bluuebunny/crossref_metadata_2025_split huggingface dataset:
A RUNX1-FPDMM rhesus macaque model reproduces the human phenotype and predicts challenges to curative gene therapies
Authors: Lee Byung-Chul , Zhou Yifan , Bresciani Erica , Ozkaya Neval , Dulau-Florea Alina , Carrington Blake , Shin Tae-Hoon , Baena Valentina , Syed Zulfeqhar A. , Hong So Gun , Zhen Tao , Calvo Katherine R. , Liu Paul , Dunbar Cynthia E. 
Published: November 2022

Abstract
Germ line loss-of-function heterozygous mutations in the RUNX1 gene cause familial platelet disorder with associated myeloid malignancies (FPDMM) characterized by thrombocytopenia and a life-long risk of hematological malignancies. Although gene therapies are being considered as promising therapeutic options, current preclinical models do not recapitulate the human phenotype and are unable to elucidate the relative fitness of mutation-corrected and RUNX1-heterozygous mutant hematopoietic stem and progenitor cells (HSPCs) in vivo long term. We generated a rhesus macaque with an FPDMM competitive repopulation model using CRISPR/Cas9 nonhomologous end joining editing in the RUNX1 gene and the AAVS1 safe-harbor control locus. We transplanted mixed populations of edited autologous HSPCs and tracked mutated allele frequencies in blood cells. In both animals, RUNX1-edited cells expanded over time compared with AAVS1-edited cells. Platelet counts remained below the normal range in the long term. Bone marrows developed megakaryocytic dysplasia similar to human FPDMM, and CD34+ HSPCs showed impaired in vitro megakaryocytic differentiation, with a striking defect in polyploidization. In conclusion, the lack of a competitive advantage for wildtype or control-edited HSPCs over RUNX1 heterozygous–mutated HSPCs long term in our preclinical model suggests that gene correction approaches for FPDMM will be challenging, particularly to reverse myelodysplastic syndrome/ acute myeloid leukemia predisposition and thrombopoietic defects.
Germ lineDDX41mutations define a unique subtype of myeloid neoplasms
Authors: Makishima Hideki , Saiki Ryunosuke , Nannya Yasuhito , Korotev Sophia , Gurnari Carmelo , Takeda June , Momozawa Yukihide , Best Steve , Krishnamurthy Pramila , Yoshizato Tetsuichi , Atsuta Yoshiko , Shiozawa Yusuke , Iijima-Yamashita Yuka , Yoshida Kenichi , Shiraishi Yuichi , Nagata Yasunobu , Kakiuchi Nobuyuki , Onizuka Makoto , Chiba Kenichi , Tanaka Hiroko , Kon Ayana , Ochi Yotaro , Nakagawa Masahiro M. , Okuda Rurika , Mori Takuto , Yoda Akinori , Itonaga Hidehiro , Miyazaki Yasushi , Sanada Masashi , Ishikawa Takayuki , Chiba Shigeru , Tsurumi Hisashi , Kasahara Senji , Müller-Tidow Carsten , Takaori-Kondo Akifumi , Ohyashiki Kazuma , Kiguchi Toru , Matsuda Fumihiko , Jansen Joop H. , Polprasert Chantana , Blombery Piers , Kamatani Yoichiro , Miyano Satoru , Malcovati Luca , Haferlach Torsten , Kubo Michiaki , Cazzola Mario , Kulasekararaj Austin G. , Godley Lucy A. , Maciejewski Jaroslaw P. , Ogawa Seishi 
Published: November 2022

