bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of 68Ga-DOTANOC and 18F-FDG PET-CT Scans in the Evaluation of Primary Tumors and Lymph Node Metastasis in Patients With Rectal Neuroendocrine Tumors
Authors: Zhou Zhihao , Wang Zhixiong , Zhang Bing , Wu Yanzhang , Li Guanghua , Wang Zhao 
Published: September 2021

BackgroundLymph node metastasis of rectal neuroendocrine tumors (RNETs) predicts poor prognosis. However, the assessment of lymph node metastasis remains a challenge. It has been reported that 68Ga-DOTANOC and 18F-FDG PET-CT scans could be employed in the work-up of rectal neuroendocrine tumors (RNETs). This study aimed to assess both tracers’ ability to identify primary tumors and lymph node (LN) metastasis in RNETs.MethodsA total of 537 patients with RNETs were enrolled from January 2014 to January 2021. Both 68Ga-DOTANOC and 18F-FDG PET-CT scans were used to evaluate primary tumors and LN group metastasis. PET images were evaluated through visual and semiquantitative assessment. Receiver Operating Characteristics (ROC) curve analysis was used to investigate the performance of SUVmax of 68Ga-DOTANOC and 18F-FDG PET in predicting LN group metastasis.ResultsFifty-two patients with preoperative 68Ga-DOTANOC with 18F-FDG PET-CT scans underwent endoscopic biopsy or dissection of the primary tumor, while 11 patients underwent rectal surgery together with regional LN dissection. For primary tumors, 68Ga-DOTANOC had a sensitivity of 89.58% and a positive predictive value (PPV) of 95.56% through visual assessment, while 18F-FDG PET-CT showed 77.08% sensitivity and 97.37% PPV. For the prediction of LN group metastasis, 68Ga-DOTANOC PET-CT had 77.78% sensitivity and 91.67% specificity, while 18F-FDG PET-CT had 38.89% sensitivity and 100% specificity according to visual assessment. The area under the ROC curves (AUC) for 68Ga-DOTANOC PET/CT was 0.852 (95%CI:0.723-0.981) with an optimal SUVmax cut-off value of 2.25, while the AUC for 18F-FDG PET were 0.664 (95%CI:0.415-0.799) with an optimal SUVmax cut-off value of 1.05.ConclusionsThis study showed that 68Ga-DOTANOC PET-CT was a promising tool for detecting LN metastasis in RNETs with high sensitivity and specificity in visual assessment and semiquantitative assessment, which was better than 18F-FDG PET-CT.
Web-Based Ultrasonic Nomogram Predicts Preoperative Central Lymph Node Metastasis of cN0 Papillary Thyroid Microcarcinoma
Authors: Huang Chunwang , Cong Shuzhen , Shang Shiyao , Wang Manli , Zheng Huan , Wu Suqing , An Xiuyan , Liang Zhaoqiu , Zhang Bo 
Published: September 2021

BackgroundMany clinicians are facing the dilemma about whether they should apply the active surveillance (AS) strategy for managing Clinically Node-negative (cN0) PTMC patients in daily clinical practice. This research plans to construct a dynamic nomogram based on network, connected with ultrasound characteristics and clinical data, to predict the risk of central lymph node metastasis (CLNM) in cN0 PTMC patients before surgery.MethodsA retrospective analysis of 659 patients with cN0 PTMC who had underwent thyroid surgery and central compartment neck dissection. Patients were randomly (2:1) divided into the development cohort (439 patients) and validation cohort (220 patients). The group least absolute shrinkage and selection operator (Group Lasso) regression method was used to select the ultrasonic features for CLNM prediction in the development cohort. These features and clinical data were screened by the multivariable regression analysis, and the CLNM prediction model and web-based calculator were established. Receiver operating characteristic, calibration curve, Clinical impact curve and decision curve analysis (DCA) were used to weigh the performance of the prediction model in the validation set.ResultsMultivariable regression analysis showed that age, tumor size, multifocality, the number of contact surface, and real-time elastography were risk factors that could predict CLNM. The area under the curve of the prediction model in the development and validation sets were 0.78 and 0.77, respectively, with good discrimination and calibration. A web-based dynamic calculator was built. DCA proved that the prediction model had excellent net benefits and clinical practicability.ConclusionsThe web-based dynamic nomogram incorporating US and clinical features was able to forecast the risk of preoperative CLNM in cN0 PTMC patients, and has good predictive performance. As a new observational indicator, NCS can provide additional predictive information.
Diagnostic Accuracy of Female Pelvic Ultrasonography in Differentiating Precocious Puberty From Premature Thelarche: A Systematic Review and Meta-analysis
Authors: Nguyen Nam Nhat , Huynh Linh Ba Phuong , Do Minh Duc , Yang Tien Yun , Tsai Meng-Che , Chen Yang-Ching 
Published: September 2021

