bluuebunny/crossref_metadata_2025_split huggingface dataset:
Noninvasive prenatal testing for assessing foetal sex chromosome aneuploidy: a retrospective study of 45,773 cases
Authors: Lu Xinran , Wang Chaohong , Sun Yuxiu , Tang Junxiang , Tong Keting , Zhu Jiansheng 
Published: January 2021

Abstract
Objective
To assess the positive predictive value (PPV) of noninvasive prenatal testing (NIPT) as a screening test for sex chromosome aneuploidy (SCA) with different maternal characteristics and prenatal decisions in positive cases.

Materials and methods
We retrospectively analysed 45,773 singleton pregnancies with different characteristics that were subjected to NIPT in the Maternity and Child Health Hospital of Anhui Province. The results were validated by karyotyping. Clinical data, diagnostic results, and data on pregnancy outcomes were collected.

Results
In total, 314 cases were SCA positive by NIPT; among those, 143 underwent invasive prenatal diagnostic testing, and 58 were true-positive. Overall, the PPVs for 45,X, 47,XXX, 47,XXY and 47,XYY were 12.5%, 51.72%, 66.67% and 83.33%, respectively. Interestingly, when only pregnant women of advanced maternal age (AMA) were screened, the PPVs for 45,X, 47,XXX, 47,XXY and 47,XYY were 23.81%, 53.33%, 78.95%, and 66.67%, respectively. The frequency of SCA was significantly higher in the AMA group than in the non-AMA group. The frequencies of 47,XXX and 47,XXY were significantly correlated with maternal age.

Conclusion
NIPT performed better in predicting sex chromosome trisomies than monosomy X, and patients with 45,X positive foetuses were more eager to terminate pregnancy than those with 47,XXX and 47,XYY. AMA may be a risk factor of having a foetus with SCA. Our findings may assist in genetic counselling of AMA pregnant women. Our pre- and posttest counselling are essential for familiarizing pregnant women with the benefits and limitations of NIPT, which may ease their anxiety and enable them to make informed choices for further diagnosis and pregnancy decisions.
Cystic fibrosis in Tuscany: evolution of newborn screening strategies over time to the present
Authors: Botti Matteo , Terlizzi Vito , Francalanci Michela , Dolce Daniela , Cavicchi Maria Chiara , Neri Anna Silvia , Galici Valeria , Mergni Gianfranco , Zavataro Lucia , Centrone Claudia , Festini Filippo , Taccetti Giovanni 
Published: January 2021

AbstractBackgroundCystic fibrosis (CF) is a life-threatening disease affecting about 1:3000 newborns in Caucasian populations. The introduction of newborn screening for cystic fibrosis (CF NBS) has improved the clinical outcomes of individuals with CF through early diagnosis and early treatment. NBS strategies have been implemented over time. CF NBS was introduced extensively in 1984 in Tuscany, a region with 3.7 million people, characterized by a high allelic heterogeneity of CFTR gene.Aim and methodsThe aim of the study is to present the results from 34 years (1984–2018) of CF NBS, retrospectively evaluating the sensitivity, specificity and predictive values of the tests. In particular, we studied the impact of the introduction of DNA molecular analysis in NBS in a region with high allelic heterogeneity, such as Tuscany.ResultsOver these 34 years, 919,520 neonates were screened, using four different NBS strategies. From 1984 to 1991, CF NBS was performed by the determination of albumin on dried meconium (sensitivity 68.75%; specificity 99.82%). Subsequently, the analysis of immunoreactive trypsinogen on a blood spot was adopted as CF NBS protocol (sensitivity 83.33%; specificity 99.77%). From 1992 to 2010, this strategy was associated with lactase meconium dosage:IRT1/IRT2 + LACT protocol(sensitivity 87.50%; specificity 99.82%). From 2011, when the existing algorithm was integrated by analysis of CF causing variants of the CFTR gene (IRT1/IRT2 + LACT + IRT1/DNA protocol), a substantial improvement in sensitivity was seen (senisitivity 96.15%; specificity 99.75%). Other improved parameters with DNA analysis in the NBS programme, compared with the previous method, were the diagnosis time (52 days vs. 38 days) and the recall rate (0.58 to 0.38%).ConclusionThe inclusion of DNA analysis in the NBS was a fundamental step in improving sensitivity, even in a region with high allelic variability.
Synchronous choroid plexus papilloma and Wilms tumor in a girl, disclosing a Li-Fraumeni syndrome
Authors: Cruz Ofelia , Caloretti Victoria , Salvador Hector , Celis Veronica , Santa-Maria Vicente , Morales La Madrid Andrés , Suñol Mariona , Puerta Patricia , Muchart Jordi , Krauel Lucas , Lavarino Cinzia 
Published: January 2021

