bluuebunny/crossref_metadata_2025_split huggingface dataset:
Splicing factor gene mutations in acute myeloid leukemia offer additive value if incorporated in current risk classification
Authors: van der Werf Inge , Wojtuszkiewicz Anna , Meggendorfer Manja , Hutter Stephan , Baer Constance , Heymans Martijn , Valk Peter J. M. , Kern Wolfgang , Haferlach Claudia , Janssen Jeroen J. W. M. , Ossenkoppele Gert J. , Cloos Jacqueline , Haferlach Torsten 
Published: August 2021

AbstractSplicing factor (SF) mutations are important contributors to the pathogenesis of hematological malignancies; however, their relevance in risk classification of acute myeloid leukemia (AML) warrants further investigation. To gain more insight into the characteristics of patients with AML carrying SF mutations, we studied their association with clinical features, cytogenetic and molecular abnormalities, and clinical outcome in a large cohort of 1447 patients with AML and high-risk myelodysplastic syndrome. SF mutations were identified in 22% of patients and were associated with multiple unfavorable clinical features, such as older age, antecedent myeloid disorders, and adverse risk factors (mutations in RUNX1 and ASXL1). Furthermore, they had significantly shorter event-free and overall survival. Notably, in European LeukemiaNet (ELN) 2017 favorable- and intermediate-risk groups, SF3B1 mutations were indicative of relatively poor prognosis. In addition, patients carrying concomitant SF mutations and RUNX1 mutations had a particularly adverse prognosis. In patients without any of the 4 most common SF mutations, RUNX1 mutations were associated with relatively good outcome, which was comparable to that of intermediate-risk patients. In this study, we propose that SF mutations be considered for incorporation into prognostic classification systems. First, SF3B1 mutations could be considered an intermediate prognostic factor when co-occurring with favorable risk features and as an adverse prognostic factor for patients currently categorized as having intermediate risk, according to the ELN 2017 classification. Second, the prognostic value of the current adverse factor RUNX1 mutations seems to be limited to its co-occurrence with SF mutations.
Alterations of structural connectivity and structural co-variance network in focal cortical dysplasia
Authors: Lee Dong Ah , Lee Ho-Joon , Kim Hyung Chan , Park Kang Min 
Published: August 2021

Abstract
Background
The aim of this study was to investigate alterations in structural connectivity and structural co-variance network in patients with focal cortical dysplasia (FCD).

Methods
We enrolled 37 patients with FCD and 35 healthy controls. All subjects underwent brain MRI with the same scanner and with the same protocol, which included diffusion tensor imaging (DTI) and T1-weighted imaging. We analyzed the structural connectivity based on DTI, and structural co-variance network based on the structural volume with T1-weighted imaging. We created a connectivity matrix and obtained network measures from the matrix using the graph theory. We tested the difference in network measure between patients with FCD and healthy controls.

Results
In the structural connectivity analysis, we found that the local efficiency in patients with FCD was significantly lower than in healthy controls (2.390 vs. 2.578, p = 0.031). Structural co-variance network analysis revealed that the mean clustering coefficient, global efficiency, local efficiency, and transitivity were significantly decreased in patients with FCD compared to those in healthy controls (0.527 vs. 0.635, p = 0.036; 0.545 vs. 0.648, p = 0.026; 2.699 vs. 3.801, p = 0.019; 0.791 vs. 0.954, p = 0.026, respectively).

Conclusions
We demonstrate that there are significant alterations in structural connectivity, based on DTI, and structural co-variance network, based on the structural volume, in patients with FCD compared to healthy controls. These findings suggest that focal lesions with FCD could affect the whole-brain network and that FCD is a network disease.
Estimating the burden of pediatric HIV in an ‘A’ category district in India: an epidemiological study
Authors: Sinha Anju , Washington Reynold , Sethumadhavan Rajeev , Potty Rajaram Subramanian , Isac Shajy , Thavraj Vasantha , Pandey Ravindra Mohan 
Published: August 2021

Abstract
Background
India lacks epidemiological information on the disease burden of pediatric HIV. The National AIDS Control Program (NACP) estimates the numbers of HIV-positive children as a proportion of adult persons living with HIV. A third of HIV-positive children die before their first birthday and a half before they reach their second birthday. The early detection of HIV is crucial for the prevention of morbidities, growth delays, and death among HIV-positive children.

