bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Between MTNR1B Polymorphisms and Obesity in African American: Findings From The Jackson Heart Study
Authors: Tosini Gianluca , Tchio Cynthia Ines Mantho , Musani Solomon K. , Quarshie Alexander
Published: October 2020

Background: Melatonin is a hormone secreted at night by the pineal gland that exerts its function by binding to MT1 and MT2 receptors encoded respectively by the MTNR1A and MTNR1B gene. Melatonin receptors are integral 7-transmembrane receptors called G-protein coupled receptors. Previous studies found that MTNR1B variants were associated with impairments in insulin secretion and increased body mass index (BMI) in individuals of European and Asian ancestries. Obesity is highly prevalent in the US, and disproportionately affect African Americans. We hypothesized here that common single nucleotide polymorphisms (SNPs) imputed in 1000 Genomes in the MTNR1B gene are associated with adiposity in African American adult men and women, and that the association is modified by insomnia. Results: We used an additive genetic model to describe the association between adiposity traits (BMI and waist circumference) and selected MTNR1B variants in 3,029 Jackson Heart Study participants with the average age 55.13±12.84 and 62% women. We regressed adiposity measures on the estimated allelic or genotypic dosage at every selected SNP and adjusted for age, sex, population stratification, and insomnia. Thirty common SNPs spanning the MTNR1B gene with minor allele frequency ≥5%, call rate ≥ 90%, Hardy-Weinberg equilibrium p-value > 10-6 were available for analysis. Conclusions: We found that allele T of rs76371840 was associated with adiposity (OR=1.47 [1.13 - 1.82]; PFDR-adjusted =0.0499 ), and allele A of rs8192552 showed significant association with waist circumference (β = 0.023 ± 0.007; PFDR-adjusted ­ =0.0077) after correcting for multiple testing. When insomnia was included in the model for the analysis of adiposity, the following four variants became significantly associated with adiposity; rs6483208, rs4388843, rs4601728, and rs12804291. In conclusion, our data indicate that polymorphisms in the MTNR1B gene are associated with obesity traits in African Americans.
The Importance of SARS-CoV-2 N-Ag Serodiagnostics for the Management of COVID-19 Pneumonia in Hospital Settings
Authors: Lebedin Yuri S. , Lyang Olga V. , Galstyan Anaida G. , Panteleeva Anna V. , Belousov Vsevolod V. , Rebrikov Denis
Published: October 2020

We report evaluation of the SARS-CoV-2 nucleocapsid antigen (N-Ag) and respective antibodies as diagnostic markers in pneumonia patients. The study was conducted at the height of COVID-19 pandemic in Moscow, Russia. It included 425 emergency patients with clinical signs of COVID-19 pneumonia, of which 280 (66%) were positive for either serum N-Ag and/or its respective antibodies. We demonstrate the total prevalence of N-Ag seroconversion in SARS-CoV-2-associated pneumonia patients within 3-5 days after hospital admission. The results indicate high feasibility of SARS-CoV-2 serodiagnostics in emergency patients.
The Novel TRPA1 Antagonist BI01305834 Inhibits Ovalbumin-Induced Bronchoconstriction in Guinea Pigs
Authors: Berg Mariska van den , Brinksma Susan Nijboer - , Bos Sophie , Berge Maarten van den , Lamb David , Faassen Martijn van , Kema Ido , Gosens Reinoud , Kistemaker Loes
Published: October 2020

