bluuebunny/crossref_metadata_2025_split huggingface dataset:
Newborn screening for spinal muscular atrophy in Germany: clinical results after 2 years
Authors: Vill Katharina , Schwartz Oliver , Blaschek Astrid , Gläser Dieter , Nennstiel Uta , Wirth Brunhilde , Burggraf Siegfried , Röschinger Wulf , Becker Marc , Czibere Ludwig , Durner Jürgen , Eggermann Katja , Olgemöller Bernhard , Harms Erik , Schara Ulrike , Kölbel Heike , Müller-Felber Wolfgang 
Published: March 2021

Abstract
Background
Spinal muscular atrophy (SMA) is the most common neurodegenerative disease in childhood. Since motor neuron injury is usually not reversible, early diagnosis and treatment are essential to prevent major disability. Our objective was to assess the impact of genetic newborn screening for SMA on outcome.

Methods
We provided clinical data from 43 SMA patients, identified via polymerase chain reaction of the SMN1 gene from dried blood spots between January 2018 and January 2020 in Germany. Follow-up included neurophysiological examinations and standardized physiotherapeutic testing.

Results
Detection of SMA with newborn screening was consistent with known incidence in Germany. Birth prevalence was 1:6910; 39.5% had 2 SMN2 copies, 23% had 3 SMN2 copies, 32.5% had 4 copies, and 4.5% had 5 copies of the SMN2 gene. Treatment with SMA-specific medication could be started at the age of 14–39 days in 21 patients. Pre-symptomatically treated patients remained throughout asymptomatic within the observation period. 47% of patients with 2 SMN2 copies showed early, presumably intrauterine onset of disease. These patients reached motor milestones with delay; none of them developed respiratory symptoms. Untreated children with 2 SMN2 copies died. Untreated children with 3 SMN2 copies developed proximal weakness in their first year. In patients with ≥ 4 SMN2 copies, a follow-up strategy of “watchful waiting” was applied despite the fact that one of them was treated from the age of 6 months. Two infant siblings with 4 SMN2 copies were identified with a missed diagnosis of SMA type 3.

Conclusion
Identification of newborns with infantile SMA and prompt SMA-specific treatment substantially improves neurodevelopmental outcome, and we recommend implementation in the public newborn screening in countries where therapy is available. Electrophysiology is a relevant parameter to support the urgency of therapy. There has to be a short time interval between a positive screening result and referral to a therapy-ready specialized treatment center.
Complex emergencies and the control and elimination of neglected tropical diseases in Africa: developing a practical approach for implementing safe and effective mapping and intervention strategies
Authors: Kelly-Hope Louise A. , Sanders Angelia M. , Harding-Esch Emma , Willems Johan , Ahmed Fatima , Vincer Fiona , Hill Rebecca 
Published: March 2021

Abstract
Background
Complex emergencies resulting from conflict and political instability are a major challenge for national neglected tropical diseases (NTDs) control and elimination programmes, especially in sub-Saharan Africa. Currently, there are no formal guidelines for national programmes to use and plan activities in these humanitarian situations, therefore the aim of this study was to develop a new methodological approach for making decisions about the implementation of safe and effective mapping and mass drug administration (MDA) intervention strategies.

Methods
The study focussed on the 47 World Health Organization’s African Region (AFR) countries. NTD data were based on five diseases controlled by preventive chemotherapy (PC; i.e. lymphatic filariasis, onchocerciasis, schistosomiasis, soil transmitted helminths, trachoma), obtained from the WHO data portals and The Global Trachoma Atlas for 2018. Data on complex emergencies were obtained from the Armed Conflict Location and Event Data Project for 2018–2019.
NTD and conflict data were summarised and mapped. A decision tree was developed using NTD mapping, endemicity, MDA and implementing partners data, together with conflict status information at district level. South Sudan was used as a case study, given its current nexus of high NTD prevalence, incidences of conflict, and the presence of a national NTD programme and supporting partners.

Results
For the five NTDs, between 26 and 41 countries required PC, 69.2–212.7 million people were treated with coverage between 54.8–71.4%. In total 15,273 conflict events were reported including high rates of violence against civilians (29.4%), protests (28.8%), and battles (18.1%). The decision tree process included four main steps including i) information gathering ii) determine a disease mapping strategy iii) determine an MDA implementation strategy and iv) create a disease and conflict database. Based on these steps, risk maps were created. The South Sudan case study on onchocerciasis found the majority of the districts requiring mapping or MDA had a conflict event, and required specialised methods adapted to context and risk, with support from implementation partners in selected areas.