AbstractGerm line DDX41 variants have been implicated in late-onset myeloid neoplasms (MNs). Despite an increasing number of publications, many important features of DDX41-mutated MNs remain to be elucidated. Here we performed a comprehensive characterization of DDX41-mutated MNs, enrolling a total of 346 patients with DDX41 pathogenic/likely-pathogenic (P/LP) germ line variants and/or somatic mutations from 9082 MN patients, together with 525 first-degree relatives of DDX41-mutated and wild-type (WT) patients. P/LP DDX41 germ line variants explained ∼80% of known germ line predisposition to MNs in adults. These risk variants were 10-fold more enriched in Japanese MN cases (n = 4461) compared with the general population of Japan (n = 20 238). This enrichment of DDX41 risk alleles was much more prominent in male than female (20.7 vs 5.0). P/LP DDX41 variants conferred a large risk of developing MNs, which was negligible until 40 years of age but rapidly increased to 49% by 90 years of age. Patients with myelodysplastic syndromes (MDS) along with a DDX41-mutation rapidly progressed to acute myeloid leukemia (AML), which was however, confined to those having truncating variants. Comutation patterns at diagnosis and at progression to AML were substantially different between DDX41-mutated and WT cases, in which none of the comutations affected clinical outcomes. Even TP53 mutations made no exceptions and their dismal effect, including multihit allelic status, on survival was almost completely mitigated by the presence of DDX41 mutations. Finally, outcomes were not affected by the conventional risk stratifications including the revised/molecular International Prognostic Scoring System. Our findings establish that MDS with DDX41-mutation defines a unique subtype of MNs that is distinct from other MNs.
FBXW7β isoform drives transcriptional activation of the proinflammatory TNF cluster in human pro-B cells
Authors: Yang Scarlett Y. , Hayer Katharina E. , Fazelinia Hossein , Spruce Lynn A. , Asnani Mukta , Black Kathryn L. , Naqvi Ammar S. , Pillai Vinodh , Barash Yoseph , Elenitoba-Johnson Kojo S. J. , Thomas-Tikhonenko Andrei 
Published: November 2022

Abstract
Noncanonical exon usage plays many important roles in cellular phenotypes, but its contribution to human B-cell development remains sketchily understood. To fill this gap, we collected various B-cell fractions from bone marrow (BM) and tonsil donors, performed RNA sequencing, and examined transcript variants. We identified 150 genes that harbor local splicing variations in all pairwise comparisons. One of them encodes FBXW7, an E3 ubiquitin ligase implicated as a driver in several blood cancers. Surprisingly, we discovered that in normal human pro-B cells, the predominant transcript used an alternative first exon to produce the poorly characterized FBXW7β isoform, previously thought to be restricted to neural tissues. The FBXW7β transcript was also abundant in cell lines and primary samples of pediatric B-cell acute lymphoblastic leukemia (B-ALL), which originates in the BM. When overexpressed in a heterologous cell system, this transcript yielded the expected protein product, as judged by anti-FLAG immunoblotting and mass spectrometry. Furthermore, in REH B-ALL cells, FBXW7β mRNA was the only FBXW7 isoform enriched in the polyribosome fraction. To shed light on possible functions of FBXW7β, we used gain- and loss-of-function approaches and identified an FBXW7-dependent inflammatory gene signature, apparent in a subset of B-ALL with high FBXW7β expression. This signature contained several members of the tumor necrosis factor superfamily, including those comprising the HLA Class III cluster (LTB, LST1, NCR3, LTA, and NFKBIL1). Our findings suggest that FBXW7β expression drives proinflammatory responses, which could contribute to normal B-cell development, leukemogenesis, and responses to anticancer therapies.
Prognostic factors for mortality, intensive care unit and hospital admission due to SARS-CoV-2: a systematic review and meta-analysis of cohort studies in Europe
Authors: Vardavas Constantine I. , Mathioudakis Alexander G. , Nikitara Katerina , Stamatelopoulos Kimon , Georgiopoulos Georgios , Phalkey Revati , Leonardi-Bee Jo , Fernandez Esteve , Carnicer-Pont Dolors , Vestbo Jørgen , Semenza Jan C. , Deogan Charlotte , Suk Jonathan E. , Kramarz Piotr , Lamb Favelle , Penttinen Pasi 
Published: November 2022

BackgroundAs mortality from coronavirus disease 2019 (COVID-19) is strongly age-dependent, we aimed to identify population subgroups at an elevated risk for adverse outcomes from COVID-19 using age-/gender-adjusted data from European cohort studies with the aim to identify populations that could potentially benefit from booster vaccinations.MethodsWe performed a systematic literature review and meta-analysis to investigate the role of underlying medical conditions as prognostic factors for adverse outcomes due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including death, hospitalisation, intensive care unit (ICU) admission and mechanical ventilation within three separate settings (community, hospital and ICU). Cohort studies that reported at least age and gender-adjusted data from Europe were identified through a search of peer-reviewed articles published until 11 June 2021 in Ovid Medline and Embase. Results are presented as odds ratios with 95% confidence intervals and absolute risk differences in deaths per 1000 COVID-19 patients.FindingsWe included 88 cohort studies with age-/gender-adjusted data from 6 653 207 SARS-CoV-2 patients from Europe. Hospital-based mortality was associated with high and moderate certainty evidence for solid organ tumours, diabetes mellitus, renal disease, arrhythmia, ischemic heart disease, liver disease and obesity, while a higher risk, albeit with low certainty, was noted for chronic obstructive pulmonary disease and heart failure. Community-based mortality was associated with a history of heart failure, stroke, diabetes and end-stage renal disease. Evidence of high/moderate certainty revealed a strong association between hospitalisation for COVID-19 and solid organ transplant recipients, sleep apnoea, diabetes, stroke and liver disease.InterpretationThe results confirmed the strong association between specific prognostic factors and mortality and hospital admission. Prioritisation of booster vaccinations and the implementation of nonpharmaceutical protective measures for these populations may contribute to a reduction in COVID-19 mortality, ICU and hospital admissions.
Recurrent headache and visual symptoms in a young man: a rare neuronal intranuclear inclusion disease case report
Authors: Su Ning , Mao He-Jiao , Mao Chen-Hui , Cui Li-Ying , Zhu Yi-Cheng , Zhou Yan , Ni Jun 
Published: November 2022

