Mayur , Basopia Hensi , Shah Darshana , Patil Jitendra , Dholakia Vyom , Suthar Yash , Tarning Joel , Mukaka Mavuto , Taylor Walter R.
Published: June 2024

Background

With only one 15 mg primaquine tablet registered by a stringent regulatory authority and marketed, more quality-assured primaquine is needed to meet the demands of malaria elimination.

Methods

A classic, two sequence, crossover study, with a 10-day wash out period, of 15 mg of IPCA-produced test primaquine tablets and 15 mg of Sanofi reference primaquine tablets was conducted. Healthy volunteers, aged 18–45 years, without glucose-6-phosphate dehydrogenase deficiency, a baseline haemoglobin ≥ 11 g/dL, creatinine clearance ≥ 70 mL/min/1.73 ms, and body mass index of 18.5–30 kg/m2 were randomized to either test or reference primaquine, administered on an empty stomach with 240 mL of water. Plasma primaquine and carboxyprimaquine concentrations were measured at baseline, then 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 h by liquid chromatography coupled to tandem mass spectrometry. Primaquine pharmacokinetic profiles were evaluated by non-compartmental analysis and bioequivalence concluded if the 90% confidence intervals (CI) of geometric mean (GM) ratios of test vs. reference formulation for the peak concentrations (Cmax) and area under the drug concentration–time (AUC0–t) were within 80.00 to 125.00%.

Results

47 of 50 volunteers, median age 33 years, completed both dosing rounds and were included in the bioequivalence analysis. For primaquine, GM Cmax values for test and reference formulations were 62.12 vs. 59.63 ng/mL, resulting in a GM ratio (90% CI) of 104.17% (96.92–111.96%); the corresponding GM AUC0–t values were 596.56 vs. 564.09 ngxh/mL, for a GM ratio of 105.76% (99.76–112.08%). Intra-subject coefficient of variation was 20.99% for Cmax and 16.83% for AUC0–t. Median clearances and volumes of distribution were similar between the test and reference products: 24.6 vs. 25.2 L/h, 189.4 vs. 191.0 L, whilst the median half-lives were the same, 5.2 h.

Conclusion

IPCA primaquine was bioequivalent to the Sanofi primaquine. This opens the door to prequalification, registration in malaria endemic countries, and programmatic use for malaria elimination.

Trial registration The trial registration reference is ISRCTN 54640699
Comparing the EQ-5D-5L and stroke impact scale 2.0 in stroke patients: an analysis of measurement properties
Authors: Schmidt Juliana , Düvel Juliane Andrea , Elkenkamp Svenja , Greiner Wolfgang
Published: June 2024

Background

Stroke has evolved to become a chronic disease and a major public health challenge. To adequately capture the full disease burden of stroke patients, the assessment of health-related quality of life (HRQoL) and thus the performance of respective measures is increasingly relevant. The aim of this analysis was to compare the measurement properties of two self-report instruments, the EQ-5D-5L and the Stroke Impact Scale 2.0.

Methods

The data used for the analysis was derived from a quasi-experimental case management study for mildly to moderately affected incident stroke and transient ischemic attack (TIA) patients aged ≥ 18 in Germany. Data was collected patient-individually at 3, 6 and 12 months after initial stroke. The EQ-5D-5L and SIS 2.0 were compared in terms of feasibility, ceiling and floor effects, responsiveness and known-groups validity (Kruskal-Wallis H and Wilcoxon rank-sum test).

Results

A response for all three follow-ups is available for n = 855 patients. The feasibility of the EQ-5D-5L is determined as good (completion rate: 96.4–96.6%, ≥ one item missing: 3.2 − 3.3%), whereas the SIS 2.0 is moderately feasible (overall completion rate: 44.9–46.1%, ≥ one item missing in domains: 4.7 − 28.7%). The SIS 2.0 shows substantial ceiling effects in comparable domains (physical function: 10.4 − 13%, others: 3.5–31.3%) which are mainly larger than ceiling effects in the EQ-5D-5L index (17.1–21.5%). In terms of responsiveness, the EQ-5D-5L shows small to moderate change while the SIS 2.0 presents with moderate to large responsiveness. The EQ-5D-5L index, mobility, usual activities and Visual Analogue Scale show known-groups validity (p < 0.05). Content-related domains of the SIS 2.0 show known-groups validity as well (p < 0.05). However, it is compromised in the emotion domain in both measures (p > 0.05).

Conclusions

The EQ-5D-5L seems to be slightly more suitable for this cohort. Nonetheless, the results of both measures indicate limited suitability for TIA patients. Large-scale studies concerning responsiveness and known-groups validity are encouraged.

Trial registration

The study was registered in the German Clinical Trials Register, retrospective registration on 21.09.2022. Registration ID: DRKS00030297.
Implementation of health-related quality of life in the German TraumaRegister DGU® – first results of a pilot study
Authors: Jaekel Carina , Nienaber Ulrike , Neubert Anne , Kamp Oliver , Wienhöfer Lisa , Nohl Andre , Maegele Marc , Duesing Helena , Erichsen Christoph J. , Frenzel Stephan , Lefering Rolf , Flohe Sascha , Bieler Dan ,   Outcome Study Group of the Committee on Emergency Medicine, Intensive Care, Trauma Management (Sektion NIS) of the German Trauma Society (DGU), Gnass I. , Heining S. M. , Kaske S. , Kollig E. , Polak U. , Simmel S. , Sturm J. , Thelen S. , Volland R.
Published: June 2024

Background

Approximately 30,000 people are affected by severe injuries in Germany each year. Continuous progress in prehospital and hospital care has significantly reduced the mortality of polytrauma patients. With increasing survival rates, the functional outcome, health-related quality (hrQoL) of life and ability to work are now gaining importance. Aim of the study is, the presentation of the response behavior of seriously injured patients on the one hand and the examination of the factors influencing the quality of life and ability to work 12 months after major trauma on the other hand. Building on these initial results, a standard outcome tool shall be integrated in the established TraumaRegister DGU® in the future.