Abstract
Background
Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome characterized by the early-onset of multiple primary cancers which can occur at different moments (metachronous onset) or, more rarely, coincidentally (synchronous onset). Here we describe a previously unreported patient with presentation of synchronous Wilms tumor and Choroid plexus papilloma, leading to the diagnosis of a Li-Fraumeni Syndrome (LFS).

Case presentation
A 6-year-old girl without previous complains presented with abdominal pain. Abdominal US and MRI showed a left renal tumor with subcapsular hematoma. Due to mild headaches, the diagnostic workup included a brain MRI that unexpectedly identified a large left parietal lobe tumor. Histopathological analysis determined the diagnosis of classic Wilms tumor and choroid-plexus papilloma (CPP), respectively. Both neoplasms showed intense nuclear p53 immunostaining associated with the pathogenic TP53 mutation c.844C > T (p.Arg282Trp). Our patient and her father shared the same heterozygous germline TP53 mutation, confirming the diagnosis of familiar Li-Fraumeni syndrome in the girl. The treatment was tailored to simultaneous tumor presentations.

Conclusions
LFS has been associated with Choroid plexus carcinoma (CPC), but rarely with CPP as in our patient. That suggests that it may be advisable to consider the possibility of analyzing TP53 mutation, not only in all patients with CPC, but also in some patients with CPP, especially when histological or clinical evidences point out to perform this study. The dissimilar presentation of LFS among our patient’s father, not having so far any neoplasia diagnosed, while her daughter presented precociously with two simultaneous different tumors, could be related to possible effects of modifier genes on the underlying mutant p53 genotype.
Mechanical power during extracorporeal membrane oxygenation and hospital mortality in patients with acute respiratory distress syndrome
Authors: Chiu Li-Chung , Lin Shih-Wei , Chuang Li-Pang , Li Hsin-Hsien , Liu Pi-Hua , Tsai Feng-Chun , Chang Chih-Hao , Hung Chen-Yiu , Lee Chung-Shu , Leu Shaw-Woei , Hu Han-Chung , Huang Chung-Chi , Wu Huang-Pin , Kao Kuo-Chin 
Published: January 2021

Abstract
Background
Mechanical power (MP) refers to the energy delivered by a ventilator to the respiratory system per unit of time. MP referenced to predicted body weight (PBW) or respiratory system compliance have better predictive value for mortality than MP alone in acute respiratory distress syndrome (ARDS). Our objective was to assess the potential impact of consecutive changes of MP on hospital mortality among ARDS patients receiving extracorporeal membrane oxygenation (ECMO).

Methods
We performed a retrospective analysis of patients with severe ARDS receiving ECMO in a tertiary care referral center in Taiwan between May 2006 and October 2015. Serial changes of MP during ECMO were recorded.

Results
A total of 152 patients with severe ARDS rescued with ECMO were analyzed. Overall hospital mortality was 53.3%. There were no significant differences between survivors and nonsurvivors in terms of baseline values of MP or other ventilator settings. Cox regression models demonstrated that mean MP alone, MP referenced to PBW, and MP referenced to compliance during the first 3 days of ECMO were all independently associated with hospital mortality. Higher MP referenced to compliance (HR 2.289 [95% CI 1.214–4.314], p = 0.010) was associated with a higher risk of death than MP itself (HR 1.060 [95% CI 1.018–1.104], p = 0.005) or MP referenced to PBW (HR 1.004 [95% CI 1.002–1.007], p < 0.001). The 90-day hospital mortality of patients with high MP (> 14.4 J/min) during the first 3 days of ECMO was significantly higher than that of patients with low MP (≦ 14.4 J/min) (70.7% vs. 46.8%, p = 0.004), and the 90-day hospital mortality of patients with high MP referenced to compliance (> 0.53 J/min/ml/cm H2O) during the first 3 days of ECMO was significantly higher than that of patients with low MP referenced to compliance (≦ 0.53 J/min/ml/cm H2O) (63.6% vs. 29.7%, p < 0.001).