Conclusions
The paper presents a new methodological approach for implementing safe and effective mapping and intervention strategies in NTD endemic countries with ongoing complex emergencies, which will help to address challenges and make progress toward the NTD Roadmap targets of 2030.
Characterizing individuals accessing mental health services in the UAE: a focus on youth living in Dubai
Authors: Barbato Mariapaola , Al Hemeiri Shaikha , Nafie Shorouk , Dhuhair Baraa A. , Dabbagh Nadia T. 
Published: March 2021

Abstract
Background
Most mental health issues develop during adolescence, therefore identifying youth mental health needs and pathways to care is critical to improve prevention. To date, studies have typically focused on Western samples, while the impact of cultural diversity on perception of health and illness, and pathways to care, remain poorly understood. To address the shortage of studies conducted in the Arab world, and particularly in the United Arab Emirates (UAE), the present investigation aims to identify the characteristics of youth accessing mental health services in Dubai.

Methods
Data was collected retrospectively from patients’ records at Rashid Hospital Child Psychiatry Service. Information collected included demographics, life stressors, symptoms duration, main diagnosis, and presence/absence of psychotic features in patients’ symptomatology. The relationship between demographic and clinical variables was explored using Chi-square tests and negative binomial regression models.

Results
The sample included 99 treatment-seeking young patients (mean age 15.3; SD = 1.7); 47.5 % were Emirati (UAE national) and 52.5 % were non-Emirati patients. In our treatment-seeking youth sample Depressive disorders represented the most frequent diagnosis, followed by Bipolar and related disorders, Anxiety and stress related disorders, and Schizophrenia and psychotic disorders. Compared to Emirati patients, non-Emirati patients were more likely to report relationships with friends as a source of stress. Female help-seekers, compared to males, were more likely to report stressful relationships with family members, and to receive a diagnosis of Depressive disorders. The duration of symptoms before seeking help was significantly predicted by family stress, gender, self-harm behavior, a symptomatology with psychotic features, and a diagnosis of Anxiety disorders.

Conclusions
The present study contributes to characterizing youth accessing mental health services at Rashid Hospital’s Child Psychiatry service in Dubai. An overall prevalence of poor family functioning among help-seeking youth, and the importance of peer support for expatriate youth were highlighted. Gender differences in perceived stressors, diagnoses and help-seeking behavior suggest the need to promote help-seeking among young boys. While presentation with psychotic features seems to lead to quicker access to medical care, self-harm and anxiety appear to delay help-seeking. The potential implications of our results for promoting youth wellbeing in the region are discussed.
Prediction of short-term mortality in acute heart failure patients using minimal electronic health record data
Authors: Radhachandran Ashwath , Garikipati Anurag , Zelin Nicole S. , Pellegrini Emily , Ghandian Sina , Calvert Jacob , Hoffman Jana , Mao Qingqing , Das Ritankar 
Published: March 2021

Abstract
Background
Acute heart failure (AHF) is associated with significant morbidity and mortality. Effective patient risk stratification is essential to guiding hospitalization decisions and the clinical management of AHF. Clinical decision support systems can be used to improve predictions of mortality made in emergency care settings for the purpose of AHF risk stratification. In this study, several models for the prediction of seven-day mortality among AHF patients were developed by applying machine learning techniques to retrospective patient data from 236,275 total emergency department (ED) encounters, 1881 of which were considered positive for AHF and were used for model training and testing. The models used varying subsets of age, sex, vital signs, and laboratory values. Model performance was compared to the Emergency Heart Failure Mortality Risk Grade (EHMRG) model, a commonly used system for prediction of seven-day mortality in the ED with similar (or, in some cases, more extensive) inputs. Model performance was assessed in terms of area under the receiver operating characteristic curve (AUROC), sensitivity, and specificity.

Results
When trained and tested on a large academic dataset, the best-performing model and EHMRG demonstrated test set AUROCs of 0.84 and 0.78, respectively, for prediction of seven-day mortality. Given only measurements of respiratory rate, temperature, mean arterial pressure, and FiO2, one model produced a test set AUROC of 0.83. Neither a logistic regression comparator nor a simple decision tree outperformed EHMRG.

Conclusions
A model using only the measurements of four clinical variables outperforms EHMRG in the prediction of seven-day mortality in AHF. With these inputs, the model could not be replaced by logistic regression or reduced to a simple decision tree without significant performance loss. In ED settings, this minimal-input risk stratification tool may assist clinicians in making critical decisions about patient disposition by providing early and accurate insights into individual patient’s risk profiles.
MITF induces escape from innate immunity in melanoma
Authors: Sánchez-del-Campo Luis , Martí-Díaz Román , Montenegro María F. , González-Guerrero Rebeca , Hernández-Caselles Trinidad , Martínez-Barba Enrique , Piñero-Madrona Antonio , Cabezas-Herrera Juan , Goding Colin R. , Rodríguez-López José Neptuno 
Published: March 2021

Abstract
Background
The application of immune-based therapies has revolutionized cancer treatment. Yet how the immune system responds to phenotypically heterogeneous populations within tumors is poorly understood. In melanoma, one of the major determinants of phenotypic identity is the lineage survival oncogene MITF that integrates diverse microenvironmental cues to coordinate melanoma survival, senescence bypass, differentiation, proliferation, invasion, metabolism and DNA damage repair. Whether MITF also controls the immune response is unknown.