Abstract
Background
Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease. Patients with NIID may present with heterogeneous clinical symptoms, including episodic encephalopathy, dementia, limb weakness, cerebellar ataxia, and autonomic dysfunction. Among the NIID cases reported in China, patients often have complicated and severe manifestations. Therefore, many clinicians do not consider the disease when the patient presents with relatively minor complaints.

Case presentation
We present the case of a 39-year-old man showing migraine-aura-like symptoms for the past 3 years. Brain magnetic resonance imaging (MRI) revealed hyperintense signals in the splenium of the corpus callosum and corticomedullary junction on diffusion-weighted imaging (DWI) over time. In addition, brain atrophy that was not concomitant with the patient’s age was detected while retrospectively reviewing the patient’s imaging results. Genetic analysis and skin biopsy confirmed a diagnosis of NIID. The patient was treated with sibelium, and the symptoms did not recur.

Discussion and Conclusions
Migraine-aura-like symptoms may be the predominant clinical presentation in young patients with NIID. Persistent high-intensity signals on DWI in the brain and early-onset brain atrophy might be clues for the diagnosis of NIID.
Secundiparas following a failed vacuum delivery—factors associated with a successful vaginal delivery: a historical prospective cohort
Authors: Reichman Orna , Ehrlich Zvi , Suday Ramy , Sela Hen , Gold Gila , Samueloff Arnon , Grisaru-Granovsky Sorina 
Published: November 2022

Abstract
Background
Few studies have focused on the delivery subsequent to a failed vacuum delivery (failed-VD) in secundiparas. The objective of the current study was to examine the factors associated with a vaginal delivery following a failed-VD.

Methods
An historical prospective cohort. Obstetric characteristics of secundiparas who underwent a planned caesarean delivery (CD) were compared to those who elected a trial of labour (TOLAC) at single medical-centre, throughout 2006–2019. The latter were further analysed to study for factures associated with successful vaginal birth (VBAC).

Results
Among the 115 secundiparas included, 89 (77%) underwent TOLAC. Compared to women who underwent an elective CD, those who underwent TOLAC were younger by a mean of 4 years, were more likely to have conceived spontaneously, and had a more advanced gestation by a mean of 10 days. VBAC was achieved in 62 women (70%). New-borns of women with VBAC had in average a lower birth weight compared to those with failed TOLAC, (-)195 g ± 396 g versus ( +)197 g ± 454 g respectively, P < 0.01. Having a higher neonatal birthweight at P2 by increments of 500 g, 400 g or 300 g was associated with a failed TOLAC; OR of 9.7 (95%CI; 2.3, 40.0), 11.5 (95%CI; 2.8, 46.7) and 4.5 (95%CI; 1.4, 13.9), respectively.

Conclusions
Among secundiparas with a previous CD due to a failed-VD, the absolute difference of neonatal BW was found to be significantly associated with achieving VBAC.
Utilization of health belief model in comprehending diarrheal disease dynamics: a case of cryptosporidiosis in Uganda
Authors: Kankya Clovice , Okello Justine , Wambi Rogers , Ninsiima Lesley Rose , Tubihemukama Methodius , Kulabako Christine Tricia , Asaba Richard , Baguma James Natweta , Munyeme Musso , Muleme James 
Published: November 2022

Abstract
Background
Diarrheal diseases contribute greatly to the reported global childhood mortality and morbidity with related social, economic consequences. This study was conducted to analyze the utilization of the Health Belief Model (HBM) theory to comprehend diarrheal disease dynamics in Uganda.