BackgroundThe gonadotropin-releasing hormone (GnRH) stimulation test is the benchmark for diagnosing precocious puberty (PP). However, it is invasive, time-consuming, costly, and may create an unpleasant experience for participants. Moreover, some overlaps may occur between PP and premature thelarche (PT) in the early stage of PP. Female pelvic ultrasonography may provide additional information to help differentiate PP from PT and subsequently initiate early treatment. In this study, we aimed to first directly compare pelvic ultrasonography parameters between PP and PT groups and secondly, investigate their diagnostic accuracy compared with the GnRH stimulation test.MethodsA systematic search of the PubMed/MEDLINE, EMBASE, Scopus, and Cochrane Library databases was performed up to March 31, 2021. All types of studies, except for case reports and review articles, were included. The GnRH stimulation test was used to confirm PP diagnosis. Those whose organic conditions might cause PP were excluded. The mean, standard deviation, sensitivity, and specificity of each parameter were documented. Forest plots were constructed to display the estimated standardized mean differences (SMDs) from each included study and the overall calculations. A bivariate model was used to calculate the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR).ResultsA total of 13 studies were included for analysis. The SMDs (95% confidence interval – CI) in ovarian volume, fundal-cervical ratio, uterine length, uterine cross-sectional area, and uterine volume between PP and PT groups were 1.12 (0.78–1.45; p &lt; 0.01), 0.90 (0.07–1.73; p = 0.03), 1.38 (0.99–1.78; p &lt; 0.01), 1.06 (0.61–1.50; p &lt; 0.01), and 1.21 (0.84–1.58; p &lt;0.01), respectively. A uterine length of 3.20 cm yielded a pooled sensitivity of 81.8% (95% CI 78.3%–84.9%), specificity of 82.0% (95% CI 61.0%–93.0%), PLR of 4.56 (95% CI 2.15–9.69), NLR of 0.26 (95% CI 0.17–0.39), and DOR of 19.62 (95% CI 6.45–59.68). The area under the summary receiver operating characteristics curve was 0.82.ConclusionFemale pelvic ultrasonography may serve as a complementary tool to the GnRH stimulation test in differentiating PP from PT.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021232427, ID: CRD42021232427.
Clinical Characteristics and Follow-Up of 19 Children With Hashimoto’s Thyroiditis Aged Below 3 Years: A Single-Center Retrospective Analysis
Authors: Tang Shi , Yang Min , Zhang Dan , Tong Ya-jie , Xin Ying 
Published: September 2021

AimTo analyze the clinical characteristics of Hashimoto’s thyroiditis (HT) in children below 3 years of age in order to improve the understanding of the disease, avoid misdiagnosis, and achieve early diagnosis and treatment.MethodsThe study retrospectively analyzed the clinical data of 19 patients diagnosed with HT in the first three years of life.ResultsThe patients (12 female, 7 male) had an average age of 26.1 ± 8.2 months (range 10–36 months). At presentation, one patient had euthyroidism, ten had hypothyroidism, seven had subclinical hypothyroidism, and one had hyperthyroidism. The most common reasons for doctor’s visits were thyroid enlargement (21.1%), global developmental delay (21.1%), and routine thyroid function tests in patients with type 1 diabetes (26.3%). Sixteen patients provided follow-up data, and the mean follow-up time was 23.31 ± 16.44 months (range 1–48 months). In the hypothyroidism group, one patient stopped levothyroxine (LT4) treatment after 2 months; the remaining patients had been treated with LT4 since their diagnosis. In the subclinical hypothyroidism group, one patient whose thyroid function returned to normal after 1 month of being diagnosed was not treated. The remaining patients received LT4 treatment at their diagnosis or during follow-up. The patient with hyperthyroidism was treated with methimazole after diagnosis, but treatment was discontinued 11 months later and LT4 was initiated 26 months after diagnosis. One in four patients with global developmental delay approached normal mental development after LT4 treatment. Four in six patients with short stature achieved height catch-up.ConclusionAt their initial HT diagnosis, most of the children showed hypothyroidism or subclinical hypothyroidism. Children with global developmental delay require continual screening, even if the thyroid function is normal after birth, to determine whether they have HT-induced hypothyroidism. Thyroxine replacement could partially relieve the clinical manifestations of hypothyroidism and early diagnosis and treatment are essential for improving patient prognosis.
Hologene 5: A Phase II/III Clinical Trial of Combined Cell and Gene Therapy of Junctional Epidermolysis Bullosa
Authors: De Rosa Laura , Enzo Elena , Zardi Giulia , Bodemer Christine , Magnoni Cristina , Schneider Holm , De Luca Michele 
Published: September 2021

