bluuebunny/crossref_metadata_2025 huggingface dataset:
Research on decentralized resource operation optimization of virtual power plant with 5G base station
Authors: Ma Dongjuan , Liu Zehui , Guo Min , Jing Weizhe , Jing Feng , Li Rui , Yang Hua , Zheng Huiping
Published: April 2024

The extensive construction and promotion of 5G base stations (5GBSs) have led to a surge in communication energy consumption, as 5G energy consumption is about three to five times that of 4G. To reduce the energy consumption of 5GBS, this article incorporates 5GBS into power demand side management and proposes a flexible resource collaborative optimization method that integrates 5GBS with virtual power plants (VPPs). Firstly, starting from the basic structure of 5GBS, the adjustable potential of 5GBS and the paths for participating in VPP optimization were analyzed. Secondly, with the minimum operating cost as the optimization objective and considering the constraints of 5GBS and various decentralized resources, a demand side decentralized resource collaborative optimization model for VPP integrating 5GBS was established. This model can be solved using the Non-dominated sorting genetic algorithm II (NSGA-II) algorithm. The results indicate that the participation of 5GBS in power demand side management can reduce their comprehensive energy consumption and operating costs.
Analysis of the indoor thermal environment and livability of traditional residences in summer in Northeast Sichuan, China
Authors: Hou Chaoping , Gao Weijun , Gao Yanan
Published: April 2024

With the rapid development of the national economy, increasing attention has been given to the living environment in rural areas, especially indoor thermal and wind environments. This study conducted onsite measurements and questionnaire surveys during summer in the indoor environment of five villages in northeastern Sichuan. A total of 89 traditional residences were selected to investigate their fundamental characteristics, indoor thermal environment, humidity conditions and comfort levels. The results showed that when expressed as neutral temperature and humidity, the temperature difference was 1.35°C and the humidity difference was 8.14%. Local residents exhibited higher tolerance toward the local thermal and humidity environment compared to nonlocal volunteers, who displayed greater sensitivity toward it. In addition, local residents had a thermal comfort value of 0.03 and a thermal acceptance value of 1.16, whereas nonlocal volunteers had a thermal comfort value of 1.42 and a thermal acceptance value of −0.45.
Tumour-reactive plasma cells in antitumour immunity: current insights and future prospects
Authors: Chen Peng , Chu Yiwei , Liu Ronghua
Published: April 2024

Tumour-reactive plasma cells (TRPCs) have been reported to be positively associated with the long-term survival of patients with various cancers. However, unlike tumour-specific antigen (TSA)-induced T cells which have precise effects against tumours, plasma cells require TSA to obtain specific responses. Therefore, the search for a TSA suitable for B-cell recognition is urgent. In this review, we discuss the functions of tumour-reactive plasma cells. Further, this review also explores the concept of screening for neoantigen-reactive plasma cells, drawing inspiration from T-cell screening methods. While challenges exist, such as epitope prediction and efficient screening, the development of novel techniques may lead to the discovery of highly specific plasma cells for adoptive cell therapy. In conclusion, tumour-reactive plasma cells are emerging as powerful players in cancer immunotherapy. Their ability to produce antibodies against a variety of antigens, especially neoantigens, opens new avenues for personalised treatments. Overcoming challenges in epitope prediction and screening will be crucial in harnessing the full potential of these plasma cells for the benefit of cancer patients.
High-throughput quantitative assessments of the chemical complementarity of celiac disease-related IGH CDR3s and a gliadin epitope
Authors: Jain Rahul , Bressler Max , Chobrutskiy Andrea , Chobrutskiy Boris I , Blanck George
Published: April 2024

The long-term value of efficient antigen discovery includes gaining insights into the variety of potential cancer neoantigens, effective vaccines lacking adverse effects, and adaptive immune receptor (IR) targets for blocking adaptive IR-antigen interactions in autoimmunity. While the preceding goals have been partially addressed via big data approaches to HLA (human leukocyte antigen)-epitope binding, there has been little such progress in the big data setting for adaptive IR-epitope binding. This delay in progress for the latter is likely due to, among other things, the much more complicated adaptive IR repertoire in an individual compared to individual HLA alleles. Thus, results described here represent the application of an algorithm for efficient assessment of immunoglobulin heavy chain complementarity determining region-3 (IGH CDR3)-gliadin epitope interactions, with a focus on epitopes known to be associated with an immune response in celiac disease. The hydrophobic, chemical complementarity between celiac case IGH CDR3s and known celiac epitopes was found to be greater in comparison to the hydrophobic, chemical complementarity between the same celiac case IGH CDR3s and a series of control epitopes. Thus, the approaches indicated here likely offer guidance for the development of conveniently applied algorithms for antigen verification and discovery.
The Cooptation Dilemma: Explaining US Contestation of the Liberal Trade Order
Authors: Heinkelmann-Wild Tim , Kruck Andreas , Zangl Bernhard
Published: April 2024

