bluuebunny/crossref_metadata_2025 huggingface dataset:
Broad respiratory testing to identify SARS-CoV-2 viral co-circulation and inform diagnostic stewardship in the COVID-19 pandemic
Authors: Marshall Natalie C. , Kariyawasam Ruwandi M. , Zelyas Nathan , Kanji Jamil N. , Diggle Mathew A.
Published: May 2021

Background

SARS-CoV-2 infection can present with a broad clinical differential that includes many other respiratory viruses; therefore, accurate tests are crucial to distinguish true COVID-19 cases from pathogens that do not require urgent public health interventions. Co-circulation of other respiratory viruses is largely unknown during the COVID-19 pandemic but would inform strategies to rapidly and accurately test patients with respiratory symptoms.

Methods

This study retrospectively examined 298,415 respiratory specimens collected from symptomatic patients for SARS-CoV-2 testing in the three months since COVID-19 was initially documented in the province of Alberta, Canada (March-May, 2020). By focusing on 52,285 specimens that were also tested with the Luminex Respiratory Pathogen Panel for 17 other pathogens, this study examines the prevalence of 18 potentially co-circulating pathogens and their relative rates in prior years versus since COVID-19 emerged, including four endemic coronaviruses.

Results

SARS-CoV-2 was identified in 2.2% of all specimens. Parallel broad multiplex testing detected additional pathogens in only 3.4% of these SARS-CoV-2-positive specimens: significantly less than in SARS-CoV-2-negative specimens (p < 0.0001), suggesting very low rates of SARS-CoV-2 co-infection. Furthermore, the overall co-infection rate was significantly lower among specimens with SARS-CoV-2 detected (p < 0.0001). Finally, less than 0.005% of all specimens tested positive for both SARS-CoV-2 and any of the four endemic coronaviruses tested, strongly suggesting neither co-infection nor cross-reactivity between these coronaviruses.

Conclusions

Broad respiratory pathogen testing rarely detected additional pathogens in SARS-CoV-2-positive specimens. While helpful to understand co-circulation of respiratory viruses causing similar symptoms as COVID-19, ultimately these broad tests were resource-intensive and inflexible in a time when clinical laboratories face unprecedented demand for respiratory virus testing, with further increases expected during influenza season. A transition from broad, multiplex tests toward streamlined diagnostic algorithms targeting respiratory pathogens of public health concern could simultaneously reduce the overall burden on clinical laboratories while prioritizing testing of pathogens of public health importance. This is particularly valuable with ongoing strains on testing resources, exacerbated during influenza seasons.
Giant vascular eccrine spiradenoma: the first case in the scrotum and review of the literature author
Authors: Li Zan , Li Gang , Jiang Xin , Fu Xiaoming
Published: May 2021

Background

Giant vascular eccrine spiradenoma is a rare variant of eccrine spiradenoma. It is different from the eccrine spiradenoma in its larger size and greater degree of vascularity. It is often clinically confusedwith a vascular or malignant tumor.

Case presentation

Here, we report a case of a 67-year-old man who presented with a tumor in the scrotum scrotal region for 6 years. The tumor had begun as a small nodule and had grown slowly with over time. Surgical excision and pathological examination revealed that the lesion was the a giant vascular eccrine spiradenoma.

Conclusion

This study reports the first case of giant vascular eccrine spiradenoma in the scrotum.
Danon disease: a case report and literature review
Authors: Xu Jiamin , Li Zhu , Liu Yihai , Zhang Xinlin , Niu Fengnan , Zheng Hongyan , Wang Lian , Kang Lina , Wang Kun , Xu Biao
Published: May 2021

Background

Danon disease (DD) is a rare x-linked dominant multisystemic disorder with a clinical triad of severe cardiomyopathy, skeletal myopathy, and mental retardation. It is caused by a defect in the lysosomal-associated membrane protein-2 (LAMP2) gene, which leads to the formation of autophagic vacuoles containing glycogen granule deposits in skeletal and cardiac muscle fibers. So far, more than 50 different mutations inLAMP2 have been identified.

Case presentation

Here, we report an 18-year-old male patient who was hospitalized for heart failure. Biopsy of the left lateral femoral muscle revealed scattered autophagic vacuoles in the muscle fibers with increased glycogen. Next generation sequencing (NGS) was used to detect gene mutations of the proband sample and a novel frameshift mutation (c.1052delG) has been identified in exon 8 ofLAMP2, which leads to truncation of the protein.

Conclusion

We found a novel frameshift mutation, a hemizygous mutation (c.1052delG) in exon 8 ofLAMP2, identified as presenting the hypertrophic cardiomyopathy (HCM) phenotype. Genetic analysis is the gold standard for the diagnosis of DD and is essential to determine appropriate treatment strategies and to confirm the genetic risk of family members.
Qualitative assessment of patients’ perspectives and needs from community pharmacists in substance use disorder management
Authors: Fatani Sarah , Bakke Daniel , D’Eon Marcel , El-Aneed Anas
Published: May 2021

Background

Non-medical use of psychoactive substances is a common harmful behavior that leads to the development of Substance Use Disorders (SUDs). SUD is a significant health concern that causes adverse health consequences and elevates the economic burden on the health care system. SUD treatment plans that utilize a patient-centered approach have demonstrated improved treatment outcomes. It is essential for health care providers, including community pharmacists, to understand patients’ needs and prioritize them. Therefore, this study was conducted to explore the perspective of patients living with SUDs or who used substances non-medically regarding community pharmacist services and the delivery of services in a community pharmacy setting. The study took place in Saskatoon, a small urban center of Saskatchewan, Canada.

