bluuebunny/crossref_metadata_2025 huggingface dataset:
Continuous and differential improvement in worldwide access to hematopoietic cell transplantation: activity has doubled in a decade with a notable increase in unrelated and non-identical related donors
Authors: Atsuta Yoshiko , Baldomero Helen , Neumann Daniel , Sureda Anna , DeVos Jakob D. , Iida Minako , Karduss Amado , Purtill Duncan , Elhaddad Alaa M. , Bazuaye Nosa G. , Bonfim Carmem , De la Camara Rafael , Chaudhri Naeem A. , Ciceri Fabio , Correa Cinthya , Frutos Cristobal , Galeano Sebastian , Garderet Laurent , Gonzalez-Ramella Oscar , Greco Raffaella , Hamad Nada , Hazenberg Mette D. , Horowitz Mary M. , Kalwak Krzysztof , Ko Bor-Sheng , Kodera Yoshihisa , Koh Mickey BC , Liu Kaiyan , McLornan Donal P. , Moon Joon Ho , Neven Benedicte , Okamoto Shinichiro , Pasquini Marcelo C , Passweg Jakob R. , Paulson Kristjan , Rondelli Damiano , Ruggeri Annalisa , Seber Adriana , Snowden John A. , Srivastava Alok , Szer Jeff , Weisdorf Daniel , Worel Nina , Greinix Hildegard , Saber Wael , Aljurf Mahmoud , Niederwieser Dietger
Published: May 2024

Promoting access to and excellence in hematopoietic cell transplantation (HCT) by collecting and disseminating data on global HCT activities is one of the principal activities of the Worldwide Network for Blood and Marrow Transplantation, a non-governmental organization in working relations with the World Health Organization. HCT activities are recorded annually by member societies, national registries and individual centers including indication, donor type (allogeneic/autologous), donor match and stem cell source (bone marrow/peripheral blood stem cells/cord blood). In 2018, 1,768 HCT teams in 89 countries (6 World Health Organization regions) reported 93,105 (48,680 autologous and 44,425 allogeneic) HCT. Major indications were plasma cell disorders and lymphoma for autologous, and acute leukemias and MDS/MPN for allogeneic HCT. HCT numbers increased from 48,709 in 2007. Notable increases were seen for autoimmune diseases in autologous and hemoglobinopathies in allogeneic HCT. The number of allogeneic HCT more than doubled with significant changes in donor match. While HCT from HLA-identical siblings has seen only limited growth, HCT from non-identical related donors showed significant increase worldwide. Strongest correlation between economic growth indicator of gross national income/capita and HCT activity/10 million population was observed for autologous HCT (correlation coefficient [r]=0.79). HCT from unrelated donors showed strong correlation (r=0.68), but only moderate correlation was detected from related donors (r=0.48 for HLA-identical sibling; r=0.45 for other). The use of HCT doubled in about a decade worldwide at different speed and with significant changes regarding donor match as a sign of improved access to HCT worldwide. Although narrowing, significant gaps remain between developing and non-developing countries.
Doanh nghiệp nhỏ và vừa trong hội nhập kinh tế quốc tế: Thực trạng, vấn đề và giải pháp đối với nhóm ngành dệt, sản xuất trang phục và điện tử
Authors: Hồ Đình Bảo , Nguyễn Thanh Tùng
Published: May 2024

Hội nhập kinh tế quốc tế là một xu hướng tất yếu và mang lại nhiều cơ hội cho nền kinh tế Việt Nam. Tuy nhiên, thực tế cho thấy nhóm được hưởng lợi chính vẫn là khối doanh nghiệp có vốn đầu tư nước ngoài (FDI). Trong khi đó, doanh nghiệp nhỏ và vừa (DNNVV) còn gặp nhiều khó khăn trong việc tham gia vào chuỗi giá trị toàn cầu cũng như hoạt động xuất nhập khẩu. Nghiên cứu này đánh giá các yếu tố khách quan ảnh hưởng tới khả năng tham gia thương mại quốc tế của DNNVV trong nhóm ngành dệt, sản xuất trang phục và điện tử. Phân tích định lượng cho thấy một số yếu tố thể chế như tiếp cận đất đai, chi phí không chính thức và chất lượng lao động có ảnh hưởng lớn tới quá trình tiếp cận thị trường quốc tế của DNNVV. Từ đó, nhóm nghiên cứu đưa ra những khuyến nghị chính sách nhằm nâng cao năng lực cạnh tranh và gia tăng sự hiện diện của DNNVV Việt Nam trong chuỗi giá trị toàn cầu.
Suomalainen matkailun historiantutkimus 2004–2023
Authors: Manka Mikko
Published: May 2024