While the United States (US) acted as a liberal hegemon in setting up the Liberal International Order (LIO), it is increasingly contesting the inclusive legacy institutions underpinning the LIO and is instead moving towards alternative, more exclusive institutions. Why is the US contesting the institutions it once set up to stabilize the LIO? We argue that hegemonic contestation is the result of a reactive sequence that is endogenous to cooptation-based orders where hegemons face a trade-off between inclusion and control. This Cooptation Dilemma is particularly pronounced in strongly institutionalized liberal (sub-)orders, such as the international trade regime. It unfolds in three stages: Privileging control, the liberal hegemon first creates exclusive institutions, which are likely to breed contestation by excluded states. To tame their contestation, the hegemon secondly includes previously excluded states into the order, making the previously exclusive institutions more and more inclusive. To compensate for the related control loss, the hegemon finally promotes alternative, more exclusive institutions, successively turning away from the inclusive legacy institutions. We demonstrate this reactive sequence by tracing the process that led to the US contestation of the World Trade Organization (WTO). Our findings suggest that cooptation-based orders in general and strongly institutionalized liberal orders in particular are prone to dynamic instability.
Bridging ecological assembly process and community stability upon bacterial invasions
Authors: Liu Xipeng , Salles Joana Falcão
Published: April 2024

Understanding the link between microbial community stability and assembly processes is crucial in microbial ecology. Here, we investigated whether the impact of biotic disturbances would depend on the processes controlling community assembly. For that, we performed an experiment using soil microcosms in which microbial communities assembled through different processes were invaded by Escherichia coli. We show that the ecological assembly process of the resident community plays a significant role in invader-resident competition, invader survival, and compositional stability of the resident community. Specifically, the resident communities primarily assembled through stochastic processes were more susceptible to invader survival. Besides, E. coli invasion acts as a biotic selection pressure, leading to competition between the invader and resident taxa, suppressing the stochasticity in the resident community. Taken together, this study provides empirical evidence for the interpretation of microbial community assemblage on their (potential) ecosystem functions and services, such as the prevention of pathogen establishment and the pathogenic states of soil microbiomes.
Genetic and clinical predictors of rifapentine and isoniazid pharmacokinetics in paediatrics with tuberculosis infection
Authors: Phaisal Weeraya , Albitar Orwa , Chariyavilaskul Pajaree , Jantarabenjakul Watsamon , Wacharachaisurapol Noppadol , Ghadzi Siti Maisharah Sheikh , Zainal Hadzliana , Harun Sabariah Noor
Published: April 2024

Objectives

Twelve weekly doses of rifapentine and isoniazid (3HP regimen) are recommended for TB preventive therapy in children with TB infection. However, they present with variability in the pharmacokinetic profiles. The current study aimed to develop a pharmacokinetic model of rifapentine and isoniazid in 12 children with TB infection using NONMEM.

Methods

Ninety plasma and 41 urine samples were collected at Week 4 of treatment. Drug concentrations were measured using a validated HPLC–UV method. MassARRAY® SNP genotyping was used to investigate genetic factors, including P-glycoprotein (ABCB1), solute carrier organic anion transporter B1 (SLCO1B1), arylacetamide deacetylase (AADAC) and N-acetyl transferase (NAT2). Clinically relevant covariates were also analysed.

Results

A two-compartment model for isoniazid and a one-compartment model for rifapentine with transit compartment absorption and first-order elimination were the best models for describing plasma and urine data. The estimated (relative standard error, RSE) of isoniazid non-renal clearance was 3.52 L·h−1 (23.1%), 2.91 L·h−1 (19.6%), and 2.58 L·h−1 (20.0%) in NAT2 rapid, intermediate and slow acetylators. A significant proportion of the unchanged isoniazid was cleared renally (2.7 L·h−1; 8.0%), while the unchanged rifapentine was cleared primarily through non-renal routes (0.681 L·h−1; 3.6%). Participants with the ABCB1 mutant allele had lower bioavailability of rifapentine, while food prolonged the mean transit time of isoniazid.

Conclusions

ABCB1 mutant allele carriers may require higher rifapentine doses; however, this must be confirmed in larger trials. Food did not affect overall exposure to isoniazid and only delayed absorption time.
Is shorter also better in the treatment of Clostridioides difficile infection?
Authors: Duricek M , Halmova K , Krutova M , Sykorova B , Benes J
Published: April 2024

Objectives

To assess the effectiveness of shortened regimens of vancomycin or fidaxomicin in the treatment of Clostridioides difficile infection (CDI).

Methods

Adult patients with CDI hospitalized from January 2022 to May 2023 were included in this observational study. In patients with CDI treated with vancomycin or fidaxomicin, antibiotic treatment was discontinued after either 5 or 7 days of vancomycin or 5 days of fidaxomicin if there was a clinical response and improvement in laboratory parameters. The control cohort was treated with the standard 10 day regimen of either vancomycin or fidaxomicin. The follow-up was 60 days. Causative C. difficile strains were characterized by ribotyping and toxin gene detection when available.

Results

Twenty-five patients (median age 76 years) received shortened treatment with vancomycin (n = 21), or fidaxomicin (n = 4). Five cases fulfilled the criteria for severe CDI. Twenty-three patients completed follow-up; two died from causes other than CDI, and two developed recurrent CDI (8.0%). Ribotypes (RTs) 001 and 014 were the most prevalent with 20% each. In two C. difficile isolates, binary toxin genes were detected (RTs 078 and 023). In the control group of 22 patients recurrent CDI developed in 5 patients (22.7%). No statistically significant differences were found between the groups.