Methods

In 2018, patients [Injury Severity Score (ISS) ≥ 16; age:18–75 years] underwent multicenter one-year posttraumatic follow-up in six study hospitals. In addition to assessing hrQoL by using the Short-Form Health Survey (SF-12), five additional questions (treatment satisfaction; ability to work; trauma-related medical treatment; relevant physical disability, hrQoL as compared with the prior to injury status) were applied.

Results

Of the 1,162 patients contacted, 594 responded and were included in the analysis. The post-injury hrQoL does not show statistically significant differences between the sexes. Regarding age, however, the younger the patient at injury, the better the SF-12 physical sum score. Furthermore, the physically perceived quality of life decreases statistically significantly in relation to the severity of the trauma as measured by the ISS, whereas the mentally perceived quality of life shows no differences in terms of injury severity. A large proportion of severely injured patients were very satisfied (42.2%) or satisfied (39.9%) with the treatment outcome. It should be emphasized that patients with a high injury severity (ISS > 50) were on average more often very satisfied with the treatment outcome (46.7%). A total of 429 patients provided information on their ability to work 12 months post-injury. Here, 194 (45.2%) patients had a full employment, and 58 (13.5%) patients were had a restricted employment.

Conclusion

The present results show the importance of a structured assessment of the postinjury hrQoL and the ability to work after polytrauma. Further studies on the detection of influenceable risk factors on hrQoL and ability to work in the intersectoral course of treatment should follow to enable the best possible outcome of polytrauma survivors.
Sex-dependent effects of carbohydrate source and quantity on caspase-1 activity in the mouse central nervous system
Authors: Valiauga Rasa , Talley Sarah , Khemmani Mark , Fontes Noronha Melline , Gogliotti Rocco , Wolfe Alan J. , Campbell Edward
Published: June 2024

Background

Mounting evidence links glucose intolerance and diabetes as aspects of metabolic dysregulation that are associated with an increased risk of developing dementia. Inflammation and inflammasome activation have emerged as a potential link between these disparate pathologies. As diet is a key factor in both the development of metabolic disorders and inflammation, we hypothesize that long term changes in dietary factors can influence nervous system function by regulating inflammasome activity and that this phenotype would be sex-dependent, as sex hormones are known to regulate metabolism and immune processes.

Methods

5-week-old male and female transgenic mice expressing a caspase-1 bioluminescent reporter underwent cranial window surgeries and were fed control (65% complex carbohydrates, 15% fat), high glycemic index (65% carbohydrates from sucrose, 15% fat), or ketogenic (1% complex carbohydrates, 79% fat) diet from 6 to 26 weeks of age. Glucose regulation was assessed with a glucose tolerance test following a 4-h morning fast. Bioluminescence in the brain was quantified using IVIS in vivo imaging. Blood cytokine levels were measured using cytokine bead array. 16S ribosomal RNA gene amplicon sequencing of mouse feces was performed to assess alterations in the gut microbiome. Behavior associated with these dietary changes was also evaluated.

Results

The ketogenic diet caused weight gain and glucose intolerance in both male and female mice. In male mice, the high glycemic diet led to increased caspase-1 biosensor activation over the course of the study, while in females the ketogenic diet drove an increase in biosensor activation compared to their respective controls. These changes correlated with an increase in inflammatory cytokines present in the serum of test mice and the emergence of anxiety-like behavior. The microbiome composition differed significantly between diets; however no significant link between diet, glucose tolerance, or caspase-1 signal was established.

Conclusions

Our findings suggest that diet composition, specifically the source and quantity of carbohydrates, has sex-specific effects on inflammasome activation in the central nervous system and behavior. This phenotype manifested as increased anxiety in male mice, and future studies are needed to determine if this phenotype is linked to alterations in microbiome composition.
The role of blood related inflammatory factors on age-related macular degeneration (AMD)
Authors: Ojaghi Habib , Poorsheykhian Shirin , Najafi Amin , Iranpour Sohrab
Published: June 2024

Background

Age-related macular degeneration (AMD) is a significant retinal disease that leads to irreversible low vision, particularly in developing countries. The variation in AMD prevalence among different racial groups and highlighted role of inflammation on disease pathology from previous studies which yielded in inconsistent findings, It seems to be of great importance to do more investigation in this field.

Methods

This case control study involved 204 participants, divided into four groups of equal size (51 individuals per group). Three groups represented AMD cases of varying severity according to Beckman classification (3 groups) and one healthy control group. Sampling was conducted exhaustively until the desired sample size was reached. The control group comprised healthy individuals without any infectious or inflammatory systemic, ophthalmic disease. Blood samples were collected to measure inflammatory factors, including lymphocytes, monocytes, neutrophils, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP). Collected data were analyzed by statistical methods in SPSS version 21.