Methods

Qualitative methodology was used for this research inquiry. Four focus groups were conducted, with a total of 20 individuals who had experienced substance use and accessed community pharmacy services. The discussion of the four focus groups was transcribed verbatim and analyzed independently by two researchers. Agreement on the emergent themes was reached through discussion between the two researchers.

Results

Data analysis resulted in four themes that described participants’ perspectives about community pharmacists. The four emergent themes are: 1) conflicted experiences with community pharmacists, 2) lack of knowledge concerning community pharmacists’ extended services, 3) negative experiences in Opioid Agonist Therapy (OAT) program, and 4) needs from community pharmacists.

Conclusion

There is significant potential for the patient-pharmacist relationship to address the varying needs of patients who use substances and improve their overall health care experience. Patients who use substances are receptive to pharmacists’ services beyond dispensary; however, respectful communication, provision of drug-related information, and counseling are among the primary demands. Future research should focus on studying the impact of meeting the needs of patients on their treatment outcomes.
Quality assurance of radiotherapy in the ongoing EORTC 1420 “Best of” trial for early stage oropharyngeal, supraglottic and hypopharyngeal carcinoma: results of the benchmark case procedure
Authors: Stelmes J-J , Vu E. , Grégoire V. , Simon C. , Clementel E. , Kazmierska J. , Grant W. , Ozsahin M. , Tomsej M. , Vieillevigne L. , Fortpied C. , Hurkmans E. C. , Branquinho A. , Andratschke N. , Zimmermann F. , Weber D.-C.
Published: May 2021

Introduction

The current phase III EORTC 1420 Best-of trial (NCT02984410) compares the swallowing function after transoral surgery versus intensity modulated radiotherapy (RT) in patients with early-stage carcinoma of the oropharynx, supraglottis and hypopharynx. We report the analysis of the Benchmark Case (BC) procedures before patient recruitment with special attention to dysphagia/aspiration related structures (DARS).

Materials and methods

Submitted RT volumes and plans from participating centers were analyzed and compared against the gold-standard expert delineations and dose distributions. Descriptive analysis of protocol deviations was conducted. Mean Sorensen-Dice similarity index (mDSI) and Hausdorff distance (mHD) were applied to evaluate the inter-observer variability (IOV).

Results

65% (23/35) of the institutions needed more than one submission to achieve Quality assurance (RTQA) clearance. OAR volume delineations were the cause for rejection in 53% (40/76) of cases. IOV could be improved in 5 out of 12 OARs by more than 10 mm after resubmission (mHD). Despite this, final IOV for critical OARs in delineation remained significant among DARS by choosing an aleatory threshold of 0.7 (mDSI) and 15 mm (mHD).

Conclusions

This is to our knowledge the largest BC analysis among Head and neck RTQA programs performed in the framework of a prospective trial. Benchmarking identified non-common OARs and target delineations errors as the main source of deviations and IOV could be reduced in a significant number of cases after this process. Due to the substantial resources involved with benchmarking, future benchmark analyses should assess fully the impact on patients’ clinical outcome.
Clinical characteristics and risk factors for culture-negative periprosthetic joint infections
Authors: Watanabe Shintaro , Kobayashi Naomi , Tomoyama Akito , Choe Hyonmin , Yamazaki Etsuko , Inaba Yutaka
Published: May 2021

Background

Culture-negative periprosthetic joint infections (PJIs) can complicate diagnosis and management of PJI. This study aimed to identify risk factors for culture-negative PJI and differences in clinical characteristics between culture-positive and culture-negative PJI group.

Methods

This retrospective, cross-sectional study evaluated PJI cases obtained between January 2013 and October 2019 at our institution. These PJI cases were divided into culture-positive and culture-negative groups and then compared. The demographics, laboratory findings, and details of patient’s clinical characteristics were investigated. Univariate and multivariate logistic regression analysis were performed to investigate risk factors for culture-negative PJI.

Results

A total of 109 PJI cases were included in the analysis: 82 (75%) culture-positive and 27 (25%) culture-negative. The mean serum white blood cell (WBC) count, C-reactive protein level, and erythrocyte sedimentation rate in the culture-negative group were significantly lower than those in the culture-positive group (p < 0.05). There were no significant differences between the two groups regarding history of prior antibacterial administration or treatment success rates. Multivariate analysis identified a low serum WBC count as a risk factor for culture-negative PJI (odds ratio = 0.78; 95% confidence interval [CI] = 0.63–0.97; p = 0.027).