Epidermolysis bullosa (EB) is a group of devastating genetic diseases characterized by skin and mucosal fragility and formation of blisters, which develop either spontaneously or in response to minor mechanical trauma. There is no definitive therapy for any form of EB. Intermediate junctional EB (JEB) caused by mutations in the gene LAMB3 has been the first genetic skin disease successfully tackled by ex vivo gene therapy. Here, we present a multicenter, open-label, uncontrolled phase II/III study that aims at confirming the efficacy of Hologene 5, a graft consisting of cultured transgenic keratinocytes and epidermal stem cells and meant to combine cell and gene therapy for the treatment of LAMB3-related JEB. Autologous clonogenic keratinocytes will be isolated from patients’ skin biopsies, genetically corrected with a gamma-retroviral vector (γRV) carrying the full-length human LAMB3 cDNA and plated onto a fibrin support (144cm2). The transgenic epidermis will be transplanted onto surgically prepared selected skin areas of at least six JEB patients (four pediatric and two adults). Evaluation of clinical efficacy will include, as primary endpoint, a combination of clinical parameters, such as percentage of re-epithelialization, cellular, molecular, and functional parameters, mechanical stress tests, and patient-reported outcome (PRO), up to 12months after transplantation. Safety and further efficacy endpoints will also be assessed during the clinical trial and for additional 15years in an interventional non-pharmacological follow-up study. If successful, this clinical trial would provide a therapeutic option for skin lesions of JEB patients with LAMB3 mutations and pave the way to a combined cell and gene therapy platform tackling other forms of EB and different genodermatoses.Clinical Trial Registration: EudraCT Number: 2018-000261-36.
From Infection to Immunity: Understanding the Response to SARS-CoV2 Through In-Silico Modeling
Authors: Castiglione Filippo , Deb Debashrito , Srivastava Anurag P. , Liò Pietro , Liso Arcangelo 
Published: September 2021

BackgroundImmune system conditions of the patient is a key factor in COVID-19 infection survival. A growing number of studies have focused on immunological determinants to develop better biomarkers for therapies.AimStudies of the insurgence of immunity is at the core of both SARS-CoV-2 vaccine development and therapies. This paper attempts to describe the insurgence (and the span) of immunity in COVID-19 at the population level by developing an in-silico model. We simulate the immune response to SARS-CoV-2 and analyze the impact of infecting viral load, affinity to the ACE2 receptor, and age in an artificially infected population on the course of the disease.MethodsWe use a stochastic agent-based immune simulation platform to construct a virtual cohort of infected individuals with age-dependent varying degrees of immune competence. We use a parameter set to reproduce known inter-patient variability and general epidemiological statistics.ResultsBy assuming the viremia at day 30 of the infection to be the proxy for lethality, we reproduce in-silico several clinical observations and identify critical factors in the statistical evolution of the infection. In particular, we evidence the importance of the humoral response over the cytotoxic response and find that the antibody titers measured after day 25 from the infection are a prognostic factor for determining the clinical outcome of the infection. Our modeling framework uses COVID-19 infection to demonstrate the actionable effectiveness of modeling the immune response at individual and population levels. The model developed can explain and interpret observed patterns of infection and makes verifiable temporal predictions. Within the limitations imposed by the simulated environment, this work proposes quantitatively that the great variability observed in the patient outcomes in real life can be the mere result of subtle variability in the infecting viral load and immune competence in the population. In this work, we exemplify how computational modeling of immune response provides an important view to discuss hypothesis and design new experiments, in particular paving the way to further investigations about the duration of vaccine-elicited immunity especially in the view of the blundering effect of immunosenescence.
Function of Protein S-Palmitoylation in Immunity and Immune-Related Diseases
Authors: Zhang Yuqi , Qin Ziran , Sun Wenhuan , Chu Feng , Zhou Fangfang 
Published: September 2021