Results

Of the participants, 51% were women, and their ages ranged from 47 to 89 years (62.2 ± 8). According to multiple logistic regression analysis, age exhibited a statistically significant positive association with AMD severity (P = 0.038, odds ratio [OR] = 1.034). ANOVA results indicated a significant association between neutrophil count and AMD severity (P < 0.001). As the disease severity increased, the number of neutrophils decreased. The mean ± SD neutrophil counts for early, intermediate and advanced AMD were 3849 ± 800, 3702 ± 734, and 3342 ± 823, respectively. No statistically significant associations were found between lymphocyte count, monocyte count, neutrophil-to-lymphocyte ratio, CRP, and AMD.

Conclusion

There was a significant relationship between the number of neutrophils in peripheral blood and the severity of AMD in study participants which needs more evaluation for the potential utility of this factor in the prognosis of AMD. There was not any significant relationship among the other factors and AMD.
The mutation of Japanese encephalitis virus envelope protein residue 389 attenuates viral neuroinvasiveness
Authors: Huang Rong , He Yajing , Zhang Chenghua , Luo Yue , Chen Chen , Tan Ning , Ren Yang , Xu Kui , Yuan Lei , Yang Jian
Published: June 2024

The envelope (E) protein of the Japanese encephalitis virus (JEV) is a key protein for virus infection and adsorption of host cells, which determines the virulence of the virus and regulates the intensity of inflammatory response. The mutation of multiple aa residues in the E protein plays a critical role in the attenuated strain of JEV. This study demonstrated that the Asp to Gly, Ser, and His mutation of the E389 site, respectively, the replication ability of the viruses in cells was significantly reduced, and the viral neuroinvasiveness was attenuated to different degrees. Among them, the mutation at E389 site enhanced the E protein flexibility contributed to the attenuation of neuroinvasiveness. In contrast, less flexibility of E protein enhanced the neuroinvasiveness of the strain. Our results indicate that the mechanism of attenuation of E389 aa mutation attenuates neuroinvasiveness is related to increased flexibility of the E protein. In addition, the increased flexibility of E protein enhanced the viral sensitivity to heparin inhibition in vitro, which may lead to a decrease in the viral load entering brain. These results suggest that E389 residue is a potential site affecting JEV virulence, and the flexibility of the E protein of aa at this site plays an important role in the determination of neuroinvasiveness.
Increased expression of REG3A promotes tumorigenic behavior in triple negative breast cancer cells
Authors: Jin Xiaoxia , Yang Shuyun , Lu Xiaoyun , Chen Xudong , Dai Wencheng
Published: June 2024

Background

Identifying new targets in triple negative breast cancer (TNBC) remains critical. REG3A (regenerating islet-derived protein 3 A), a calcium-dependent lectin protein, was thoroughly investigated for its expression and functions in breast cancer.

Methods

Bioinformatics and local tissue analyses were employed to identify REG3A expression in breast cancer. Genetic techniques were employed to modify REG3A expression, and the resulting effects on the behaviors of breast cancer cells were examined. Subcutaneous xenograft models were established to investigate the involvement of REG3A in the in vivo growth of breast cancer cells.

Results

Analysis of the TCGA database uncovered increased REG3A levels in human breast cancer tissues. Additionally, REG3A mRNA and protein levels were elevated in TNBC tissues of locally treated patients, contrasting with low expression in adjacent normal tissues. In primary human TNBC cells REG3A shRNA notably hindered cell proliferation, migration, and invasion while triggering caspase-mediated apoptosis. Similarly, employing CRISPR-sgRNA for REG3A knockout showed significant anti-TNBC cell activity. Conversely, REG3A overexpression bolstered cell proliferation and migration. REG3A proved crucial for activating the Akt-mTOR cascade, as evidenced by decreased Akt-S6K1 phosphorylation upon REG3A silencing or knockout, which was reversed by REG3A overexpression. A constitutively active mutant S473D Akt1 (caAkt1) restored Akt-mTOR activation and counteracted the proliferation inhibition and apoptosis induced by REG3A knockdown in breast cancer cells. Crucially, REG3A played a key role in maintaining mTOR complex integrity. Bioinformatics identified zinc finger protein 680 (ZNF680) as a potential REG3A transcription factor. Knocking down or knocking out ZNF680 reduced REG3A expression, while its overexpression increased it in primary breast cancer cells. Additionally, enhanced binding between ZNF680 protein and the REG3A promoter was observed in breast cancer tissues and cells. In vivo, REG3A shRNA significantly inhibited primary TNBC cell xenograft growth. In REG3A-silenced xenograft tissues, reduced REG3A levels, Akt-mTOR inhibition, and activated apoptosis were evident.

Conclusion

ZNF680-caused REG3A overexpression drives tumorigenesis in breast cancer possibly by stimulating Akt-mTOR activation, emerging as a promising and innovative cancer target.
Imprinted DNA methylation of the H19 ICR is established and maintained in vivo in the absence of Kaiso
Authors: Matsuzaki Hitomi , Kimura Minami , Morihashi Mizuki , Tanimoto Keiji
Published: June 2024

Background

Paternal allele-specific DNA methylation of the imprinting control region (H19 ICR) controls genomic imprinting at the Igf2/H19 locus. We previously demonstrated that the mouse H19 ICR transgene acquires imprinted DNA methylation in preimplantation mouse embryos. This activity is also present in the endogenous H19 ICR and protects it from genome-wide reprogramming after fertilization. We also identified a 118-bp sequence within the H19 ICR that is responsible for post-fertilization imprinted methylation. Two mutations, one in the five RCTG motifs and the other a 36-bp deletion both in the 118-bp segment, caused complete and partial loss, respectively, of methylation following paternal transmission in each transgenic mouse. Interestingly, these mutations overlap with the binding site for the transcription factor Kaiso, which is reportedly involved in maintaining paternal methylation at the human H19 ICR (IC1) in cultured cells. In this study, we investigated if Kaiso regulates imprinted DNA methylation of the H19 ICR in vivo.