Background: We hypothesized that TRPA1 channels contribute to airway hyperresponsiveness (AHR) and inflammation in asthma. We evaluated the efficacy of the novel TRPA1 antagonist BI01305834 in a guinea pig model of asthma. Methods: First a pilot study was performed in a guinea pig model of allergic asthma to find the optimal dose of BI01305834. Next, the effect of BI01305834 on AHR to inhaled histamine after the early and late asthmatic reaction (EAR and LAR), magnitude of EAR and LAR and airway inflammation was assessed. Precision-cut lung slices and trachea strips were used to investigate the bronchoprotective and bronchodilating effect of BI01305834. Statistical evaluation of differences of in vivo data was performed using a Mann-Whitney U test or One-way nonparametric Kruskal-Wallis ANOVA, for ex vivo data One- or Two-way ANOVA was used, all with Dunnett’s post-hoc test where appropriate.Results: A dose of 1 mg/kg BI01305834 was selected based on AHR and exposure data in blood samples from the pilot study. In the subsequent study 1 mg/kg BI01305834 inhibited AHR after the EAR, and the development of EAR and LAR elicited by ovalbumin in ovalbumin-sensitized guinea pigs. BI01305834 did not inhibit allergen-induced total and differential cells in the lavage fluid and interleukin-13 gene expression in lung homogenates. Furthermore, BI01305834 was able to inhibit allergen and histamine-induced airway narrowing in guinea pig lung slices, without affecting histamine release, and reverse allergen-induced bronchoconstriction in guinea pig trachea strips.Conclusions: TRPA1 inhibition protects against AHR and the EAR and LAR in vivo and allergen and histamine-induced airway narrowing ex vivo, and reverses allergen-induced bronchoconstriction, independently of inflammation. This effect was partially dependent upon histamine, suggesting a neuronal and possible non-neuronal role for TRPA1 in allergen-induced bronchoconstriction.
Is the preservation of the left colic artery an ideal choice for colorectal cancer surgery? A meta-analysis
Authors: Qu Ruize , Li Fei , Wang Bingyan , Lu Siyi , Ma Junren , Ma Yanpeng , Meng Yan , Wang Junwei , Zhou Xin , Fu Wei
Published: October 2020

Background: Left colic artery (LCA) preservation or non-preservation in radical resection for colorectal cancer is still under debate. This study aimed to compare the perioperative and oncological outcomes between the two procedures.Methods: Systematic search was performed in PubMed, Medline, Embase, Web of Science, and China National Knowledge Infrastructure databases for relevant randomized and non-randomized clinical trials published between 2011 and 2019. The primary endpoints were 5-year overall survival (OS), 5-year disease-free survival (DFS), total lymph nodes harvested, and anastomotic leakage. Secondary endpoints included the number of metastatic lymph nodes, intraoperative blood loss, urinary dysfunction, bowel obstruction, and operation time. Results: Twenty-eight studies with 10545 patients (LCA non-preservation surgery, 4920; LCA preservation surgery, 5625) were included. Data of 7142 rectal cancer patients (LCA non-preservation surgery, 3468; LCA preservation surgery, 3674) were extracted for subgroup analysis. There was significantly lower incidence of anastomotic leakage (odds ratio=1.21; 95% confidence interval |1.04, 1.41|; P=0.015) in colorectal cancer patients with LCA preservation. When rectal cancer was independently analyzed, no significant difference was found in anastomotic leakage between the groups. There were significantly more metastatic lymph nodes and significantly shorter operation time in colorectal cancer and rectal cancer patients with LCA non-preservation. No significant difference was found regarding 5-year OS, 5-year DFS, total lymph nodes harvested, intraoperative blood loss, urinary dysfunction, and bowel obstruction for colorectal and rectal cancer.Conclusions: LCA non-preservation was not proved to increase anastomotic leakage in rectal cancer surgery and was associated with more harvested metastatic lymph nodes and shorter operation time. Trial registration: A review protocol was registered on PROSPERO (registration number: CRD42020183906) and http://www.researchregistry.com (registration number: reviewregistry841).
Problems with Bazett QTc Correction in Paediatric Screening of Prolonged QTc Interval
Authors: Andršová Irena , Hnatkova Katerina , Helánová Kateřina , Šišáková Martina , Novotný Tomáš , Kala Petr , Malik Marek
Published: October 2020