Katsauksessa käydään läpi suomalainen, matkailuilmiön menneisyyteen kohdistuva tutkimus ja tutkimuksellinen kirjallisuus vuosilta 2004–2023. Tutkimuksia etsittiin tekemällä hakuja Finnassa, Google Scholarissa ja tiedejatutkimus.fi-tietokannassa. Tuloksista suodatettiin pois aihealueeseen liittymättömät hakutulokset. Viimeisen vajaan kahdenkymmenen Suomessa on tehty suhteellisen vähän suoraan matkailun historiaan liittyvää tutkimusta. Esimerkiksi Matkailututkimus-lehden olemassaolon ajalta matkailun historiaa koskevia artikkelia on kaikkiaan kuusi. Määrällisesti suurin yksittäinen matkailun historiantutkimuksen teema-alue viimeisen kahdenkymmenen vuoden ajalta on matkakertomusten ja -kuvausten tutkimus, jolla on muutenkin pitkä traditio. Muita esiinnousseita tutkimusteemoja olivat muun muassa matkailun kehittämisen historia; identifikaatiot, kansallisvaltio ja kulttuuriperintö matkailussa. Lisäksi Suomessa on tehty muuta, teemoiltaan hyvin vaihtelevaa matkailun historian tutkimusta monella eri tieteenalalla.
Katsauksen valossa suomalaisessa matkailun historiantutkimuksessa ei ole yhtä dominoivaa teemaa. Esimerkiksi tutkijoiden eläköityminen tai tutkimusintressien vaihtuminen rahoitusinstrumenttien vaateiden tai yhteiskunnan tarpeiden muuttuessa voi näkyä nopeasti matkailuun liittyvän historiantutkimuksen määrässä ja aihevalinnoissa. Matkailun historiasta tehtyjen opinnäytteiden määrä näyttää aikakaudella hieman laskeneen. Uusille matkailun historian tutkimusavauksille olisi Suomessa hyvin tilaa: esimerkiksi ajankohtaiset teemat, kuten kestävyys tai vähemmistökysymykset, huomioivalle matkailun historian yleisesitykselle olisi tarvetta. Lisäksi historiantutkimuksessa yleisesti tapahtuneet muutokset, kuten ylirajainen käänne tai digihistorian nousu, tarjoavat mahdollisuuksia uusille tulkinnoille koko matkailun historiasta.
Kestävä matkailu: katsaus tutkimusteemoihin ja -tarpeisiin
Authors: Saarinen Jarkko
Published: May 2024

Kestävyys on yksi matkailututkimuksen keskeisistä tutkimusteemoista ja matkailutalouden kehittämisen tavoitteista. Tämä tekee kestävän matkailun tarkastelusta sekä akateemisesti että matkailupoliittisesti tärkeää. Tässä katsauksessa tarkastellaan kestävän matkailun tutkimuksen keskeisiä teemoja erityisesti Matkailututkimus -lehdessä vuosina 2005–2023 julkaistujen artikkelien perusteella. Tavoitteena on luoda yleiskuva kestävän matkailun tutkimuksen teemoista suhteessa alan kansainväliseen tutkimuskenttään, ja tunnistaa sen avulla nykyisiä ja tulevaisuuden tutkimustarpeita. Matkailututkimus -lehdessä julkaistujen artikkelien perusteella keskeisiä kestävän matkailun tutkimusteemoja ovat olleet: (1) Luonnonsuojelualueiden kestävä matkailu ja sen hallinta; (2) Kestävä matkailu ja lähi-ilmiöt; (3) Kulttuuri, paikallisuus ja yhteisöt kestävässä matkailussa; (4) Ilmastonmuutos ja matkailun kestävyys; ja (5) Maaseutumatkailu ja kestävyys. Näiden teemojen perusteella Matkailututkimus -lehden kestävän matkailun tutkimus on seurannut hyvin aikaansa, ja se on pysynyt temaattisesti kiinni alan kansainvälisessä tutkimuskentässä. Toisaalta Matkailututkimus -lehdessä julkaistujen teemojen osalta on havaittavissa katvealueita suhteessa kestävän matkailun kansainväliseen tutkimukseen. Keskeisin näistä on kestävän matkailun kehittämisen tutkimus luonnonsuojelualuekontekstin ulkopuolella. Lisäksi kansainväliseen kestävän matkailun hallinnon tutkimukseen olennaisesti liittyvät kestävyyden indikaattorien, YK:n kestävän kehityksen tavoitteiden ja matkailun globaaliin vastuuseen ja oikeudenmukaisuuteen liittyvät tarkastelut pääosin puuttuvat. Tulevaisuudessa matkailun, kestävän kehityksen ja ilmastonmuutoksen poleemisen suhteen lisätutkimukselle on myös tarvetta. Tässä mielessä matkailun kasvun irtikytkentä hiilidioksidipäästöjen kasvusta muodostaa tärkeän tutkimustarpeen.
The Contribution of Some Anthropometric Measurements and Pulmonary Volumes to The Digital achievement of the Sprint 400-meter Competition Among Elite Runners in Palestine
Authors: Hanon Loai , Salameh Hamed , Qadoume Ali , Abualia Motasem , Qadoume Khaled , Khalifa Riadh
Published: May 2024

The study aimed to identify the contribution of some anthropometric measurements and pulmonary volumes to the digital achievement of the sprint 400-meter running distance among elite runners in Palestine. A total of 18 elite runners in Palestine, (age: 20.16+1.15 years; body mass: 67.75+5.04 kg; height: 173.11+6.01 m; body mass index (BMI):23.3 +3.1 kg/m2) were categorized as. Anthropometric measurements and Pulmonary volume measurements were taken (VC, FVC, FEV1, FWV1/FVC%, MVV, TV, RV, IC). The authors used Multiple linear Regression. Simple Linear Regression (T) and (Beta) to determine the regression line equation. It was determined that there was no statistically significant relationship between some anthropometric measurements (≤0.05). In order to determine the contribution of measurements chest circumference (r=*0.599), chest circumference (r=*0.573) in inspiration, thigh circumference (r=*0.773) calf (Gastrocnemius) muscle circumference(r=*0.554) it was determined that there was a statistically significant relationship between the digital success of the 400 meter sprint run. It was determined that there was no statistically significant relationship (α≤0.05) between lung volume measurements (FVC, FEV1, FWV1/FVC%, MVV). It was determined that there was no statistically significant relationship (α≤0.05) between lung volume measurements (FVC, FEV1, FWV1/FVC%, MVV). However, VC (p = 0.00); It was determined that there was a significant relationship in terms of (R2 = 0.616). In conclusin researchers recommend the necessity of using the predictive equations that have been developed as a predictor of digital achievement in the sprint 400-meter running competition.
Extrahepatic malignancies and antiviral drugs for chronic hepatitis B: A nationwide cohort study
Authors: Hur Moon Haeng , Lee Dong Hyeon , Lee Jeong-Hoon , Kim Mi-Sook , Park Jeayeon , Shin Hyunjae , Chung Sung Won , Cho Hee Jin , Park Min Kyung , Jang Heejoon , Lee Yun Bin , Yu Su Jong , Lee Sang Hyub , Jung Yong Jin , Kim Yoon Jun , Yoon Jung-Hwan
Published: May 2024