Conclusions
MP during the first 3 days of ECMO was the only ventilatory variable independently associated with 90-day hospital mortality, and MP referenced to compliance during ECMO was more predictive for mortality than was MP alone.
Acquired mutations and transcriptional remodeling in long-term estrogen-deprived locoregional breast cancer recurrences
Authors: Priedigkeit Nolan , Ding Kai , Horne William , Kolls Jay K. , Du Tian , Lucas Peter C. , Blohmer Jens-Uwe , Denkert Carsten , Machleidt Anna , Ingold-Heppner Barbara , Oesterreich Steffi , Lee Adrian V. 
Published: January 2021

Abstract
Background
Endocrine therapy resistance is a hallmark of advanced estrogen receptor (ER)-positive breast cancer. In this study, we aimed to determine acquired genomic changes in endocrine-resistant disease.

Methods
We performed DNA/RNA hybrid-capture sequencing on 12 locoregional recurrences after long-term estrogen deprivation and identified acquired genomic changes versus each tumor’s matched primary.

Results
Despite being up to 7 years removed from the primary lesion, most recurrences harbored similar intrinsic transcriptional and copy number profiles. Only two genes, AKAP9 and KMT2C, were found to have single nucleotide variant (SNV) enrichments in more than one recurrence. Enriched mutations in single cases included SNVs within transcriptional regulators such as ARID1A, TP53, FOXO1, BRD1, NCOA1, and NCOR2 with one local recurrence gaining three PIK3CA mutations. In contrast to DNA-level changes, we discovered recurrent outlier mRNA expression alterations were common—including outlier gains in TP63 (n = 5 cases [42%]), NTRK3 (n = 5 [42%]), NTRK2 (n = 4 [33%]), PAX3 (n = 4 [33%]), FGFR4 (n = 3 [25%]), and TERT (n = 3 [25%]). Recurrent losses involved ESR1 (n = 5 [42%]), RELN (n = 5 [42%]), SFRP4 (n = 4 [33%]), and FOSB (n = 4 [33%]). ESR1-depleted recurrences harbored shared transcriptional remodeling events including upregulation of PROM1 and other basal cancer markers.

Conclusions
Taken together, this study defines acquired genomic changes in long-term, estrogen-deprived disease; highlights the importance of longitudinal RNA profiling; and identifies a common ESR1-depleted endocrine-resistant breast cancer subtype with basal-like transcriptional reprogramming.
A comparison of approaches for combining predictive markers for personalised treatment recommendations
Authors: Pierce Matthias , Emsley Richard 
Published: January 2021

Abstract
Background
In the presence of heterogeneous treatment effects, it is desirable to divide patients into subgroups based on their expected response to treatment. This is formalised via a personalised treatment recommendation: an algorithm that uses biomarker measurements to select treatments. It could be that multiple, rather than single, biomarkers better predict these subgroups. However, finding the optimal combination of multiple biomarkers can be a difficult prediction problem.

Methods
We described three parametric methods for finding the optimal combination of biomarkers in a personalised treatment recommendation, using randomised trial data: a regression approach that models outcome using treatment by biomarker interactions; an approach proposed by Kraemer that forms a combined measure from individual biomarker weights, calculated on all treated and control pairs; and a novel modification of Kraemer’s approach that utilises a prognostic score to sample matched treated and control subjects. Using Monte Carlo simulations under multiple data-generating models, we compare these approaches and draw conclusions based on a measure of improvement under a personalised treatment recommendation compared to a standard treatment. The three methods are applied to data from a randomised trial of home-delivered pragmatic rehabilitation versus treatment as usual for patients with chronic fatigue syndrome (the FINE trial). Prior analysis of this data indicated some treatment effect heterogeneity from multiple, correlated biomarkers.

Results
The regression approach outperformed Kraemer’s approach across all data-generating scenarios. The modification of Kraemer’s approach leads to improved treatment recommendations, except in the case where there was a strong unobserved prognostic biomarker. In the FINE example, the regression method indicated a weak improvement under its personalised treatment recommendation algorithm.

