bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide screening and functional validation of methylation barriers near promoters
Authors: Shu Jingmin , Jelinek Jaroslav , Chen Hai , Zhang Yan , Qin Taichun , Li Ming , Liu Li , Issa Jean-Pierre J
Published: April 2024

CpG islands near promoters are normally unmethylated despite being surrounded by densely methylated regions. Aberrant hypermethylation of these CpG islands has been associated with the development of various human diseases. Although local genetic elements have been speculated to play a role in protecting promoters from methylation, only a limited number of methylation barriers have been identified. In this study, we conducted an integrated computational and experimental investigation of colorectal cancer methylomes. Our study revealed 610 genes with disrupted methylation barriers. Genomic sequences of these barriers shared a common 41-bp sequence motif (MB-41) that displayed homology to the chicken HS4 methylation barrier. Using the CDKN2A (P16) tumor suppressor gene promoter, we validated the protective function of MB-41 and showed that loss of such protection led to aberrant hypermethylation. Our findings highlight a novel sequence signature of cis-acting methylation barriers in the human genome that safeguard promoters from silencing.
ProTox 3.0: a webserver for the prediction of toxicity of chemicals
Authors: Banerjee Priyanka , Kemmler Emanuel , Dunkel Mathias , Preissner Robert
Published: April 2024

Interaction with chemicals, present in drugs, food, environments, and consumer goods, is an integral part of our everyday life. However, depending on the amount and duration, such interactions can also result in adverse effects. With the increase in computational methods, the in silico methods can offer significant benefits to both regulatory needs and requirements for risk assessments and the pharmaceutical industry to assess the safety profile of a chemical. Here, we present ProTox 3.0, which incorporates molecular similarity and machine-learning models for the prediction of 61 toxicity endpoints such as acute toxicity, organ toxicity, clinical toxicity, molecular-initiating events (MOE), adverse outcomes (Tox21) pathways, several other toxicological endpoints and toxicity off-targets. All the ProTox 3.0 models are validated on independent external sets and have shown strong performance. ProTox envisages itself as a complete, freely available computational platform for in silico toxicity prediction for toxicologists, regulatory agencies, computational chemists, and medicinal chemists. The ProTox 3.0 webserver is free and open to all users, and there is no login requirement and can be accessed via https://tox.charite.de. The web server takes a 2D chemical structure as input and reports the toxicological profile of the compound for each endpoint with a confidence score and overall toxicity radar plot and network plot.
HDAC10 inhibition represses melanoma cell growth and BRAF inhibitor resistance via upregulating SPARC expression
Authors: Ling Hongbo , Li Yixuan , Peng Changmin , Yang Shengyu , Seto Edward
Published: April 2024

Secreted protein acidic and rich in cysteine (SPARC), a conserved secreted glycoprotein, plays crucial roles in regulating various biological processes. SPARC is highly expressed and has profound implications in several cancer types, including melanoma. Understanding the mechanisms that govern SPARC expression in cancers has the potential to lead to improved cancer diagnosis, prognosis, treatment strategies, and patient outcomes. Here, we demonstrate that histone deacetylase 10 (HDAC10) is a key regulator of SPARC expression in melanoma cells. Depletion or inhibition of HDAC10 upregulates SPARC expression, whereas overexpression of HDAC10 downregulates it. Mechanistically, HDAC10 coordinates with histone acetyltransferase p300 to modulate the state of acetylation of histone H3 at lysine 27 (H3K27ac) at SPARC regulatory elements and the recruitment of bromodomain-containing protein 4 (BRD4) to these regions, thereby fine-tuning SPARC transcription. HDAC10 depletion and resultant SPARC upregulation repress melanoma cell growth primarily by activating AMPK signaling and inducing autophagy. Moreover, SPARC upregulation due to HDAC10 depletion partly accounts for the resensitization of resistant cells to a BRAF inhibitor. Our work reveals the role of HDAC10 in gene regulation through indirect histone modification and suggests a potential therapeutic strategy for melanoma or other cancers by targeting HDAC10 and SPARC.
Three-year follow-up analysis of phase 1/2 study on tirabrutinib in patients with relapsed or refractory primary central nervous system lymphoma
Authors: Yonezawa Hajime , Narita Yoshitaka , Nagane Motoo , Mishima Kazuhiko , Terui Yasuhito , Arakawa Yoshiki , Asai Katsunori , Fukuhara Noriko , Sugiyama Kazuhiko , Shinojima Naoki , Aoi Arata , Nishikawa Ryo
Published: April 2024

Background

The ONO-4059-02 phase 1/2 study showed favorable efficacy and acceptable safety profile of tirabrutinib, a second-generation Bruton’s tyrosine kinase inhibitor, for relapsed/refractory primary central nervous system lymphoma (PCNSL). Here, we report the long-term efficacy and safety after a 3-year follow-up.

Methods

Eligible patients were aged ≥ 20 years with histologically diagnosed PCNSL and KPS of ≥ 70. Patients received oral tirabrutinib once daily at 320 or 480 mg, or 480 mg under fasted conditions.

Results

Between October 19, 2017, and June 13, 2019, 44 patients were enrolled: 33 and 9 had relapsed and refractory, respectively. The 320, 480, and 480 mg fasted groups included 20, 7, and 17 patients, respectively. The median follow-up was 37.1 months. The overall response rate was 63.6% (95% CI: 47.8–77.6) with complete response (CR), unconfirmed CR, and partial response in 9, 7, and 12 patients, respectively. The median duration of response (DOR) was 9.2 months, with a DOR rate of 19.8%; the median progression-free survival (PFS) and median overall survival (OS) were 2.9 months and not reached, respectively, with PFS and OS rates of 13.9% and 56.7%, respectively. Adverse events occurred in 38 patients (86.4%): grade ≥ 3 in 23 (52.3%) including 1 patient with grade 5 events. KPS and quality of life (QoL) scores were well maintained among patients receiving long-term treatment.