Conclusions

Shortened treatment regimens for CDI with vancomycin and fidaxomicin were shown to be effective in our cohort of patients compared with 10 days of treatment. The recurrence rate was lower in the study group. A larger, prospective, double-blind, randomized, multicentre study is needed to support our findings.
Ethical Considerations for Acutely Injured and Future Burn Patients Who Smoke While on Home Oxygen Therapy
Authors: Khoo Kimberly H , Yoon Joshua S , Carrese Joseph A , Lerman Sheera F , Hultman C Scott , Caffrey Julie A
Published: April 2024

Home oxygen therapy (HOT) is prescribed to patients with pulmonary dysfunction to improve survival and quality of life. However, ignition of oxygen can lead to burns with significant morbidity and mortality. Providers who routinely treat this patient population face an ethical issue: balancing the obligation to provide beneficial treatment to a patient with the responsibility to protect that patient from suffering avoidable burn injuries. A thorough review was conducted to assess the literature regarding ethical considerations involved in managing patients who have been burned while smoking on HOT and who continue to smoke. Various aspects of this problem and potential approaches to address it were analyzed with respect to 4 core ethical principles of health care: beneficence, nonmaleficence, autonomy, and justice. For patients who repeatedly present with burns acquired secondary to smoking while on oxygen, the authors consider it ethically unacceptable to withhold standard-of-care intervention for acute burns because refusal to treat acute burns conflicts with all 4 ethical principles. A preventive strategy would encourage a more judicious prescription of HOT, supporting the principles of nonmaleficence and beneficence. Additional preventive strategies include upstream solutions such as longitudinal patient education about smoking cessation and the risks of smoking on HOT. Physicians are tasked with the responsibility of both providing optimal care for this patient population and preventing future burn injuries. They may be able to address this challenging situation by thinking more critically about potential solutions while bearing in mind key ethical considerations and obligations.
COAALA: A Novel Approach to Understanding Extreme Stock–Bond Comovement
Authors: Allard Anne-Florence , Hanbali Hamza , Smedts Kristien
Published: April 2024

This article proposes a novel copula model to understand the dependence between extreme variations in stock and government bond returns. This model is used to introduce a tail-based extension of the safe haven concept, which we refer to as a tail risk dampener. Our findings reveal significant cross-country differences in stock–bond local tail dependence and tail risk dampening abilities. Some countries’ bond market can lessen the impact on portfolio returns of extreme negative stock returns, while for others no such negative tail comovement is found. This tail comovement is also not always aligned with global comovement between stocks and bonds. The article concludes that a comprehensive understanding of the comovement and the resulting diversification potential between stock and bond returns necessitates complementing global measures of dependence with local tail measures.
Optimization of method for cross-section hydrogels preparation using high-pressure freezing
Authors: Ichihashi Shuichi , Kuwata Masahiko , Kikuchi Kodai , Matsuyama Tatsushi , Shimizu Akio
Published: April 2024

High-pressure water freeze fracturing is a method for preparing water-containing samples such as hydrogels for scanning electron microscopy (SEM), in which a sample is placed in a divisible pressure vessel, filled with water, sealed, frozen with liquid nitrogen and then vacuum dried after the vessel is divided. The pressure (∼200 MPa) generated by the phase transition from water to ice is expected to inhibit ice crystal formation that causes large deformation of microstructure in the sample. To maximize the useable sample size, where SEM observation is not affected by ice crystal growth, preparation conditions including the size of pressure vessel were examined in this work. Using pressure vessels 8.0 mm, 5.5 mm and 4.5 mm in diameter, agarose gel, gelatin gel, wheat starch hydrogel, wheat flour noodle and cellulose hydrogel were used to prepare SEM samples. With agarose gel, an area of 3.6 mm in diameter in the 5.5 mm vessel was achieved as the maximum size of the area observable without ice crystal growth. The observable size of other samples was comparable, except for gelatin gel. As a result, observation of the three-dimensional network structure of hydrogels could be performed over a wider range than with the conventional method without shredding or chemical treatment of the samples. Additionally, usability of agarose gel for sample support matrix in high-pressure water freeze fracturing was demonstrated.
Can Conversational Thinking serve as a suitable pedagogical approach for philosophy education in African schools?
Authors: Chimakonam Jonathan O , Ogbonnaya L Uchenna
Published: April 2024

This article investigates whether Conversational Thinking can suitably serve as a pedagogical approach for philosophy education in African schools (primary and secondary levels). We argue that there is a need to introduce and teach philosophy in schools in Africa. Additionally, we argue that it would be apropos to adopt a decolonial approach in developing such curricula, which, amongst others, could accommodate African approaches to philosophy. We contend that African homegrown frameworks, such as Conversational Thinking, can serve as appropriate decolonial strategies for philosophy education in parts of Africa. Our reason is that the proposed approach can train the emerging young generations in Africa, not only to be critical, creative, and innovative, but also to view reality from African epistemic perspectives. This stems from the fact that Conversational Thinking is one strategy amongst others that can promote African culture-inspired approaches to knowledge that combine with basic thinking skills to offer truly African forms of epistemic liberation.
Surgical technique for epigastric incisional hernia after omphalocele repair: bilateral modified composite flaps using the upper rectus abdominis muscle and the vertically inverted flap of the lower rectus abdominis fascia
Authors: Tatekawa Yukihiro , Tsuzuki Yukihiro , Oshiro Kiyotetsu , Fukuzato Yoshimitsu
Published: April 2024