Background/Aims: Chronic hepatitis B (CHB) is related to an increased risk of extrahepatic malignancy (EHM), and antiviral treatment is associated with an incidence of EHM comparable to controls. We compared the risks of EHM and intrahepatic malignancy (IHM) between entecavir (ETV) and tenofovir disoproxil fumarate (TDF) treatment.Methods: Using data from the National Health Insurance Service of Korea, this nationwide cohort study included treatment-naïve CHB patients who initiated ETV (n=24,287) or TDF (n=29,199) therapy between 2012 and 2014. The primary outcome was the development of any primary EHM. Secondary outcomes included overall IHM development. E-value was calculated to assess the robustness of results to unmeasured confounders.Results: The median follow-up duration was 5.9 years, and all baseline characteristics were well balanced after propensity score matching. EHM incidence rate differed significantly between within versus beyond 3 years in both groups (P<0.01, Davies test). During the first 3 years, EHM risk was comparable in the propensity score-matched cohort (5.88 versus 5.84/1,000 person-years; subdistribution hazard ratio [SHR]=1.01, 95% confidence interval [CI]=0.88–1.17, P=0.84). After year 3, however, TDF was associated with a significantly lower EHM incidence compared to ETV (4.92 versus 6.91/1,000 person-years; SHR=0.70, 95% CI=0.60–0.81, P<0.01; E-value for SHR=2.21). Regarding IHM, the superiority of TDF over ETV was maintained both within (17.58 versus 20.19/1,000 person-years; SHR=0.88, 95% CI=0.81–0.95, P<0.01) and after year 3 (11.45 versus 16.20/1,000 person-years; SHR=0.68, 95% CI=0.62–0.75, P<0.01; E-value for SHR=2.30).Conclusions: TDF was associated with approximately 30% lower risks of both EHM and IHM than ETV in CHB patients after 3 years of antiviral therapy.
The Death of Debate?
Authors: Kerr Liam
Published: May 2024

This personal essay outlines the ways in which debate has developed and functioned over time. It focuses upon the performative nature of much of what passes for ‘debate’ in the current Scottish Parliament. It suggests ways in which parliamentary business could be reshaped towards more meaningful and productive exchanges of opinion and evidence.
Mathematical modeling of two strains tuberculosis and COVID-19 vaccination model: a co-infection study with cost-effectiveness analysis
Authors: Appiah Raymond Fosu , Jin Zhen , Yang Junyuan , Asamoah Joshua Kiddy K. , Wen Yuqi
Published: May 2024

Tuberculosis and COVID-19 co-infection is currently the major issue of public health in many nations, including Ghana. Therefore, to explore the effects of the two Tuberculosis strains on COVID-19, we suggest a Tuberculosis and COVID-19 co-infection model. The study also provides the most economical and effective control methods to reduce the co-infection of tuberculosis and COVID-19. Based on the behavioral patterns of the two Tuberculosis strains and COVID-19 reproduction numbers, the stability of the co-infection model is examined. We explore the sensitivity of the parameters to examine the effect of the drug-resistant and drug-sensitive strain of Tuberculosis on the co-infection of COVID-19. We determine the most cost-effective and optimal treatment strategies that aim to maximize outcomes while minimizing tuberculosis and/or COVID-19 incidences, cost-effectiveness, and optimization approaches. The outcomes of this work contribute to a better understanding of Tuberculosis and COVID-19 epidemiology and provide insights into implementing interventions needed to minimize Tuberculosis and COVID-19 burden in similar settings worldwide.
Characterization and functional prediction of the dental plaque microbiome in patients with alveolar clefts
Authors: Zhang Yuehua , Zhi Qiang , Shi Jiajun , Jin Zehua , Zhou Zhuojun , Chen Zhenqi
Published: May 2024

Introduction

Alveolar cleft (AC) is a common congenital defect in people with cleft lip and palate (CLP). Alveolar bone grafting (ABG) is typically performed during adolescence, resulting in the fissure remaining in the mouth for a longer length of time. Patients with AC have a greater rate of oral diseases such as dental caries than the normal population, and the precise characteristics of the bacterial alterations caused by AC are unknown.

Methods

We recruited a total of 87 subjects and collected dental plaque samples from AC adolescents (AAP), post-operative ABG adolescents (PAP), healthy control adolescents (CAP), AC young adults (AYP), post-operative ABG young adults (PYP), and healthy control young adults (CYP). The sequencing of 16S rRNA genes was performed.

Results

The microbial composition of plaque from alveolar cleft patients differed significantly from age-matched healthy controls. Linear discriminant analysis effect size (LEfSe) analysis revealed that AAP was enriched for Neisseria, Haemophilus, Fusobacterium, Rhodococcus, Aggregatibacter, Gemella, and Porphyromonas, whereas AYP was enriched for Capnocytophaga, Rhodococcus, and Actinomyces-f0332. There were phenotypic differences in facultatively anaerobic, Gram-negative, Gram-positive, and oxidative stress tolerance between the AYP group with longer alveolar cleft and the healthy control group according to Bugbase phenotypic predictions. Alveolar bone grafting did not alter the functional phenotype of alveolar cleft patients but reduced the number of differential genera between alveolar cleft patients and healthy controls at both ages.