Conclusions

The results demonstrated the long-term clinical benefit of tirabrutinib, with deep and durable response in a subset of patients and acceptable safety profile, while KPS and QoL scores were maintained.
Nonclinical pharmacodynamics of boron neutron capture therapy using direct intratumoral administration of a folate receptor targeting novel boron carrier
Authors: Tsujino Kohei , Kashiwagi Hideki , Nishimura Kai , Fujikawa Yoshiki , Kayama Ryo , Fukuo Yusuke , Hiramatsu Ryo , Nonoguchi Naosuke , Takata Takushi , Tanaka Hiroki , Suzuki Minoru , Hu Naonori , Ono Koji , Wanibuchi Masahiko , Nakai Kei , Nakamura Hiroyuki , Kawabata Shinji
Published: April 2024

Background

Boron neutron capture therapy (BNCT) is a precise particle radiation therapy known for its unique cellular targeting ability. The development of innovative boron carriers is crucial for the advancement of BNCT technologies. Our previous study demonstrated the potential of PBC-IP administered via convection-enhanced delivery (CED) in an F98 rat glioma model. This approach significantly extended rat survival in neutron irradiation experiments, with half achieving long-term survival, akin to a cure, in a rat brain tumor model. Our commitment to clinical applicability has spurred additional nonclinical pharmacodynamic research, including an investigation into the effects of cannula position and the time elapsed post-CED administration.

Methods

In comprehensive in vivo experiments conducted on an F98 rat brain tumor model, we meticulously examined the boron distribution and neutron irradiation experiments at various sites and multiple time intervals following CED administration.

Results

The PBC-IP showed substantial efficacy for BNCT, revealing minimal differences in tumor boron concentration between central and peripheral CED administration, although a gradual decline in intratumoral boron concentration post-administration was observed. Therapeutic efficacy remained robust, particularly when employing cannula insertion at the tumor margin, compared to central injections. Even delayed neutron irradiation showed notable effectiveness, albeit with a slightly reduced survival period. These findings underscore the robust clinical potential of CED-administered PBC-IP in the treatment of malignant gliomas, offering adaptability across an array of treatment protocols.

Conclusions

This study represents a significant leap forward in the quest to enhance BNCT for the management of malignant gliomas, opening promising avenues for clinical translation.
Summary of the Centers for Disease Control and Prevention/National Institute of Allergy and Infectious Diseases Joint Workshop on Genital Herpes: 3–4 November 2022
Authors: Connolly Kristie L , Bachmann Laura , Hiltke Thomas , Kersh Ellen N , Newman Lori M , Wilson Lydia , Mena Leandro , Deal Carolyn
Published: April 2024

Genital herpes is caused by infection with herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) and currently has no cure. The disease is the second-most common sexually transmitted infection in the United States, with an estimated 18.6 million prevalent genital infections caused by HSV-2 alone. Genital herpes diagnostics and treatments are not optimal, and no vaccine is currently available. The Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases convened a workshop entitled “CDC/NIAID Joint Workshop on Genital Herpes.” This report summarizes 8 sessions on the epidemiology of genital herpes, neonatal HSV, HSV diagnostics, vaccines, treatments, cures, prevention, and patient advocacy perspective intended to identify opportunities in herpes research and foster the development of strategies to diagnose, treat, cure, and prevent genital herpes.
Imaging of labile Fe2+ and Fe3+ in living Arabidopsis thaliana roots
Authors: Alcon Carine , Comte Arnaud , Curie Catherine , Xiong Tou Cheu
Published: April 2024

Adapting fluorescent iron imaging to living plants enables visualizing labile Fe2+ and Fe3+ pools, revealing the heterogeneous distribution of iron redox status at the tissue and cellular levels.
Linguistic imposters
Authors: Kazankov Denis , Yi Edison
Published: April 2024

There is a widespread phenomenon that we call linguistic imposters. Linguistic imposters are systematic misuses of expressions that misusers mistake with their conventional usages because of misunderstanding their meaning. Our paper aims to provide an initial framework for theorising about linguistic imposters that will lay the foundation for future philosophical research about them. We focus on the misuses of the expressions ‘grooming’ and ‘critical race theory’ as our central examples of linguistic imposters. We show that linguistic imposters present a distinctive phenomenon by comparing them to some adjacent phenomena, namely conceptual engineering, linguistic hijacking and dogwhistles. We also address four objections about the extensional adequacy of our definition of linguistic imposters. Finally, we argue that, as linguistic imposters spread, they make some inferences featuring misused expressions more cognitively accessible and seemingly socially licensed to misusers and discuss four types of harms that linguistic imposters are conducive to through these effects.
BASDAI versus ASDAS in evaluating axial involvement in patients with psoriatic arthritis: a pooled analysis of two phase 3 studies
Authors: Baraliakos Xenofon , Gladman Dafna D , Chakravarty Soumya D , Gong Cinty , Shawi May , Rampakakis Emmanouil , Kishimoto Mitsumasa , Soriano Enrique R , Mease Philip J
Published: April 2024

Objective

In the absence of axial psoriatic arthritis (axPsA)-specific tools, the BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS) are used to assess axial symptoms in patients with PsA. Here, we assessed the performance of BASDAI and ASDAS in patients with PsA.

