bluuebunny/crossref_metadata_2025 huggingface dataset:
Más allá de lo habitual. El espectro de síndromes de sobrecrecimiento relacionado con PIK3CA
Authors: Puertas-Miranda David , Pérez-García María Luisa , Crisolino-Pozas Ángel Pedro , Gutiérrez-Sampedro Nora Sabrina , Llamas-Alonso Claudia María
Published: April 2023

Presentamos el caso de una mujer de 91 años que ingresa en Medicina Interna por una posible rectorragia. El hallazgo a la exploración de unas anomalías vasculares vulvovaginales crónicas, junto con otros antecedentes vasculares, nos lleva a pensar en la posibilidad diagnóstica de una entidad denominada Klippel-Trenaunay. Esta enfermedad minoritaria forma parte de un grupo de síndromes que conforman el espectro de PROS. El descubrimiento reciente de una mutación compartida, el gen PIK3CA (fosfotidilinositol-4,5-bifosfonato-3-kinasa), ha generado interés y la búsqueda de nuevas terapias dirigidas.
Sustained Work from Home Post-Pandemic? A Swedish Case
Authors: Vilhelmson Bertil , Thulin Eva , Brundin Louise
Published: April 2023

We investigate whether office workers will continue to work from home after COVID-19 pandemic restrictions. Office workers at Swedish public agencies were surveyed concerning the pre-pandemic experience of work from home, current practices, and willingness to continue work from home post-pandemic. Results indicate that willingness increased greatly during the pandemic. Most surveyed workers wanted to continue to work from home at least three days per week, and the greater the experience of remote work, the greater the inclination to increase the number of days of working from home. Job type, housing, public transport commuting, and living region affected the willingness.
Forest management drives evolution of understorey herbs
Authors: Møller Charlotte , De Frenne Pieter , March-Salas Martí , Vanneste Thomas , Verheyen Kris , Scheepens J
Published: April 2023

Forest management has a strong impact on the forest structure and subsequently on the biotic and abiotic forest understorey environment. Forest understorey herbs can thus be expected to evolutionary respond to management-induced environmental variation (provided sufficient time for adaptation), but this has been little tested to date. Here we use a common garden, to test for genetically based variation in phenotypic traits in populations of forest herbs sampled along a forest management intensity gradient. Five different herbaceous species were sampled from 70-100 populations in three regions in Germany and were tested for genetically based variation in flowering start, proportion of flowering ramets, and plant height. Additionally, we investigated the effects of management-induced environmental variation and performed structural equation modelling to study how forest management drives trait differentiation via its effects on the microenvironment. We found that the studied forest understorey herbs varied genetically in the measured functional and phenological traits among the sampled populations. Forest management likely affected the traits in various directions and strengths depending on the species, either directly through variation in forest structural attributes or indirectly through changes in the microclimatic environment on the forest floor. We show that forest management can have evolutionary consequences for forest understorey plants. In an applied context, diverse forest management actions within landscapes thus creates heterogeneity that selects for different plant traits and thus helps conserving genetic diversity.
Acceptability, fidelity and trial experience of four intervention components to support medication adherence in women with breast cancer: A process evaluation protocol for a pilot fractional factorial trial
Authors: Green Sophie M.C. , Hall Louise H. , Rousseau Nikki , French David P. , Graham Christopher D. , Collinson Michelle , Mason Ellen , Wilkes Hollie , Howdon Daniel , Foy Robbie , Walwyn Rebecca , Clark Jane , Parbutt Catherine , Raine Erin , Ellison Rachel , Buxton Jacqueline , Moore Sally J. L. , Velikova Galina , Farrin Amanda , Smith Samuel G.
Published: April 2023

Background The Refining and Optimising a behavioural intervention to Support Endocrine Therapy Adherence (ROSETA) programme has developed four intervention components aiming to improve medication adherence in women with early-stage breast cancer. These are (a) text messages, (b) information leaflet, (c) Acceptance and Commitment Therapy-based guided self-help (ACT), (d) side-effect management website. Guided by the Multiphase Optimisation Strategy, our pilot trial will use a fractional factorial design to evaluate the feasibility of undertaking a larger optimisation trial. The pilot will include a process evaluation to maximise learning regarding the fidelity and acceptability of the intervention components before proceeding with a larger trial. The trial process evaluation has three aims: to assess the (1) fidelity and (2) acceptability of the intervention components; and (3) to understand participant’s trial experience, and barriers and facilitators to recruitment and retention. Methods The process evaluation will use multiple methods. Fidelity of the intervention components will be assessed using self-reported questionnaire data, trial data on intervention component adherence, and observations of the ACT sessions. Acceptability of the intervention components and trial experience will be explored using an acceptability questionnaire and interviews with patients and trial therapists. Trial experience will be assessed using a questionnaire and interviews with participants, while barriers and facilitators to recruitment and retention will be assessed using a questionnaire completed by research nurses and participant interviews. The pilot trial opened for recruitment on 20th May 2022 and was open at the time of submission. Conclusions This process evaluation will provide information regarding whether the intervention components can be delivered with fidelity within a national healthcare setting and are acceptable to participants. We will also better understand participant experience in a pilot trial with a fractional factorial design, and any barriers and facilitators to recruitment and retention. Registration ISRCTN registry (ISRCTN10487576, 16/12/2021).
Digitalization in Ukraine: evolutionary transformations
Authors: Halushchak Olha , Halushchak Mykhailo , Mashliy Halyna
Published: April 2023