Results

Neither Kaiso deletion nor mutation of Kaiso binding sites in the 118-bp region affected DNA methylation of the mouse H19 ICR transgene. The endogenous mouse H19 ICR was methylated in a wild-type manner in Kaiso-null mutant mice. Additionally, the human IC1 transgene acquired imprinted DNA methylation after fertilization in the absence of Kaiso.

Conclusions

Our results indicate that Kaiso is not essential for either post-fertilization imprinted DNA methylation of the transgenic H19 ICR in mouse or for methylation imprinting of the endogenous mouse H19 ICR.
Colorectal cancer microbiome programs DNA methylation of host cells by affecting methyl donor metabolism
Authors: Liu Zhi , Zhang Qingqing , Zhang Hong , Yi Zhongyuan , Ma Huihui , Wang Xiaoyi , Wang Jingjing , Liu Yang , Zheng Yi , Fang Weijia , Huang Ping , Liu Xingyin
Published: June 2024

Background

Colorectal cancer (CRC) arises from complex interactions between host and environment, which include the gut and tissue microbiome. It is hypothesized that epigenetic regulation by gut microbiota is a fundamental interface by which commensal microbes dynamically influence intestinal biology. The aim of this study is to explore the interplay between gut and tissue microbiota and host DNA methylation in CRC.

Methods

Metagenomic sequencing of fecal samples was performed on matched CRC patients (n = 18) and healthy controls (n = 18). Additionally, tissue microbiome was profiled with 16S rRNA gene sequencing on tumor (n = 24) and tumor-adjacent normal (n = 24) tissues of CRC patients, while host DNA methylation was assessed through whole-genome bisulfite sequencing (WGBS) in a subset of 13 individuals.

Results

Our analysis revealed substantial alterations in the DNA methylome of CRC tissues compared to adjacent normal tissues. An extensive meta-analysis, incorporating publicly available and in-house data, identified significant shifts in microbial-derived methyl donor-related pathways between tumor and adjacent normal tissues. Of note, we observed a pronounced enrichment of microbial-associated CpGs within the promoter regions of genes in adjacent normal tissues, a phenomenon notably absent in tumor tissues. Furthermore, we established consistent and recurring associations between methylation patterns of tumor-related genes and specific bacterial taxa.

Conclusions

This study emphasizes the pivotal role of the gut microbiota and pathogenic bacteria in dynamically shaping DNA methylation patterns, impacting physiological homeostasis, and contributing to CRC tumorigenesis. These findings provide valuable insights into the intricate host-environment interactions in CRC development and offer potential avenues for therapeutic interventions in this disease.
Pathogenic sequence variant and microdeletion affecting HMGA2 in Silver–Russell syndrome: case reports and literature review
Authors: Yamoto Kaori , Saitsu Hirotomo , Ohkubo Yumiko , Kagami Masayo , Ogata Tsutomu
Published: June 2024

Silver–Russell syndrome (SRS) is a representative imprinting disorder characterized by pre- and postnatal growth failure. We encountered two Japanese SRS cases with a de novo pathogenic frameshift variant of HMGA2 (NM_003483.6:c.138_141delinsCT, p.(Lys46Asnfs*16)) and a de novo ~ 3.4 Mb microdeletion at 12q14.2–q15 involving HMGA2, respectively. Furthermore, we compared clinical features in previously reported patients with various genetic conditions leading to compromised IGF2 expression, i.e., HMGA2 aberrations, PLAG1 aberrations, IGF2 aberrations, and H19/IGF2:IG-DMR epimutations (hypomethylations). The results provide further support for HMGA2 being involved in the development of SRS and imply some characteristic features in patients with HMGA2 aberrations.
Intrauterine chilled saline instillation reduces endometrial impairment on MRI after ultrasound-guided percutaneous microwave ablation of uterine adenomyosis
Authors: Zhang Hui-Li , Deng Er-Ya , Zhu Jing-E , Li Jia-Xin , Fu Le , Sun Li-Ping , Peng Cheng-Zhong , Li Xiao-Long , Yu Song-Yuan , Xu Hui-Xiong
Published: June 2024

Objective

To investigate whether intrauterine chilled saline can reduce endometrial impairment during US-guided percutaneous microwave ablation (PMWA) of adenomyosis.

Methods

An open-label, randomized trial was conducted with sixty symptomatic adenomyosis patients who were randomly assigned (1:1) to receive PMWA treatment assisted by intrauterine saline instillation (study group) or traditional PMWA treatment alone (control group). The primary endpoint was endometrial perfusion impairment grade on post-ablation contrast-enhanced MRI. The secondary endpoints were endometrial dehydration grade, ablation rate, and intra-ablation discomfort.

Results

The baseline characteristics of the two groups were similar. The incidence rates of endometrial perfusion impairment on MRI in the study and control groups were 6.7% (2/30) and 46.7% (14/30), respectively (p < 0.001). There were 28 (93.3%), 2 (6.7%), 0, and 0 patients in the study group and 16 (53.3%), 7 (23.3%), 5 (16.7%), and 2 (6.7%) in the control group (p < 0.001) who had grade 0, 1, 2, and 3 perfusion impairment, respectively. Additionally, there were 27 (90%), 3 (10%), and 0 patients in the study group and 19 (63.3%), 10 (33.3%), and 1 (3.3%) in the control group who had grade 0, 1, and 2 endometrial dehydration (p = 0.01). The ablation rates achieved in the study and control groups were 93.3 ± 17% (range: 69.2–139.6%) and 99.7 ± 15.7% (range: 71.5–129.8%), and they were not significantly different (p = 0.14). No significant difference was found in the intra-ablation discomfort.