We present a patient who developed an incisional hernia, from epigastrium to umbilicus, after omphalocele repair. The hernia gradually enlarged to a 10 cm × 10 cm defect with significant rectus abdominis muscle diastasis at the costal arch attachment point. At 6 years of age, the abdominal wall defect in the umbilical region was closed using the components separation technique. For the muscle defect of the epigastric region, composite flaps were made by suturing together the flap of the upper rectus abdominis muscle, after peeling it away from the costal arch attachment point, and the vertically inverted flap of the lower rectus abdominis fascia, created with a U-shaped incision. The composite flaps from each side were reversed in the midline to bring them closer and then sutured; the abdominal wall and skin were then closed. Five months after surgery, the patient had no recurrent incisional hernia and no wound complications.
A case report of a distal radius fracture treated with a dorsal spanning plate augmented with fragment specific fixation
Authors: Chen Andrew L , Hernandez Evan J , MacKay Brendan J
Published: April 2024

Dorsal spanning plates are frequently utilized to manage comminuted intra-articular distal radius fractures, but there is little literature on combining them with augmented fixation in complex cases. We present a 43-year-old man who fell 5 ft onto his outstretched right hand. On examination, there was gross swelling and tenderness of the right wrist with no neurovascular deficit. Radiographs confirmed a comminuted intra-articular displaced distal radius fracture. He was treated with a dorsal spanning plate fixation combined with radiostyloid and volar buttress plates. Follow-up at 2 months showcased intact hardware with good fracture healing. The dorsal spanning plate was removed 4 months after the procedure with radiographs demonstrating adequate alignment and healing without failure. The patient reported no complaints and minimal functional disability. We highlight a case of augmenting a dorsal spanning plate with fragment-specific plate fixation for a comminuted intra-articular displaced distal radius fracture.
The Patterns of Codon Usage between Chordates and Arthropods are Different but Co-evolving with Mutational Biases
Authors: Kotari Ioanna , Kosiol Carolin , Borges Rui
Published: April 2024

Different frequencies amongst codons that encode the same amino acid (i.e. synonymous codons) have been observed in multiple species. Studies focused on uncovering the forces that drive such codon usage showed that a combined effect of mutational biases and translational selection works to produce different frequencies of synonymous codons. However, only few have been able to measure and distinguish between these forces that may leave similar traces on the coding regions. Here, we have developed a codon model that allows the disentangling of mutation, selection on amino acids and synonymous codons, and GC-biased gene conversion (gBGC) which we employed on an extensive dataset of 415 chordates and 191 arthropods. We found that chordates need 15 more synonymous codon categories than arthropods to explain the empirical codon frequencies, which suggests that the extent of codon usage can vary greatly between animal phyla. Moreover, methylation at CpG sites seems to partially explain these patterns of codon usage in chordates but not in arthropods. Despite the differences between the two phyla, our findings demonstrate that in both, GC-rich codons are disfavored when mutations are GC-biased, and the opposite is true when mutations are AT-biased. This indicates that selection on the genomic coding regions might act primarily to stabilize its GC/AT content on a genome-wide level. Our study shows that the degree of synonymous codon usage varies considerably among animals, but is likely governed by a common underlying dynamic.
A case of eosinophilic granulomatosis with polyangiitis associated with diffuse alveolar haemorrhage: A case report and case-based review
Authors: Kawaguchi Rira , Usagawa Hirohisa , Miyawaki Yoshia , Oiwa Hiroshi
Published: April 2024

A 76-year-old man with bronchial asthma was admitted for respiratory failure and bloody sputum. A significant drop in haemoglobin and multiple consolidations supported clinical diagnosis of diffuse alveolar haemorrhage (AH). Myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) was positive and urinalysis suggested glomerulonephritis. Based on eosinophilia, sinusitis, peripheral nerve involvement, and leukocytoclastic vasculitis, he was diagnosed with eosinophilic granulomatosis with polyangiitis (EGPA) associated with AH. Our case-based review suggested that male predominance (65%), high positivity for ANCA (88%), and a high frequency of renal involvement (45%) may be characteristic of AH in EGPA. Although AH is rare in EGPA, we should be aware of this life-threatening complication.
Multiple lymphadenopathies in eosinophilic granulomatosis with polyangiitis: Differentiating from IgG4-related lymphadenopathy
Authors: Kurashina Jun-ichi , Shimojima Yasuhiro , Kishida Dai , Ichikawa Takanori , Uehara Takeshi , Sekijima Yoshiki
Published: April 2024