It was investigated the evolutionary changes of digitalization process in Ukraine and established the characteristic features of each stage of the transformation of digital technologies. So, at the first stage, the formation of digital infrastructure for the purpose of wide access to the Internet is traced, the obtained information is used more for familiarization and not for the implementation of entrepreneurial activity. The second stage is characterized by a significant increase in the digital competences of consumers, creation and protection of electronic information resources and introduction of electronic flow of documents. The next stage is the stage of introduction of electronic management and provision of public electronic services. The using of artificial intelligence, cloud technologies, drones, cobots, the Internet of things and services, processing of big data, the using of «smart city», «smart enterprise» and «smart home» systems are the characteristics of the fourth stage of the development of digitalization, at which we are now. The authors have analyzed the features of digital innovations in various fields, in particular, in jurisprudence, education and health care. The possibility of receiving the electronic services on the Government portal should be included to positive results of the development of digital society. Ukraine’s accession to the Digital Europe Program, which provides the financing of projects, is related to the using of artificial intelligence, cloud services, digital technologies in business and society, and to the improvement of digital skills, can be considered a significant achievement. Investigation of the dynamics of Ukraine's digital competitiveness ranking among 64 countries was also conducted and it was established that our country is slowly improving its position. This is a positive trend, despite russia's invasion to Ukraine in 2014. Comparative analysis of Ukraine's place in the ranking of countries in the world according to level of digital competitiveness indicates that Ukraine has a significant potential for the introduction of digital innovations, appropriate legislative base and the experience of using the innovations.
Digitalization opportunities of national economy of Ukraine
Authors: Samoilenko Alla
Published: April 2023

The article explores the directions of digitalization development in Ukraine and presents key digital trends. The author analyzes the legal and regulatory documents on the basis of which the modernization and construction of digital infrastructure, strengthening of cyber defense, and further development of new digital technologies are carried out. It is determined that digitalization opens up new opportunities for Ukrainian business entities, in particular, the right to participate on a competitive basis in the European Union's Digital Europe Program until 2027 to build digital infrastructure with a total program fund of 7.6 billion euros. The author presents the structure of regulatory and legal support for digitalization processes, which specifies the purpose of regulatory instruments in the digital industry. The emphasis is placed on the fact that legal acts and regulatory instruments of the complex branch of legislation in the digital sphere create an important basis for realizing the opportunities for digitalization of the national economy. The activity of Ukrainian enterprises in the online environment is studied. The share of Ukrainian enterprises by type of economic activity that use digitalization tools as of 2021 is determined. It is noted that the only alternative way to further develop modern business is its digital transformation in today's highly competitive markets. An analysis of current trends in the use of modern information technologies by domestic enterprises indicates their significant role in the industrial and service sectors. It is noted that the digitalization of Ukraine's national economy should be focused on international, European and regional cooperation with a view to integrating Ukraine's information space into the European community. It is substantiated that the possibilities of digitalization are marked by the existing trends and patterns of this process. The tendencies of further digitalization of the national economy are identified, among which a significant role is given to the digitalization and virtualization of financial transactions, e-government, personalization of needs and production by means of IT. The key tasks of Ukraine on the way to building digital platforms, especially in terms of developing electronic business interaction, are proposed.
EFECTO DEL CONTENIDO PASTA Y AGREGADOS FINOS SOBRE LAS PROPIEDADES DEL HORMIGÓN DRENANTE
Authors: Fogliatti Fernando Luis , Carrasco María Fernanda , Beltramini Loreley Betina , Defagot Carlos Antonio , Grether Rudy Omar
Published: April 2023

Se evaluaron hormigones drenantes, elaborados con cemento portland compuesto, agregados gruesos graníticos, contenidos variables de agregado fino entre 0 y 16 % y de pasta desde 15 % a 25 % e incorporación de aditivos químicos.

En estado fresco se evaluó la consistencia mediante el tronco de cono de Abrams y la prueba Hand-Squeeze. En estado endurecido, la resistencia a compresión a 7 y 28 días, la densidad seca aparente, la absorción, el contenido de vacíos, la permeabilidad y el espesor de la pasta circundante al agregado grueso.

Se estudió la distribución de tamaño de los poros internos y se realizó una comparación entre la porosidad medida de forma convencional y por medio de análisis de imágenes.