Methods

Patients with active PsA in DISCOVER-1 and DISCOVER-2 (ClinicalTrials.gov: NCT03162796 and NCT03158285, respectively) with or without axPsA but with available baseline BASDAI information were analysed; those with investigator-identified axial symptoms and imaging-confirmed sacroiliitis comprised the axPsA cohort. Correlations between BASDAI/ASDAS and clinical variables were assessed with Pearson’s coefficient (r). Longitudinal effects of enthesitis (Leeds Enthesitis Index [LEI]), swollen joint count and presence versus absence of axPsA on BASDAI/ASDAS (normalized 0–10 scale) were analysed with mixed models for repeated measures.

Results

At baseline in the axPsA (n = 312) and non-axPsA (n = 124) cohorts, BASDAI scores showed no or weak correlation with swollen joint count (0.18–0.20), tender joint count (0.12–0.29), LEI (–0.04 to 0.24) and physician global assessment (0.35–0.43); moderate correlation with fatigue (both −0.56); and strong correlation with patient global assessment of disease activity (0.62–0.69) and patient-reported pain (0.66–0.70). Similar correlations were observed for ASDAS. Axial involvement versus non-involvement was associated with higher BASDAI scores and ASDAS (all β ≥ 0.5), without differences between instruments; longitudinal associations between swollen joint count (β ≤ 0.06)/LEI (β ≤ 0.19) and BASDAI/ASDAS were clinically unimportant.

Conclusion

BASDAI and ASDAS performed similarly in patients with active PsA and axial involvement, independent of peripheral disease involvement, supporting their performance in assessing axial disease activity.

Trial registration

ClinicalTrials.gov, http://clinicaltrials.gov, NCT03162796 and NCT03158285.
Prevalence and progression of arterial calcifications on computed tomography in humans with knee osteoarthritis
Authors: de Jong Pim A , Harlianto Netanja I , Foppen Wouter , Renkli Nağme Ö , Spiering Wilko , Weinans Harrie , Mali Willem P Th M , Mastbergen Simon C , Jansen Mylène P
Published: April 2024

Objectives

Ectopic bone deposition plays an important role in OA and in arterial wall disease. We aimed to investigate the prevalence and progression of arterial calcifications on whole-body CT in persons with knee OA.

Methods

We included 118 (36 male) participants who satisfied the clinical ACR classification criteria for knee OA. Baseline investigations included WOMAC and Kellgren–Lawrence grading. At baseline and after 2 years, a whole-body CT was performed using the same scanner and protocol. Calcifications were quantified in the carotid, brachiocephalic, coronary, thoracic aortic, abdominal aortic, iliac, femoropopliteal and crural arteries. Multivariable linear and logistic regression modelling was used for analyses.

Results

At baseline males were 66.9 ± 7.7 and females were 68.0 ± 5.6 years old. Calcifications were common, all participants except two females had some calcification, and prevalence ranged between 41.8% and 94.4% for various arterial beds. Baseline femoropopliteal calcifications were associated with a higher Kellgren–Lawrence grade (more severe knee OA). Median annual progression rate was 13.1% in males and 15.7% in females. Structural OA severity was not associated with progression, but a five points lower (worse) WOMAC was associated with 1% faster progression of arterial calcifications (P = 0.008).

Conclusion

Around age 70 years nearly all persons with knee OA have arterial calcifications, which progress substantially. For further investigation into shared causality intervention studies are needed.
ChatGPT4’s proficiency in addressing patients’ questions on systemic lupus erythematosus: a blinded comparative study with specialists
Authors: Xu Dan , Zhao Jinxia , Liu Rui , Dai Yijun , Sun Kai , Wong Priscilla , Ming Samuel Lee Shang , Wearn Koh Li , Wang Jiangyuan , Xie Shasha , Zeng Lin , Mu Rong , Xu Chuanhui
Published: April 2024

Objectives

The efficacy of artificial intelligence (AI)-driven chatbots like ChatGPT4 in specialized medical consultations, particularly in rheumatology, remains underexplored. This study compares the proficiency of ChatGPT4’ responses with practicing rheumatologists to inquiries from patients with SLE.

Methods

In this cross-sectional study, we curated 95 frequently asked questions (FAQs), including 55 in Chinese and 40 in English. Responses for FAQs from ChatGPT4 and five rheumatologists were scored separately by a panel of rheumatologists and a group of patients with SLE across six domains (scientific validity, logical consistency, comprehensibility, completeness, satisfaction level and empathy) on a 0–10 scale (a score of 0 indicates entirely incorrect responses, while 10 indicates accurate and comprehensive answers).

Results

Rheumatologists’ scoring revealed that ChatGPT4-generated responses outperformed those from rheumatologists in satisfaction level and empathy, with mean differences of 0.537 (95% CI, 0.252–0.823; P < 0.01) and 0.460 (95% CI, 0.227–0.693; P < 0.01), respectively. From the SLE patients’ perspective, ChatGPT4-generated responses were comparable to the rheumatologist-provided answers in all six domains. Subgroup analysis revealed ChatGPT4 responses were more logically consistent and complete regardless of language and exhibited greater comprehensibility, satisfaction and empathy in Chinese. However, ChatGPT4 responses were inferior in comprehensibility for English FAQs.