We report a case of eosinophilic granulomatosis with polyangiitis in a 75-year-old man who developed mononeuritis multiplex and purpura in the lower legs concomitantly presenting with lymphadenopathies. Biopsied lymph node tissue pathologically demonstrated fibrinoid necrotising vasculitis with perivascular eosinophil infiltration, resulting in eosinophilic granulomatosis with polyangiitis diagnosis. Additionally, abundant immunoglobulin (Ig) G4-positive plasma cell infiltration exhibiting >70% IgG4/IgG ratio, without storiform pattern fibrosis and obliterative phlebitis, was observed in the biopsied lymph node. Clinical improvement was observed after corticosteroid therapy. IgG4-related lymphadenopathy has been defined as a distinct clinical category regardless of fulfilling IgG4-related disease classification criteria. However, some autoimmune diseases, including eosinophilic granulomatosis with polyangiitis, can develop lymphadenopathy pathologically similar to IgG4-related lymphadenopathy.
Molecular mechanism for target RNA recognition and cleavage of Cas13h
Authors: Chen Fugen , Zhang Chendi , Xue Jialin , Wang Feng , Li Zhuang
Published: April 2024

RNA-targeting type VI CRISPR-Cas effectors are widely used in RNA applications. Cas13h is a recently identified subtype of Cas13 ribonuclease, with strong RNA cleavage activity and robust in vivo RNA knockdown efficiency. However, little is known regarding its biochemical properties and working mechanisms. Biochemical characterization of Cas13h1 indicated that it lacks in vitro pre-crRNA processing activity and adopts a central seed. The cleavage activity of Cas13h1 is enhanced by a R(G/A) 5′-PFS, and inhibited by tag:anti-tag RNA pairing. We determined the structures of Cas13h1-crRNA binary complex at 3.1 Å and Cas13h1-crRNA-target RNA ternary complex at 3.0 Å. The ternary complex adopts an elongated architecture, and encodes a nucleotide-binding pocket within Helical-2 domain to recognize the guanosine at the 5′-end of the target RNA. Base pairing between crRNA guide and target RNA disrupts Cas13h1-guide interactions, leading to dramatic movement of HEPN domains. Upon target RNA engagement, Cas13h1 adopts a complicated activation mechanism, including separation of HEPN catalytic residues and destabilization of the active site loop and NTD domain, to get activated. Collectively, these insights expand our understanding into Cas13 effectors.
Implementation of an Automated Antibiotic Time-out at a Comprehensive Cancer Center
Authors: Tverdek Frank P , Aitken Samuel L , Mulanovich Victor E , Adachi Javier , Wu Cai , Cantu Sherry S , McDaneld Patrick M , Chemaly Roy F
Published: April 2024

Background

Antimicrobial stewardship programs can optimize antimicrobial use and have been federally mandated in all hospitals. However, best stewardship practices in immunocompromised patients with cancer are not well established.

Methods

An antimicrobial time out, in the form of an email, was sent to physicians caring for hospitalized patients reaching 5 days of therapy for targeted antimicrobials (daptomycin, linezolid, tigecycline, vancomycin, imipenem/cilastatin, meropenem) in a comprehensive cancer center. Physicians were to discontinue the antimicrobial if unnecessary or document a rationale for continuation. This is a quasi-experimental, interrupted time series analysis assessing antimicrobial use during the following times: period 1 (before time-out: January 2007-June 2010) and period 2 (after time-out: July 2010-March/2015). The primary antimicrobial consumption metric was mean duration of therapy. Days of therapy per 1000 patient-days were also assessed.

Results

Implementation of the time-out was associated with a significant decrease in mean duration of therapy for the following antimicrobials; daptomycin: −0.89 days (95% confidence interval [CI], −1.38 to −.41); linezolid: −0.89 days (95% CI, −1.27 to −.52); meropenem: −0.97 days (95% CI, −1.39 to −.56); tigecycline: −1.41 days (95% CI, −2.19 to −.63); P < .001 for each comparison. Days of therapy/1000 patient-days decreased significantly for meropenem (−43.49; 95% CI, −58.61 to −28.37; P < .001), tigecycline (−35.47; 95% CI, −44.94 to −26.00; P < .001), and daptomycin (−9.47; 95% CI, −15.25 to −3.68; P = .002).

Discussion

A passive day 5 time-out was associated with reduction in targeted antibiotic use in a cancer center and could potentially be successfully adopted to several settings and electronic health records.
CDK9 inhibition activates innate immune response through viral mimicry
Authors: Yalala Shivani , Gondane Aishwarya , Poulose Ninu , Liang Jing , Mills Ian G. , Itkonen Harri M.
Published: April 2024

Cancer cells frequently exhibit hyperactivation of transcription, which can lead to increased sensitivity to compounds targeting the transcriptional kinases, in particular CDK9. However, mechanistic details of CDK9 inhibition‐induced cancer cell‐selective anti‐proliferative effects remain largely unknown. Here, we discover that CDK9 inhibition activates the innate immune response through viral mimicry in cancer cells. In MYC over‐expressing prostate cancer cells, CDK9 inhibition leads to the gross accumulation of mis‐spliced RNA. Double‐stranded RNA (dsRNA)‐activated kinase can recognize these mis‐spliced RNAs, and we show that the activity of this kinase is required for the CDK9 inhibitor‐induced anti‐proliferative effects. Using time‐resolved transcriptional profiling (SLAM‐seq), targeted proteomics, and ChIP‐seq, we show that, similar to viral infection, CDK9 inhibition significantly suppresses transcription of most genes but allows selective transcription and translation of cytokines related to the innate immune response. In particular, CDK9 inhibition activates NFκB‐driven cytokine signaling at the transcriptional and secretome levels. The transcriptional signature induced by CDK9 inhibition identifies prostate cancers with a high level of genome instability. We propose that it is possible to induce similar effects in patients using CDK9 inhibition, which, we show, causes DNA damage in vitro. In the future, it is important to establish whether CDK9 inhibitors can potentiate the effects of immunotherapy against late‐stage prostate cancer, a currently lethal disease.
An update on migraine
Authors: Hervias Teddy
Published: April 2024