Conclusions

A low serum WBC count is a risk factor for culture-negative PJI, but prior antimicrobial therapy is not. The results suggest that PJI cases with lower levels of systemic inflammation are likely to be culture-negative; therefore, the possibility of a culture-negative result should be considered in suspected cases of PJI with low inflammatory markers, regardless of prior antibiotic exposure.
The predictive value of creatinine clearance for mortality in patients undergoing revascularization
Authors: Ram Eilon , Beckerman Pazit , Segev Amit , Shlomo Nir , Atlas-Lazar Abigail , Sternik Leonid , Raanani Ehud
Published: May 2021

Background

Renal function plays a significant role in the prognosis and management of patients with multi-vessel coronary artery disease (CAD) referred for revascularization. Current data lack precise risk stratification using estimated glomerular filtration rate (eGFR) and creatinine clearance.

Methods

This prospective study includes a three-year follow-up of 1112 consecutive patients with multi-vessel CAD enrolled in the 22 hospitals in Israel that perform coronary angiography.

Results

The Mayo formula yielded the highest mean eGFR (90 ± 26 mL/min per 1.73m2) and chronic kidney disease-epidemiology collaboration (CKD-EPI) the lowest (76 ± 24 mL/min per 1.73m2). Consequently, the Mayo formula classified more patients (56%) as having normal renal function. There was a significant and strong correlation between the values obtained from all five formulas using Cockcroft-Gault as the reference formula: Mayo: r = 0.80, p < 0.001; CKD-EPI: r = 0.87, p < 0.001; modification of diet in renal disease (MDRD): r = 0.84, p < 0.001; inulin clearance-based: r = 0.99, p < 0.001). Multivariable analysis demonstrated that decreased renal function is an independent predictor of 3-year mortality in all five formulas, with risk increasing by 15–25% for each 10-unit decrease in eGFR. Despite the similarities between the formulas, the ability to predict mortality was highest in the Mayo formula and lowest in MDRD.

Conclusions

Our data suggest that while the Mayo formula is not currently recommended by any nephrology guidelines, it may be an alternative formula to predict mortality among patients with multivessel CAD, including to the widely used MDRD formula.
Lung cancer with partial anomalous pulmonary venous connection in a different lobe: a case report
Authors: Watanabe Hikaru , Kanauchi Naoki , Abe Kouhei , Matsuo Soumei
Published: May 2021

Background

Anomalous pulmonary venous connection (APVC) is a congenital malformation in which the pulmonary veins connect to the systemic venous system but not to the left atrium. APVC can be classified as total or partial (PAPVC). PAPVC is rare among surgical patients with lung cancer, and most cases are detected incidentally during surgery. We herein report a patient with lung cancer in whom PAPVC was diagnosed before surgery, which made it difficult to determine the surgical procedure.

Case presentation

A 71-year-old man was followed-up as an outpatient after surgery for renal cell carcinoma. Chest computed tomography showed a 22-mm nodule in the right lower lobe and PAPVC in the right upper lobe. He was diagnosed with lung adenocarcinoma (cT1cN0M0 stage IA3) and scheduled for surgery. Preoperative catheterization showed a pulmonary to systemic flow ratio (Qp/Qs) of 1.64 and mean pulmonary artery pressure (MPAP) of 16 mmHg. Surgical repair of PAPVC is indicated when a patient is symptomatic and has a Qp/Qs ≥1.5–2.0. The patient was scheduled for right lower lobectomy, but postoperative worsening of right heart strain was considered. Concomitant PAPVC repair was therefore considered, but he had no atrial septal defect and was asymptomatic; therefore, PAPVC treatment was considered unnecessary. However, we planned to perform concomitant PAPVC repair if his circulatory dynamics worsened during surgery or if his MPAP exceeded 25 mmHg. His MPAP was 20 mmHg and his circulatory dynamics remained stable, and right lower lobectomy was therefore completed. His postoperative course was favorable. Follow-up catheterization at 6 months showed a Qp/Qs of 1.19 and MPAP of 18 mmHg, with no evidence of increased right heart strain. There was no evidence of right heart failure or recurrence of lung cancer at last follow-up at 18 months after surgery.

Conclusions

We present a case of right lower lung cancer complicated by PAPVC in the right upper lobe. This case suggests that concomitant repair of PAPVC in the right upper lobe may not be necessary when performing right lower lobectomy, although the patient’s Qp/Qs and MPAP should be considered.
Ocular manifestations of ectodermal dysplasia
Authors: Landau Prat Daphna , Katowitz William R. , Strong Alanna , Katowitz James A.
Published: May 2021

Purpose

The ectodermal dysplasias (EDs) constitute a group of disorders characterized by abnormalities in two or more ectodermal derivatives, including skin, hair, teeth, and sweat glands. The purpose of the current study was to evaluate ocular manifestations in pediatric patients with ED.

Methods

Retrospective case series including consecutive ED subjects who were treated in the ophthalmology department at the Children’s Hospital of Philadelphia over a 12-year period (2009–2020). Main Outcome Measures were ocular and ocular adnexal abnormalities.

Results

Thirty subjects were included: 20 males (67%), mean age of 4.5 years (range 0.3–18). Patients with different subtypes were included, with the hypohidrotic ED and ectrodactyly-ectodermal dysplasia-clefting variants being most prevalent. Most common findings were: lacrimal drainage obstruction in 12 (40%) including punctal agenesis in 10 (33%), refractive errors in 13 (43%) and amblyopia in 6 (20%). A new finding of eyelid ptosis or eyelash ptosis was demonstrated in 11 subjects (37%), mostly associated with TP63 or EDA1 genes variants.