BackgroundBazett formula is frequently used in paediatric screening for the long QT syndrome (LQTS) and proposals exist that using standing rather than supine electrocardiograms (ECG) improves the sensitivity of LQTS diagnosis. Nevertheless, compared to adults, children have higher heart rates (especially during postural provocations) and Bazett correction is also known to lead to artificially prolonged QTc values at increased heart rates. This study assessed the incidence of erroneously increased QTc values in normal children without QT abnormalities.MethodsContinuous 12-lead ECGs were recorded in 332 healthy children (166 girls) aged 10.7±2.6 years while they performed postural manoeuvring consisting of episodes (in the following order) of supine, sitting, standing, supine, standing, sitting, and supine positions, each lasting 10 minutes. Detailed analyses of QT/RR profiles confirmed the absence of prolonged individually corrected QTc interval in each child. Heart rate and QT intervals were measured in 10-second ECG segments and in each segment, QTc intervals were obtained using Bazett, Fridericia, and Framingham formulas. In each child, the heart rates and QTc values obtained during supine, sitting and standing positions were averaged. QTc durations by the three formulas were classified to <440 ms, 440-460 ms, 460-480 ms, and >480 ms. ResultsAt supine position, averaged heart rate was 77.5±10.5 beat per minute (bpm) and Bazett, Fridericia and Framingham QTc intervals were 425.3±15.8, 407.8±13.9, and 408.2±13.1 ms, respectively. At sitting and standing, averaged heart rate increased to 90.9±10.1 and 100.9±10.5 bpm, respectively. While Fridericia and Framingham formulas showed only minimal QTc changes, Bazett correction led to QTc increases to 435±15.1 and 444.9±15.9 ms at sitting and standing, respectively. At sitting, Bazett correction identified 51, 4, and 0 children as having the QTc intervals 440-460, 460-480, and >480 ms, respectively. At sitting, these numbers increased to 118, 11, and 1, while on standing these numbers were 151, 45, and 5, respectively. Irrespective of the postural position, Fridericia and Framingham formulas identified only a small number (<7) of children with QT interval between 440 and 460 ms and no children with longer QTc.ConclusionDuring screening for LQTS in children, the use of Bazett formula leads to a high number of false positive cases especially if the heart rates are increased (e.g. by postural manoeuvring). The use of Fridericia formula can be recommended to replace the Bazett correction not only for adult but also for paediatric ECGs.
Reducing False Triggering Caused by Irrelevant Mental Activities in Brain-Computer Interface Based on Motor Imagery
Authors: Zhou Lujia , Tao Xuewen , He Feng , Zhou Peng , Qi Hongzhi
Published: October 2020

Background: In recent years, the brain-computer interface (BCI) based on motor imagery (MI) has been considered as a potential post-stroke rehabilitation technology. However, the recognition of MI relies on the event-related desynchronization (ERD) feature, which has poor task specificity. Further, there is the problem of false triggering (irrelevant mental activities recognized as the MI of the target limb). Methods: In this paper, we discuss the feasibility of reducing the false triggering rate using a novel paradigm, in which the steady-state somatosensory evoked potential (SSSEP) is combined with the MI (MI-SSSEP). Data from the target (right hand MI) and nontarget task (rest) were used to establish the recognition model, and three kinds of interference tasks were used to test the false triggering performance. In the MI-SSSEP paradigm, ERD and SSSEP features modulated by MI could be used for recognition, while in the MI paradigm, only ERD features could be used. Results: The results showed that the false triggering rate of interference tasks with SSSEP features was reduced to 29.3%, which was far lower than the 55.5% seen under the MI paradigm with ERD features. Moreover, in the MI-SSSEP paradigm, the recognition rate of the target and nontarget task was also significantly improved. Further analysis showed that the specificity of SSSEP was significantly higher than that of ERD (p<0.05), but the sensitivity was not significantly different. Conclusions: These results indicated that SSSEP modulated by MI could more specifically decode the target task MI, and thereby may have potential in achieving more accurate rehabilitation training.
Effects of a Robot-aided Somatosensory Training on Proprioception and Motor Function in Stroke Survivors
Authors: Yeh I-Ling , Holst-Wolf Jessica , Elangovan Naveen , Cuppone Anna Vera , Lakshminarayan Kamakshi , Capello Leonardo , Masia Lorenzo , Konczak Jürgen
Published: October 2020