Conclusions
The method proposed by Kraemer does not perform better than a regression approach for combining multiple biomarkers. All methods are sensitive to misspecification of the parametric models.
Reporting guidelines for clinical trials of artificial intelligence interventions: the SPIRIT-AI and CONSORT-AI guidelines
Authors: Ibrahim Hussein , Liu Xiaoxuan , Rivera Samantha Cruz , Moher David , Chan An-Wen , Sydes Matthew R. , Calvert Melanie J. , Denniston Alastair K. 
Published: January 2021

Abstract
Background
The application of artificial intelligence (AI) in healthcare is an area of immense interest. The high profile of ‘AI in health’ means that there are unusually strong drivers to accelerate the introduction and implementation of innovative AI interventions, which may not be supported by the available evidence, and for which the usual systems of appraisal may not yet be sufficient.

Main text
We are beginning to see the emergence of randomised clinical trials evaluating AI interventions in real-world settings. It is imperative that these studies are conducted and reported to the highest standards to enable effective evaluation because they will potentially be a key part of the evidence that is used when deciding whether an AI intervention is sufficiently safe and effective to be approved and commissioned. Minimum reporting guidelines for clinical trial protocols and reports have been instrumental in improving the quality of clinical trials and promoting completeness and transparency of reporting for the evaluation of new health interventions. The current guidelines—SPIRIT and CONSORT—are suited to traditional health interventions but research has revealed that they do not adequately address potential sources of bias specific to AI systems. Examples of elements that require specific reporting include algorithm version and the procedure for acquiring input data. In response, the SPIRIT-AI and CONSORT-AI guidelines were developed by a multidisciplinary group of international experts using a consensus building methodological process. The extensions include a number of new items that should be reported in addition to the core items. Each item, where possible, was informed by challenges identified in existing studies of AI systems in health settings.

Conclusion
The SPIRIT-AI and CONSORT-AI guidelines provide the first international standards for clinical trials of AI systems. The guidelines are designed to ensure complete and transparent reporting of clinical trial protocols and reports involving AI interventions and have the potential to improve the quality of these clinical trials through improvements in their design and delivery. Their use will help to efficiently identify the safest and most effective AI interventions and commission them with confidence for the benefit of patients and the public.
A fixed nitrous oxide/oxygen mixture as an analgesic for patients with postherpetic neuralgia: study protocol for a randomized controlled trial
Authors: Gao Hai-Xiang , Zhang Jun-Jun , Liu Ning , Wang Yi , Ma Chun-Xiang , Gao Lu-Lu , Liu Qiang , Zhang Ting-Ting , Wang Yi-Ling , Bao Wen-Qiang , Li Yu-Xiang 
Published: January 2021

Abstract
Background
The pain management of postherpetic neuralgia (PHN) remains a major challenge, with no immediate relief. Nitrous oxide/oxygen mixture has the advantages of quick analgesic effect and well-tolerated. The purpose of this study is to investigate the analgesic effect and safety of nitrous oxide/oxygen mixture in patients with PHN.

Methods/design
This study is a single-center, two-group (1:1), randomized, placebo-controlled, double-blind clinical trial. A total of 42 patients with postherpetic neuralgia will be recruited and randomly divided into the intervention group and the control group. The control group will receive routine treatment plus oxygen, and the intervention group will receive routine treatment plus nitrous oxide/oxygen mixture. Data collectors, patients, and clinicians are all blind to the therapy. The outcomes of each group will be monitored at baseline (T0), 5 min (T1), and 15 min (T2) after the start of the therapy and at 5 min after the end of the therapy (T3). The primary outcome measure will be the pain intensity. Secondary outcomes included physiological parameters, adverse effects, patients’ acceptance of analgesia, and satisfaction from patients.

Discussion
Previous studies have shown that nitrous oxide/oxygen mixture can effectively relieve cancer patients with breakthrough pain. This study will explore the analgesic effect of oxide/oxygen mixture on PHN. If beneficial to patients with PHN, it will contribute to the pain management of PHN.