Conclusions

Our study systematically characterized the supragingival plaque microbiota of alveolar cleft patients, post-alveolar bone grafting patients, and matched healthy controls in two ages to gain a better understanding of plaque ecology and microbiology associated with alveolar clefts.
Unique root anatomy of mandibular second premolars: clinical strategies for effective disinfection and preservation of dentine structure in root canal treatment—a case report
Authors: Jeong Ji Wook , Gonzalez Erika Silguero , Makins Scott R. , Kirkpatrick Timothy
Published: May 2024

It is difficult to predict the outcomes of non-surgical root canal treatment (NSRCT) for mandibular second premolars with multiple root canals. In these teeth, the complicated anatomy with fin(s), or a C-shape, and possible secondary canal(s) varies unpredictably. The morphology of the root canals provides shelters for bacteria to remain, regrow, and form biofilms despite the endodontic treatment. Moreover, the prevalence of mandibular second premolars with multiple canals is extremely infrequent. Therefore, the clinical management of NSRCT in such cases is not sufficiently reported. This case report introduces two cases of NSRCT for mandibular second premolars with a radicular groove and also presents the appropriate clinical strategies and techniques. Cone-beam computed tomography (CBCT) imaging was used preoperatively. After the completion of NSRCT, CBCT was reused to review the completed procedures using the Nerve Canal tool in CS 3D Imaging v3.2.9 and v3.8.7. Five canals were obturated in case 1, and four canals in case 2 along with a C-shape morphology. Analyzing the configuration of the root canals by CBCT was critical to achieve successful NSRCT because the numbers, exits, configurations, and volumes of the secondary canals were not anticipated after reviewing 2D radiographs. Based on the interpretation, the advanced protocols of NSRCT were planned: first, augmentation of chemo-mechanical cleaning, but minimizing the loss of dentine; second, the tactile examination to locate and negotiate the orifices of the secondary canals; and lastly, the optimized plan and technique for root canal filling of the complex canal systems.
Physics schemes in the first version of NCEP operational hurricane analysis and forecast system (HAFS)
Authors: Wang Weiguo , Han Jongil , Shin Junghoon , Chen Xiaomin , Hazelton Andrew , Zhu Lin , Kim Hyun-Sook , Li Xu , Liu Bin , Liu Qingfu , Steffen John , Sun Ruiyu , Zheng Weizhong , Zhang Zhan , Yang Fanglin
Published: May 2024

This document summarizes the physics schemes used in two configurations of the first version of the operational Hurricane Analysis and Forecast System (HAFSv1) at NOAA NCEP. The physics package in HAFSv1 is the same as that used in NCEP global forecast system (GFS) version 16 except for an additional microphysics scheme and modifications to sea surface roughness lengths, boundary layer scheme, and the entrainment rate in the deep convection scheme. Those modifications are specifically designed for improving the simulation of tropical cyclones (TCs). The two configurations of HAFSv1 mainly differ in the adopted microphysics schemes and TC-specific modifications in addition to model initialization. Experiments are made to highlight the impacts of TC-specific modifications and different microphysics schemes on HAFSv1 performance. Challenges and developmental plans of physics schemes for future versions of operational HAFS are discussed.
Exploring teachers' understanding and implementation of STEAM: one size does not fit all
Authors: Boice Katherine L. , Alemdar Meltem , Jackson Justina R. , Kessler Talia C. , Choi Jasmine , Grossman Sabrina , Usselman Marion
Published: May 2024

Introduction

In recent years, STEAM (science, technology, engineering, arts, and math) education has become an increasingly popular tool to promote student learning and engagement across disciplines. However, researchers and practitioners continue to note the lack of clarity around definitions of STEAM, its intended purpose, and the nature of discipline integration. In this paper, we explore teachers' understandings and implementation of STEAM as they participated in a teacher professional learning program.

Methods

Using a mixed-methods approach, we analyzed data from 4 years of program implementation with K-12 teachers across multiple schools and districts (n = 61).

Results

Participants' understanding of STEAM was deepened through their involvement in the professional learning program, with many reflecting on their initial, often shallow, (mis)conceptualizations of STEAM. Using an integration continuum developed by the authors, we identified ways in which integration varied across the STEAM lessons teachers developed, contextualizing these findings within the changing educational landscape of the COVID-19 pandemic, as teachers transitioned between remote, hybrid, and in-person instruction. Participants shared their reflections on the personal, professional, and contextual factors that supported and hindered successful STEAM integration.

Discussion

We found that, when provided with sustained, collaborative pedagogical and material support, teachers could successfully improve their understanding of STEAM and implement STEAM lessons tailored to their grade-level and disciplinary context. Our findings reinforce that teachers need support, autonomy, and flexibility to adopt an approach to STEAM integration that best fits their classroom and school context. We discuss the implications of these findings for researchers and practitioners working to provide effective STEAM teacher professional learning.
Early life exposure to vitamin D deficiency impairs molecular mechanisms that regulate liver cholesterol biosynthesis, energy metabolism, inflammation, and detoxification
Authors: Knuth Megan M. , Xue Jing , Elnagheeb Marwa , Gharaibeh Raad Z. , Schoenrock Sarah A. , McRitchie Susan , Brouwer Cory , Sumner Susan J. , Tarantino Lisa , Valdar William , Rector R. Scott , Simon Jeremy M. , Ideraabdullah Folami
Published: May 2024

Introduction

Emerging data suggests liver disease may be initiated during development when there is high genome plasticity and the molecular pathways supporting liver function are being developed.

Methods

Here, we leveraged our Collaborative Cross mouse model of developmental vitamin D deficiency (DVD) to investigate the role of DVD in dysregulating the molecular mechanisms underlying liver disease. We defined the effects on the adult liver transcriptome and metabolome and examined the role of epigenetic dysregulation. Given that the parental origin of the genome (POG) influences response to DVD, we used our established POG model [POG1-(CC011xCC001)F1 and POG2-(CC001xCC011)F1] to identify interindividual differences.