Conclusion

ChatGPT4 demonstrated comparable, possibly better in certain domains, to address FAQs from patients with SLE, when compared with the answers provided by specialists. This study showed the potential of applying ChatGPT4 to improve consultation in SLE patients.
Prospective dose monitoring using a manual dose management system: experience in brain computed tomography from a tertiary hospital in Nigeria
Authors: Garba Idris , Penelope Engel-Hills , Davidson Florence , Ismail Anas
Published: April 2024

A manual radiation dose management system was developed to track the radiation dose and scan parameters of patients for brain computed tomography (CT). Radiation dose in volume computed tomography dose index (CTDIvol) and dose length product (DLP) were monitored to identify procedures that may require optimisation using notification values. The data were analysed and compared with national and international diagnostic reference levels (DRLs). A total of 596 brain CTs were monitored and grouped as <1: 36, 1–<5: 38, 5–<10: 25, 10–<15: 31 and adult: 466. The CTDIvol notification value identified the following number of examinations having high CTDIvol in <1 y: 1, 1–<5: 1, 5–<10: 0, 10–<15: 0 and adult (>15): 11. Furthermore, the DLP notification values identified the following examinations with high DLP in <1 y: 1, 1–<5:1, 5–<10:1, 10–<15: 1 and adults (>15): 18. The established local paediatric DLP DRLs were 2–3 times higher than the international paediatric DLP DRLs. This calls for a total protocol review and optimisation considering the local CT practices for paediatric imaging.
Re-analysis of single-cell RNA-seq data reveals the origin and roles of cycling myeloid cells
Authors: Zhang Jiawei , Shi Jingsong , Wang Liangge , Liu Xinjie , Cao Zemin , Ruan Cihan , Ning Guangzhi , Feng Shiqing , Yao Xue , Gao Shan
Published: April 2024

Cycling myeloid cells (CMCs) are often detected from various tissues using single-cell RNA sequencing (scRNA-seq) datasets, however, their research value was not noticed before.

For the first time, our study preliminarily revealed the origin, differentiation, and roles of CMCs in physiological processes. Particularly, subgroup a of cycling myeloid cells (aCMCs) were conclusively identified as belonging to a specific cell type. In an active state, aCMCs rapidly proliferate during the early stages of an embryonic development. With an individual maturing, most aCMCs differentiate into specialized cells, while a small portion of them enter an inactive or dormant state. Under pathological conditions, aCMCs restore their proliferative and differentiation capacities via activation or revival.

The present study has set the stage for future research on CMCs by linking them with progenitors of immune cells, and provided a crucial starting point to understand the origin, differentiation, and roles of CMCs in various physiological and pathological processes, particularly those related to traumatic injury, cancer, and pathogen infection, leading to develop targeted therapies or interventions.
The Czech trust fund in the international context
Authors: Hollmann Jakub
Published: April 2024

In the Czech legal system, the institute of trust funds first appeared after the recodification of private law with effect from 1 January 2014. The Czech trust fund serves as a flexible asset management tool, allowing diversification of risk and intergenerational transfer of assets. Trust funds are not the only entity which may be used for asset management. The other possibility is the endowment fund which unlike the trust fund has a legal personality. Trust funds and endowment funds do have their similarities and differences which might be crucial in order to choose the best option for founders’ needs. Czech trust funds were inspired by the Quebec legislation, while both Quebec and Czech law treat trust funds as separate properties without an owner.
Non-protein nitrogen supplementation on in vitro fermentation profile, methane production, and microbial nitrogen synthesis in a corn silage-based substrate
Authors: Vargas Juan de J , Tarnonsky Federico , Podversich Federico , Maderal Araceli , Fernández-Marenchino Ignacio , Cuervo Wilmer , Schulmeister Tessa M , Ruiz-Ascacibar Isabel , Ipharraguerre Ignacio R , DiLorenzo Nicolás
Published: April 2024

Non-protein nitrogen (NPN) supplements improve animal performance in backgrounding diets. However, there is scarce information regarding the effect of different NPN sources and combinations on ruminal fermentation profile. The current study aimed to evaluate the effect of different NPN sources and their combinations on in vitro fermentation, microbial N synthesis, and methane (CH4) production in a backgrounding diet. Incubations were conducted on three separate days for 24 h using corn silage and cotton gin byproduct (70% and 30% of DM, respectively) as substrate. Treatments were control (without NPN), urea, and five different proportions of urea–biuret and nitrate (100:0, 75:25, 50:50, 25:75, and 0:100). Each treatment, except control, was formulated to be isonitrogenous and equivalent to 1% urea inclusion. Ruminal fluid was collected from two ruminally cannulated Angus crossbred steers fed ad libitum corn silage and cotton gin byproduct plus 100 g of a urea–biuret–nitrate mixture. The concentration of volatile fatty acids (VFAs) and ammonia nitrogen (NH3-N) were determined at 12 and 24 h of incubation. Final pH, in vitro dry and organic matter digestibility, total gas production, and concentration of CH4 were determined at 24 h. The supplementation of NPN increased (P < 0.05) the concentration of NH3-N at 12 and 24 h. Although NPN supplementation increased (P < 0.05) the concentration of total VFA and acetate at 12 h, treatments did not differ (P > 0.05) at 24 h. Supplementation of NPN increased (P < 0.05) the proportion of acetate at 12 and 24 h but tended to reduce (P = 0.054) the proportion of propionate only at 12 h. Digestibility and pH were not different (P > 0.05) among treatments. Increasing nitrates in the NPN supplement increased (P < 0.05) the proportion of acetate and reduced (P < 0.05) the proportion of butyrate at 12 and 24 h. The supplementation of NPN increased (P < 0.05) microbial N synthesis. Furthermore, increasing nitrate proportion in the NPN supplement increased (P < 0.05) the microbial N synthesis and efficiency of N use. Supplementation of NPN did not modify (P > 0.05) total gas or CH4 production. However, increasing nitrate proportion in the NPN supplement linearly reduced (P < 0.05) CH4 production. Supplementation of NPN increased NH3-N concentration and microbial N while increasing the inclusion of nitrate decreased the production of CH4 and increased the microbial N synthesis in a corn silage-based substrate under in vitro conditions.
Association study between SNP markers located in meat quality candidate genes with intramuscular fat content in an endangered dual-purpose cattle population
Authors: Halli Kathrin , König Sven , Giambra Isabella J
Published: April 2024