Methods
The study aimed to estimate the disease burden of pediatric HIV among children in ‘A’ category district of a high HIV prevalence state. An ‘A’ category district is defined by the presence of > 1% HIV prevalence among the general population, as estimated by HIV Sentinel Surveillance. The study used an innovative three-pronged strategy combining cross-sectional and longitudinal methods. The overall burden of pediatric HIV was calculated as a product of cases detected multiplied by a net inflation factor, for each of three strategies.

Results
The existing pool of HIV infection in the district is estimated to be 3266 (95% CI: 2621–4197) HIV positive children < 15 years of age, in a mid-year (2013) projected child population of about 1.4 million, thus giving an HIV prevalence of 0.23% (CI: 0.19–0.30) among children (0–14 years of age). The proportion of children among all people living with HIV in the district works out to 10.4% (CI: 8.6–13.5%).

Conclusions
The study estimate of 0.23% HIV prevalence among children (0–14 years of age) is higher than the NACP estimates (0.02) and is 2.5 higher than the Karnataka state estimate (0.09)22. Similarly, the proportion of children among all persons living with HIV in Belgaum district is 10.4% in this study, as against 6.54% for India. The study methodology is replicable for other settings and other diseases.
Anti-allergic activities of Umbelliferone against histamine- and Picryl chloride-induced ear edema by targeting Nrf2/iNOS signaling in mice
Authors: Younas  , Khan Ashrafullah , Shehzad Omer , Seo Eun Kyoung , Onder Alev , Khan Salman 
Published: August 2021

Abstract
Background
The current study was aimed to investigate the anti-allergic activities of the Umbelliferone (UMB) against the acute Histamine and chronic Picryl chloride (PiCl)-induced allergy in mice. UMB is a coumarin derivative (isolated from Angelica decursiva) found in various parts of the plants such as flowers, roots and, stems isolated from the plants of Umbelliferae family.

Methods
The UMB (1, 10, 50 mg/kg) was administered intraperitoneally (i.p) half an h before or 2 h after the induction of allergic ear edema. The acute ear edema was induced by histamine (intradermally, i.d), while the chronic ear edema was induced by painting the PiCl (sensitized with the toluene) on the ear. The antioxidants and oxidative stress markers were assessed. The histological changes were assessed using Hematoxylin and eosin (H and E) and giemsa staining. The immunohistochemistry studies were performed to assess the expression of the nuclear factor erythroid 2-related factor 2 (Nrf2) and inducible nitric oxide synthase (iNOS). The data was analyzed using one-way ANOVA tests followed by Tukey’s test with p < 0.05 was chosen as criteria for statistical significance.

Results
UMB treatment markedly reduced the allergic ear edema and ear weight compared to the negative control. Furthermore, the UMB attenuated the oxidative stress markers, while induced the antioxidants enzymes. Similarly, the UMB treatment significantly attenuated the serum immunoglobulin E (IgE) level. The UMB treatment markedly improved the histological parameters using H and E staining and Giemsa staining. The UMB administration induced the Nrf2 expression, while attenuated the iNOS expression. Furthermore, the computational analysis was performed to assess the interaction of the UMB with the various protein targets and to determine the mechanism of interaction with the target proteins.

Conclusion
In conclusion, the UMB treatment significantly alleviated the allergic symptoms, attenuating the oxidative stress, improved the histological features using in vivo and computational approaches.
Developing a hospital accreditation model: a Delphi study
Authors: Mosadeghrad Ali Mohammad , Ghazanfari Fatemeh 
Published: August 2021

Abstract
Background
Hospital accreditation (HA) is an external evaluation of a hospital’s structures, processes and results by an independent professional accreditation body using pre-established optimum standards. The Iranian hospital accreditation system faces several challenges. The overall aim of this study was to develop a model for Iran national hospital accreditation program.