Conclusion

Intrauterine chilled saline can effectively reduce endometrial impairment after PMWA treatment for adenomyosis.

Critical relevance statement

This trial demonstrated that the instillation of intrauterine chilled saline reduced endometrial impairment on MRI during PMWA of adenomyosis. This approach allows more precise and safe ablation in clinical practice.

Key Points

Endometrial impairment occurs in the PMWA treatment of adenomyosis.

Intrauterine chilled saline can reduce endometrial impairment during PMWA for adenomyosis.

An intrauterine catheter is a practical endometrial protecting method during thermal ablation.

Trial registration:

Chinese Clinical Trial Registry, ChiCTR2100053582. Registered 24 November 2021, www.chictr.org.cn/showproj.html?proj=141090.

Graphical Abstract
Mind the gap: knowledge, attitudes and perceptions on antimicrobial resistance, antimicrobial stewardship and infection prevention and control in long-term care facilities for people with disabilities in the Netherlands
Authors: Hidad S. , de Greeff S. C. , Haenen A. , de Haan F. , Leusink G. L. , Timen A.
Published: June 2024

Background

Antimicrobial resistance (AMR) has become one of the major public health threats worldwide, emphasizing the necessity of preventing the development and transmission of drug resistant microorganisms. This is particularly important for people with vulnerable health conditions, such as people with intellectual disabilities (ID) and long-term care residents. This study aimed to assess the current status of AMR, antimicrobial stewardship (AMS) and infection prevention and control (IPC) in Dutch long-term care facilities for people with intellectual disabilities (ID-LTCFs).

Methods

A web-based cross-sectional survey distributed between July and November 2023, targeting (both nonmedically and medically trained) healthcare professionals working in ID-LTCFs in The Netherlands, to study knowledge, attitudes and perceptions regarding AMR, AMS and IPC.

Results

In total, 109 participants working in 37 long-term care organizations for people with intellectual disabilities throughout the Netherlands completed the questionnaire. The knowledge levels of AMR and IPC among nonmedically trained professionals (e.g., social care professionals) were lower than those among medically trained professionals (p = 0.026). In particular regarding the perceived protective value of glove use, insufficient knowledge levels were found. Furthermore, there was a lack of easy-read resources and useful information regarding IPC and AMR, for both healthcare professionals as well as people with disabilities. The majority of the participants (> 90%) reported that AMR and IPC need more attention within the disability care sector, but paradoxically, only 38.5% mentioned that they would like to receive additional information and training about IPC, and 72.5% would like to receive additional information and training about AMR.

Conclusion

Although the importance of AMR and IPC is acknowledged by professionals working in ID-LTCFs, there is room for improvement in regards to appropriate glove use and setting-specific IPC and hygiene policies. As nonmedically trained professionals comprise most of the workforce within ID-LTCFs, it is also important to evaluate their needs. This can have a substantial impact on developing and implementing AMR, AMS and/or IPC guidelines and policies in ID-LTCFs.
Single-cell and bulk RNA-seq unveils the immune infiltration landscape associated with cuproptosis in cerebral cavernous malformations
Authors: Chen Chengwei , Bao Yuting , Ju Sihan , Jiang Conglin , Zou Xiang , Zhang Xin , Chen Liang
Published: June 2024

Background

Cerebral cavernous malformations (CCMs) are vascular abnormalities associated with deregulated angiogenesis. Their pathogenesis and optimal treatment remain unclear. This study aims to investigate the molecular signatures of cuproptosis, a newly identified type of cell death, associated with CCMs development.

Methods

Bulk RNA sequencing (RNA-seq) from 15 CCM and 6 control samples were performed with consensus clustering and clustered to two subtypes based on expression levels of cuproptosis-related genes (CRGs). Differentially expressed genes and immune infiltration between subtypes were then identified. Machine learning algorithms including the least absolute shrinkage and selection operator and random forest were employed to screen for hub genes for CCMs associated with cuproptosis. Furthermore, Pathway enrichment and correlation analysis were used to explore the functions of hub genes and their association with immune phenotypes in CCMs. An external dataset was then employed for validation. Finally, employing the Cellchat algorithm on a single-cell RNA-seq dataset, we explored potential mechanisms underlying the participation of these hub genes in cell-cell communication in CCMs.

Results

Our study revealed two distinct CCM subtypes with differential pattern of CRG expression and immune infiltration. Three hub genes (BTBD10, PFDN4, and CEMIP) were identified and validated, which may significantly associate with CCM pathogenesis. These genes were found to be significantly upregulated in CCM endothelial cells (ECs) and were validated through immunofluorescence and western blot analysis. Single-cell RNA-seq analysis revealed the cellular co-expression patterns of these hub genes, particularly highlighting the high expression of BTBD10 and PFDN4 in ECs. Additionally, a significant co-localization was also observed between BTBD10 and the pivotal cuproptosis gene FDX1 in Mki67+ tip cells, indicating the crucial role of cuproptosis for angiogenesis in CCMs. The study also explored the cell-cell communication between subcluster of ECs expressing these hub genes and immune cells, particularly M2 macrophages, suggesting a role for these interactions in CCM pathogenesis.