Conclusion

Ectodermal dysplasias are associated with various ocular pathologies and amblyopia in the pediatric population. We report a possible genetic association between lash ptosis and EDA1 gene, and eyelid ptosis and TP63 or EDA1 genes variants.
How to design a registry for undiagnosed patients in the framework of rare disease diagnosis: suggestions on software, data set and coding system
Authors: Berger Alexandra , Rustemeier Anne-Kathrin , Göbel Jens , Kadioglu Dennis , Britz Vanessa , Schubert Katharina , Mohnike Klaus , Storf Holger , Wagner Thomas O. F.
Published: May 2021

Background

About 30 million people in the EU and USA, respectively, suffer from a rare disease. Driven by European legislative requirements, national strategies for the improvement of care in rare diseases are being developed. To improve timely and correct diagnosis for patients with rare diseases, the development of a registry for undiagnosed patients was recommended by the German National Action Plan. In this paper we focus on the question on how such a registry for undiagnosed patients can be built and which information it should contain.

Results

To develop a registry for undiagnosed patients, a software for data acquisition and storage, an appropriate data set and an applicable terminology/classification system for the data collected are needed. We have used the open-source software Open-Source Registry System for Rare Diseases (OSSE) to build the registry for undiagnosed patients. Our data set is based on the minimal data set for rare disease patient registries recommended by the European Rare Disease Registries Platform. We extended this Common Data Set to also include symptoms, clinical findings and other diagnoses. In order to ensure findability, comparability and statistical analysis, symptoms, clinical findings and diagnoses have to be encoded. We evaluated three medical ontologies (SNOMED CT, HPO and LOINC) for their usefulness. With exact matches of 98% of tested medical terms, a mean number of five deposited synonyms, SNOMED CT seemed to fit our needs best. HPO and LOINC provided 73% and 31% of exacts matches of clinical terms respectively. Allowing more generic codes for a defined symptom, with SNOMED CT 99%, with HPO 89% and with LOINC 39% of terms could be encoded.

Conclusions

With the use of the OSSE software and a data set, which, in addition to the Common Data Set, focuses on symptoms and clinical findings, a functioning and meaningful registry for undiagnosed patients can be implemented. The next step is the implementation of the registry in centres for rare diseases. With the help of medical informatics and big data analysis, case similarity analyses could be realized and aid as a decision-support tool enabling diagnosis of some undiagnosed patients.
“Strengthening data quality and reporting from small-scale surveys in humanitarian settings: a case study from Yemen, 2011–2019”
Authors: Ogbu Thomas Jideofor , Guha-Sapir Debarati
Published: May 2021

Background

Under-five death rate is one of the major indicators used in assessing the level of needs and severity of humanitarian crisis. Over the years, a number of small-scale surveys based on Standardized Monitoring and Assessment of Relief and Transitions methodology has been conducted in Yemen, these serve as a guide for policy maker and the humanitarian community. The aim of this study is to identify critical methodological and reporting weaknesses that are easy to correct and would improve substantively the quality of the results.

Methods

We obtained seventy-seven surveys conducted across 22 governorates in Yemen between 2011 and 2019 and divided the analysis period into pre-crisis (2011–2014) and crisis period (2015–2019) for comparison. We analysed survey qualities such as sampling methodology, completeness of reporting of Under-five death rate and mortality sample size for children less than five (children < 5) years old.

Results

Seventy-seven (71.9%) out of 107 surveys met the eligibility criteria to be included in the study. The methodological quality and reporting are as varied as the surveys. 23.4% (n = 18) met the criteria for quality of sampling methodology, while 77.9%(n = 60) presented required information for the estimation of required mortality sample size and 40.3%(n = 31) met the quality check for reporting of Under-five death rate.

Conclusions

Our assessment indicated that there is no strict adherence to the sampling methodology set out in Standardized Monitoring and Assessment of Relief and Transitions guidelines, and reporting of mortality and sample size data. Adherence to methodological guidelines and complete reporting of surveys in humanitarian settings will vastly improve both the quality and uptake of key data on health and nutrition of the affected population.
The safety of Covid-19 mRNA vaccines: a review
Authors: Anand Pratibha , Stahel Vincent P.
Published: May 2021

The novel coronavirus disease 2019 (COVID-19) has infected more than 100 million people globally within the first year of the pandemic. With a death toll surpassing 500,000 in the United States alone, containing the pandemic is predicated on achieving herd immunity on a global scale. This implies that at least 70-80 % of the population must achieve active immunity against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), either as a result of a previous COVID-19 infection or by vaccination against SARS-CoV-2. In December 2020, the first two vaccines were approved by the FDA through emergency use authorization in the United States. These vaccines are based on the mRNA vaccine platform and were developed by Pfizer/BioNTech and Moderna. Published safety and efficacy trials reported high efficacy rates of 94-95 % after two interval doses, in conjunction with limited side effects and a low rate of adverse reactions. The rapid pace of vaccine development and the uncertainty of potential long-term adverse effects raised some level of hesitation against mRNA vaccines in the global community. A successful vaccination campaign is contingent on widespread access to the vaccine under appropriate storage conditions, deployment of a sufficient number of vaccinators, and the willingness of the population to be vaccinated. Thus, it is important to clarify the objective data related to vaccine safety, including known side effects and potential adverse reactions. The present review was designed to provide an update on the current state of science related to the safety and efficacy of SARS-CoV-2 mRNA vaccines.
Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies
Authors: Tian Zheng , Liu Ming , Zhang Ya , Wang Xin
Published: May 2021