Protein S-palmitoylation is a covalent and reversible lipid modification that specifically targets cysteine residues within many eukaryotic proteins. In mammalian cells, the ubiquitous palmitoyltransferases (PATs) and serine hydrolases, including acyl protein thioesterases (APTs), catalyze the addition and removal of palmitate, respectively. The attachment of palmitoyl groups alters the membrane affinity of the substrate protein changing its subcellular localization, stability, and protein-protein interactions. Forty years of research has led to the understanding of the role of protein palmitoylation in significantly regulating protein function in a variety of biological processes. Recent global profiling of immune cells has identified a large body of S-palmitoylated immunity-associated proteins. Localization of many immune molecules to the cellular membrane is required for the proper activation of innate and adaptive immune signaling. Emerging evidence has unveiled the crucial roles that palmitoylation plays to immune function, especially in partitioning immune signaling proteins to the membrane as well as to lipid rafts. More importantly, aberrant PAT activity and fluctuations in palmitoylation levels are strongly correlated with human immunologic diseases, such as sensory incompetence or over-response to pathogens. Therefore, targeting palmitoylation is a novel therapeutic approach for treating human immunologic diseases. In this review, we discuss the role that palmitoylation plays in both immunity and immunologic diseases as well as the significant potential of targeting palmitoylation in disease treatment.
Molecular Insights Into Neutrophil Biology From the Zebrafish Perspective: Lessons From CD18 Deficiency
Authors: Bader Almke , Gao Jincheng , Rivière Thibaud , Schmid Bettina , Walzog Barbara , Maier-Begandt Daniela 
Published: September 2021

Neutrophils are key players in innate immunity and originate from the bone marrow of the adult mammalian organism. In mammals, mature neutrophils are released from the bone marrow into the peripheral blood where they circulate until their recruitment to sites of inflammation in a multistep adhesion cascade. Here, adhesion molecules of the β2integrin family (CD11/CD18) are critically required for the initial neutrophil adhesion to the inflamed endothelium and several post-adhesion steps allowing their extravasation into the inflamed tissue. Within the mammalian tissue, interstitial neutrophil migration can occur widely independent of β2integrins. This is in sharp contrast to neutrophil recruitment in zebrafish larvae (Danio rerio) where neutrophils originate from the caudal hematopoietic tissue and mainly migrate interstitially to sites of lesion upon the early onset of inflammation. However, neutrophils extravasate from the circulation to the inflamed tissue in zebrafish larvae at later-time points. Although zebrafish larvae are a widely accepted model system to analyze neutrophil traffickingin vivo, the functional impact of β2 integrins for neutrophil trafficking during acute inflammation is completely unknown in this model. In this study, we generated zebrafish with a genetic deletion of CD18, the β subunit of β2integrins, using CRISPR/Cas9 technology. Sequence alignments demonstrated a high similarity of the amino acid sequences between zebrafish and human CD18 especially in the functionally relevant I-like domain. In addition, the cytoplasmic domain of CD18 harbors two highly conserved NXXF motifs suggesting that zebrafish CD18 may share functional properties of human CD18. Accordingly, CD18 knock-out (KO) zebrafish larvae displayed the key symptoms of patients suffering from leukocyte adhesion deficiency (LAD) type I due to defects inITGB2, the gene for CD18. Importantly, CD18 KO zebrafish larvae showed reduced neutrophil trafficking to sites of sterile inflammation despite the fact that an increased number of neutrophils was detectable in the circulation. By demonstrating the functional importance of CD18 for neutrophil trafficking in zebrafish larvae, our findings shed new light on neutrophil biology in vertebrates and introduce a new model organism for studying LAD type I.
Will the Inducing and Maintaining Remission of Non-biological Agents and Biological Agents Differ for Crohn's Disease? The Evidence From the Network Meta-Analysis
Authors: Rui Mingjun , Fei Zhengyang , Wang Yingcheng , Shi Fenghao , Meng Rui , Shang Ye , Ma Aixia , Li Hongchao 
Published: September 2021