Methods
By using several mouse melanoma models, we examine the potential role of MITF to modulate the anti-melanoma immune response. ChIP-seq data analysis, ChIP-qPCR, CRISPR-Cas9 genome editing, and luciferase reporter assays were utilized to identify ADAM10 as a direct MITF target gene. Western blotting, confocal microscopy, flow cytometry, and natural killer (NK) cytotoxicity assays were used to determine the underlying mechanisms by which MITF-driven phenotypic plasticity modulates melanoma NK cell-mediated killing.

Results
Here we show that MITF regulates expression of ADAM10, a key sheddase that cleaves the MICA/B family of ligands for NK cells. By controlling melanoma recognition by NK-cells MITF thereby controls the melanoma response to the innate immune system. Consequently, while melanoma MITFLow cells can be effectively suppressed by NK-mediated killing, MITF-expressing cells escape NK cell surveillance.

Conclusion
Our results reveal how modulation of MITF activity can impact the anti-melanoma immune response with implications for the application of anti-melanoma immunotherapies.
Trends in reasons for emergency calls during the COVID-19 crisis in the department of Gironde, France using artificial neural network for natural language classification
Authors: Gil-Jardiné Cédric , Chenais Gabrielle , Pradeau Catherine , Tentillier Eric , Revel Philippe , Combes Xavier , Galinski Michel , Tellier Eric , Lagarde Emmanuel 
Published: March 2021

Abstract
Objectives
During periods such as the COVID-19 crisis, there is a need for responsive public health surveillance indicators in order to monitor both the epidemic growth and potential public health consequences of preventative measures such as lockdown. We assessed whether the automatic classification of the content of calls to emergency medical communication centers could provide relevant and responsive indicators.

Methods
We retrieved all 796,209 free-text call reports from the emergency medical communication center of the Gironde department, France, between 2018 and 2020. We trained a natural language processing neural network model with a mixed unsupervised/supervised method to classify all reasons for calls in 2020. Validation and parameter adjustment were performed using a sample of 39,907 manually-coded free-text reports.

Results
The number of daily calls for flu-like symptoms began to increase from February 21, 2020 and reached an unprecedented level by February 28, 2020 and peaked on March 14, 2020, 3 days before lockdown. It was strongly correlated with daily emergency room admissions, with a delay of 14 days. Calls for chest pain and stress and anxiety, peaked 12 days later. Calls for malaises with loss of consciousness, non-voluntary injuries and alcohol intoxications sharply decreased, starting one month before lockdown. No noticeable trends in relation to lockdown was found for other groups of reasons including gastroenteritis and abdominal pain, stroke, suicide and self-harm, pregnancy and delivery problems.

Discussion
The first wave of the COVID-19 crisis came along with increased levels of stress and anxiety but no increase in alcohol intoxication and violence. As expected, call related to road traffic crashes sharply decreased. The sharp decrease in the number of calls for malaise was more surprising.

Conclusion
The content of calls to emergency medical communication centers is an efficient epidemiological surveillance data source that provides insights into the societal upheavals induced by a health crisis. The use of an automatic classification system using artificial intelligence makes it possible to free itself from the context that could influence a human coder, especially in a crisis situation. The COVID-19 crisis and/or lockdown induced deep modifications in the population health profile.
Disulfide bond engineering of AppA phytase for increased thermostability requires co-expression of protein disulfide isomerase in Pichia pastoris
Authors: Navone Laura , Vogl Thomas , Luangthongkam Pawarisa , Blinco Jo-Anne , Luna-Flores Carlos H. , Chen Xiaojing , von Hellens Juhani , Mahler Stephen , Speight Robert 
Published: March 2021

Abstract
Background
Phytases are widely used commercially as dietary supplements for swine and poultry to increase the digestibility of phytic acid. Enzyme development has focused on increasing thermostability to withstand the high temperatures during industrial steam pelleting. Increasing thermostability often reduces activity at gut temperatures and there remains a demand for improved phyases for a growing market.

Results
In this work, we present a thermostable variant of the E. coli AppA phytase, ApV1, that contains an extra non-consecutive disulfide bond. Detailed biochemical characterisation of ApV1 showed similar activity to the wild type, with no statistical differences in kcat and KM for phytic acid or in the pH and temperature activity optima. Yet, it retained approximately 50% activity after incubations for 20 min at 65, 75 and 85 °C compared to almost full inactivation of the wild-type enzyme. Production of ApV1 in Pichia pastoris (Komagataella phaffi) was much lower than the wild-type enzyme due to the presence of the extra non-consecutive disulfide bond. Production bottlenecks were explored using bidirectional promoters for co-expression of folding chaperones. Co-expression of protein disulfide bond isomerase (Pdi) increased production of ApV1 by ~ 12-fold compared to expression without this folding catalyst and restored yields to similar levels seen with the wild-type enzyme.