Migraine headache is a common and potentially debilitating disorder often treated by physician associates/assistants (PAs) and other providers. With the recent advances in new drugs and device technology for the treatment of migraine, the American Headache Society has released a consensus statement on both preventive and acute strategies for clinical practice. The US FDA has recently approved various types of medications and devices for the treatment and prevention of migraine attacks including several calcitonin gene-related peptide (CGRP) receptor inhibitors, a selective serotonin receptor agonist (SSRA), noninvasive vagus nerve stimulation (nVNS), external trigeminal nerve stimulation (e-TNS), and external concurrent occipital and trigeminal neurostimulation (eCOT-NS), among other pharmacologic and nonpharmacologic options. This article provides a review of migraine prevention and acute treatment protocol, highlighting new approaches to both.
Axial spondyloarthritis guidelines – aiming for maximum impact
Authors: Choufani Mathieu , Kay Jonathan , Ermann Joerg
Published: April 2024

Purpose of review

This review discusses international clinical practice guidelines (CPGs) for axial spondyloarthritis (axSpA) focusing on methodology, guideline quality, and implementation.

Recent findings

The Assessment of SpondyloArthritis International Society/European Alliance of Associations for Rheumatology (ASAS/EULAR) and Pan-American League of Associations for Rheumatology (PANLAR) recently published axSpA CPGs and updates of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network (ACR/SAA/SPARTAN) and Asia-Pacific League of Associations for Rheumatology (APLAR) CPGs are expected. GRADE has emerged as the dominant framework for CPG development and has been used by three of the four international axSpA guidelines. Notable differences exist among these guidelines in the way that the recommendations are presented. Two of the four acknowledge the need for implementation strategies, but little detail about this is provided. The few studies that have evaluated the implementation of axSpA CPGs have identified poor adherence to recommendations on physical therapy/exercise and disease activity monitoring. Implementation science has identified many barriers and facilitators affecting guideline uptake, including those related to healthcare professionals and to the guidelines themselves. Creation of a tailored implementation plan simultaneously with the CPG is recommended.

While methodological rigor in the creation of evidence-based recommendations is the focus of CPG development, recommendations must be presented in a user-friendly format that makes them easy to apply. ‘Living guidelines’ could facilitate keeping content up to date. Implementation is critical for the success of a CPG and should be emphasized in future axSpA guideline updates. Further research is needed to better understand the factors impacting the successful implementation of axSpA CPGs.
The elevation of red blood cell distribution width is an independent prognostic factor for juvenile myelomonocytic leukemia
Authors: Liang Weiru , Liu Chenmeng , Zhang Jingliao , Yi Meihui , Cai Yuli , Zhang Aoli , Liu Lipeng , Zhang Li , Chen Xiaojuan , Zou Yao , Chen Yumei , Guo Ye , Zhang Yingchi , Zhu Xiaofan , Yang Wenyu
Published: April 2024

Juvenile myelomonocytic leukemia (JMML) is a disorder characterized by the simultaneous presence of myeloproliferative and myelodysplastic features, primarily affecting infants and young children. Due to the heterogeneous genetic background among patients, the current clinical and laboratory prognostic features are insufficient for accurately predicting outcomes. Thus, there is a pressing need to identify novel prognostic indicators. Red cell distribution width (RDW) is a critical parameter reflecting the variability in erythrocyte size. Recent studies have emphasized that elevated RDW serves as a valuable predictive marker for unfavorable outcomes across various diseases. However, the prognostic role of RDW in JMML remains unclear. Patients with JMML from our single-center cohort between January 2008 and December 2019 were included. Overall, 77 patients were eligible. Multivariate Cox proportional hazard models showed that patients with red cell distribution width coefficient of variation (RDW-CV) >17.35% at diagnosis were susceptible to much worse overall survival rate (hazard ratio [HR] = 5.22, confidence interval [CI] = 1.50–18.21, P = .010). Besides, the combination of RDW elevation and protein phosphatase non-receptor type 11 (PTPN11) mutation was likely to predict a subgroup with the worst outcomes in our cohort. RDW is an independent prognostic variable in JMML subjects. RDW may be regarded as an inexpensive biomarker to predict the clinical outcome in patients with JMML.
Treatment With Topical Ivermectin 1% Once a Month to Control Demodex Blepharitis
Authors: Rivera Salazar Jorge , Lara Peñaranda Jesús , González del Valle Fernando , Gálvez Martínez Javier , Valdés González José Juan , Olalla Gallardo José María , Juárez Tosina Rocío , Calzas Durán José Manuel , Arias Ángel , Tejera-Muñoz Antonio
Published: April 2024

Purpose:

The study aimed to assess the effectiveness of a monthly application of topical 1% ivermectin cream, for 3 months, to the eyelids and eyelids margin, accompanied by gentle squeezing of meibomian glands and microexfoliation to the base of eyelashes, in the management of Demodex blepharitis.