Harnessing the power of immune cells, especially T cells, to enhance anti-tumor activities has become a promising strategy in clinical management of hematologic malignancies. The emerging bispecific antibodies (BsAbs), which recruit T cells to tumor cells, exemplified by bispecific T cell engagers (BiTEs), have facilitated the development of tumor immunotherapy. Here we discussed the advances and challenges in BiTE therapy developed for the treatment of hematologic malignancies. Blinatumomab, the first BiTE approved for the treatment of acute lymphocytic leukemia (ALL), is appreciated for its high efficacy and safety. Recent studies have focused on improving the efficacy of BiTEs by optimizing treatment regimens and refining the molecular structures of BiTEs. A considerable number of bispecific T cell-recruiting antibodies which are potentially effective in hematologic malignancies have been derived from BiTEs. The elucidation of mechanisms of BiTE action and neonatal techniques used for the construction of BsAbs can improve the treatment of hematological malignancies. This review summarized the features of bispecific T cell-recruiting antibodies for the treatment of hematologic malignancies with special focus on preclinical experiments and clinical studies.
Pyroptosis: a new paradigm of cell death for fighting against cancer
Authors: Tan Yixin , Chen Quanzhu , Li Xiaoling , Zeng Zhaoyang , Xiong Wei , Li Guiyuan , Li Xiayu , Yang Jianbo , Xiang Bo , Yi Mei
Published: May 2021

Background

Unraveling the mystery of cell death is one of the most fundamental progresses of life sciences during the past decades. Regulated cell death (RCD) or programmed cell death (PCD) is not only essential in embryonic development, but also plays an important role in the occurrence and progression of diseases, especially cancers. Escaping of cell death is one of hallmarks of cancer.

Main body

Pyroptosis is an inflammatory cell death usually caused by microbial infection, accompanied by activation of inflammasomes and maturation of pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). Gasdermin family proteins are the executors of pyroptosis. Cytotoxic N-terminal of gasdermins generated from caspases or granzymes proteases mediated cleavage of gasdermin proteins oligomerizes and forms pore across cell membrane, leading to release of IL-1β, IL-18. Pyroptosis exerts tumor suppression function and evokes anti-tumor immune responses. Therapeutic regimens, including chemotherapy, radiotherapy, targeted therapy and immune therapy, induce pyroptosis in cancer, which potentiate local and systemic anti-tumor immunity. On the other hand, pyroptosis of normal cells attributes to side effects of anti-cancer therapies.

Conclusion

In this review, we focus on the regulatory mechanisms of pyroptosis and the tumor suppressive function of pyroptosis. We discuss the attribution of pyroptosis in reprogramming tumor microenvironments and restoration of anti-tumor immunity and its potential application in cancer immune therapy.
ROS and TGFβ: from pancreatic tumour growth to metastasis
Authors: Chang Chao-Hui , Pauklin Siim
Published: May 2021

Transforming growth factor β (TGFβ) signalling pathway switches between anti-tumorigenic function at early stages of cancer formation and pro-tumorigenic effects at later stages promoting cancer metastasis. A similar contrasting role has been uncovered for reactive oxygen species (ROS) in pancreatic tumorigenesis. Down-regulation of ROS favours premalignant tumour development, while increasing ROS level in pancreatic ductal adenocarcinoma (PDAC) enhances metastasis. Given the functional resemblance, we propose that ROS-mediated processes converge with the spatial and temporal activation of TGFβ signalling and thereby differentially impact early tumour growth versus metastatic dissemination. TGFβ signalling and ROS could extensively orchestrate cellular processes and this concerted function can be utilized by cancer cells to facilitate their malignancy. In this article, we revisit the interplay of canonical and non-canonical TGFβ signalling with ROS throughout pancreatic tumorigenesis and metastasis. We also discuss recent insight that helps to understand their conflicting effects on different stages of tumour development. These considerations open new strategies in cancer therapeutics.
Management of oxygen saturation monitoring in preterm newborns in the NICU: the Italian picture
Authors:   on behalf of the National Study Group of Neonatal Clinical Biochemistry of the Italian Society of Neonatology, Perrone Serafina , Giordano Maurizio , De Bernardo Giuseppe , Lugani Paola , Sarnacchiaro Pasquale , Stazzoni Gemma , Buonocore Giuseppe , Esposito Susanna , Tataranno Maria Luisa
Published: May 2021

Background

Although many studies emphasize the importance of using oxygen saturation (SpO2) targets in the NICUs, there is a wide variability in used saturation ranges among centers. Primary aim was to draw a representative picture on how the management of oxygen monitoring is performed in the Italian NICUs. Second aim was to identify healthcare-professionals related factors associated with oxygen targeting in the preterm population.

Methods

Cross-sectional study with data collection via an electronic survey form. A questionnaire containing pre-piloted and open questions on monitoring and management of the SpO2 was administered to neonatologists across the network of the Italian Society of Neonatology. The questions focused on: the infrastructure, specific training, healthcare professionals and patients-related factors. The results of the survey were anonymously collected, summarized and analyzed.