Conclusion

This study identifies molecular signatures linking cuproptosis to CCMs pathogenesis. Three hub genes—PFDN4, CEMIP, and BTBD10—may influence disease progression by modulating immunity. Further research is needed to understand their precise disease mechanisms and evaluate their potential as biomarkers or therapeutic targets for CCMs.
A systematic review on EEG-based neuromarketing: recent trends and analyzing techniques
Authors: Khondakar Md. Fazlul Karim , Sarowar Md. Hasib , Chowdhury Mehdi Hasan , Majumder Sumit , Hossain Md. Azad , Dewan M. Ali Akber , Hossain Quazi Delwar
Published: June 2024

Neuromarketing is an emerging research field that aims to understand consumers’ decision-making processes when choosing which product to buy. This information is highly sought after by businesses looking to improve their marketing strategies by understanding what leaves a positive or negative impression on consumers. It has the potential to revolutionize the marketing industry by enabling companies to offer engaging experiences, create more effective advertisements, avoid the wrong marketing strategies, and ultimately save millions of dollars for businesses. Therefore, good documentation is necessary to capture the current research situation in this vital sector. In this article, we present a systematic review of EEG-based Neuromarketing. We aim to shed light on the research trends, technical scopes, and potential opportunities in this field. We reviewed recent publications from valid databases and divided the popular research topics in Neuromarketing into five clusters to present the current research trend in this field. We also discuss the brain regions that are activated when making purchase decisions and their relevance to Neuromarketing applications. The article provides appropriate illustrations of marketing stimuli that can elicit authentic impressions from consumers' minds, the techniques used to process and analyze recorded brain data, and the current strategies employed to interpret the data. Finally, we offer recommendations to upcoming researchers to help them investigate the possibilities in this area more efficiently in the future.
Successful R0 resection after chemotherapy, including nivolumab, for gastric cancer with liver metastases: three case reports
Authors: Kawai Junpei , Yasufuku Itaru , Fukada Masahiro , Asai Ryuichi , Sato Yuta , Tajima Yu Jesse , Saigo Chiemi , Kiyama Shigeru , Makiyama Akitaka , Tanaka Yoshihiro , Okumura Naoki , Murase Katsutoshi , Miyazaki Tatsuhiko , Matsuhashi Nobuhisa
Published: June 2024

Background

Advances in chemotherapy have increased clinical experience with conversion surgery for inoperable advanced gastric cancer. This report describes three patients with unresectable gastric cancer accompanied by multiple liver metastases. In all three patients, nivolumab resolved the liver metastases and subsequent conversion surgery achieved a pathological complete response.

Case presentation

In Case 1, a 68-year-old man with clinical Stage IVB gastric cancer and multiple liver metastases initiated first-line therapy with SOX plus nivolumab. The patient completed 13 cycles; however, only nivolumab was continued for 3 cycles because of adverse events. Distal gastrectomy and partial hepatic resection were performed because of a significant reduction in the size of the liver metastases as observed on magnetic resonance imaging (MRI). In Case 2, a 72-year-old man with clinical Stage IVB gastric cancer and multiple liver metastases initiated first-line therapy with SOX. Because of the subsequent emergence of new liver metastases, the patient transitioned to ramucirumab plus paclitaxel as second-line therapy. Third-line therapy with nivolumab was initiated because of side effects. MRI revealed necrosis within the liver metastasis, and the patient underwent proximal gastrectomy and partial hepatectomy. In Case 3, a 51-year-old woman with clinical Stage IVB gastric cancer accompanied by multiple metastases of the liver and para-aortic lymph nodes began first-line therapy with SOX plus nivolumab. The patient completed 10 cycles; however, only nivolumab was continued for 5 cycles because of adverse events. Computed tomography showed a significant decrease in the size of the para-aortic lymph nodes, while MRI indicated the presence of a singular liver metastasis. Distal gastrectomy and partial hepatic resection were subsequently performed. In all three cases, MRI revealed the presence of liver metastases; however, pathological examination showed no viable tumor cells.

Conclusions

We herein present three cases in which chemotherapy, including nivolumab, elicited a response in patients with multiple unresectable liver metastases, ultimately culminating in R0 resection through conversion surgery. Although MRI showed liver metastases, pathological analysis revealed no cancer, underscoring the beneficial impact of chemotherapy.
Exploring the evolution of facial feminization and masculinization surgery: a bibliometric analysis and visualization study
Authors: Uranbey Omer , Kaygisiz Omer Faruk , Ayrancı Ferhat , Yanik Saim
Published: June 2024

Background

This study aims to conduct a bibliometric analysis of the current literature related to facial feminization surgery (FFS) and facial masculinization surgery (FMS) to understand the patterns, trends, and evolution of research topics. In addition, it aims to objectively identify the important articles that constitute the primary backbone of the FFS/FMS literature and provide a resource for education and new studies in this emerging field.

Results

Using the principles of the Leiden Manifesto, 384 publications from the Web of Science from 1987 to 2023 were analyzed. The analysis included cross-country collaboration, keyword trends, affiliations, co-citation networks, and clustering. The results showed an increasing trend in FFS/FMS publications, with the USA leading in both publications (n = 238) and citations (n = 2420). The most cited journal was the Journal of Plastic and Reconstructive Surgery. The results indicate a high growth rate, with an H-index of 34 and an average citation of 11.41 per article. Co-occurrence analysis revealed evolving keywords such as “forehead” (n = 52) and “quality of life” (n = 44). The timeline view illustrated the terms reflecting current areas of interest such as #patient satisfaction and #gender-affirming care.