Background- Proprioceptive deficits after stroke are associated with poor upper limb function, slower motor recovery, and decreased self-care ability. Improving proprioception should enhance motor control in stroke survivors, but current evidence is inconclusive. Thus, this study examined whether a robot-aided somatosensory-based training requiring increasingly accurate active wrist movements improves proprioceptive acuity and motor performance in chronic stroke. Methods - Twelve adults with chronic stroke completed a 2-day training (age range: 42 – 74 years; median time-after-stroke: 12 months; median Fugl-Meyer UE: 65). Retention was assessed at Day 5. Grasping the handle of a wrist-robotic exoskeleton, participants trained to roll a virtual ball to a target through continuous wrist adduction/abduction movements. During training vision was occluded, but participants received real-time, vibro-tactile feedback on their forearm about ball position and speed. Primary outcome was the just-noticeable-difference (JND) wrist position sense threshold as a measure of proprioceptive acuity. Secondary outcomes were spatial error in an untrained wrist tracing task and somatosensory-evoked potentials (SEP) as a neural correlate of proprioceptive function. Ten neurologically-intact adults were recruited to serve as non-stroke controls for age, gender and hand dominance (age range: 44 to 79 years; 6 women, 4 men).Results – Participants significantly reduced JND thresholds at posttest and retention (F(2, 38) = 4.54, p = 0.017, ηp2 = 0.20) in both groups. A higher pretest JND threshold was associated with a higher threshold reduction at posttest and retention (r = -0.86, -0.90, p ≤ 0.001) among the stroke participants. Error in the untrained tracing task was reduced by 22% at posttest, yielding an effect size of w = 0.13. Stroke participants exhibited significantly reduced P27-N30 peak-to-peak SEP amplitude at pretest (U = 11, p = 0.03) compared to the non-stroke group. SEP measures did not change systematically with training.Conclusion - This study provides proof-of-concept that non-visual, proprioceptive training can induce fast, measurable improvements in proprioceptive function in chronic stroke survivors. There is encouraging but inconclusive evidence that such somatosensory learning transfers to untrained motor tasks.Trial Registration Clinicaltrials.gov; Registration ID: NCT02565407; Date of registration: 01/10/2015; URL: https://clinicaltrials.gov/ct2/show/NCT02565407
Insights Into the First Seven-months of COVID-19 Pandemic in Bangladesh: Lessons Learned from a High-risk Country
Authors: Siam Md. Hasanul Banna , Hasan Md.Mahbub , Tashrif Shazed Mohammad , Khan Md. Hasinur Rahaman , Raheem Enayetur , Hossain Mohammad Sorowar
Published: October 2020

BackgroundSouth Asian countries including Bangladesh have been struggling to control the COVID-19 pandemic despite imposing months of lockdown and other public health measures. In-depth epidemiological information from these countries is lacking. From the perspective of Bangladesh, this study aims at understanding the epidemiological features and gaps in public health preparedness and risk communication. MethodsThe study used publicly available data of seven months (8 March 2020–10 September 2020) from the respective health departments of Bangladesh and Johns Hopkins University Coronavirus Resource Centre. Human mobility data were obtained from Google COVID-19 Community Mobility Reports. Spatial distribution maps were created using ArcGIS Desktop. Descriptive statistics was used to report the incidence, case fatality rates (CFR), and trend analysis. Results Despite nationwide lockdown, an increase in human mobility linked to specific public events was observed. During this period, a total of 47,153 cases and 650 deaths were reported. As lockdown ended, the incidence rate was increased by around 50% within a week. In seven months, about 350,000 cases were identified with a CFR of 1.4%. Males were disproportionately affected in terms of infection (71%) and death (77%) than females. The CFR for males was higher than females (1.4% versus 1.11%). Over 50% of infected cases were reported among young adults (20-40-year age group). Trends of the cumulative incidence were slower in South Asia with lower mortality compared to the EU and USA. As of 10 September 2020, over 20,000 frontline health workers were affected, and more than 2100 unofficial deaths were reported. Reduced testing capacity was observed as compared to other countries. Although a downward trend in laboratory test positive percentage was seen, the number of new deaths per day remained largely unchanged. ConclusionWe identified critical gaps in public health preparedness and risk communication in battling COVID-19 pandemic. We believe our findings, observations and recommendations will function as a valuable resource to facilitate better public health decisions for managing current and future infectious disease like COVID-19 in the settings of developing countries.
Metal-free atom transfer radical polymerization: reaching ppm catalyst loading under sunlight
Authors: Ma Qiang , Song Jinshuai , Zhang Xun , Jiang Yu , Ji Li , Liao Saihu
Published: October 2020