La resistencia aumentó con el contenido de finos, con el incremento del contenido de pasta y con el espesor de pasta y simultáneamente, se redujeron el contenido de vacíos y la permeabilidad.
Cuidados paliativos e esquizofrenia: uma reflexão sobre a dificuldade do cuidado paliativo em doentes com esquizofrenia
Authors: Takatori Mylena Miuki Ogatha , Rigo Rosangela Silva
Published: April 2023

Introdução: A esquizofrenia é uma doença psiquiátrica crônica e grave, além de extremamente debilitante e que traz consigo um estigma muito grande para os seus portadores. É uma das doenças que mais causa incapacitação e por isso o paciente precisa de um cuidado integral, visando não só a resolução do quadro psiquiátrico, mas também do bem-estar e a diminuição do sofrimento. Objetivo: Este trabalho visa revisar a literatura sobre cuidados paliativos em pacientes com esquizofrenia e identificar a aplicabilidade e importância de tal prática. Método: revisão narrativa de literatura, utilizando as bases de dados: Scientific Electronic Library Online (ScieELO), UpToDate e Medical Literature Analysis and Retrieval System Online (MEDLINE). Utilizando as seguintes palavras-chave: “Cuidados Paliativos”, “Esquizofrenia” e “Saúde Mental”. Os critérios de inclusão e exclusão foram aplicados e um total de 61 artigos foram utilizados. Resultados e Discussão: A esquizofrenia é uma doença mental crônica grave que resulta em marginalização e estigma para os pacientes. Aproximadamente quatro a sete milhões de pessoas em todo o mundo sofrem de esquizofrenia grave resistente ao tratamento. Esses pacientes podem apresentar um alto nível de sintomas negativos, levando a comprometimento da qualidade de vida e do funcionamento social. A gama de abordagens de cuidados paliativos na medicina é muito ampla, desde medidas direcionadas de curto prazo para alívio de sintomas angustiantes até sedação paliativa. Os serviços de cuidados paliativos para pessoas com esquizofrenia devem adotar uma abordagem inclusiva. Conclusão: Os cuidados paliativos poderão oferecer conforto aos pacientes com esquizofrenia e seus familiares, em especial aos marginalizados.
Individualized risk prediction of cardiovascular and kidney outcomes in high risk patients
Authors:   , Østergaard Helena Bleken
Published: April 2023

The number of patients with type 2 diabetes, cardiovascular disease and chronic kidney disease is increasing rapidly worldwide. The above diseases are highly interrelated, with shared risk factors. In this thesis, we investigate and identify the relationship between risk factors and the development of cardiovascular and chronic kidney disease in "high-risk" patients with established cardiovascular disease and/or type 2 diabetes. A number of treatments already exist to reduce the risk of cardiovascular and chronic kidney disease, however, these treatments are associated with a risk of side effects, an increase in the number of pills patients must take and, for some therapies, high costs. Therefore, it is important to be able to identify which patients are at increased risk and which would benefit most from preventive medication. Currently, this is done by predicting individual short-term risk of disease. It is important that models for such predictions are accurate and contemporary. In this thesis, we developed DIAL-ESKD, a prediction model developed and validated in approximately 1,000,000 individuals with type 2 diabetes, allowing for 10-year and lifetime predictions of end-stage kidney disease as well as estimated benefit from preventive treatment. Furthermore, we developed SCORE2-diabetes and DIAL2, prediction models for predicting individual 10-year and lifetime risk, respectively, of cardiovascular disease in people with type 2 diabetes and the models were geographically and temporally recalibrated to European regions. These more accurate predictions can be used to improve shared decision making between practitioner and patient in a clinical setting.
More than words
Authors:   , Selten Iris Susanna
Published: April 2023

Developmental Language Disorder (DLD) is a neurodevelopmental disorder affecting approximately
3-7% of children in the general population. In addition to persistent language difficulties, many children with DLD experience symptoms of various neuropsychiatric disorders. However, the relationship between neuropsychiatric symptoms and language difficulties in DLD is insufficiently clear. A better understanding of this relationship, might improve our ability to identify those children with DLD who are most likely to develop neuropsychiatric symptoms and therefore potentially benefit from targeted intervention. The exact cause of DLD remains unknown and varies from child-to-child. Consequently, the relationship between language difficulties and neuropsychiatric symptoms is likely to vary among children with DLD as well. This variability might have prevented previous research to uncover this relationship in the group of children with DLD. Therefore, studying a population of children who all share the same genetic origin could provide an opportunity to identify relationships between language difficulties neuropsychiatric symptoms. This was the approach central to this dissertation. Children with DLD were compared to a group of children with a genetic condition: children with the 22q11.2 deletion syndrome (22q11DS). Similar to DLD, 22q11DS is associated with language difficulties and neuropsychiatric symptoms. However, these difficulties in 22q11DS have a shared cause, consisting of missing a small part of chromosome 22. Results of this dissertation provide new insights on the impact of language difficulties on the occurrence of neuropsychiatric symptoms in 22q11DS. The findings provide leads for future research and clinical care for children with 22q11DS and children with DLD.
Regulation of Syk activity by antiviral adaptor MAVS in FcεRI signaling pathway
Authors: Kawakami Yuko , Kimura Miho , Widjaja Christella , Kasakura Kazumi , Ando Tomoaki , Kawakami Yu , Obar Joshua J. , Kawakami Toshiaki
Published: April 2023

Background

Mast cells are the major effector cell type for IgE-mediated allergic reactions. Recent studies revealed a role for mast cells in orchestrating the host response to viral infections.

Objective

We studied the relationship between FcεRI (high-affinity IgE receptor) and RIG-I-like receptor (RLR)-mediated antiviral signaling pathways.