Methods
Our study utilized a qualitative cross-sectional design among adult livestock farmers in selected farming communities. A total of 80 individuals were recruited and interviewed through Focus Discussion Groups (FDGs) (n = 6) and Key Informant Interviews (KIIs) (n = 8) to evaluate diarrheal disease dynamics. The scope of dynamics included but not limited to exposure risks, knowledge, and attitudes. Our results were presented using the five (5) constructs of the HBM.

Results
Perceived susceptibility; communities believed that both humans and their animals are at high risk of different kinds of diarrheal infections. The farmers believed that majority of these diarrhea infections are hard to treat especially among animals. Perceived severity; farmers believed that diarrheal diseases are characterized by loss of weight, fever, emaciation, dry eyes, severe prolonged diarrhea and sudden death. Perceived barriers; limited knowledge and misconceptions about the diarrheal infections were great inhibitors to successful disease prevention and control. Self-efficacy; farmers had fear of laxity that interventions being suggested and put in place to curb diarrheal diseases such as cryptosporidiosis would wither away with time thus endemicity of the problem in the community. Modifying factors and cues to action; most of the farmers treat animals by themselves based on; probability, traditional knowledge and previous experience.

Conclusion
Sustained public health interventional activities should therefore be undertaken by both human and animal health sectors with maximum community involvement. Communities suggested the need to increase preventive measures and promote household hygiene efforts to always wash hands with soap and running water in order to reduce the burden of diarrhea diseases such as cryptosporidiosis.
Nutritional deficiency induces nucleus pulposus cell apoptosis via the ATF4-PKM2-AKT signal ﻿axis
Authors: Zhou Ningfeng , Shen Bin , Bai Chong , Ma Liang , Wang Shanjin , Wu Desheng 
Published: November 2022

Abstract
Background
The intervertebral disc is the largest avascular tissue in the human body. The nucleus pulposus (NP) consumes glucose and oxygen to generate energy to maintain cellular metabolism via nutrients that diffuse from the cartilage endplate. The microenvironment in the intervertebral disc becomes nutritionally deficient during degeneration, and nutritional deficiency has been shown to inhibit the viability and proliferation of NP cells.

Methods
To investigate the molecular mechanism by which nutritional deficiency reduces viability and decreases proliferation, we created an in vitro model by using decreasing serum concentration percentages.

Results
In this study, we found that nutritional deficiency reduced NP cell viability and increased cell apoptosis and that the upregulation of ATF4 expression and the downregulation of PKM2 expression were involved in this process. Moreover, we found that PKM2 inhibition can reduce the cell apoptosis induced by ATF4 silence under nutritional deficiency.

Conclusion
Our findings revealed that PKM2 inhibition reduces the cell apoptosis induced by ATF4 silence under nutritional deficiency by inhibiting AKT phosphate. Revealing the function and mechanism of NP cell development under nutritional deficiency will provide new insights into the etiology, diagnosis, and treatment of intervertebral disc and related diseases.
Magnitude of diabetic peripheral neuropathy in Saudi Arabia: a systematic review and meta-analysis
Authors: Owolabi Lukman Femi , Alghamdi Mushabab , Adamu Bappa , Taura Magaji Garba , Jibo Abubakar , Almansour Mohammed , Alaklabi Saeed Naseer , Alghamdi Mohammed Ali , Alotaibi Yousef Ayesh , Imam Isa Adamu , Abdelrazak Reda , Rafaat Ahmad , Aliyu Muktar Hassan 
Published: November 2022