Organocatalytic atom transfer radical polymerization (O-ATRP) is recently emerging as an appealing method for the synthesis of metal-free polymer materials with well-defined microstructures and architectures. However, the development of highly effective catalysts that can be employed at a practical low loading are still a challenging task. Herein, we introduce a catalyst design logic based on heteroatom-doping of polycyclic arenes, which led to the discovery of oxygen-doped antratherene (ODA) as a new class of organic photoredox catalysts for O-ATRP. In comparison with known organocatalysts, ODAs feature strong visible-light absorption together with high molar extinction coefficient (ε455nm up to 23950 M–1cm–1), which allow for the establishment of a controlled polymerization under sunlight at low ppm levels of catalyst loading.
Seven Things to Know About The Homicides of Doctors. A Review of 30 Years From Italy.
Authors: Lorettu Liliana , Nivoli Alessandra MA , Daga Irma , Milia Paolo , Depalmas Cristiano , Nivoli Giancarlo , Bellizzi Saverio
Published: October 2020

Background. Healthcare workers have a 16 times greater risk of suffering workplace violence than workers in other sectors and around 50% experience workplace violence in the course of their career. The objective of this study is to explore the characteristics and circumstances of work-related killings of doctors. Methods. Work-related homicides of doctors over the period 1988-2019 were identified retrospectively through the Italian national statistical agencies. Variables such as perpetrator, motive and location of the crime were obtained through forensic psychiatric work. After classification, the absolute and percent values of the main characteristics of the homicides were calculated. Results. Over the period considered, 21 doctors were killed in Italy in connection with their professional activity. In 52% (n=11) of cases, the killer was one of the doctor’s patients, in 29% (n=6) of cases it was a patient’s relative, in 19% (n=4) an occasional patient (first consultation). The location of the homicide was a community clinic in 48% (n=10) of cases, the street in 19% (n=4) of cases, the doctor’s home in 14% (n=3), the hospital in 14% (n=3) and the patient’s home in 5% (n=1). In 57% (n=12) of cases the perpetrator was not affected by any mental disorders. The motive for the homicide was revenge without previous threats in 52.4% (n=11) of cases; in 28.6% (n=6) the revenge was preceded by stalking. Conclusions. Doctors should be aware that the risk of being killed is not limited to hospital settings and that their patients’ family members might also pose a threat to them.
Health Seeking Behavior and Associated Factors among Individuals with Cough in Yiwu, China: A Population-based Study
Authors: sun xiaoyan , Luo Shuying , Lou Lingqiao , Cheng Hang , Ye Zhen , Jia Jianwei , Wei Yina , Tao Jingbo , He Hanqing
Published: October 2020