Conclusion

The study reveals the influence of countries, institutions, authors, and emerging trends, supporting the anticipation that FFS/FMS will be a critical field of study in the future. The findings contribute to understanding the global landscape of FFS/FMS research, facilitating informed decision-making for researchers, and clinicians in the field of maxillofacial surgery.
CommanderUAP: a practical and transferable universal adversarial attacks on speech recognition models
Authors: Sun Zheng , Zhao Jinxiao , Guo Feng , Chen Yuxuan , Ju Lei
Published: June 2024

Most of the adversarial attacks against speech recognition systems focus on specific adversarial perturbations, which are generated by adversaries for each normal example to achieve the attack. Universal adversarial perturbations (UAPs), which are independent of the examples, have recently received wide attention for their enhanced real-time applicability and expanded threat range. However, most of the UAP research concentrates on the image domain, and less on speech. In this paper, we propose a staged perturbation generation method that constructs CommanderUAP, which achieves a high success rate of universal adversarial attack against speech recognition models. Moreover, we apply some methods from model training to improve the generalization in attack and we control the imperceptibility of the perturbation in both time and frequency domains. In specific scenarios, CommanderUAP can also transfer attack some commercial speech recognition APIs.
Revolutionizing Rural Oncology: Innovative Models and Global Perspectives
Authors: Munhoz Rodrigo , Sabesan Sabe , Thota Ramya , Merrill Janette , Hensold Jack Oliver
Published: June 2024

For individuals living in rural areas, access to cancer care can be difficult. Barriers to access cross international boundaries and have a negative impact on treatment outcomes. Current models to increase rural access in the United States are reviewed, as is a system-wide approach to this problem in Australia. Ongoing efforts to increase access to clinical trials for patients in rural areas are also discussed.
Results from the randomized phase 3 DREAMM-8 study of belantamab mafodotin plus pomalidomide and dexamethasone (BPd) vs pomalidomide plus bortezomib and dexamethasone (PVd) in relapsed/refractory multiple myeloma (RRMM).
Authors: Trudel Suzanne , Beksac Meral , Pour Luděk , Delimpasi Sosana , Quach Hang , Vorobyev Vladimir I. , Cavo Michele , Suzuki Kazuhito , Robak Pawel , Morris Kristin , Phillips-Jones Amy , Zhou Xiaoou Linnette , Fulci Giulia , Sule Neal , Kremer Brandon , Opalinska Joanna , Mateos Maria-Victoria , Dimopoulos Meletios Athanasios
Published: June 2024

LBA105

Background: Use of triplet/quadruplet therapies for 1L MM raises the need for novel combinations at first relapse, which belantamab mafodotin (belamaf) combos may address. In DREAMM-7, BVd led to a significant improvement in progression-free survival (PFS) and a strong trend in improved overall survival (OS) vs daratumumab-Vd in patients (pts) with ≥1 prior therapy. We report results from DREAMM-8 (NCT04484623), which tested a different belamaf combo (BPd) and met its primary endpoint of independent review committee–assessed PFS at a prespecified interim analysis. Methods: DREAMM-8 is a phase 3, open-label, randomized, multicenter trial evaluating the efficacy and safety of BPd vs PVd in RRMM pts who received ≥1 prior line of therapy (LoT), including lenalidomide. Pts were randomly assigned 1:1 to BPd (28-d cycles): belamaf 2.5 mg/kg IV (D1, C1), 1.9 mg/kg (D1, C2+) + pom 4 mg (D1-21, all C) + dex 40 mg (D1, QW, all C), or PVd (21-d cycles): pom 4 mg (D1-14, all C) + bortezomib 1.3 mg/m2 SC (D1, 4, 8, 11 [C1-8]; and D1, 8 [C9+]) + dex 20 mg (day of and 1 day after bortezomib dose). Results: 155 pts were randomly assigned to BPd and 147 to PVd. With a median (range) follow-up of 21.78 mo (0.03-39.23), median PFS (95% CI) was not reached (NR; 20.6-NR) with BPd vs 12.7 mo (9.1-18.5) with PVd (HR, 0.52; 95% CI, 0.37-0.73; P<0.001). 12-month PFS rate (95% CI) was 71% (63-78%) with BPd vs 51% (42-60%) with PVd. ORR (95% CI) was 77% (70.0-83.7%) with BPd vs 72% (64.1-79.2%) with PVd; rate of complete response or better (95% CI) was 40% (32.2-48.2%) with BPd vs 16% (10.7-23.3%) with PVd. Median duration of response (95% CI) was NR (24.9-NR) with BPd vs 17.5 mo (12.1-26.4) with PVd. A positive trend favoring BPd was seen for OS (HR, 0.77; 95% CI, 0.53-1.14); follow up for OS is ongoing. Adverse events (AEs) were reported in >99% and 96% of pts in the BPd and PVd arms, respectively. Of pts treated with BPd, 89% had ocular AEs (CTCAE grade 3/4, 43%) vs 30% (grade 3/4, 2%) in the PVd arm. AEs were generally manageable, and broadly consistent with known safety profile of individual agents. Conclusions: The DREAMM-8 study demonstrated a statistically significant and clinically meaningful PFS benefit with BPd vs PVd in RRMM with >1 prior LoT. BPd also led to deeper and more durable responses, showed a favorable OS trend, and had a manageable safety profile. Clinical trial information: NCT04484623 . [Table: see text]
Atezolizumab in patients (pts) with tumor mutational burden (TMB)–high tumors from the TAPISTRY trial.
Authors: Dziadziuszko Rafal , Barlesi Fabrice , Kim Jeong Eun , Gadgeel Shirish M. , Krzakowski Maciej , Jeong Jae Ho , Daniele Gennaro , Chen David , Hu Youyou , Wilson Timothy R. , Simmons Brian P. , Thomas David Morgan
Published: June 2024