Results

We found that DVD altered the adult liver transcriptome, primarily downregulating genes controlling liver development, response to injury/infection (detoxification & inflammation), cholesterol biosynthesis, and energy production. In concordance with these transcriptional changes, we found that DVD decreased liver cell membrane-associated lipids (including cholesterol) and pentose phosphate pathway metabolites. Each POG also exhibited distinct responses. POG1 exhibited almost 2X more differentially expressed genes (DEGs) with effects indicative of increased energy utilization. This included upregulation of lipid and amino acid metabolism genes and increased intermediate lipid and amino acid metabolites, increased energy cofactors, and decreased energy substrates. POG2 exhibited broader downregulation of cholesterol biosynthesis genes with a metabolomics profile indicative of decreased energy utilization. Although DVD primarily caused loss of liver DNA methylation for both POGs, only one epimutation was shared, and POG2 had 6.5X more differentially methylated genes. Differential methylation was detected at DEGs regulating developmental processes such as amino acid transport (POG1) and cell growth & differentiation (e.g., Wnt & cadherin signaling, POG2).

Conclusions

These findings implicate a novel role for maternal vitamin D in programming essential offspring liver functions that are dysregulated in liver disease. Importantly, impairment of these processes was not rescued by vitamin D treatment at weaning, suggesting these effects require preventative measures. Substantial differences in POG response to DVD demonstrate that the parental genomic context of exposure determines offspring susceptibility.
The effect of epigenetic aging on neurodegenerative diseases: a Mendelian randomization study
Authors: Fan Jingqi , Liu Qing , Liu Xin , Gong Mengjiao , Leong Ian I. , Tsang YauKeung , Xu Xiaoyan , Lei Suying , Duan Lining , Zhang Yifan , Liao Muxi , Zhuang Lixing
Published: May 2024

Background

Aging has always been considered as a risk factor for neurodegenerative diseases, but there are individual differences and its mechanism is not yet clear. Epigenetics may unveil the relationship between aging and neurodegenerative diseases.

Methods

Our study employed a bidirectional two-sample Mendelian randomization (MR) design to assess the potential causal association between epigenetic aging and neurodegenerative diseases. We utilized publicly available summary datasets from several genome-wide association studies (GWAS). Our investigation focused on multiple measures of epigenetic age as potential exposures and outcomes, while the occurrence of neurodegenerative diseases served as potential exposures and outcomes. Sensitivity analyses confirmed the accuracy of the results.

Results

The results show a significant decrease in risk of Parkinson’s disease with GrimAge (OR = 0.8862, 95% CI 0.7914–0.9924, p = 0.03638). Additionally, we identified that HannumAge was linked to an increased risk of Multiple Sclerosis (OR = 1.0707, 95% CI 1.0056–1.1401, p = 0.03295). Furthermore, we also found that estimated plasminogen activator inhibitor-1(PAI-1) levels demonstrated an increased risk for Alzheimer’s disease (OR = 1.0001, 95% CI 1.0000–1.0002, p = 0.04425). Beyond that, we did not observe any causal associations between epigenetic age and neurodegenerative diseases risk.

Conclusion

The findings firstly provide evidence for causal association of epigenetic aging and neurodegenerative diseases. Exploring neurodegenerative diseases from an epigenetic perspective may contribute to diagnosis, prognosis, and treatment of neurodegenerative diseases.
Metabolic predictors of COVID-19 mortality and severity: a survival analysis
Authors: Abdallah Abdallah Musa , Doudin Asmma , Sulaiman Theeb Osama , Jamil Omar , Arif Rida , Sada Fatima Al , Yassine Hadi M. , Elrayess Mohamed A. , Elzouki Abdel-Naser , Emara Mohamed M. , Thillaiappan Nagendra Babu , Cyprian Farhan S.
Published: May 2024

Introduction

The global healthcare burden of COVID-19 pandemic has been unprecedented with a high mortality. Metabolomics, a powerful technique, has been increasingly utilized to study the host response to infections and to understand the progression of multi-system disorders such as COVID-19. Analysis of the host metabolites in response to SARS-CoV-2 infection can provide a snapshot of the endogenous metabolic landscape of the host and its role in shaping the interaction with SARS-CoV-2. Disease severity and consequently the clinical outcomes may be associated with a metabolic imbalance related to amino acids, lipids, and energy-generating pathways. Hence, the host metabolome can help predict potential clinical risks and outcomes.

Methods

In this prospective study, using a targeted metabolomics approach, we studied the metabolic signature in 154 COVID-19 patients (males=138, age range 48-69 yrs) and related it to disease severity and mortality. Blood plasma concentrations of metabolites were quantified through LC-MS using MxP Quant 500 kit, which has a coverage of 630 metabolites from 26 biochemical classes including distinct classes of lipids and small organic molecules. We then employed Kaplan-Meier survival analysis to investigate the correlation between various metabolic markers, disease severity and patient outcomes.

Results

A comparison of survival outcomes between individuals with high levels of various metabolites (amino acids, tryptophan, kynurenine, serotonin, creatine, SDMA, ADMA, 1-MH and carnitine palmitoyltransferase 1 and 2 enzymes) and those with low levels revealed statistically significant differences in survival outcomes. We further used four key metabolic markers (tryptophan, kynurenine, asymmetric dimethylarginine, and 1-Methylhistidine) to develop a COVID-19 mortality risk model through the application of multiple machine-learning methods.

Conclusions

Metabolomics analysis revealed distinct metabolic signatures among different severity groups, reflecting discernible alterations in amino acid levels and perturbations in tryptophan metabolism. Notably, critical patients exhibited higher levels of short chain acylcarnitines, concomitant with higher concentrations of SDMA, ADMA, and 1-MH in severe cases and non-survivors. Conversely, levels of 3-methylhistidine were lower in this context.
Case report: Is severe toxicity the price to pay for high sensitivity to checkpoint inhibitors immunotherapy in desmoplastic melanoma?
Authors: Squicciarini Teresa , Villani Rossella , Apollonio Benedetta , Fucci Livia , Zambetti Milena , Rossini Michele , Pinto Rosamaria , Tommasi Stefania , De Roma Ileana , Strippoli Sabino , Guida Michele
Published: May 2024

Background

Desmoplastic melanoma (DM) is a rare subtype of melanoma characterized by high immunogenicity which makes it particularly suitable for immune checkpoint inhibitors (ICIs) treatment.