Background: Previous studies have shown that a certain proportion of the population did not seek medical treatment after coughing, and understanding the potential reasons is crucial for disease prevention and control. Method: A population-based study was conducted with the probability proportional to population size sampling in Yiwu, Zhejiang, China. A total of 5,855 individuals aged ≥ 15 years lived in Yiwu, China for more than 6 months were included. All participants completed a pad-based questionnaire to collect detailed information by a face-to-face interview. Characteristics of individuals were described by categories of health seeking behavior using frequency and percentage. Univariate and multivariate logistic regression analyses were performed to estimate the associations of social-demographic and cough characteristics with health seeking behavior. Results: 19.3% (1,129/5,855) of participants had a cough in the past month, 40% (452/1,129) had sought medical treatment. Of these, 26.5% (120/452) chose hospitals at county level or above. Individuals aged ≥65 years old (OR=2.25, 95%CI: 1.23, 4.12), female (OR=1.57, 95%CI: 1.21, 2.06), living in rural areas (OR=1.30, 95%CI: 1.003, 1.69), persistent cough for 3-8 weeks (OR=2.91, 95%CI: 1.72, 4.92) and with more accompanying symptoms (P trend<0.001) were more likely to seek medical treatment, but those coughed for >8 weeks were not (p>0.5). Female (OR=0.33, 95%CI: 0.21, 0.54) and people living in rural areas (OR=0.57, 95%CI: 0.36, 0.92) were less likely to choose hospitals at county level or above while the higher educated were more likely to (OR=3.29, 95% CI: 1.35, 8.02). Those who coughed for more than 2 weeks were more likely to choose hospitals at or above the county level. But the number of accompanying symptoms does not show any significant relationship with the choice of medical facility.Conclusion: The present study found that age, gender, living areas and features of cough were associated with health seeking behavior. It is worth noting that coughing too long(e.g. >8 weeks) instead of seeking medical treatment. Targeted measures should be developed based on the key factors found in this study to guide persons to seek medical treatment more scientifically.
Cardiac Resynchronization Therapy and its Effects in Patients with type 2 DIAbetes Mellitus OPTimized in Automatic vs. Echo Guided Approach. Data from the DIA-OPTA Investigators
Authors: Sardu Celestino , Paolisso Pasquale , Ducceschi Valentino , Santamaria Matteo , Sacra Cosimo , Massetti Massimo , Ruocco Antonio , Marfella Raffaele
Published: October 2020

Objectives: To evaluate the effects of cardiac resynchronization therapy (CRTd) in patients with type 2 diabetes mellitus (T2DM) optimized via automatic vs. echocardiographic guided approach. Background: Suboptimal optimization of atrio-ventricular (AV) and inter-ventricular (VV) timings reduces CRTd response. Thus, we hypothesize that automatic CRTd optimization could ameliorate clinical outcomes in T2DM patients.Methods: We designed a prospective, multicenter study to recruit, from October 2016 to June 2019, 191 patients with T2DM and heart failure (HF) candidate to receive a CRTd. Study outcomes were CRTd responders rate, hospitalizations for HF worsening, cardiac deaths and all cause of deaths in T2DM patients treated with a CRTd and randomly optimized via automatic (n 93) vs. echocardiographic (n 98) guided approach at 12 months of follow-up.Results: We had a significant difference in CRTd responders rate (68 (73.1%) vs. 58 (59.2%), p 0.038), and hospitalization for HF worsening (12 (16.1%) vs. 22 (22.4%), p 0.030) in automatic vs. echo-guided group of patients. At multivariate Cox regression analysis, automatic guided approach (3.636 [1.271-10.399], CI 95%, p 0.016) and baseline highest values of atrium pressure (automatic SonR values, 2.863 [1.537-6.231], CI 95%, p 0.006) predicted CRTd responders rate. In automatic group, we had significant difference in SonR values comparing CRTd responders vs. non responders (1.24 ± 0.72 g vs. 0.58 ± 0.46 g (follow-up), p 0.001), hospital admission for HF worsening events (0.48 ± 0.29 g vs. 1.18 ± 0.43 g, p 0.001), and cardiac deaths ( 1.13 ± 0.72 g vs. 0.65 ± 0.69 g, p 0.047).Conclusions: automatic optimization increased CRTd responders rate, and reduced hospitalizations for HF worsening. Intriguingly, automatic CRTd and highest baseline values of SonR could predict the outcome of CRTd responders. Notably, there is a significant difference in SonR values for CRTd responders vs. non responders, hospitalizations for HF worsening and cardiac deaths. Clinical trial: ClinicalTrials.gov Identifier NCT04547244;
The Cost‑utility of Early use of High-flow Nasal Cannula in Bronchiolitis
Authors: Buendia Jefferson Antonio , Acuña-Cordero Ranniery , Rodriguez-Martinez Carlos E.
Published: October 2020