Methods
This research uses the modified Delphi technique to develop and verify a model of hospital accreditation. The first draft of the HA model was introduced through a critical review of 20 pioneer accreditation models and semi-structured interviews with 151 key informants from Public, private, semi-public, charity and military hospitals in Iran. Three rounds of Delphi were conducted with 28 experts of hospital accreditation to verify the proposed model. Panel members were selected from authors of research articles and key speakers in the area of hospital accreditation, senior managers of the country’s health system, university professors in the fields of health policy and management across the country.

Results
A comprehensive model for hospital accreditation was introduced and verified in this study. The HA model has ten constructs of which seven are enablers (“Management and leadership”, “Planning”, “Education and Research”, “employee management”, “patient management”, “resource management”, and “process management”) and three are the results (“employee results”, “patient and society results” and “hospital results”). These constructs were further broken into 43 sub-constructs. The enablers and results scored 65 and 35% of the model’s total scores respectively. Then, about 150 accreditation standards were written and verified.

Conclusions
A comprehensive hospital accreditation model was developed and verified. Proper attention to structures, processes and outcomes and systemic thinking during the development of the model is one of the advantages of the hospital accreditation model developed in this study. Hospital accreditation bodies can use this model to develop or revise their hospital accreditation models.
Molecular and morphological analysis of the developing nemertean brain indicates convergent evolution of complex brains in Spiralia
Authors: Gąsiorowski Ludwik , Børve Aina , Cherneva Irina A. , Orús-Alcalde Andrea , Hejnol Andreas 
Published: August 2021

AbstractBackgroundThe brain anatomy in the clade Spiralia can vary from simple, commissural brains (e.g., gastrotrichs, rotifers) to rather complex, partitioned structures (e.g., in cephalopods and annelids). How often and in which lineages complex brains evolved still remains unclear. Nemerteans are a clade of worm-like spiralians, which possess a complex central nervous system (CNS) with a prominent brain, and elaborated chemosensory and neuroglandular cerebral organs, which have been previously suggested as homologs to the annelid mushroom bodies. To understand the developmental and evolutionary origins of the complex brain in nemerteans and spiralians in general, we investigated details of the neuroanatomy and gene expression in the brain and cerebral organs of the juveniles of nemerteanLineus ruber.ResultsIn the juveniles, the CNS is already composed of all major elements present in the adults, including the brain, paired longitudinal lateral nerve cords, and an unpaired dorsal nerve cord, which suggests that further neural development is mostly related with increase in the size but not in complexity. The ultrastructure of the juvenile cerebral organ revealed that it is composed of several distinct cell types present also in the adults. The 12 transcription factors commonly used as brain cell type markers in bilaterians show region-specific expression in the nemertean brain and divide the entire organ into several molecularly distinct areas, partially overlapping with the morphological compartments. Additionally, several of the mushroom body-specific genes are expressed in the developing cerebral organs.ConclusionsThe dissimilar expression of molecular brain markers betweenL. ruberand the annelidPlatynereis dumeriliiindicates that the complex brains present in those two species evolved convergently by independent expansions of non-homologous regions of a simpler brain present in their last common ancestor. Although the same genes are expressed in mushroom bodies and cerebral organs, their spatial expression within organs shows apparent differences between annelids and nemerteans, indicating convergent recruitment of the same genes into patterning of non-homologous organs or hint toward a more complicated evolutionary process, in which conserved and novel cell types contribute to the non-homologous structures.
Risk of incident fractures in individuals hospitalised due to unexplained syncope and orthostatic hypotension
Authors: Johansson Madeleine , Rogmark Cecilia , Sutton Richard , Fedorowski Artur , Hamrefors Viktor 
Published: August 2021

Abstract
Background
Impaired orthostatic blood pressure response and syncope confer a high risk of falls and trauma. The relationship between a history of unexplained syncope and orthostatic hypotension (OH) with subsequent fractures, however, has not been thoroughly examined. In this study, we aimed to investigate the relationship between previous hospital admissions due to unexplained syncope and OH and incident fractures in a middle-aged population.

Methods
We analysed a large population-based prospective cohort of 30,399 middle-aged individuals (age, 57.5 ± 7.6; women, 60.2%). We included individuals hospitalised due to unexplained syncope or OH as the main diagnosis. Multivariable-adjusted Cox regression analysis was applied to assess the impact of unexplained syncope and OH hospitalisations on subsequent incident fractures.