Case presentation

We report the case of a 53-year-old man with metastatic DM successfully treated with the combination of anti-CTLA-4 and anti-PD-1 antibodies, who developed serious immune-related adverse events (irAEs). The primary tumor was characterized by absent PD-L1 expression and no-brisk lymphocytes infiltration. NGS showed absence of BRAF mutation, a high tumor mutational burden, and an UV-induced DNA damage signature. Metastatic lesions regressed rapidly after few cycles of ICIs until complete response, however the patient developed serious irAEs including hypothyroidism, adrenal deficiency, and acute interstitial nephritis which led to the definitive suspension of treatment. Currently, the patient has normal renal functionality and no disease relapse after 26 months from starting immunotherapy, and after 9 months from its definitive suspension.

Conclusion

Efficacy and toxicity are two sides of the same coin of high sensitivity to ICIs in DM. For this reason, these patients should be closely monitored during ICIs therapy to promptly identify serious side effects and to correctly manage them.
Low-dose M.tb infection but not BCG or MTBVAC vaccination enhances heterologous antibody titres in non-human primates
Authors: Peralta Alvarez Marco Polo , Jones Holly , Redondo Azema Hugo , Davis Chloe , White Andrew D. , Sarfas Charlotte , Dennis Mike , Li Shuailin , Wright Daniel , Puentes Eugenia , Kimuda Simon , Belij-Rammerstorfer Sandra , Aguilo Nacho , Martin Carlos , Sharpe Sally , McShane Helen , Tanner Rachel
Published: May 2024

Introduction

Mycobacteria are known to exert a range of heterologous effects on the immune system. The mycobacteria-based Freund’s Complete Adjuvant is a potent non-specific stimulator of the immune response used in immunization protocols promoting antibody production, and Mycobacterium bovis Bacille Calmette Guérin (BCG) vaccination has been linked with decreased morbidity and mortality beyond the specific protection it provides against tuberculosis (TB) in some populations and age groups. The role of heterologous antibodies in this phenomenon, if any, remains unclear and under-studied.

Methods

We set out to evaluate antibody responses to a range of unrelated pathogens following infection with Mycobacterium tuberculosis (M.tb) and vaccination with BCG or a candidate TB vaccine, MTBVAC, in non-human primates.

Results

We demonstrate a significant increase in the titer of antibodies against SARS-CoV-2, cytomegalovirus, Epstein-Barr virus, tetanus toxoid, and respiratory syncytial virus antigens following low-dose aerosol infection with M.tb. The magnitude of some of these responses correlated with TB disease severity. However, vaccination with BCG administered by the intradermal, intravenous or aerosol routes, or intradermal delivery of MTBVAC, did not increase antibody responses against unrelated pathogens.

Discussion

Our findings suggest that it is unlikely that heterologous antibodies contribute to the non-specific effects of these vaccines. The apparent dysregulation of B cell responses associated with TB disease warrants further investigation, with potential implications for risk of B cell cancers and novel therapeutic strategies.
Zinc about it – zinc and calf immunity
Authors: Kesler Kathryn W. , Abuelo Angel
Published: May 2024

Micronutrients, such as vitamins and trace minerals, are critical for supporting growth, performance, health and maintaining redox balance. Zinc (Zn), an essential micronutrient, aids the functioning of innate and adaptive immune cells. This scoping review aims to assemble and evaluate the evidence available for the role of Zn within calf immunity. Relevant literature was identified within Web of Science, PubMed, and CABI using search terms specific to the major innate and adaptive immune cell populations. There was no evidence that Zn supplementation altered neutrophil, natural killer cell, or T-cell functions. However, there was limited evidence to support Zn supplementation with reduced monocyte numbers, but there was no evidence to associate the monocytopenia with improvements in monocyte function. There is moderate evidence to suggest that Zn supplementation was beneficial for maintaining epithelial barriers of integumental and mucosal surfaces. The evidence supports supplementation above the current industry recommendations for improving immunoglobulin (Ig) production, with the strongest results being observed for IgG and IgM. Moreover, Zn supplementation was associated with reduced proinflammatory cytokine production, which may reduce inflammation-associated hypophagia and warrants further investigation. Furthermore, Zn reduced the duration of clinical signs in animals facing respiratory disease and diarrhea. However, consensus is needed about the optimal dose, route, and Zn formulation most appropriate for supporting immunity. In conclusion, while the literature supports that Zn could enhance calf immunity, there is insufficient evidence to adequately determine the extent to which Zn impacts innate immune cell and T-cell functions. Determination of the immune cell functions susceptible to modification by Zn supplementation is an important knowledge gap for enhancing the understanding of Zn and calf immunity.
Ascaris suum infection in juvenile pigs elicits a local Th2 response in a setting of ongoing Th1 expansion
Authors: Oser Larissa , Midha Ankur , Schlosser-Brandenburg Josephine , Rausch Sebastian , Mugo Robert M. , Kundik Arkadi , Elizalde-Velázquez Luis E. , Adjah Joshua , Musimbi Zaneta D. , Klopfleisch Robert , Helm Christina S. , von Samson-Himmelstjerna Georg , Hartmann Susanne , Ebner Friederike
Published: May 2024