Conclusions
Overall, the results show that protein engineering for enhanced enzymatic properties like thermostability may result in folding complexity and decreased production in microbial systems. Hence parallel development of improved production strains is imperative to achieve the desirable levels of recombinant protein for industrial processes.
A polo-like kinase modulates cytokinesis and flagella biogenesis in Giardia lamblia
Authors: Park Eun-Ah , Kim Juri , Shin Mee Young , Park Soon-Jung 
Published: March 2021

Abstract
Background
Polo-like kinases (PLKs) are conserved serine/threonine kinases that regulate the cell cycle. To date, the role of Giardia lamblia PLK (GlPLK) in cells has not been studied. Here, we report our investigation on the function of GlPLK to provide insight into the role of this PKL in Giardia cell division, especially during cytokinesis and flagella formation.

Methods
To assess the function of GIPLK, Giardia trophozoites were treated with the PLK-specific inhibitor GW843286X (GW). Using a putative open reading frame for the PLK identified in the Giardia genomic database, we generated a transgenic Giardia expressing hemagglutinin (HA)-tagged GlPLK and used this transgenic for immunofluorescence assays (IFAs). GlPLK expression was knocked down using an anti-glplk morpholino to observe its effect on the number of nuclei number and length of flagella. Giardia cells ectopically expressing truncated GlPLKs, kinase domain + linker (GlPLK-KDL) or polo-box domains (GlPLK-PBD) were constructed for IFAs. Mutant GlPLKs at Lys51, Thr179 and Thr183 were generated by site-directed mutagenesis and then used for the kinase assay. To elucidate the role of phosphorylated GlPLK, the phosphorylation residues were mutated and expressed in Giardia trophozoites

Results
After incubating trophozoites with 5 μM GW, the percentage of cells with > 4 nuclei and longer caudal and anterior flagella increased. IFAs indicated that GlPLK was localized to basal bodies and flagella and was present at mitotic spindles in dividing cells. Morpholino-mediated GlPLK knockdown resulted in the same phenotypes as those observed in GW-treated cells. In contrast to Giardia expressing GlPLK-PBD, Giardia expressing GlPLK-KDL was defective in terms of GIPLK localization to mitotic spindles and had altered localization of the basal bodies in dividing cells. Kinase assays using mutant recombinant GlPLKs indicated that mutation at Lys51 or at both Thr179 and Thr183 resulted in loss of kinase activity. Giardia expressing these mutant GlPLKs also demonstrated defects in cell growth, cytokinesis and flagella formation.

Conclusions
These data indicate that GlPLK plays a role in Giardia cell division, especially during cytokinesis, and that it is also involved in flagella formation.

Graphical Abstract
Early-life undernutrition induces enhancer RNA remodeling in mice liver
Authors: Wang Yinyu , Mao Yiting , Zhao Yiran , Yi Xianfu , Ding Guolian , Yu Chuanjin , Sheng Jianzhong , Liu Xinmei , Meng Yicong , Huang Hefeng 
Published: March 2021

Abstract
Background
Maternal protein restriction diet (PRD) increases the risk of metabolic dysfunction in adulthood, the mechanisms during the early life of offspring are still poorly understood. Apart from genetic factors, epigenetic mechanisms are crucial to offer phenotypic plasticity in response to environmental situations and transmission. Enhancer-associated noncoding RNAs (eRNAs) transcription serves as a robust indicator of enhancer activation, and have potential roles in mediating enhancer functions and gene transcription.

Results
Using global run-on sequencing (GRO-seq) of nascent RNA including eRNA and total RNA sequencing data, we show that early-life undernutrition causes remodeling of enhancer activity in mouse liver. Differentially expressed nascent active genes were enriched in metabolic pathways. Besides, our work detected a large number of high confidence enhancers based on eRNA transcription at the ages of 4 weeks and 7 weeks, respectively. Importantly, except for ~ 1000 remodeling enhancers, the early-life undernutrition induced instability of enhancer activity which decreased in 4 weeks and increased in adulthood. eRNA transcription mainly contributes to the regulation of some important metabolic enzymes, suggesting a link between metabolic dysfunction and enhancer transcriptional control. We discovered a novel eRNA that is positively correlated to the expression of circadian gene Cry1 with increased binding of epigenetic cofactor p300.

Conclusions
Our study reveals novel insights into mechanisms of metabolic dysfunction. Enhancer activity in early life acts on metabolism-associated genes, leading to the increased susceptibility of metabolic disorders.