Results
During a follow-up period of 17.8 + 6.5 years, 8201 (27%) subjects suffered incident fractures. The mean time from baseline and first admission for syncope (n = 493) or OH (n = 406) was 12.6 ± 4.2 years, and the mean age of the first hospitalisation was 74.6 ± 7.4 years. Individuals with incident fractures were older, more likely to be women, and had lower BMI, higher prevalence of prevalent fractures, and family history of fractures. Multivariable-adjusted Cox regression showed an increased risk of incident fractures following hospitalisations due to unexplained syncope (HR 1.20; 95% CI 1.02–1.40; p = 0.025) and OH (HR 1.42; 95% CI 1.21–1.66; p < 0.001) compared with unaffected individuals.

Conclusions
Individuals hospitalised due to unexplained syncope and orthostatic hypotension have an increased risk of subsequent fractures. Our findings suggest that such individuals should be clinically assessed for their syncope aetiology, with preventative measures aimed at fall and fracture risk assessment and management.
A first report of a rare TP53 variant associated with Li-Fraumeni syndrome manifesting as invasive breast cancer and malignant solitary fibrous tumor
Authors: Prejac Juraj , Dedić Plavetić Natalija , Gotovac Jerčić Kristina , Borovečki Fran 
Published: August 2021

Abstract
Background
Li-Fraumeni is a rare autosomal dominant cancer predisposition syndrome. The basis is a germline mutation of TP53 gene which encodes tumor suppressor protein resulting in early onset of tumors, most often breast cancer, soft tissue sarcomas, brain tumors, adrenocortical carcinomas, and leukemia.

Case report
We present a case of a young woman with a positive family history for cancer diagnosed with malignant solitary fibrous tumor and luminal B-like invasive breast cancer. Breast cancer and sarcomas account for the majority of tumors associated with Li-Fraumeni syndrome, yet solitary fibrous tumor is a rare clinical entity with no established guidelines for treatment. Even though both primary tumors were successfully resected, the sarcoma relapsed in the form of lung metastases. The NGS analysis revealed single nucleotide variant (c.1101-1G>A) in TP53 gene, affecting the acceptor splice site at intron 10. Until now, only one case of this genetic variant has been documented with conflicting interpretations of pathogenicity.

Conclusions
The knowledge of TP53 mutation status is essential since the management of these patients requires different approach to avoid excessive toxicity due to the risk of developing secondary malignancy. Using the clinical criteria to screen for affected individuals facilitates appropriate early genetic counseling of patients and their families. Following the American College of Medical Genetics criteria, we believe that the reported single nucleotide variant (c.1101-1G>A) in TP53 gene should be considered pathogenic.
Footprint measurement methods for the assessment and classification of foot types in subjects with Down syndrome: a systematic review
Authors: Gutiérrez-Vilahú Lourdes , Guerra-Balic Myriam 
Published: August 2021

Abstract
Background
Musculoskeletal disorders, especially in the feet, are common in people with Down syndrome (DS). Evaluation of podiatric footprints is important to prevent and manage orthopedic symptoms. The reliability of a wide variety of footprint measurement methods has been evaluated in healthy people, but few studies have considered the specific morphotype features of the feet in subjects with DS. The aim of this systematic review was to identify the podometric measurement tools used to typologically classify the footprints in the population with DS.

Methods
The following electronic databases were searched for studies describing footprint measurement tools to assess and classify the foot types in patients with DS published from inception to December 2020: PubMed, Web of Science, CINAHL, and Scopus. Articles were initially searched by screening titles and abstracts. Potentially relevant studies were then further screened by reviewing full texts. Studies that met the inclusion criteria were included in the review.

Results
Of the 122 articles identified by the search strategy, 14 full texts were retained to assess for eligibility, of which 11 studies met the inclusion criteria and were included. All the studies used footprint measurement methods to classify the foot types in subjects with DS, but only two studies assessed the reliability of those methods for the population with DS. The footprint measurement tools identified were a podoscope, a pressure-sensitive mat, a PressureStatTM carbon paper, and a 3D scanner. The Arch Index was the most common footprint measurement analyzed (seven studies). Two studies used the “gold standard” indexes that include Hernández-Corvo Index, Chippaux-Smirak Index, Staheli Index, and Clarke Angle to measure footprints.