Background: High-flow nasal cannula (HFNC) oxygen is a non-invasive ventilation system that was introduced as an alternative to CPAP (continuous positive airway pressure), with a marked increase in its use in pediatric care settings .This study aimed to evaluate the cost-effectiveness of early use of HFNC compared to oxygen by nasal cannula in an infant with bronchiolitis in the emergency setting. Methods: A decision tree model was used to estimate the cost-effectiveness of HFNC compared with oxygen by nasal cannula (control strategy) in an infant with bronchiolitis in the emergency setting. Cost data were obtained from a retrospective study on bronchiolitis from tertiary centers in Rionegro, Colombia, while utilities were collected from the literature. Results:The QALYs per patient calculated in the base-case model were 0.9141 (95% CI 0.913- 0.915) in the HFNC and 0.9105 (95% CI 0.910- 0.911) in control group. The cost per patient was US$368 (95% CI US$ 323- 411) in HFNC and US$441 (95% CI US$ 384-498) per patient in the control group.Conclusions: HFNC in emergency settings was cost-effective for the hospital treatment of an infant with bronchiolitis
A Rare Pulmonary Myoepithelial Tumor With Novel TRPS1-PLAG1 Fusions
Authors: ZHENG Qiang , LI Shenglei , BAI Qianming , ZHOU Xiaoyan , WANG Yue , Li Yuan
Published: October 2020

Background: Little is known about the morphological and molecular features of intra-thoracic myoepithelial tumors. Here, we describe a rare pulmonary myoepithelial tumor with novel TRPS1-PLAG1 fusions.Case presentation: A 30-year-old male presented with multiple lung nodules that detected by routine computed tomography (CT) scan 3 years ago. Positron emission tomography-computed tomography (PET-CT) demonstrated a well-circumscribed mass with a diameter of 3cm in the left pulmonary hilum and multiple nodules in bilateral lungs. No other extra-thoracic primary lesion and distant metastasis was found. The clinical history was not other specified. Microscopically, these lesions were well-defined, showed nodular growth pattern filling the bronchioles and alveoli. The tumor cells were epithelioid to plasmacytoid with slightly eosinophilic cytoplasm, arranged in aggregates, nests and cords. Myxoid background presented in some foci. Nuclear pleomorphism was mild and mitotic activity was not prominent. No distinct gland formation was identified. Immunostains demonstrated that the tumor cells were diffusely positive for pan-cytokeratin (AE1/AE3), CK5/6, S100, SOX10, and negative for calponin. Noticeably, a TRPS1-PLAG1 gene fusion was identified in this tumor by targeted RNA sequencing involved TRPS1 exon1 and PLAG1 exon2, this rare rearrangement was validated by fluorescence in situ hybridization (FISH) for PLAG1 break-apart probe, and 30% tumor cells showed break apart signals. Conclusions: Here we present the first case of a disseminated thoracic myoepithelial tumor with novel TRPS1-PLAG1 fusions. Targeted RNA sequencing strongly facilitates precise classification and providing opportunities for unknown fusion partner discovery, which is significant for risk stratification and development of potential therapeutic targets.
Protocol for a systematic review on classification, outcomes and follow-up of patients undergoing reconstructive surgery after Noma disease-
Authors: Speiser Sophie , Langridge Benjamin , Birkl Moira Melina , Kubiena Harald , Rodgers Will
Published: October 2020