AbstractBackgroundDiabetic peripheral neuropathy (DPN), due to its potential for causing morbidity and disability from foot ulcers and amputations, is increasingly becoming a source of concern in Saudi Arabia and worldwide. However, wide variability exists in the prevalence of DPN reported in previous studies in Saudi Arabia, limiting the utility of existing data in national public health policy. Therefore, the aim of this study was to systematically evaluate the magnitude of DPN in patients living with DM in Saudi Arabia in order to inform policymakers during the implementation of appropriate preventive and treatment strategies for DPN.MethodsPubMed, Google Scholar, African Journals Online, Scopus, Web of Science, Embase, and Wiley Online Library were searched systematically to acquire relevant articles based on preset criteria. We evaluated heterogeneity and publication bias and employed a random-effects model to estimate the pooled prevalence of DPN from the included studies. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in conducting the meta-analysis. Analysis was performed using the STATA Version 12 software.ResultsTwelve studies with a total of 4,556 participants living with DM, of whom 2,081 were identified as having DPN were included in the meta-analysis. The overall prevalence of DPN was 39% (95% CI [30%, 49%]). Subgroup analysis based on diagnostic method showed that prevalence estimates for DPN using screening questionnaires and clinical examination were 48% (95% CI [46%, 50%]) and 40% (95% CI: [38%, 42%]), respectively, while the estimated prevalence using nerve conduction studies was 26% (95% CI [15%, 36%]).ConclusionThis study showed a high magnitude of DPN in Saudi Arabia (39%), thus highlighting the need for sustained efforts to reduce the prevalence of diabetes mellitus and DPN in the kingdom.
The work-related stress experienced by registered nurses at municipal aged care facilities during the COVID-19 pandemic: a qualitative interview study
Authors: Arén Cilmara , Jaçelli Armand , Gesar Berit , From Ingrid 
Published: November 2022

Abstract
Background
Stress can originate from many different unsatisfying work situations. Registered nurses working in municipal care have experience of work-related stress in different ways.

Aim
The purpose of this study was to describe the work-related stress experienced by registered nurses caring for older people at municipal aged care facilities.

Methods
Qualitative semi-structured interviews according to Polit and Beck were carried out in clinical work at six different municipal aged care facilities in Sweden. Twelve registered nurses participated in the study.

Results
The results outlined in one main central theme: Feelings of inadequacy and dissatisfaction contribute to work-related stress and three categories: Difficulty coping with work tasks, Insufficient support, Work-related stress affects private lives. Areas identified were lack of time, staff shortages, high number of patients, lack of communication and teamwork in the working group, showing that inadequacy and dissatisfaction can contribute to work-related stress. This can contribute to work-related stress, and it can be a result of problems in the organizational and social work environment.

Conclusion
This study showed the everyday experiences of registered nurses’ stress at work. The reasons that registered nurses experience a heavy workload were found to be similar in several municipal care facilities. Future interventions should consider the areas of stress found in this study to reduce the risk of further increasing the work-related stress experienced by registered nurses working in municipal aged care.
Factors associated with formal and informal resource utilization in nursing home patients with and without dementia: cross-sectional analyses from the COSMOS trial
Authors: Vislapuu Maarja , Berge Line Iden , Angeles Renira C. , Kjerstad Egil , Mannseth Janne , Achterberg Wilco P. , Husebo Bettina S. 
Published: November 2022

Abstract
Objectives
To investigate the association between clinical, demographic, and organizational factors and formal (health professionals) and informal (relatives) resource utilization in nursing home patients with and without dementia.

Methods
Baseline data from the multicomponent cluster randomized control COSMOS trial including 33 Norwegian nursing homes and 723 residents with and without dementia. Nursing home staff (n = 117) participated as proxy raters to approximate formal and informal resource use in daily care.

Measurements
The primary outcome was the Resource Utilization in Dementia - Formal Care scale to assess formal and informal care time in hours/month regarding basic activities of daily living (ADL), instrumental ADL, and supervision. Secondary outcomes were hours/week spent on formal and informal leisure activities. Behavioral and psychological symptoms in dementia (BPSD) were assessed by the Neuropsychiatric Inventory-Nursing Home version, physical function by the Physical Self-Maintenance Scale, and psychotropic drug use by the Anatomical Therapeutic Chemical classification system. Organizational factors were ward size and staff ratio.

Results
Generalized linear mixed-effect models and two-part modelling revealed an association between increased formal care time and poorer physical function, higher agitation and psychotropic drug use and lower cognitive function (all p < .05). Enhanced formal leisure time was related to better ADL function (p < .05) and smaller wards (p < .05). The family related leisure time was associated with agitation, decline in ADL function, smaller wards, and better staffing ratio (all p < .05). Married patients received more informal direct care (p < .05) and leisure time (p < .05) compared to unmarried/widowed.

Conclusion
For nursing home staff, higher agitation and psychotropic drug use, and lower cognitive function, is associated with more direct care time, whereas leisure time activities are less prioritized in people with lower physical function. Informal caregivers’ engagement is encouraged by smaller nursing homes and better staff ratio. Therefore, we recommend stakeholders and healthcare professionals to consider these clinical and organizational factors to optimize treatment and leisure time activities in nursing home patients with various needs.

Trial registration
ClinicalTrials.gov; NCT02238652.