Conclusions
There is a need to determine the reliability and validity of the footprint measurement methods used for clinical classification of the foot types in subjects with DS. This can contribute to an early diagnosis of foot abnormalities that would help to reduce mobility impairments, improving the quality of life of patients with DS.
Effect of drugs on bone mineral density in postmenopausal osteoporosis: a Bayesian network meta-analysis
Authors: Migliorini Filippo , Maffulli Nicola , Colarossi Giorgia , Eschweiler Jörg , Tingart Markus , Betsch Marcel 
Published: August 2021

Abstract
Background
Osteoporosis affects mostly postmenopausal women, leading to deterioration of the microarchitectural bone structure and low bone mass, with an increased fracture risk with associated disability, morbidity and mortality. This Bayesian network meta-analysis compared the effects of current anti-osteoporosis drugs on bone mineral density.

Methods
The present systematic review and network meta-analysis follows the PRISMA extension statement to report systematic reviews incorporating network meta-analyses of health care interventions. The literature search was performed in June 2021. All randomised clinical trials that have investigated the effects of two or more drug treatments on BMD for postmenopausal osteoporosis were accessed. The network comparisons were performed through the STATA Software/MP routine for Bayesian hierarchical random-effects model analysis. The inverse variance method with standardised mean difference (SMD) was used for analysis.

Results
Data from 64 RCTs involving 82,732 patients were retrieved. The mean follow-up was 29.7 ± 19.6 months. Denosumab resulted in a higher spine BMD (SMD −0.220; SE 3.379), followed by pamidronate (SMD −5.662; SE 2.635) and zoledronate (SMD −10.701; SE 2.871). Denosumab resulted in a higher hip BMD (SMD −0.256; SE 3.184), followed by alendronate (SMD −17.032; SE 3.191) and ibandronate (SMD −17.250; SE 2.264). Denosumab resulted in a higher femur BMD (SMD 0.097; SE 2.091), followed by alendronate (SMD −16.030; SE 1.702) and ibandronate (SMD −17.000; SE 1.679).

Conclusion
Denosumab results in higher spine BMD in selected women with postmenopausal osteoporosis. Denosumab had the highest influence on hip and femur BMD.

Level of evidence
Level I, Bayesian network meta-analysis of RCTs
Efficacy and cost-effectiveness of universal pre-operative iron studies in total hip and knee arthroplasty
Authors: Varghese Viju Daniel , Liu David , Ngo Donald , Edwards Suzanne 
Published: August 2021

Abstract
Background
The prevalence of anaemia in patients planned for total hip and knee arthroplasty is about 20%. Optimising pre-operative haemoglobin levels by iron supplementation has been shown to decrease transfusion rates, complications and associated morbidity. The need for universal screening with iron studies of all elective arthroplasty patients is not clearly defined at present.

Methods
Retrospective review of 2 sequential cohorts of patients undergoing primary hip or knee arthroplasty by a single surgeon at a single centre between January 2013 and December 2017. The first group of patients underwent pre-operative iron studies only if found to be anaemic, with a haemoglobin below 12g/dl. From January 2015, all patients irrespective of the presence of anaemia were screened with a complete iron profile before surgery. Patients with a confirmed iron deficiency were administered with intravenous iron prior to surgery. The 2 cohorts were compared with regard to blood transfusion rate post-operatively and cost efficiency for universal screening with iron studies.

Results
There was a net decrease in the allogenic blood transfusion rate from 4.76 to 2.92% when universal iron studies were introduced but the difference was not statistically significant. Obtaining universal pre-operative iron studies is cost neutral with the price of allogenic blood transfusion in a similar cohort. We also diagnosed 5 patients with occult malignancies.

Conclusions
Universal screening with pre-operative iron studies and iron infusion in elective arthroplasty patients may reduce allogenic blood requirements and is cost neutral. An additional benefit is the potential to diagnose asymptomatic malignancies. Further studies are required to show the true benefit of universal pre-operative iron screening.