The aim of this study was to associate single nucleotide polymorphisms (SNP) of the bovine calcium-activated neutral protease µ-calpain, calpastatin, diacylglycerol-O-acyltransferase, adipose fatty acid binding protein, retinoic acid receptor-related orphan receptor C (RORC), and thyroglobulin (TG) gene with intramuscular fat content (IMF). Therefore, 542 animals of the cattle breed “Rotes Höhenvieh” (RHV) were phenotyped for IMF. Genotyping of the animals was performed using polymerase chain reaction-restriction fragment length polymorphism tests for six SNP from candidate genes for meat quality traits. In addition, we calculated allele substitution and dominance effects on IMF. A subgroup of animals (n = 44, reduced dataset) with extraordinary high IMF was analyzed separately. The mean IMF content was 2.5% (SD: 2.8) but ranged from 0.02% to 23.9%, underlining the breeds’ potential for quality meat production. Allele and genotype frequencies for all SNP were similar in the complete and reduced dataset. Association analyses in the complete dataset revealed the strongest effects of RORC on IMF (P = 0.075). The log-transformed least-squares mean for IMF of genotype g.3290GG was 0.45 ± 0.16, 0.26 ± 0.14 for genotype g.3290GT, and 0.32 ± 0.14 for genotype g.3290TT. In the reduced dataset, we found a significant effect (P < 0.05) of the g.422C>T-SNP of TG on IMF, with highest IMF for genotype CT (0.91 ± 0.17), lowest IMF for genotype TT (0.37 ± 0.25), and medium IMF for genotype CC (0.59 ± 0.16; log-transformed values). Compared to the complete dataset, allele substitution effects increased in the reduced dataset for most of the SNP, possibly due to the selective genotyping strategy, with focus on animals with highest IMF implying strong phenotypic IMF contrast. Dominance effects were small in both datasets, related to the high heritability of IMF. Results indicated RHV breed particularities regarding the effects of meat quality genes on IMF. An explanation might be the breeding history of RHV with focus on adaptation and resilience in harsh outdoor systems. Consequently, it is imperative to develop breed-specific selection strategies. Allele substitution and dominance effects were in a similar direction in both datasets, suggesting the same breeding approaches for different RHV strains in different regions. Nevertheless, a selective genotyping approach (reduced dataset), contributed to more pronounced genotype effect differences on IMF and dominance values.
Rhodopsin mislocalization drives ciliary dysregulation in a novel autosomal dominant retinitis pigmentosa knock‐in mouse model
Authors: Takita Shimpei , Jahan Sultana , S. Imanishi Sanae , Harikrishnan Hemavathy , LePage David , Mann Rachel J. , Conlon Ronald A. , Miyagi Masaru , Imanishi Yoshikazu
Published: April 2024

Rhodopsin mislocalization encompasses various blind conditions. Rhodopsin mislocalization is the primary factor leading to rod photoreceptor dysfunction and degeneration in autosomal dominant retinitis pigmentosa (adRP) caused by class I mutations. In this study, we report a new knock‐in mouse model that harbors a class I Q344X mutation in the endogenous rhodopsin gene, which causes rod photoreceptor degeneration in an autosomal dominant pattern. In RhoQ344X/+ mice, mRNA transcripts from the wild‐type (Rho) and RhoQ344X mutant rhodopsin alleles are expressed at equal levels. However, the amount of RHOQ344X mutant protein is 2.7 times lower than that of wild‐type rhodopsin, a finding consistent with the rapid degradation of the mutant protein. Immunofluorescence microscopy indicates that RHOQ344X is mislocalized to the inner segment and outer nuclear layers of rod photoreceptors in both RhoQ344X/+ and RhoQ344X/Q344X mice, confirming the essential role of the C‐terminal VxPx motif in promoting OS delivery of rhodopsin. The mislocalization of RHOQ344X is associated with the concurrent mislocalization of wild‐type rhodopsin in RhoQ344X/+ mice. To understand the global changes in proteostasis, we conducted quantitative proteomics analysis and found attenuated expression of rod‐specific OS membrane proteins accompanying reduced expression of ciliopathy causative gene products, including constituents of BBSome and axonemal dynein subunit. Those studies unveil a novel negative feedback regulation involving ciliopathy‐associated proteins. In this process, a defect in the trafficking signal leads to a reduced quantity of the trafficking apparatus, culminating in a widespread reduction in the transport of ciliary proteins.
Risk Factors of Intraoperative Pressure Injury in Adult Patients Undergoing Neurologic Surgery
Authors: Peng Xin , Xiao Yingping , He Jiqun
Published: April 2024

GENERAL PURPOSE

To present research investigating the incidence of and risk factors associated with intraoperative pressure injury in patients undergoing neurologic surgery at Xiangya Hospital, Central South University in China.

TARGET AUDIENCE

This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and registered nurses with an interest in skin and wound care.