Results

Out of 378 questionnaires, 93 were correctly filled. Thirty-six different SpO2 ranges were observed. Centers using written standard operating procedures on oxygen management and SpO2 monitoring maintained a correct average range of SpO2 90–95%, avoided hyperoxia and reconsidered saturation targets in relation to comorbidities. 39.8% of responders disabled alarms during neonatal care. One center used biomarkers for complete monitoring of neonatal oxygenation status.

Conclusions

There is considerable variation in SpO2 targets for preterm infants in the Italian NICUs. Standard operating procedures and specific training for health care personnel are the main factors playing a role for the correct maintenance of the recommended oxygen targets in preterms.
Prevention and contrast of child abuse and neglect in the practice of European paediatricians: a multi-national pilot study
Authors: Nigri Paola , Corsello Giovanni , Nigri Luigi , Bali Donjeta , Kuli-Lito Giorgina , Plesca Doina , Pop Tudor Lucian , Carrasco-Sanz Angel , Namazova-Baranova Leyla , Mestrovic Julije , Vural Mehmet , Giardino Ida , Losonczi Laszlo , Somekh Eli , Balducci Maria Teresa , Pettoello-Mantovani Massimo , Ferrara Pietro
Published: May 2021

Background

Child abuse and neglect, or maltreatment, is a serious public health problem, which may cause long-term effects on children’s health and wellbeing and expose them to further adulthood vulnerabilities. Studies on child maltreatment performed in Europe are scarce, and the number of participants enrolled relatively small. The aim of this multi-national European pilot study, was to evaluate the level of understanding and perception of the concepts of child abuse and neglect by European paediatricians working in different medical settings, and the attitude toward these forms of maltreatment in their practice.

Methods

The study was performed by a cross-sectional, descriptive, online survey, made available online to European paediatricians members of 50 national paediatric, who belonged to four different medical settings: hospital, family care, university centres and private practice.

The questionnaire, designed as a multiple choice questions survey, with a single answer option consisted of 22 questions/statements. Frequency analyses were applied. Most of the data were described using univariate analysis and Chi-squared tests were used to compare the respondents and answers and a significance level ofp ≤ 0.05 applied.

Results

Findings show that European paediatricians consider the training on child maltreatment currently provided by medical school curricula and paediatric residency courses to be largely insufficient and continuing education courses were considered of great importance to cover educational gaps. Physical violence was recognized by paediatricians mostly during occasional visits with a significant correlation between detecting abuse during an occasional visit and being a primary care paediatrician. Results also showed a reluctance by paediatricians to report cases of maltreatment to the competent judicial authorities.

Conclusions

Data of this study may provide useful contribution to the current limited knowledge about the familiarity of European paediatricians with child maltreatment and their skills to recognize, manage and contrast abusive childhood experiences in their practice. Finally, they could provide local legislators and health authorities with information useful to further improve public health approaches and rules able to effectively address shared risk and protective factors, which could prevent child abuse and neglect from ever occurring.
What are the risk factors for admission to the pediatric intensive unit among pediatric patients with COVID-19?
Authors: Esposito Susanna , Caramelli Fabio , Principi Nicola
Published: May 2021

Background

Although with exceptions, evidence seems to indicate that children have lower susceptibility than adults to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. When infected, children generally remain asymptomatic or develop mild disease. A small number of pediatric cases required admission to the pediatric intensive care unit (PICU), respiratory support with a mechanical ventilation and additional life-saving interventions. Even if rarely, death can occur. Aim of this manuscript is to highlight the risk factors associated with severe outcome among pediatric patients with COVID-19.

Main findings

Early identification of SARS-CoV-2-infected children at risk of developing severe COVID-19 is vital for service planning, as severely affected pediatric patients require high-quality care and should be followed only where an adequately structured PICU is available. However, early identification of children who must be carefully monitored for substantial risk of severe COVID-19 remains difficult. An underlying comorbidity and heart involvement are frequently observed in severe paediatric cases. Reduced left ventricular systolic function with an ejection fraction < 60%; diastolic dysfunction; and arrhythmias, including ST segment changes, QTc prolongation, and premature atrial or ventricular beat, are the earliest manifestations of heart involvement. Inclusion of heart enzyme serum levels and evaluation of ventricular function among predictive markers could lead to a more effective evaluation of children at risk with proper selection of those to admit to the PICU and with more adequate treatment in case of more severe clinical manifestations.