Ascaris spp. undergo extensive migration within the body before establishing patent infections in the small intestinal tract of humans and pigs. However, whether larval migration is critical for inducing efficient type 2 responses remains poorly understood. Therefore, we investigated systemic versus local adaptive immune responses along the hepato-tracheal migration of Ascaris suum during primary, single infections in conventionally raised pigs. Neither the initial invasion of gut tissue nor migration through the liver resulted in discernable Th2 cell responses. In contrast, lung-stage larvae elicited a Th2-biased pulmonary response, which declined after the larvae had left the lungs. In the small intestine, we observed an accumulation of Th2 cells upon the arrival of fourth-stage larvae (L4) to the small intestinal lumen. In parallel, we noticed robust and increasing Th1 responses in circulation, migration-affected organs, and draining lymph nodes. Phenotypic analysis of CD4+ T cells specifically recognizing A. suum antigens in the circulation and lung tissue of infected pigs confirmed that the majority of Ascaris-specific T cells produced IL-4 (Th2) and, to a much lesser extent, IL-4/IFN-g (Th2/1 hybrids) or IFN-g alone (Th1). These data demonstrate that lung-stage but not the early liver-stage larvae lead to a locally restricted Th2 response. Significant Th2 cell accumulation in the small intestine occurs only when L4 complete the body migration. In addition, Th2 immunity seems to be hampered by the concurrent, nonspecific Th1 bias in growing pigs. Together, the late onset of Th2 immunity at the site of infection and the Th1-biased systemic immunity likely enable the establishment of intestinal infections by sufficiently large L4 stages and pre-adult worms, some of which resist expulsion mechanisms.
Exploring the intersection of epigenetics, DNA repair, and immunology from studies of ICF syndrome, an inborn error of immunity
Authors: Unoki Motoko
Published: May 2024

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, a rare autosomal recessive disorder, manifests with hypoglobulinemia and chromosomal instability accompanied by DNA hypomethylation. Pathological variants in the DNMT3B, ZBTB24, CDCA7, or HELLS genes underlie its etiology. Activated lymphocytes from patients often display distinctive multiradial chromosomes fused via pericentromeric regions. Recent studies have provided deeper insights into how pathological variants in ICF-related proteins cause DNA hypomethylation and chromosome instability. However, the understanding of the molecular pathogenesis underlying immunodeficiency is still in its nascent stages. In the past half-decade, the roles of CDCA7, HELLS, and ZBTB24 in classical non-homologous end joining during double-strand DNA break repair and immunoglobulin class-switch recombination (CSR) have been unveiled. Nevertheless, given the decreased all classes of immunoglobulins in most patients, CSR deficiency alone cannot fully account for the immunodeficiency. The latest finding showing dysregulation of immunoglobulin signaling may provide a clue to understanding the immunodeficiency mechanism. While less common, a subgroup of patients exhibits T-cell abnormalities alongside B-cell anomalies, including reduced regulatory T-cells and increased effector memory T- and follicular helper T-cells. The dysregulation of immunoglobulin signaling in B-cells, the imbalance in T-cell subsets, and/or satellite RNA-mediated activation of innate immune response potentially explain autoimmune manifestations in a subset of patients. These findings emphasize the pivotal roles of ICF-related proteins in both B- and T-cell functions. ICF syndrome studies have illuminated many fundamental mechanisms. Further investigations will certainly continue to unveil additional mechanisms and their interplay.
Hepatitis B-related hepatocellular carcinoma: classification and prognostic model based on programmed cell death genes
Authors: Tian Jinyue , Meng Jiao , Yang Zhenkun , Song Li , Jiang Xinyi , Zou Jian
Published: May 2024

Instruction

Hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Programmed cell death (PCD) is a critical process in suppressing tumor growth, and alterations in PCD-related genes may contribute to the progression of HBV-HCC. This study aims to develop a prognostic model that incorporates genomic and clinical information based on PCD-related genes, providing novel insights into the molecular heterogeneity of HBV-HCC through bioinformatics analysis and experimental validation.

Methods

In this study, we analyzed 139 HBV-HCC samples from The Cancer Genome Atlas (TCGA) and validated them with 30 samples from the Gene Expression Omnibus (GEO) database. Various bioinformatics tools, including differential expression analysis, gene set variation analysis, and machine learning algorithms were used for comprehensive analysis of RNA sequencing data from HBV-HCC patients. Furthermore, among the PCD-related genes, we ultimately chose DLAT for further research on tissue chips and patient cohorts. Besides, immunohistochemistry, qRT-PCR and Western blot analysis were conducted.

Results

The cluster analysis identified three distinct subgroups of HBV-HCC patients. Among them, Cluster 2 demonstrated significant activation in DNA replication-related pathways and tumor-related processes. Analysis of copy number variations (CNVs) of PCD-related genes also revealed distinct patterns in the three subgroups, which may be associated with differences in pathway activation and survival outcomes. DLAT in tumor tissues of HBV-HCC patients is upregulated.

Discussion

Based on the PCD-related genes, we developed a prognostic model that incorporates genomic and clinical information and provided novel insights into the molecular heterogeneity of HBV-HCC. In our study, we emphasized the significance of PCD-related genes, particularly DLAT, which was examined in vitro to explore its potential clinical implications.
The effects of turbulence on the growth of three different diatom species
Authors: Liu Yijing , Yu Lin , Yao Zhongzhi , Shen Yunwen , Pan Yiwen
Published: May 2024

The effects of turbulence on phytoplankton growth have received considerable attentions. However, the complexity of turbulence poses a significant challenge to its systematic characterization in the laboratory, resulting in relatively limited data on the effects of turbulence on several algal species. Here, a laboratory turbulence simulation system was set up to systematically investigate the growth of three common diatom species (Thalassiosira pseudonana, Skeletonema costatum, and Phaeodactylum tricornutum) under stationary and turbulent conditions (at 60, 120, 180 rpm), and measurements were taken for the algal biomass, algal photosynthetic activity, and nutrients consumption. By comparing the growth of three algae species under different turbulence exposure intensities, this study found that different algae exhibit varying sensitivities to turbulence, and therefore have different shear thresholds. Meanwhile, cell morphology is the key factor influencing the different shear threshold values observed in the three diatom species. Additionally, turbulence could impact algal aggregation and light availability, and dramatically improve nutrient uptake by phytoplankton. Our study will provides theoretical support for future endeavors in using turbulence to cultivate phytoplankton or combat algal blooms.
The biobehavioural pain and movement questionnaire (BioPMovQ): development and psychometric validation of a new questionnaire
Authors: La Touche Roy , Paris-Alemany Alba , Pardo-Montero Joaquín , Miñambres-Martín Diego , Mercado-Romero Francisco , de la Rosa-Díaz Irene , Sorrel Miguel A. , Grande-Alonso Mónica
Published: May 2024

Objective

The purpose of this research was to design and psychometrically validate a new instrument (the Biobehavioural Pain and Movement Questionnaire/BioPMovQ), which assesses the relationship between pain and various factors related to motor behaviour from a biobehavioural perspective.