LEARNING OBJECTIVES/OUTCOMES

After participating in this educational activity, the participant will:

1. Identify the incidence of intraoperative pressure injuries (PIs) in patients undergoing neurologic surgery at Xiangya Hospital, Central South University in China.

2. Describe risk factors for intraoperative PI.

3. Outline strategies to help mitigate intraoperative PI risk.

BACKGROUND

Intraoperative pressure injury (PI) development is an adverse event that impacts thousands of patients globally and is associated with extended hospital stays and increased risk of mortality.

OBJECTIVE

To investigate the incidence of intraoperative PI in patients undergoing neurologic surgery and identify associated risk factors.

METHODS

A total of 1,728 patients who underwent neurosurgery in Xiangya Hospital, Central South University between January 2021 and December 2022 were included in this retrospective study. The authors collected patients’ demographic data and clinical characteristics and used univariate and multivariate regression to evaluate significant PI risk factors.

RESULTS

Intraoperative PI was observed in 1.8% of all surgical cases (n = 31). Having a body mass index greater than 24 kg/m2 (odds ratio, 3.87; 95% CI, 1.62–9.23; P = .002), being in a lateral position (odds ratio, 2.53; 95% CI, 1.04–6.17; P = .042) or a prone position (odds ratio, 10.43; 95% CI, 3.37–32.23; P < .001), and having a longer operation time (cutoff point at 7.92 hours for increased risk of PI; odds ratio, 1.36; 95% CI, 1.21–1.53; P < .001) were significant risk factors for intraoperative PI.

CONCLUSION

This study identified three independent risk factors for intraoperative PI development: body position, surgery duration, and high body mass index. These findings can help OR nurses identify patients who are vulnerable to intraoperative PI and provide appropriate preventive measures. For these patients, perioperative protection and frequent microrepositioning during surgery would be indispensable.
The Mediating Role of Self-efficacy and Coping Mode Between Powerlessness and Quality of Life in Patients with Venous Leg Ulcers
Authors: Shan Hui , Li Qi , Xu Xiaoqing , Wang Xiaoying , Han Jing , Zhang Ju
Published: April 2024

OBJECTIVE

To explore the mediating effect of self-efficacy and coping mode between powerlessness and quality of life in patients with a venous leg ulcer (VLU).

METHODS

The authors used a convenience sampling method to select 208 patients with a VLU in four tertiary grade A hospitals in Qingdao and Tianjin from June 2021 to August 2022. Instruments included the Powerlessness Assessment Tool, Venous Leg Ulcer Self-efficacy Tool, Medical Coping Modes Questionnaire, and Venous Leg Ulcer Quality of Life Questionnaire. The authors used descriptive statistics, Pearson correlation, and PROCESS macros for data analysis.

RESULTS

The powerlessness score was significantly negatively associated with self-efficacy and confrontation coping mode scores and positively associated with patients’ quality-of-life scores. In addition, self-efficacy and confrontation coping modes separately and sequentially mediated the relationship between powerlessness and quality of life.

CONCLUSIONS

Self-efficacy and confrontation coping mode play important mediating roles between powerlessness and quality of life in patients with VLUs. By decreasing patients’ sense of powerlessness, boosting their self-efficacy, and encouraging them to adopt confrontation coping mode, health professionals can improve patients’ quality of life.
Everyday Prevention: The Impact of Daily Comprehensive Skin Assessments on Pressure Injury Healing in the General ICU
Authors: Yilmaz Akyaz Dilek , Cevizci Tugba , Sengul Tuba
Published: April 2024

OBJECTIVE

To investigate the effect of daily versus weekly comprehensive skin assessments on wound healing status in patients with pressure injuries (PIs) treated in the general ICU.

METHODS

This quasi-experimental study was conducted at a foundation hospital from November 15, 2022, to March 15, 2023. The sample consisted of 193 patients with PIs who met the inclusion criteria. The Braden Scale, Nutritional Risk Scale 2002 (NRS-2002), and Pressure Ulcer Scale for Healing (PUSH) were used. The intervention group (n = 98) underwent comprehensive skin assessment every day, whereas the control group (n = 95) followed routine procedures. The study findings were reported according to TREND (Transparent Reporting of Evaluations with Non-randomized Designs) guidelines.

RESULTS

Patients were older adults, with a mean age of 70 ± 15.45 years in the intervention group and 71 ± 13.20 years in the control group. The mean NRS-2002 score was 3 ± 2.01 in the intervention group and 2 ± 1.38 in the control group. Medical device-related PI incidence was high in both groups (intervention: 36.8%, control: 24.5%). In the intervention (14.3%) and control (50%) groups, PIs developed mostly due to antiembolic stockings. Deep-tissue PIs were the most common (intervention: 56.8%, control: 62.2%). The last PUSH scores decreased in both groups. The difference between the PUSH scores of the intervention and control groups was statistically significant (P < .05).

CONCLUSIONS

The findings of this study demonstrate the critical role of daily comprehensive skin assessment in the healing process of PIs. Especially in ICUs, the study provides compelling evidence for the need to prioritize and implement regular skin assessments to prevent PIs and support the healing process.
TSPO deficiency exacerbates acute lung injury via NLRP3 inflammasome-mediated pyroptosis
Authors: Han Jingyi , Zhang Xue , Cai Menghua , Tian Feng , Xu Yi , Chen Hui , He Wei , Zhang Jianmin , Tian Hui
Published: April 2024

Background:

Acute respiratory distress syndrome (ARDS) is a common cause of respiratory failure in many critically ill patients. Although inflammasome activation plays an important role in the induction of acute lung injury (ALI) and ARDS, the regulatory mechanism of this process is still unclear. When cells are stimulated by inflammation, the integrity and physiological function of mitochondria play a crucial part in pyroptosis. However, the underlying mechanisms and function of mitochondrial proteins in the process of pyroptosis are largely not yet known. Here, we identified the 18-kDa translocator protein (TSPO), a mitochondrial outer membrane protein, as an important mediator regulating nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome activation in macrophages during ALI.