Conclusions

To appropriately manage severe pediatric COVID-19 cases, greater attention should be paid to risk factors in children and adolescents, especially to cardiovascular alterations (e.g., heart enzyme serum levels and evaluation of ventricular function). Further studies are needed and the development of a validated score based on all the most common presumed markers of disease severity seems essential.
Functional consequences of a rare missense BARD1 c.403G>A germline mutation identified in a triple-negative breast cancer patient
Authors: Zheng Yuanting , Li Bingying , Pan Dejing , Cao Jun , Zhang Jian , Wang Xiaolin , Li Xiangnan , Hou Wanwan , Bao Ding , Ren Luyao , Yang Jingcheng , Wang Shangzi , Qiu Yangyang , Zhou Fei , Liu Zhiwei , Zhu Sibo , Zhang Lei , Qing Tao , Wang Yi , Yu Ying , Wu Jiaxue , Hu Xichun , Shi Leming
Published: May 2021

We identified a rare missense germline mutation in BARD1 (c.403G>A or p.Asp135Asn) as pathogenic using integrated genomics and transcriptomics profiling of germline and tumor samples from an early-onset triple-negative breast cancer patient who later was administrated with a PARP inhibitor for 2 months. We demonstrated in cell and mouse models that, compared to the wild-type, (1) c.403G>A mutant cell lines were more sensitive to irradiation, a DNA damage agent, and a PARP inhibitor; (2) c.403G>A mutation inhibited interaction between BARD1 and RAD51 (but not BRCA1); and (3) c.403G>A mutant mice were hypersensitive to ionizing radiation. Our study shed lights on the clinical interpretation of rare germline mutations of BARD1.
Deep sequencing of pre-translational mRNPs reveals hidden flux through evolutionarily conserved alternative splicing nonsense-mediated decay pathways
Authors: Kovalak Carrie , Donovan Scott , Bicknell Alicia A. , Metkar Mihir , Moore Melissa J.
Published: May 2021

Background

Alternative splicing, which generates multiple mRNA isoforms from single genes, is crucial for the regulation of eukaryotic gene expression. The flux through competing splicing pathways cannot be determined by traditional RNA-Seq, however, because different mRNA isoforms can have widely differing decay rates. Indeed, some mRNA isoforms with extremely short half-lives, such as those subject to translation-dependent nonsense-mediated decay (AS-NMD), may be completely overlooked in even the most extensive RNA-Seq analyses.

Results

RNA immunoprecipitation in tandem (RIPiT) of exon junction complex components allows for purification of post-splicing mRNA-protein particles (mRNPs) not yet subject to translation (pre-translational mRNPs) and, therefore, translation-dependent mRNA decay. Here we compare exon junction complex RIPiT-Seq to whole cell RNA-Seq data from HEK293 cells. Consistent with expectation, the flux through known AS-NMD pathways is substantially higher than that captured by RNA-Seq. Our RIPiT-Seq also definitively demonstrates that the splicing machinery itself has no ability to detect reading frame. We identify thousands of previously unannotated splicing events; while many can be attributed to splicing noise, others are evolutionarily conserved events that produce new AS-NMD isoforms likely involved in maintenance of protein homeostasis. Several of these occur in genes whose overexpression has been linked to poor cancer prognosis.

Conclusions

Deep sequencing of RNAs in post-splicing, pre-translational mRNPs provides a means to identify and quantify splicing events without the confounding influence of differential mRNA decay. For many known AS-NMD targets, the nonsense-mediated decay-linked alternative splicing pathway predominates. Exon junction complex RIPiT-Seq also revealed numerous conserved but previously unannotated AS-NMD events.
Schema: metric learning enables interpretable synthesis of heterogeneous single-cell modalities
Authors: Singh Rohit , Hie Brian L. , Narayan Ashwin , Berger Bonnie
Published: May 2021

A complete understanding of biological processes requires synthesizing information across heterogeneous modalities, such as age, disease status, or gene expression. Technological advances in single-cell profiling have enabled researchers to assay multiple modalities simultaneously. We present Schema, which uses a principled metric learning strategy that identifies informative features in a modality to synthesize disparate modalities into a single coherent interpretation. We use Schema to infer cell types by integrating gene expression and chromatin accessibility data; demonstrate informative data visualizations that synthesize multiple modalities; perform differential gene expression analysis in the context of spatial variability; and estimate evolutionary pressure on peptide sequences.
A generalization of t-SNE and UMAP to single-cell multimodal omics
Authors: Do Van Hoan , Canzar Stefan
Published: May 2021

Emerging single-cell technologies profile multiple types of molecules within individual cells. A fundamental step in the analysis of the produced high-dimensional data is their visualization using dimensionality reduction techniques such as t-SNE and UMAP. We introduce j-SNE and j-UMAP as their natural generalizations to the joint visualization of multimodal omics data. Our approach automatically learns the relative contribution of each modality to a concise representation of cellular identity that promotes discriminative features but suppresses noise. On eight datasets, j-SNE and j-UMAP produce unified embeddings that better agree with known cell types and that harmonize RNA and protein velocity landscapes.
Serum proteomic profiling in patients with advanced Schistosoma japonicum-induced hepatic fibrosis
Authors: Huang Jing , Yin Xinguang , Zhang Lifang , Yao Ming , Wei Dahai , Wu Yiming
Published: May 2021

Background

Schistosoma japonicum is a parasitic flatworm that is the aetiological agent of human schistosomiasis, an important cause of hepatic fibrosis. Schistosomiasis-induced hepatic fibrosis is a consequence of the highly fibrogenic nature of egg-induced granulomatous lesions, which are the main pathogenic features of schistosomiasis. Although global awareness of the association between schistosomiasis-induced hepatic fibrosis and S. japonicum infection is increasing, little is known about the molecular differences associated with rapid progression to schistosomiasis in cirrhotic patients.

Methods

We systematically used data-independent acquisition (DIA)-based liquid chromatography-mass spectrometry to identify differentially expressed proteins in serum samples from patients with advanced S. japonicum-induced hepatic fibrosis.