Methods

Mast cells (BMMCs) were cultured from bone marrow cells from mice deficient in MAVS or other RLR signaling molecules. MAVS expression was restored by retroviral transduction of MAVS-deficient BMMCs. These cells were stimulated with IgE and antigen and their activation (degranulation and cytokine production/secretion) was quantified. FcεRI-mediated signaling events such as protein phosphorylation and Ca2+ flux were analyzed by western blotting and enzyme assays. WT and mutant mice as well as mast cell-deficient KitW−sh/W−sh mice engrafted with BMMCs were subjected to passive cutaneous anaphylaxis.

Results

Unexpectedly, we found that mast cells devoid of the adaptor molecule MAVS exhibit dramatically increased cytokine production upon FcεRI stimulation, despite near-normal degranulation. Consistent with these observations, MAVS inhibited tyrosine phosphorylation, thus catalytic activity of Syk kinase, the key signaling molecule for FcεRI-mediated mast cell activation. By contrast, mast cells deficient in RIG-I, MDA5 or IRF3, which are antiviral receptor and signaling molecules upstream or downstream of MAVS, exhibited reduced or normal mast cell activation. MAVS-deficient mice showed enhanced late-phase responses in passive cutaneous anaphylaxis.

Conclusion

This study demonstrates that the adaptor MAVS in the RLR innate immune pathway uniquely intersects with the adaptive immune FcεRI signaling pathway.
BMI1 fine-tunes gene repression and activation to safeguard undifferentiated spermatogonia fate
Authors: Liu Ruiqi , Peng Yonglin , Du Wenfei , Wu Yunqiang , Zhang Wen , Hu Congxia , Liu Min , Liu Xinhua , Wu Ji , Sun Jielin , Zhao Xiaodong
Published: April 2023

Introduction: Spermatogenesis is sustained by the homeostasis of self-renewal and differentiation of undifferentiated spermatogonia throughout life, which is regulated by transcriptional and posttranscriptional mechanisms. B cell-specific Moloney murine leukemia virus integration site 1 (BMI1), one of spermatogonial stem cell markers, is a member of Polycomb repressive complex 1 (PRC1) and important to spermatogenesis. However, the mechanistic underpinnings of how BMI1 regulates spermatogonia fate remain elusive.

Methods: We knocked down BMI1 by siRNA to investigate the role of BMI1 in undifferentiated spermatogonia. Differentially expressed genes were identified by RNA-seq and used for KEGG pathway analysis. We performed ChIP-seq analysis in wild type and BMI1 knockdown cells to explore the underlying molecular mechanisms exerted by BMI1. BMI1-associated alterations in repressive histone modifications were detected via Western blotting and ChIP-seq. Furthermore, we performed mass spectrometry and Co-immunoprecipitation assays to investigate BMI1 co-factors. Finally, we demonstrated the genomic regions occupied by both BMI1 and its co-factor.

Results: BMI1 is required for undifferentiated spermatogonia maintenance by both repressing and activating target genes. BMI1 preserves PI3K-Akt signaling pathway for spermatogonia proliferation. Decrease of BMI1 affects the deposition of repressive histone modifications H2AK119ub1 and H3K27me3. BMI also positively regulates H3K27ac deposited genes which are associated with proliferation. Moreover, we demonstrate that BMI1 interacts with Sal-like 4 (SALL4), the transcription factor critical for spermatogonia function, to co-regulate gene expression.

Discussion: Overall, our study reveals that BMI1 safeguards undifferentiated spermatogonia fate through multi-functional roles in regulating gene expression programs of undifferentiated spermatogonia.
Case report: Diagnosis of apical hypertrophic cardiomyopathy that escaped clinical and echocardiographic investigations for twenty years: Reasons and clinical implications
Authors: Caiati Carlo , Stanca Alessandro , Lepera Mario Erminio
Published: April 2023

Background

Apical hypertrophic cardiomyopathy (ApHCM) is a rare form of hypertrophic cardiomyopathy which predominantly affects the apex of the left ventricle. The diagnosis can be challenging due to several factors, ranging from no typical clinical and electrocardiogram (EKG) findings to potential difficulties in executing and interpreting the echocardiographic examination.

Case presentation

We report the case of an 84-year-old woman who came to our echo-lab to undergo a routine echocardiogram. She had a history of permanent atrial fibrillation, paced rhythm and previous episodes of heart failure (HF), allegedly explained by a diagnosis of hypertensive heart disease that had been confirmed many times over the previous 20 years. The clinical examination and the EKG were unremarkable. The echocardiographic images were poor quality. But a senior cardiologist, expert in imaging and echocardiography, noted the lack of delineation of the endocardial border of the left ventricular (LV) apex region. Contrast echocardiography was performed and severe apical hypertrophy discovered.

Conclusion

ApHCM can be a challenging diagnosis. Contrast echocardiography must always be applied in cases of poor delineation of the LV apical endocardial border at baseline echocardiography. Timely detection and appropriate lifestyle intervention might slow the development of LV hypertrophy, and possibly minimize and delay heart failure (HF) related symptoms and arrhythmias. The prognosis remains relatively benign during long term follow-up.
Overview of distinct 5-methylcytosine profiles of messenger RNA in normal and knock-down NSUN2 colorectal cancer cells
Authors: Lin Yu , Zhao Zhifang , Nie Wenqiang , Huang Manting , Cai Jiazhong , Wang Yadong , Wang Hesong , Huang Yongmei , Bai Yang
Published: April 2023

Background: Colorectal cancer (CRC) is a harmful cancer with high morbidity and poor prognosis. There is growing evidence that RNA methylation is closely related to the occurrence of cancer and its malignant biological behavior. N6-methyladenosine (m6A) methylation is the most common RNA modification in eukaryotes, and its multiple regulatory mechanisms in CRC have been elucidated from multiple perspectives. At the same time, the role of 5-methylcytosine (m5C), another important and widely distributed methylation modification, in CRC is far from being elucidated.