Trial registration
Chinese Clinical Trial Register ChiCTR1900023730. Registered on 9 June 2019
Lymphocyte subset abnormalities in early diffuse cutaneous systemic sclerosis
Authors: Fox David A. , Lundy Steven K. , Whitfield Michael L. , Berrocal Veronica , Campbell Phillip , Rasmussen Stephanie , Ohara Ray , Stinson Alexander , Gurrea-Rubio Mikel , Wiewiora Evan , Spino Catherine , Bush Erica , Furst Daniel , Pillai Shiv , Khanna Dinesh 
Published: January 2021

Abstract
Background
Abnormalities in lymphocyte surface markers and functions have been described in systemic sclerosis (SSc), but conflicting results abound, and these studies often examined patients with heterogeneous disease duration, severity, clinical phenotype, and concurrent immunosuppressive agents. We studied a clinically homogeneous group of early diffuse cutaneous SSc patients not exposed to immunosuppressive drugs who were enrolled in a clinical trial and compared their immune parameters to healthy control subjects.

Methods
Lymphocyte subsets were enumerated by multi-parameter flow cytometry of peripheral blood mononuclear cells at baseline visit. Production of the cytokines IL-4 and IL-17 was measured by intracellular flow cytometry following T cell activation.

Results
SSc patients had increased percentages of CD4+ T cells but lower percentages of CD8+ T cells versus controls. The CD28-negative population was expanded in SSc, in the CD4 subset. Striking expansion of CD319+ T cells was noted among the CD4+ cells, in which they were barely detectable in healthy subjects. Frequencies of IL-4 producing cells did not differ between SSc and controls, but expansion of IL-17 producing cells was observed in SSc. A higher proportion of CD319+ cells produced cytokines, compared to other CD4+ cells. Numbers of activated T cells, regulatory T cells, and B cells were similar in SSc and control groups. Circulating follicular helper but not peripheral helper T cells were slightly expanded in SSc.

Conclusion
In this carefully selected group of early diffuse cutaneous SSc patients, analysis of immune cell parameters has identified abnormalities that likely reflect disease pathogenesis and that are candidate biomarkers for sub-classification and targeted treatment. The CD4+CD319+ (SLAM-F7+) cells are cytotoxic and oligoclonal, were recently shown to be a dominant T cell population in perivascular lymphocytic infiltrates in SSc skin, actively secrete cytokines, and are emerging as a target for novel treatments of SSc.
Catechin synergistically potentiates mast cell-stabilizing property of caffeine
Authors: Yashima Misaki , Sato Yukine , Kazama Itsuro 
Published: January 2021

AbstractCaffeine and catechin, contained in coffee and tea, are commonly consumed substances worldwide. Studies revealed their health promoting functions, such as anti-oxidant, anti-cancer and anti-bacterial properties. Additionally, studies also revealed their roles in ameliorating the symptoms of allergic disorders, indicating their anti-allergic properties. In the present study, using the differential-interference contrast (DIC) microscopy, we examined the effects of caffeine and catechin on the degranulation from rat peritoneal mast cells. Both caffeine and catechin dose-dependently decreased the numbers of degranulating mast cells. At concentrations equal to or higher than 25 mM, caffeine and catechin markedly suppressed the numbers of degranulating mast cells. In contrast, at relatively lower concentrations, both substances did not significantly affect the numbers of degranulating mast cells. However, surprisingly enough, low concentrations of catechin (1, 2.5 mM) synergistically enhanced the suppressive effect of 10 mM caffeine on mast cell degranulation. These results provided direct evidence for the first time that caffeine and catechin dose-dependently inhibited the process of exocytosis. At relatively lower concentrations, caffeine or catechin alone did not stabilize mast cells. However, low concentrations of catechin synergistically potentiated the mast cell-stabilizing property of caffeine.
Three cases of BRAF mutation negative Erdheim-Chester disease with a challenging distinction from IgG4-related disease
Authors: Spoerl David , André Raphaël , Bornand Aurélie , Seebach Jörg D. 
Published: January 2021

Abstract
Background
Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytosis with slow progression over the years that is particularly difficult to diagnose.

Cases
Here we report three cases of ECD without BRAF mutation presenting with a renal mass, hairy kidney appearance, and a rather benign course, for which the diagnosis of ECD was delayed, characterized by multiple investigations and unsuccessful treatments attempts. In two cases the distinction from IgG4-related disease required multiple investigations and reevaluation of the clinical, radiological, histological, and immunological characteristics.

Conclusion
A correct diagnosis of ECD may take several years and often requires revisiting previous hypotheses. Reassessment of histological slides and more modern complementary exams such as PET-CT or BRAF and MAPK-ERK mutation analysis can help to confirm the diagnosis of ECD and to select effective therapy.