Results

Our analysis identified 1144 proteins, among which 66 were differentially expressed between the healthy control group and the group of patients with advanced S. japonicum-induced hepatic fibrosis stage F2 (SHF-F2) and 214 were differentially expressed between the SHF-F2 and SHF-F4 groups (up- or downregulation of at least 1.5-fold in serum samples). The results also indicated that two selected proteins (C1QA and CFD) are potential biomarkers for distinguishing between patients with SHF-F2 and those with SHF-F4 due to S. japonicum infection.

Conclusions

We provide here the first global proteomic profile of serum samples from patients with advanced S. japonicum-induced hepatic fibrosis. The proteins C1QA and CFD are potential diagnostic markers for patients with SHF-F2 and SHF-F4 due to S. japonicum infection, although further large-scale studies are needed. Our DIA-based quantitative proteomic analysis revealed molecular differences among individuals at different stages of advanced S. japonicum-induced hepatic fibrosis and may provide fundamental information for further detailed investigations.

Graphical Abstract
DNA methylation profiling for molecular classification of adult diffuse lower-grade gliomas
Authors: Ferreyra Vega Sandra , Olsson Bontell Thomas , Corell Alba , Smits Anja , Jakola Asgeir Store , Carén Helena
Published: May 2021

Background

DNA methylation profiling has facilitated and improved the classification of a wide variety of tumors of the central nervous system. In this study, we investigated the potential utility of DNA methylation profiling to achieve molecular diagnosis in adult primary diffuse lower-grade glioma (dLGG) according to WHO 2016 classification system. We also evaluated whether methylation profiling could provide improved molecular characterization and identify prognostic differences beyond the classical histological WHO grade together withIDHmutation status and 1p/19q codeletion status. All patients diagnosed with dLGG in the period 2007–2016 from the Västra Götaland region in Sweden were assessed for inclusion in the study.

Results

A total of 166 dLGG cases were subjected for genome-wide DNA methylation analysis. Of these, 126 (76%) were assigned a defined diagnostic methylation class with a class prediction score ≥ 0.84 and subclass score ≥ 0.50. The assigned methylation classes were highly associated with theirIDHmutation status and 1p/19q codeletion status.IDH-wildtype gliomas were further divided into subgroups with distinct molecular features.

Conclusion

The stratification of the patients by methylation profiling was as effective as the integrated WHO 2016 molecular reclassification at predicting the clinical outcome of the patients. Our study shows that DNA methylation profiling is a reliable and robust approach for the classification of dLGG into molecular defined subgroups, providing accurate detection of molecular markers according to WHO 2016 classification.
TRPC7 regulates the electrophysiological functions of embryonic stem cell-derived cardiomyocytes
Authors: Liu Xianji , Zhao Rui , Ding Qianqian , Yao Xiaoqiang , Tsang Suk Ying
Published: May 2021

Background

Biological pacemakers consisting of pluripotent stem cell-derived cardiomyocytes are potentially useful for treating bradycardia. However, tachyarrhythmia caused by derived cardiomyocytes themselves is one of main barriers hampering their clinical translation. An in-depth understanding of the mechanisms underlying the spontaneous action potential (a.k.a. automaticity) might provide potential approaches to solve this problem. The aim of this project is to study the role of canonical transient receptor potential isoform 7 (TRPC7) channels in regulating the automaticity of embryonic stem cell-derived cardiomyocytes (ESC-CMs).

Methods and results

By Western blotting, the expression of TRPC7 was found to be increased during the differentiation of mouse ESC-CMs (mESC-CMs). Adenovirus-mediated TRPC7 knockdown decreased while overexpression increased the frequency of Ca2+transients (CaTs), local Ca2+releases (LCRs), and action potentials (APs) as detected by confocal microscopy and whole-cell patch-clamping. TRPC7 was found to be positively associated with the activity of ryanodine receptor 2 (RyR2), sarco/endoplasmic reticulum Ca2+-ATPase (SERCA), and sodium-calcium exchanger (NCX) but not hyperpolarization-activated, cyclic nucleotide-gated channel (HCN), and inositol trisphosphate receptor (IP3R). Knockdown or overexpression of TRPC7 did not alter the expression of HCN4, Cav1.3, Cav3.1, Cav3.2, IP3R1, RyR2, and SERCA but positively regulated the phosphorylation of RyR2 at S2814 and phospholamban (PLN) at T17. Moreover, the positive regulation of APs by TRPC7 was Ca2+-dependent, as overexpression of N-terminus of TRPC7 (dominant negative of TRPC7) which diminished the Ca2+permeability of TRPC7 decreased the AP frequency.

Conclusions

TRPC7 regulates the automaticity of mESC-CMs through two mechanisms. On the one hand, TRPC7 positively regulates the intracellular Ca2+clock through the regulation of activities of both RyR2 and SERCA; on the other hand, TRPC7 also positively regulates the membrane clock via its influence on NCX activity. Altogether, our study reveals that TRPC7 is a potential drug target to manipulate the action potential firing rate of pluripotent stem cell-derived cardiomyocyte-based biological pacemakers to prevent tachyarrhythmia, a condition that might be encountered after transplantation.