Methods

A mixed-method design combining a qualitative study with an observational and cross-sectional study was employed to develop (content validity) and psychometrically validate (construct validity, reliability and concurrent/discriminant validity) a new instrument. A total of 200 patients with chronic musculoskeletal pain were recruited.

Results

According to the exploratory factor analysis, the final version of the BioPMovQ consists of 16 items distributed across 4 subscales (1, disability, 2, self-efficacy for physical activity; 3, movement avoidance behaviours; and 4, self-perceived functional ability), all with an eigen value greater than 1, explaining 55.79% of the variance. The BioPMovQ showed high internal consistency (Cronbach’s α = 0.82; McDonald’s ω = 0.83). The intraclass correlation coefficient was 0.86 (95% confidence interval 0.76 to 0.91), which was considered to demonstrate excellent test–retest reliability. The standard error of measurement and minimal detectable change were 3.43 and 8.04 points, respectively. No floor or ceiling effects were identified. There was a positive, significant and moderate magnitude correlation with the Graded Chronic Pain Scale (r = 0.54), kinesiophobia (r = 0.60), pain catastrophising (r = 0.44) and chronic pain self-efficacy (r = −0.31).

Conclusion

The BioPMovQ showed good psychometric properties. Based on the findings of this study, the BioPMovQ can be used in research and clinical practice to assess patients with chronic musculoskeletal pain.
Friends or foes? Novel antimicrobials tackling MDR/XDR Gram-negative bacteria: a systematic review
Authors: Dan Mihai Octavian , Tǎlǎpan Daniela
Published: May 2024

Gram-negative bacteria have been one of the most studied classes in the field of microbiology, especially in the context of globally alarming antimicrobial resistance levels to these pathogens over the course of the past decades. With high numbers of these microorganisms being described as multidrug-resistant (MDR), or even extended-drug-resistant (XDR) bacteria, specialists in the field have been struggling to keep up with higher prevalence of difficult-to-treat infections caused by such superbugs. The FDA approval of novel antimicrobials, such as cefiderocol (FDC), ceftolozane/tazobactam (C/T), ceftazidime/avibactam (CZA), imipenem/relebactam (IMR), sulbactam/durlobactam (SUL-DUR) and phase 3 clinical trials’ results of aztreonam/avibactam (ATM-AVI) has proven that, while all these substances provide encouraging efficacy rates, antibiotic resistance keeps up with the pace of drug development. Microorganisms have developed more extensive mechanisms of resistance in order to target the threat posed by these novel antimicrobials, thus equiring researchers to be on a constant lookout for other potential drug candidates and molecule development. However, these strategies require a proper understanding of bacterial resistance mechanisms to gain a comprehensive outlook on the issue. The present review aims to highlight these six antibiotic agents, which have brought hope to clinicians during the past decade, discussing general properties of these substances, as well as mechanisms and patterns of resistance, while also providing a short overview on further directions in the field.

Systematic review registration

https://www.crd.york.ac.uk/prospero/#searchadvanced, Identifier CRD42024505832.
Development of a triplex quantitative reverse transcription-polymerase chain reaction for the detection of porcine epidemic diarrhea virus, porcine transmissible gastroenteritis virus, and porcine rotavirus A
Authors: Luo Tingyu , Li Kaili , Li Changwen , Xia Changyou , Gao Caixia
Published: May 2024

Porcine viral diarrhea is caused by many pathogens and can result in watery diarrhea, dehydration and death. Various detection methods, such as polymerase chain reaction (PCR) and real-time quantitative PCR (qPCR), have been widely used for molecular diagnosis. We developed a triplex real-time quantitative reverse transcription PCR (qRT-PCR) for the simultaneous detection of three RNA viruses potentially associated with porcine viral diarrhea: porcine epidemic diarrhea virus (PEDV), porcine transmissible gastroenteritis virus (TGEV), and porcine rotavirus A (PoRVA). The triplex qRT-PCR had R2 values of 0.999 for the standard curves of PEDV, TGEV and PoRVA. Importantly, the limits of detection for PEDV, TGEV and PoRVA were 10 copies/μL. The specificity test showed that the triplex qRT-PCR detected these three pathogens specifically, without cross-reaction with other pathogens. In addition, the approach had good repeatability and reproducibility, with intra-and inter-assay coefficients of variation <1%. Finally, this approach was evaluated for its practicality in the field using 256 anal swab samples. The positive rates of PEDV, TGEV and PoRVA were 2.73% (7/256), 3.91% (10/256) and 19.14% (49/256), respectively. The co-infection rate of two or more pathogens was 2.73% (7/256). The new triplex qRT-PCR was compared with the triplex RT-PCR recommended by the Chinese national standard (GB/T 36871-2018) and showed 100% agreement for PEDV and TGEV and 95.70% for PoRVA. Therefore, the triplex qRT-PCR provided an accurate and sensitive method for identifying three potential RNA viruses for porcine viral diarrhea that could be applied to diagnosis, surveillance and epidemiological investigation.