Methods: In this study, we used RNA immunoprecipitation sequencing combined with bioinformatics methods to identify the m5C peaks on messenger RNA (mRNA) in HCT15 cells and sh-NSUN2 HCT15 cells, understand which transcripts are modified by m5C, and characterize the distribution of m5C modifications. In addition, we performed further bioinformatics analysis of the detected data to initially clarify the potential function of these m5C-modified transcripts.

Results: We found significant differences in the distribution of m5C between HCT15 cells and sh-NSUN2 HCT15 cells, suggesting that m5C is likely to play a key role in the occurrence and development of CRC. Furthermore, Gene Ontology (GO) enrichment analysis showed that genes altered by m5C were mainly enriched in phylogeny, synaptic membrane, and transcription factor binding. The Kyoto Encyclopedia of Genes and Genomes (KEGG)pathway analysis showed that the genes altered by m5C are enriched in ECM receptor interaction pathway, the circadian pathway, and the cAMP signaling pathway.

Conclusion: Here, our study preliminarily revealed the different distribution patterns of m5C between HCT15 cell and sh-NSUN2 HCT15 cell. Our results open a new window to understand the role of m5C RNA methylation of mRNA in the development of CRC.
Improving access to family planning services through community pharmacies: Experience from The Challenge Initiative in three counties in Kenya
Authors: Aloo Nancy , Nyachae Paul , Mbugua Njeri , Sirera Morine , Owino Kenneth , Kagwe Peter , Nyamu Njeri , Hanif Mohammed , Ndirangu Miriam
Published: April 2023

Pharmacies play a vital role in improving access to family planning (FP) services in urban areas. They complement the resource-limited public health system and are viewed as key access points for contraceptives among young people (10–24 years) and the general population. The Challenge Initiative East Africa (TCI EA), in collaboration with the health management teams of Mombasa, Kilifi, and the Nairobi counties in Kenya and the Kenya Pharmaceutical Association (KPA) piloted an innovative public-private partnership (PPP) engagement to improve access to quality FP services offered at pharmacies in urban areas. The pilot project built the capacity of pharmacists, strengthened the referral system to public health facilities, and made FP data accessible and visible to drive informed decision-making. This paper describes the strategies employed and the outcomes. The initiative targeted 150 pharmacies across the three counties from June 2019 to December 2020 period. Our assessment shows that this intervention delivered FP commodities to 43,632 FP client visits; 71% for female clients and 21% for males. Adjusting for couple years of protection and seasonality, this translates to about 2,800 annual FP clients obtaining modern contraception in a 12-month period, including 48% injectables, 25% oral contraception, 24% emergency contraception, and 3% condoms. The majority of clients (75%) were older than 24 years, 21% were 20–24 years, 3% were 15–19 years, and 1% were less than 15 years. In addition, 327 clients were referred to a public sector facility for other methods. This intervention demonstrates the potential of pharmacies in contributing to FP uptake and provides a framework for improving access to quality FP services by pharmacies. There is potential to scale such an approach beyond the 3 counties, given the involvement and reach of KPA and the Ministry of Health (MoH) health management teams.
Outcomes with chimeric antigen receptor t-cell therapy in relapsed or refractory acute myeloid leukemia: a systematic review and meta-analysis
Authors: Shahzad Moazzam , Nguyen Andrea , Hussain Ali , Ammad-Ud-Din Mohammad , Faisal Muhammad Salman , Tariq Ezza , Ali Fatima , Butt Atif , Anwar Iqra , Chaudhary Sibgha Gull , Lutfi Forat , Ahmed Nausheen , Singh Anurag K. , Hematti Peiman , McGuirk Joseph P. , Mushtaq Muhammad Umair
Published: April 2023

Background

We conducted a systematic review and meta-analysis to evaluate outcomes following chimeric antigen receptor T cell (CAR-T) therapy in relapsed/refractory acute myeloid leukemia (RR-AML).

Methods

We performed a literature search on PubMed, Cochrane Library, and Clinicaltrials.gov. After screening 677 manuscripts, 13 studies were included. Data was extracted following PRISMA guidelines. Pooled analysis was done using the meta-package by Schwarzer et al. Proportions with 95% confidence intervals (CI) were computed.

Results

We analyzed 57 patients from 10 clinical trials and 3 case reports. The pooled complete and overall response rates were 49.5% (95% CI 0.18-0.81, I2 =65%) and 65.2% (95% CI 0.36-0.91, I2 =57%). The pooled incidence of cytokine release syndrome, immune-effector cell associated neurotoxicity syndrome, and graft-versus-host disease was estimated as 54.4% (95% CI 0.17-0.90, I2 =77%), 3.9% (95% CI 0.00-0.19, I2 =22%), and 1.6% (95%CI 0.00-0.21, I2 =33%), respectively.