LBA2509

Background: Studies have suggested that pts with TMB-high tumors could derive clinical benefit from atezolizumab, a PD-L1 inhibitor; however, these studies used inconsistent TMB cutoffs. We report efficacy and safety data of atezolizumab in adult and pediatric pts with TMB-high advanced/metastatic solid tumors from Cohort D of the TAPISTRY trial (NCT04589845), using two TMB cutoffs: ≥13 mutations [mut]/Mb and ≥16 mut/Mb. Methods: TAPISTRY is a phase II, global, open-label, multicohort basket trial evaluating the efficacy and safety of multiple therapies in pretreated pts with advanced/metastatic solid tumors. Pts in Cohort D had advanced unresectable/metastatic, PD-L1 inhibitor-naïve, TMB-high (≥13 mut/Mb) solid tumors. Atezolizumab was given every 21 days, at 1200 mg in pts ≥18 years old, and at ≥15 mg/kg (up to 1200 mg) in pts <18 years old. Tumor responses were assessed per RECIST v1.1. Primary endpoint: objective response rate (ORR) by independent review committee (IRC) in pts with TMB ≥16 mut/Mb. Secondary endpoints included ORR by IRC in pts with TMB ≥13 mut/Mb, duration of response (DoR), progression-free survival (PFS), overall survival (OS) and safety. Results: At data cut-off (Nov 9, 2023), 150 pts with TMB ≥13 mut/Mb were enrolled. In the safety-evaluable population (n = 148), median age was 63 years (range 11–86); 56% of pts were male, and 56% had received ≥2 prior lines of therapy (median 2; range 0–14). The efficacy-evaluable population included 129 pts with TMB ≥13 mut/Mb (TMB ≥16 mut/Mb; n = 111); the most common tumor types were colorectal (n = 40; 31%), breast, and gastroesophageal cancer (n = 11 each; 9%). Key outcomes are presented (Table). After a median follow-up of 9.8 months, ORR by IRC was comparable between pts with TMB ≥16 mut/Mb (22.5%) and pts with TMB ≥13 mut/Mb (20.2%). Responses were seen across a variety of tumor types. DoR 6- and 12-month event-free rates were 79% and 72%, respectively. Median PFS was short, suggesting fast disease progression in non-responders. Fatigue (22%) and anemia (20%) were the most common adverse events. Safety of atezolizumab was consistent with its known profile. Conclusions: Atezolizumab was well tolerated and led to antitumor activity in pts with TMB-high solid tumors. Responses were seen across a variety of tumor types. Clinical trial information: NCT04589845 . [Table: see text]
Prognostic utility of ctDNA detection in the monarchE trial of adjuvant abemaciclib plus endocrine therapy (ET) in HR+, HER2-, node-positive, high-risk early breast cancer (EBC).
Authors: Loi Sherene , Johnston Stephen R. D. , Arteaga Carlos L. , Graff Stephanie L. , Chandarlapaty Sarat , Goetz Matthew P. , Desmedt Christine , Sasano Hironobu , Liu Deli , Rodrik-Outmezguine Vanessa , Sireci Anthony , Sandoval Cynthia , Won Helen H , Litchfield Lacey M , Turner Nicholas C.
Published: June 2024

LBA507

Background: In monarchE (NCT03155997), 2 years of adjuvant abemaciclib + ET resulted in sustained improvement in invasive disease-free survival (IDFS; HR=0.680, 7.6% absolute benefit at 5 years) in patients (pts) with HR+, HER2-, node-positive, high-risk EBC. Here, we investigate the prognostic value of ctDNA detection and dynamics in pts from monarchE. Methods: Samples were analyzed from a selected pt subset (n=1397; abemaciclib + ET arm, n=685; ET arm, n=712), enriched for overall IDFS events compared to the total monarchE study population (IDFS event rate: 31% [433/1397] vs 18% [992/5637]). Pts had blood collected pre-study treatment (baseline) and at 3, 6, or 24 months. ctDNA detection was performed using the personalized, tumor informed Signatera ctDNA assay (Natera, Inc) and whole exome sequencing (WES) of matched primary tumor and normal required for assay design was performed. Results: Among 1397 pts, 65% (n=910) had sufficient plasma samples and WES performed, and all 910 had successful ctDNA assay testing. Among these 910 pts, the IDFS event rate was 27% (abemaciclib + ET, 23% [101/438]; ET alone, 31% [146/472]). Rates of ctDNA positivity (at baseline and any change from baseline) and associated IDFS events are shown in Table. Among pts with ctDNA positivity, 87% had an IDFS event in comparison to 15% with persistent ctDNA negative (-) status during the study. Conclusions: In a pt subset from monarchE enriched for IDFS events, ctDNA detection was relatively infrequent (<20%); however, its detection at any time during the 24 months of study therapy was adversely prognostic. As compared to pts who had remaining ctDNA positive (+), pts who had clearance of ctDNA on therapy had lower risk of IDFS events, but the event risk still remained clinically meaningful in these pts. Clinical trial information: NCT03155997 . [Table: see text]