Methods:

Thirty-eight patients diagnosed with Demodex blepharitis based on the presence of sleeves at the base of the eyelashes, telangiectasias, and signs of local inflammation with at least 4 Demodex mites observed at the lash roots were enrolled. Treatment involved applying 1% ivermectin topical cream using an eyelash brush in circular motion, gradually moving toward the eyelid margin. The procedure was repeated several times over 10 min by applying more cream. Each patient was evaluated before each treatment and 1 month after completion of the 3-month period.

Results:

Significant improvements in symptoms and signs were observed, with the disappearance of cylindrical sleeves on the base of the eyelashes, telangiectasias, signs of inflammation, and a significant decrease in night itching. The Schirmer test showed no changes, while the tear breakup time test exhibited slight yet statistically significant enhancement. No adverse events were reported during the study.

Conclusions:

The results of this investigation establish that Demodex blepharitis can be effectively managed by the application of 1% ivermectin cream once a month over a three-month period. This treatment approach, in conjunction with the gentle squeezing of meibomian glands and eyelid margin microexfoliation to the base of the eyelashes, resulted in the disappearance of objective indicators, such as cylindrical sleeves and telangiectasia, along with a significant reduction in nocturnal itching.
Discriminative stimulus properties of Cannabis sativa terpenes in rats
Authors: Carey Lawrence M. , Ghodrati Saba , France Charles P.
Published: April 2024

Cannabis is a pharmacologically complex plant consisting of hundreds of potentially active compounds. One class of compounds present in cannabis that has received little attention are terpenes. Traditionally thought to impart aroma and flavor to cannabis, it has become increasingly recognized that terpenes might exert therapeutic effects themselves. Several recent reports have also indicated terpenes might behave as cannabinoid type 1 (CB1) receptor agonists. This study aimed to investigate whether several terpenes present in cannabis produce discriminative stimulus effects similar to or enhance the effects of Δ9-tetrahydrocannabinol (THC). Subsequent experiments explored other potential cannabimimetic effects of these terpenes. Rats were trained to discriminate THC from vehicle while responding under a fixed-ratio 10 schedule of food presentation. Substitution testing was performed with the CB receptor agonist JWH-018 and the terpenes linalool, limonene, γ-terpinene and α-humulene alone. Terpenes were also studied in combination with THC. Finally, THC and terpenes were tested in the tetrad assay to screen for CB1-receptor agonist-like effects. THC and JWH-018 dose-dependently produced responding on the THC-paired lever. When administered alone, none of the terpenes produced responding predominantly on the THC-paired lever. When administered in combination with THC, none of the terpenes enhanced the potency of THC, and in the case of α-humulene, decreased the potency of THC to produce responding on the THC-paired lever. While THC produced effects in all four tetrad components, none of the terpenes produced effects in all four components. Therefore, the terpenes examined in this report do not have effects consistent with CB1 receptor agonist properties in the brain.
Vascular damage and excessive proliferation compromise liver function after extended hepatectomy in mice
Authors: De Rudder Maxime , Manco Rita , Coubeau Laurent , Fontaine Alix , Bertrand Claude , Leclercq Isabelle A. , Dili Alexandra
Published: April 2024

Background and Aims:

Surgical resection remains the gold standard for liver tumor treatment, yet the emergence of postoperative liver failure, known as the small-for-size syndrome (SFSS), poses a significant challenge. The activation of hypoxia sensors in an SFSS liver remnant initiated early angiogenesis, improving the vascular architecture, safeguarding against liver failure, and reducing mortality. The study aimed to elucidate vascular remodeling mechanisms in SFSS and their impact on hepatocyte function and subsequent liver failure.

Approach and results:

Mice underwent extended partial hepatectomy to induce SFSS, with a subset exposed to hypoxia immediately after surgery. Hypoxia bolstered posthepatectomy survival rates. The early proliferation of liver sinusoidal cells, coupled with recruitment of putative endothelial progenitor cells, increased vascular density, improved lobular perfusion, and limited hemorrhagic events in the regenerating liver under hypoxia. Administration of granulocyte colony-stimulating factor in hepatectomized mice mimicked the effects of hypoxia on vascular remodeling and endothelial progenitor cell recruitment but failed to rescue survival. Compared to normoxia, hypoxia favored hepatocyte function over proliferation, promoting functional preservation in the regenerating remnant. Injection of Adeno-associated virus serotype 8-thyroxine-binding globulin-hepatocyte nuclear factor 4 alpha virus for hepatocyte-specific overexpression of hepatocyte nuclear factor 4 alpha, the master regulator of hepatocyte function, enforced functionality in proliferating hepatocytes but did not rescue survival. The combination of hepatocyte nuclear factor 4 alpha overexpression and granulocyte colony-stimulating factor treatment rescued survival after SFSS-setting hepatectomy.