Conclusion

CAR-T therapy has demonstrated modest efficacy in RR-AML. Major challenges include heterogeneous disease biology, lack of a unique targetable antigen, and immune exhaustion.
Physiological fibrin hydrogel modulates immune cells and molecules and accelerates mouse skin wound healing
Authors: Pereira Rafaela Vaz Sousa , EzEldeen Mostafa , Ugarte-Berzal Estefania , Martens Erik , Malengier-Devlies Bert , Vandooren Jennifer , Vranckx Jan Jeroen , Matthys Patrick , Opdenakker Ghislain
Published: April 2023

Introduction

Wound healing is a complex process to restore homeostasis after injury and insufficient skin wound healing is a considerable problem in medicine. Whereas many attempts of regenerative medicine have been made for wound healing with growth factors and cell therapies, simple pharmacological and immunological studies are lagging behind. We investigated how fibrin hydrogels modulate immune cells and molecules in skin wound healing in mice.

Methods

Physiological fibrin hydrogels (3.5 mg/mL fibrinogen) were generated, biophysically analyzed for stiffness and protein contents and were structurally studied by scanning electron microscopy. Physiological fibrin hydrogels were applied to full thickness skin wounds and, after 3 days, cells and molecules in wound tissues were analyzed. Leukocytes, endothelial cells, fibroblasts and keratinocytes were explored with the use of Flow Cytometry, whereas cytokines and matrix metalloproteinases were analyzed with the use of qPCR, ELISAs and zymography. Skin wound healing was analyzed microscopically at day 3, macroscopically followed daily during repair in mice and compared with commercially available fibrin sealant Tisseel.

Results

Exogenous fibrin at physiological concentrations decreased neutrophil and increased non-classical Ly6Clow monocyte and resolutive macrophage (CD206+ and CX3CR1+) populations, at day 3 after injury. Fibrin hydrogel reduced the expression of pro-inflammatory cytokines and increased IL-10 levels. In line with these findings, gelatinase B/MMP-9 was decreased, whereas gelatinase A/MMP-2 levels remained unaltered. Frequencies of dermal endothelial cells, fibroblasts and keratinocytes were increased and keratinocyte migration was enhanced by fibrin hydrogel. Importantly, physiological fibrin accelerated the healing of skin wounds in contrast to the highly concentrated fibrin sealant Tisseel, which delayed wound repair and possessed a higher fiber density.

Conclusion

Collectively, we show that adding a tailored fibrin hydrogel scaffold to a wound bed positively influences the healing process, modulating leukocyte populations and inflammatory responses towards a faster wound repair.
Foraminifera associated with cold seeps in marine sediments
Authors: Lu Yinghan , Yang Hailin , Huang Baoqi , Liu Yujia , Lu Hailong
Published: April 2023

Cold seep foraminifera have attracted considerable attention as they provide valuable insights into the study of cold seeps. This study provides a comprehensive overview of the manifestations of foraminifera in cold seep environments and methane seepage activities. Certain taxa of benthic foraminifera, such as Uvigerina, Bolivina, Bulimina, Chilostomella, Globobulimina, Nonionella, Melonis, Epistominella, Cibicidoides, and Globocassidulina, are known to inhabit geochemical conditions induced by methane-rich environments and may feed on associated methanotrophic microbial communities. Secondary mineralization on foraminifera shells is a widespread manifestation in seep sediments, and alters the microstructure, elementary composition, and isotopic signatures of foraminifera. On one hand, the precipitation of secondary authigenic Mg-rich, Mn-rich, Sr-rich, and Ba-rich calcite coatings have been observed on microfossils. On the other hand, micron-sized crystal pyrite and gypsum aggregates can also grow on the foraminifera walls. The negative δ13C and positive δ18O anomalies in both planktonic and benthic foraminifera from seep-associated sediments can serve as proxies for tracing past seepage activities, either in their live form or being adulterated by methane-derived authigenic carbonate after deposition. Seeping activities are recognized with a significant impact on benthic foraminifera, and the presence of cold seep-related species and significant isotopic anomalies in shells can be used to reconstruct past methane seepage events. Intensive methane seepage tends to suppress benthic foraminifera populations, while moderate intensity seepage may lead to a thriving benthic foraminiferal community, with hypoxia-enduring taxa such as Uvigerina, Melonis, and Bulimina being predominant. In contrast, oxygen-loving epibenthic taxa such as Cibicidoides often occur in areas of low methane flux. Compared to planktonic foraminifera, the single species of benthic foraminifera can provide a more comprehensive record of seepage evolution. Live benthic specimens are preferred for in-situ seep studies, while the superimposition of secondary minerals on the original shells should not be ignored when observing dead individuals. The significance of the evolution of methane seepage, changes in environmental parameters of the living habitat, and species sensitivity in cold seeps are emphasized in explaining the variation in foraminiferal assemblages and fluctuations in stable isotopes.
Students' and lecturers' perspectives on the implementation of online learning in medical education due to COVID-19 in Germany: a cross-sectional pilot study
Authors: Hertling Stefan F. , Back David A. , Kaiser Mario , Loos Franziska M. , Schleußner Ekkehard , Graul Isabel
Published: April 2023

Background

During the coronavirus disease 2019 (COVID-19) crisis, many things changed in universities around the world. In-person learning was not possible. Instead, courses were offered in digital form. The sudden change posed enormous challenges to universities, students, and teachers. The aim of this study was to investigate the disadvantages as well as the advantages and opportunities of digital learning.