Background: Several drugs currently are available for the treatment of Crohn's disease, including non-biological agents such as anti-inflammatory agents, steroids, immunosuppressive agents, and biologic agents such as anti-tumor necrosis factor (TNF), anti-α4β7 integrin, anti-alpha-4 integrin and anti-interleukin 12/23. However, the choice of treatments for induction and maintenance is still a challenge. The relevant comparison between non-biologic agents and biologic agents is few. In our research, we aimed to help making decisions, as well as providing clinicians and patients with medication references.Methods: We searched MEDLINE, Embase, and the Cochrane Central Register of controlled trials for relevant randomized controlled trials published through to July 2020 and systematic reviews published from January 2011 to December 2020. Search results were screened by 2 independent reviewers first by title and abstract and then by full text. Disagreements were resolved through discussion with a third reviewer.Results: 54 randomized controlled trials were included in our analysis. For induction of remission, azathioprine (OR, 3.5; 95% Crl, 1.4–8.9), infliximab (OR, 4.1; 95% Crl, 1.2–16.0), infliximab + azathioprine (OR, 7.0; 95% Crl, 1.2–41.0) and infliximab+ methotrexate (OR, 7.8; 95% Crl, 1.2–65.0) were more effective in first-line therapy than placebo. Adalimumab showed superiority to placebo in second-line therapy, but the range of SD was wide. For maintenance of remission, adalimumab (OR,2.24;95% Crl,1.17–4.76) and azathioprine (OR,2.05; 95% Crl,1.14–3.96) were more effective than placebo. Adalimumab (OR,0.56; 95%Crl,0.27–1.2), budesonide (OR,0.63; 95%Crl,0.26–1.6) and natalizumab (OR,0.65; 95%Crl,0.30–1.4) was associated with less risk of withdrawals when compared with placebo.Conclusion: For induction of remission, azathioprine, infliximab, and infliximab + azathioprine were more effective in first-line therapy. In second-line therapy, adalimumab was more effective but should be interpreted carefully. For maintenance of remission, adalimumab and azathioprine were more effective. Besides, adalimumab, budesonide, natalizumab had lower withdrawals. Therefore, biological agents were not always better than non-biological agents and they have their own advantages in different treatment methods of Crohn's disease.
Systematic Review on the Efficacy and Safety of Oral Janus Kinase Inhibitors for the Treatment of Atopic Dermatitis
Authors: Le Michelle , Berman-Rosa Melissa , Ghazawi Feras M. , Bourcier Marc , Fiorillo Loretta , Gooderham Melinda , Guenther Lyn , Hanna Sameh , Hong H. Chih-Ho , Landells Ian , Lansang Perla , Marcoux Danielle , Wiseman Marni C. , Yeung Jensen , Lynde Charles , Litvinov Ivan V. 
Published: September 2021

Background: Atopic dermatitis is a chronic, relapsing and remitting disease that can be difficult to treat despite a recently approved biologic therapy targeting IL-4/IL-13 receptor. Oral janus kinase inhibitors (JAKi) represent a novel therapeutic class of targeted therapy to treat moderate-to-severe atopic dermatitis (AD).Objective: To review the efficacy, safety, and pharmacokinetic characteristics of oral JAKi in the treatment of AD.Methods: A PRISMA systematic review was conducted using MEDLINE, EMBASE (Ovid), and PubMed databases for studies assessing the efficacy, safety, and/or pharmacokinetic properties of oral forms of JAKi in the treatment of AD in pediatric or adult populations from inception to June 2021.Results: 496 papers were reviewed. Of 28 articles that underwent full text screening, 11 met our inclusion criteria for final qualitative review. Four studies examined abrocitinib; three studies examined baricitinib; three examined upadacitinib and one examined gusacitinib (ASN002). Significant clinical efficacy and a reassuring safety profile was reported for all JAKi agents reviewed. Rapid symptom control was reported for abrocitinib, baricitinib and upadacitinib.Limitations: Given the relatively limited evidence for each JAKi and the differences in patient eligibility criteria between studies, the data was not deemed suitable for a meta-analysis at this time.Conclusion: Given their ability to achieve rapid symptom control with a reassuring safety profile, we recommend considering the use of JAKi as a reliable systemic treatment option for adult patients with moderate-to-severe AD, who are unresponsive to topical or skin directed treatments.