Methods:

TSPO gene knockout (KO) and lipopolysaccharide (LPS)-induced ALI/ARDS mouse models were employed to investigate the biological role of TSPO in the pathogenesis of ARDS. Murine macrophages were used to further characterize the effect of TSPO on the NLRP3 inflammasome pathway. Activation of NLRP3 inflammasome was preformed through LPS + adenosine triphosphate (ATP) co-stimulation, followed by detection of mitochondrial membrane potential, reactive oxygen species (ROS) production, and cell death to evaluate the potential biological function of TSPO. Comparisons between two groups were performed with a two-sided unpaired t-test.

Results:

TSPO-KO mice exhibited more severe pulmonary inflammation in response to LPS-induced ALI. TSPO deficiency resulted in enhanced activation of the NLRP3 inflammasome pathway, promoting more proinflammatory cytokine production of macrophages in LPS-injured lung tissue, including interleukin (IL)-1β, IL-18, and macrophage inflammatory protein (MIP)-2. Mitochondria in TSPO-KO macrophages tended to depolarize in response to cellular stress. The increased production of mitochondrial damage-associated molecular pattern led to enhanced mitochondrial membrane depolarization and pyroptosis in TSPO-KO cells.

Conclusion:

TSPO may be the key regulator of cellular pyroptosis, and it plays a vital protective role in ARDS occurrence and development.
Pharmacokinetics of Brexpiprazole, Quetiapine, Risperidone, and Its Active Metabolite Paliperidone in a Postpartum Woman and Her Baby
Authors: Konishi Toru , Kitahiro Yumi , Fujiwara Naoko , Yamamoto Kazuhiro , Hashimoto Mari , Ito Takahiro , Itohara Kotaro , Fujioka Kazumichi , Imafuku Hitomi , Otsuka Ikuo , Omura Tomohiro , Yano Ikuko
Published: April 2024

Background:

Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine.

Methods:

The study used high-performance liquid chromatography–tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery.

Results:

The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%.

Conclusions:

Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%.
Population Pharmacokinetic Modeling of Posaconazole in Japanese Patients Receiving Fungal Prophylaxis
Authors: Sugimoto Mitsuhiro , Yonezawa Atsushi , Kanda Junya , Itohara Kotaro , Hira Daiki , Yamagiwa Takeo , Taniguchi Risa , Hanyu Yuta , Watanabe Mizuki , Arai Yasuyuki , Mizumoto Chisaki , Kitawaki Toshio , Kondo Tadakazu , Yamashita Kouhei , Takaori-Kondo Akifumi , Terada Tomohiro
Published: April 2024

Background:

Posaconazole is a vital drug to treat and prevent invasive fungal infections. Several factors, such as sex, body weight, total serum proteins, dietary intake, and severe mucositis, affect posaconazole pharmacokinetics (PKs). However, the relevance of other factors that affect the PKs of posaconazole in hematopoietic stem cell transplantation (HSCT) is unknown. This study explored factors influencing the PKs of posaconazole in HSCT recipients and nontransplant patients with hematological diseases.

Methods:

The authors conducted a single-institution, retrospective study. Forty-two Japanese inpatients receiving oral posaconazole tablets as prophylaxis for fungal infections were enrolled in this study. A one-compartment model with first-order absorption was used as the structural pharmacokinetic model. A population PK (PopPK) analysis was performed using a nonlinear mixed-effects modeling program, using a first-order conditional estimation method with interactions. Perl-speaks-NONMEM and R were used to evaluate the goodness of fit and visualize the output.

Results:

In 29% of the enrolled patients, the serum concentration of posaconazole was <0.5 mcg/mL, considered the effective range. PopPK analysis revealed that the patient had undergone HSCT within 1 year, diarrhea occurred more than 5 times a day, and aspartate aminotransferase were covariates that influenced apparent clearance (CL/F). The CL/F of posaconazole was 1.43-fold higher after HSCT and 1.26-fold higher during diarrhea.

Conclusions:

PopPK analysis revealed that HSCT, diarrhea, and aspartate aminotransferase were factors associated with the CL/F of posaconazole. The trough concentration of posaconazole may be below the therapeutic range in a few patients with diarrhea and/or after HSCT. As invasive fungal infections in patients with hematologic diseases can be life-threatening, therapeutic drug monitoring of posaconazole is strongly recommended, and patients should be carefully monitored.
Association between time-of-day for eating, exercise, and sleep with blood pressure in adults with elevated blood pressure or hypertension: a systematic review
Authors: Keiser Thomas , Katz Sarah , Robson Shannon M. , Greaney Jody L. , Healy Sean , Malone Susan K. , Farrahi Vahid , Patterson Freda
Published: April 2024