Objective

This study investigated the evaluation of an elective module by medical students and teachers in the traditional in-person and virtual teaching forms during the COVID-19 pandemic.

Methods

Using the elective module “Sports Medicine,” which includes both lectures and practical units, the opinions of the medical students about conventional teaching compared to digital instruction were evaluated. In the winter semester of 2019/2020, all classes were taught face-to-face but had to be switched to virtual teaching in the summer semester of 2020 on an ad hoc basis due to the pandemic. The students were asked to answer questions on general conditions, participant behavior, instructor evaluation, skill acquisition, topic selection, and overall evaluation after both forms of teaching. Likewise, the lecturers of both courses were queried in semiqualitative interviews about the same topics. Descriptive data analysis was performed to process the data.

Results

The students perceived digital teaching to be superior in most subareas compared to in-person teaching in terms of framework, instructor evaluation, skill acquisition, topic selection, and overall rating. Medical students seemed to feel better with digital teaching in most areas of evaluation. The lecturers found the new form of teaching rather unsettling and criticized the lack of verbal and especially nonverbal communication as well as the short preparation time for the new challenge. The instructors were uncomfortable with some aspects of the virtual teaching format.

Conclusion

In the wake of the COVID-19 pandemic, medical schools should rapidly digitize their teaching offerings and support faculty members in their computer-based competence with continuing education opportunities and time resources.
Effect of arsenic stress on the intestinal structural integrity and intestinal flora abundance of Cyprinus carpio
Authors: Shi Xiaodan , Xu Wei , Che Xinghua , Cui Jiawen , Shang Xinchi , Teng Xiaohua , Jia Zhiying
Published: April 2023

Aquatic organisms such as fish can accumulate high concentrations of arsenic (As), which has toxic effects on fish. However, whether the intestinal flora are involved in As damage to fish intestinal tissues and the underlying process are unclear. Common carp (Cyprinus carpio) were exposed to As (2.83 mg/L) in water for 30 days, and blood, muscle, intestine, and intestine samples were collected. Intestinal pathological sections were observed, and the lipopolysaccharide (LPS) levels in serum and the levels of As accumulation and tight junction-related factors in intestinal tissues were measured. The gut microbiota was analysed by 16S rRNA sequencing. The results showed that As treatment decreased the abundance of microbiota, increased the number of harmful bacteria, and decreased the number of beneficial bacteria in the intestine. In our experiment, the top 30 harmful and beneficial bacteria with the highest relative abundance were identified. Among the top 30 harmful and beneficial bacteria, As treatment resulted in a significant (P < 0.05) increase in harmful bacteria (such as Fusobacteriota, Bacteroidota (LPS-producing bacteria), Verrucomicrobiota, Bacteroides, Aeromonas, and Stenotrophomonas) and a significant (P < 0.05) decrease in beneficial bacteria (such as Actinobacteriota, Planctomycetota, Firmicutes, Reyranella, Akkermansia, and Pseudorhodobacter), which further demonstrated that As affects the abundance of intestinal flora. In addition, As exposure increased the LPS level in serum and the abundance of Bacteroidota (LPS-producing bacteria) in the intestine. Bacteroidota exhibits the six highest relative abundance at the phylum level, which indicates that LPS produced by Bacteroidota can increase the LPS level in serum. Additionally, the protein and gene levels of the tight junction markers ZO-1 and occludin in the intestine were reduced by As treatment, which further indicated that As exposure impaired the structural integrity of the intestine. In conclusion, the results obtained in our study indicate that the intestinal flora, LPS, and tight junctions participate in the impairment of the structural integrity of the common carp intestine resulting from As exposure.
Age-related changes in mice behavior and the contribution of lipocalin-2
Authors: Ferreira Ana Catarina , Sousa Nuno , Sousa João Carlos , Marques Fernanda
Published: April 2023

Aging causes considerable changes in the nervous system, inducing progressive and long-lasting loss of physiological integrity and synaptic plasticity, leading to impaired brain functioning. These age-related changes quite often culminate in behavioral dysfunctions, such as impaired cognition, which can ultimately result in various forms of neurodegenerative disorders. Still, little is known regarding the effects of aging on behavior. Moreover, the identification of factors involved in regenerative plasticity, in both the young and aged brain, is scarce but crucial from a regenerative point of view and for our understanding on the mechanisms that control the process of normal aging. Recently, we have identified the iron-trafficking protein lipocalin-2 (LCN2) as novel regulator of animal behavior and neuronal plasticity in the young adult brain. On the other hand, others have proposed LCN2 as a biological marker for disease progression in neurodegenerative disorders such as Alzheimer’s disease and multiple sclerosis. Still, and even though LCN2 is well accepted as a regulator of neural processes in the healthy and diseased brain, its contribution in the process of normal aging is not known. Here, we performed a broad analysis on the effects of aging in mice behavior, from young adulthood to middle and late ages (2-, 12-, and 18-months of age), and in the absence of LCN2. Significant behavioral differences between aging groups were observed in all the dimensions analyzed and, in mice deficient in LCN2, aging mainly reduced anxiety, while sustained depressive-like behavior observed at younger ages. These behavioral changes imposed by age were further accompanied by a significant decrease in cell survival and neuronal differentiation at the hippocampus. Our results provide insights into the role of LCN2 in the neurobiological processes underlying brain function and behavior attributed to age-related changes.
Genetic considerations in cerebral small vessel diseases
Authors: Bhagat Riwaj , Marini Sandro , Romero José R.
Published: April 2023