Conclusions:

In summary, SFSS arises from an imbalance and desynchronized interplay between functional regeneration and vascular restructuring. To improve survival following SFSS hepatectomy, it is essential to adopt a 2-pronged strategy aimed at preserving the function of proliferating parenchymal cells and simultaneously attenuating vascular damage.
Efficacy and safety of a single-pill versus free combination of perindopril/indapamide/amlodipine: a multicenter, randomized, double-blind study in Chinese patients with hypertension
Authors: Wang Ji-Guang , Topouchian Jirar , Bricout-Hennel Stéphanie , Mu Jianjun , Chen Lianglong , Li Ping , He Shenghu , Luo Suxin , Jiang Weihong , Jiang Yinong , Sun Yuemin , Zhang Yuqing , Asmar Roland
Published: April 2024

Background:

In China, the prevalence of hypertension is high and the use of combination antihypertensive therapy is low, which contributes to inadequate blood pressure (BP) control. The availability of simplified treatments combining complementary BP-lowering agents may help more patients achieve their goals.

Methods:

This Phase III, multicenter, randomized, double-blind, noninferiority study included Chinese adults with mild-to-moderate hypertension. Following a 1-month run-in on perindopril/indapamide bi-therapy, patients with uncontrolled systolic/diastolic BP (≥140/90 mmHg) were randomized to perindopril 5 mg/indapamide 1.25 mg/amlodipine 5 mg (Per/Ind/Aml) single-pill combination (SPC) or perindopril 4 mg/indapamide 1.25 mg plus amlodipine 5 mg (Per/Ind + Aml) for 6 months. Uptitration was permitted from month 2 onwards. The primary efficacy objective was the noninferiority of Per/Ind/Aml in lowering office systolic BP at 2 months. The secondary objectives included the effectiveness of SPC on diastolic BP, uptitration efficacy, and office BP control (systolic/diastolic <140/90 mmHg). A subgroup of patients participated in 24-h ambulatory BP monitoring (ABPM).

Results:

A total of 532 patients were randomized: Per/Ind/Aml (n = 262) and Per/Ind + Aml (n = 269). Overall, the mean (±SD) age was 55.7 ± 8.8 years, 60.7% were male, and the mean office systolic/diastolic BP at baseline on Per/Ind was 150.4/97.2 mmHg. Systolic BP decreased in both groups at 2 months from baseline: −14.99 ± 14.46 mmHg Per/Ind/Aml versus −14.49 ± 12.87 mmHg Per/Ind +Aml. A predefined noninferiority margin of 4 mmHg was observed (P < 0.001). The effectiveness of the Per/Ind/Aml SPC was also demonstrated for all secondary endpoints. ABPM demonstrated sustained BP control over 24 h. Both treatments were well tolerated.

Conclusions:

Per/Ind/Aml is an effective substitute for Per/Ind + Aml, providing at least equivalent BP control over 24 h in a single pill, with comparable safety.
High-grade Serous Carcinoma Occurring in a Serous Cystadenoma on the Background of a Serous Tubal Intraepithelial Carcinoma (STIC)-like Lesion: A Case Report With Literature Review
Authors: Novikov Filipp Vladimirovich , Anufriev Aleksandr Grigorevich , Efremov Gennadii Dmitrievich
Published: April 2024

At present, the prevailing concept is that high-grade serous carcinoma (HGSC) arises from the fallopian tubes (FTs). We report an HGSC case occurring in a serous ovarian cyst against the background of a serous tubal intraepithelial carcinoma (STIC)-like lesion. We also provide a literature review that contains references to clinical cases of the occurrence of STIC-like lesions in the ovary and phylogenetic studies that do not always reveal obvious bonds between early dysplastic serous lesions and HGSC. The article discusses cases of association between HGSCs of serous borderline tumors (SBTs) and low-grade serous carcinomas (LGSCs) in the context of their possible histogenetic relationship. We propose a concept in which high-grade serous carcinogenesis, represented by the p53-signature–STIC–HGSC continuity, occurs in the serous epithelium of both the FT and other locations.
Clinicopathologic Characteristics of a Single-institution Cohort of Ovarian Adult Granulosa Cell Tumors, With Biomarker and Therapeutic Implications Utilizing the Detection of Androgen, Estrogen, and Progesterone Hormone Receptor Expression by Immunohistochemistry
Authors: Moh Michelle , Puzyrenko Andrii , Summey Rebekah , Rader Janet S. , Herrera Cano Genaro Enrique , Gavina Jennifer V. , Rui Hallgeir , Sun Yunguang , Hopp Elizabeth
Published: April 2024

Adult granulosa cell tumors (AGCTs) are rare ovarian tumors with generally good prognosis after surgical resection; however, they do have recurrence potential. Therapeutic and management options for recurrences are currently limited, and the need for expanded adjuvant therapies is increasingly recognized. Anti-hormonal therapy is being explored as an option, which relies on the detection and assessment of hormone receptor expression (androgen, estrogen, and progesterone receptors) as a biomarker and therapeutic target. Our study identifies several clinicopathologic characteristics with significant associations for recurrence of AGCT, which were younger age, higher stage, and larger tumor size. Our study also demonstrates that androgen receptor (AR) expression may be utilized as a potential biomarker for hormonal therapy and that detection of AR expression in AGCT by immunohistochemistry (IHC) varies depending on the antibody clone used for testing. AR was detected in 95% of samples tested with antibodies derived from clone AR27. This detection rate is much higher than previously reported.