The purpose of this review is to synthesize results from studies examining the association between time-of-day for eating, exercise, and sleep with blood pressure (BP) in adults with elevated BP or hypertension. Six databases were searched for relevant publications from which 789 were identified. Ten studies met inclusion criteria. Four studies examined time-of-day for eating, five examined time-of-day for exercise, and one examined time-of-day for sleep and their associations with BP. Results suggested that later time-of-day for eating (n = 2/4) and later sleep mid-point (n = 1/1) were significantly related to higher BP in multivariable models, whereas morning (n = 3/5) and evening (n = 4/5) exercise were associated with significantly lower BP. Although this small body of work is limited by a lack of prospective, randomized controlled study designs and underutilization of 24 h ambulatory BP assessment, these results provide preliminary, hypothesis-generating support for the independent role of time-of-day for eating, exercise, and sleep with lower BP.
Visual Field Testing Frequency and Associations in Children With Glaucoma
Authors: Hekmatjah Natan , Kumar Anika , Yu Yinxi , Younessi David N. , Han Ying , Ying Gui-Shuang , Oatts Julius T.
Published: April 2024

Précis:

Children with glaucoma had an average of 1.3 visual field tests per year. Self-reported black and multiracial patients had lower visual field testing rates, whereas older children with better visual acuity had more frequent testing.

Purpose:

To evaluate frequency of visual field (VF) testing in children with glaucoma and identify characteristics associated with VF frequency.

Methods:

A retrospective cohort study of 82 children 6–18 years of age with glaucoma seen between August 2018 and May 2023. Patients were divided into those who had ≥1 VF test (303 VF tests of 61 children) and 0 VFs (21 children). Eyes were excluded if best corrected visual acuity (BCVA) was counting fingers or worse. Characteristics obtained included age, self-reported race and ethnicity, sex, primary language, glaucoma diagnosis, distance to provider, office visit frequency, follow-up compliance, insurance type, and BCVA. The main outcome measure was VF testing frequency.

Results:

Among children with ≥1 VF test, mean age at first VF was 11.8±2.8 years, mean number of VF/year was 1.3±0.8, and 44.9% of all VFs were reliable. Thirty nine percent of patients underwent <1 VF/year, 45.9% ≥1 to <2 VFs/year, and 14.8% ≥2 VF/year. Children who were black or multiracial had significantly lower VF testing frequency [estimated difference (ED) −1.2 (95% CI, −2.0 to −0.4, P=0.002) and ED −1.3 (95% CI, −2.2 to −0.3, P=0.008), respectively]. Better visual acuity and greater office visit frequency were significantly associated with higher VF testing frequency [ED 0.052 (95% CI, 0.001–0.103, P=0.045) and ED 0.2 (95% CI, 0.1–0.3, P<0.001), respectively].

Conclusions:

Most children had between 1 and 2 VF/year, although less than half of all VFs were reliable. Ophthalmologists should consider barriers to care in glaucoma monitoring.
An Update on Triad Prevalence and Exploratory Hormonal Biomarker Analyses in Ultramarathon Runners
Authors: Roche Megan , Sainani Kristin , Walker Mahala , McIntyre Abby , Kelly Rose , Hoeg Tracy , Fredericson Michael , Kraus Emily
Published: April 2024

Objective:

To update the prevalence of male and female athlete Triad risk factors in ultramarathon runners and present exploratory analyses examining correlations between bone mineral density (BMD) and hormones.

Design:

Multiyear cross-sectional study.

Setting:

Western States Endurance Run 100-mile race.

Participants:

Participants were recruited in 2018 and 2019 for our prior cohort. We added an additional cohort in 2021.

Assessment of Risk Factors:

Participants completed laboratory evaluations of sex hormones, vitamin D, and ferritin (2019 and 2021 cohorts only); dual energy x-ray absorptiometry; and surveys evaluating nutritional habits, menstrual history, and injury history.

Main Outcome Measures:

The Triad cumulative risk assessment was assessed for each participant.

Results:

One hundred seventy-nine runners participated (123 men and 56 women). 61.1% of women and 28.1% of men were at moderate or high cumulative risk for the Triad. In women, there were significant correlations between hip and femoral neck BMD and total testosterone (Spearman correlation coefficient r = 0.58, P = 0.001; r = 0.45, P = 0.01). In men, there were weak, significant correlations (r = 0.24-0.30, P = 0.01–0.04) between estradiol and vitamin D at most anatomic sites.

Conclusions:

Our results build on our prior CJSM publication. With the addition of about 50% more study participants in 2021, we observed a stable, high prevalence of Triad risk factors, which represents a more precise measurement and highlights the need for future Triad research in the ultramarathon population. We found significant exploratory associations between hormones and BMD, which varied considerably from our prior publication and should be interpreted cautiously.
Nondysraphic intramedullary spinal cord lipoma: a case report
Authors: Karki Susmin , Regmi Prakash , Parajuli Asmita , Kumari Khusbu , Thapa Bikas , Shilpakar Sushil K.
Published: April 2024

Introduction:

Intramedullary nondysraphic spinal lipomas are extremely rare among primary spinal cord tumors. These patients present with nonspecific sensory symptoms followed by deterioration of motor symptoms. As the safety margins for neurological preservation are thin, meticulously locating the extent of the tumor and choosing the resection modalities is essential.

Case report:

The authors report a rare case of a 35-year-old male who presented with progressive difficulty in walking for 6 months associated with numbness and tingling sensation in the bilateral upper and lower limbs. He was diagnosed with nondysraphic intramedullary cervicothoracic lipoma and underwent subtotal resection of the tumor.

Conclusion:

Nondysraphic intramedullary spinal cord lipomas are rare and may present as nonspecific neurological symptoms. Hence, they should be considered differentials of intramedullary spinal cord tumors. Surgery appears to be the mainstay of treatment.