Cerebral small vessel disease (CSVD) encompasses a broad clinical spectrum united by pathology of the small vessels of the brain. CSVD is commonly identified using brain magnetic resonance imaging with well characterized markers including covert infarcts, white matter hyperintensities, enlarged perivascular spaces, and cerebral microbleeds. The pathophysiology of CSVD is complex involving genetic determinants, environmental factors, and their interactions. While the role of vascular risk factors in CSVD is well known and its management is pivotal in mitigating the clinical effects, recent research has identified novel genetic factors involved in CSVD. Delineating genetic determinants can promote the understanding of the disease and suggest effective treatments and preventive measures of CSVD at the individual level. Here we review CSVD focusing on recent advances in the genetics of CSVD. The knowledge gained has advanced understanding of the pathophysiology of CSVD, offered promising early results that may improve subtype identification of small vessel strokes, has led to additional identification of mendelian forms of small vessel strokes, and is getting closer to influencing clinical care through pharmacogenetic studies.
A prediction model for short-term neurodevelopmental impairment in preterm infants with gestational age less than 32 weeks
Authors: Li Yan , Zhang Zhihui , Mo Yan , Wei Qiufen , Jing Lianfang , Li Wei , Luo Mengmeng , Zou Linxia , Liu Xin , Meng Danhua , Shi Yuan
Published: April 2023

Introduction

Early identification and intervention of neurodevelopmental impairment in preterm infants may significantly improve their outcomes. This study aimed to build a prediction model for short-term neurodevelopmental impairment in preterm infants using machine learning method.

Methods

Preterm infants with gestational age  < 32 weeks who were hospitalized in The Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region, and were followed-up to 18 months corrected age were included to build the prediction model. The training set and test set are divided according to 8:2 randomly by Microsoft Excel. We firstly established a logistic regression model to screen out the indicators that have a significant effect on predicting neurodevelopmental impairment. The normalized weights of each indicator were obtained by building a Support Vector Machine, in order to measure the importance of each predictor, then the dimension of the indicators was further reduced by principal component analysis methods. Both discrimination and calibration were assessed with a bootstrap of 505 resamples.

Results

In total, 387 eligible cases were collected, 78 were randomly selected for external validation. Multivariate logistic regression demonstrated that gestational age(p = 0.0004), extrauterine growth restriction (p = 0.0367), vaginal delivery (p = 0.0009), and hyperbilirubinemia (0.0015) were more important to predict the occurrence of neurodevelopmental impairment in preterm infants. The Support Vector Machine had an area under the curve of 0.9800 on the training set. The results of the model were exported based on 10-fold cross-validation. In addition, the area under the curve on the test set is 0.70. The external validation proves the reliability of the prediction model.

Conclusion

A support vector machine based on perinatal factors was developed to predict the occurrence of neurodevelopmental impairment in preterm infants with gestational age  < 32 weeks. The prediction model provides clinicians with an accurate and effective tool for the prevention and early intervention of neurodevelopmental impairment in this population.
In situ spatiotemporal mapping of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) inhibitor in pineapple (Ananas comosus) fruit tissue by MALDI mass spectrometry imaging
Authors: Suarez Angelica Faith L. , Juanillo Angel Ann B. , Sison Dave Clark D. , Orajay Joey I. , Javier Maria Bella B. , Baladjay Diane Monique S. , Yang Yu-Liang , Saludes Jonel P. , Dalisay Doralyn S.
Published: April 2023

Pineapple (Ananas comosus) fruit is a functional food that has become a part of healthy diets worldwide due to its nutrition and health benefits. Given this concept, the potential anti-hypercholesterolemic activity of pineapple fruit was assessed using in vitro HMG-CoA reductase (HMGCR) inhibition assay. Our findings show that pineapple fruit (PAF) extract showed HMGCR inhibition activity. These findings led to partial purification of PAF extract by gel filtration chromatography (GFC) whereby fraction PAF 06 exhibited 100.00% HMGCR inhibition at 10 mg/mL. Matrix assisted laser desorption ionization (MALDI) mass spectrometry profiling, HRMS, MS/MS, and dereplication identified N1, N10-diferuloylspermidine as potential HMGCR inhibitor in pineapple fruit. The MALDI mass spectrometry imaging (MSI) enabled the in situ spatiotemporal mapping of the HMGCR inhibitor, N1, N10-diferuloylspermidine, in the pineapple fruit tissue, with localization concentrated mainly in the tissue near the peel/shell and a gradual decrease towards the flesh and ovary. The MALDI MSI provided the first evidence of in situ spatial localization of N1, N10-diferuloylspermidine, a potential HMGCR inhibitor in pineapple while maintaining the cellular and structural features of the fruit tissues.