Background: NOMA is a significant yet neglected disease which affects children in some of the least developed countries in the world. Surgical reconstructive missions for patients affected by NOMA are undertaken regularly by surgeons from more developed countries. However, the long-term benefit and safety of these missions have recently been criticized due to a perceived lack of measurable outcomes and appropriate follow-up. We are conducting a systematic review to critically evaluate the classification systems, outcome measurement tools, and follow-up periods reported in the literature for NOMA disease. Methods: This systematic review is undertaken following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (“PRISMA”) guidelines. The databases MEDLINE, Embase and Web of Science are searched from infinity to 24th of April 2019. All original publications of studies undertaken on reconstructive surgery for NOMA disease, reporting data on outcome after surgery, follow-up time and complications are eligible for inclusion. The primary outcome of interest are the outcome measurement methods used for assessing successful reconstructive surgery after NOMA disease. Other outcomes we are assessing are methods for classification of disease severity and time to last follow-up. The quality of evidence for each summary outcome measure is assessed using the MINORS criteria. Discussion: Given the precarious situations in the countries where mission surgeons often undertake reconstructive surgery, time pressure and the lack of infrastructure on site prevent them from being able to measure the effect of their surgical outcomes. Our goal is to express the key points of debate and make recommendations for how future surgical missions can be improved. We aim to do so by comparing the current best standards of practice Publishing this protocol will help future NOMA surgeons plan their missions in a standardised and reproducible way, striving towards a future of worldwide high-quality research.Systematic review registrations: This protocol was submitted to PROSPERO on the 02.10.2020 and is currently under assessment. (ID 181931)
Assigning Protein Function from Domain-Function Associations Using DomFun
Authors: Rojano Elena , Jabato Fernando Moreno , Perkins James Richard , Caballero José Córdoba , Sillitoe Ian , Orengo Christine , Ranea Juan Antonio García , Zonjic Pedro Seoane
Published: October 2020

Background: Protein function prediction remains a key challenge. Domain composition is key to understanding protein function, and domain-based prediction methods consistently perform well in challenges such as CAFA. Here we present DomFun, a Ruby gem that uses associations between protein domains and functions, calculated using multiple indices based on tripartite network analysis. These domain-function associations are combined at the protein level, to generate protein-function predictions. Results: We analysed 14 tripartite networks connecting homologous superfamily and FunFam domains from CATH-Gene3D with functional annotations from the Gene Ontology, KEGG, Reactome and the Human Phenotype Ontology. We validated the results using the CAFA 2 benchmark platform for GO and HPO annotation, finding Simpson's index combined with Stouffer's method led to the best performance in almost all scenarios. We also found that FunFams led to better performance than superfamilies, and better results were found for GO molecular function compared to GO biological process terms. Results were similar to other high-performing domain-based methods in CAFA 2. We also implemented our own benchmark procedure, Pathway Prediction Performance (PPP), which can be used to validate function prediction for additional annotations sources, such as KEGG and Reactome. Using PPP, we found similar results to those found with CAFA 2 for GO, moreover we found good performance for the other annotation sources. As with CAFA 2, Simpson's index with Stouffer's method led to the top performance in most scenarios. Conclusions: DomFun shows comparable performance to other methods evaluated in CAFA 2 when predicting human proteins function with GO. Through our own benchmark procedure, PPP we have shown it can also make accurate predictions for KEGG and Reactome. It performs best when using FunFams, combining Simpson's index derived domain-function associations combined using Stouffer's method. The tool has been implemented so that it could be easily adapted to incorporate other protein features, such as domain data from other sources. The DomFun Ruby gem is available from https://rubygems.org/gems/DomFun and its code is available at https://github.com/ElenaRojano/DomFun .
Circulating Tight-Junction Proteins Are Potential Biomarkers for Blood-Brain Barrier Function in a Model of Neonatal Hypoxic/Ischemic Brain Injury
Authors: Andersson Axel Erik , Mallard Carina , Ek Carl Joakim
Published: October 2020

BackgroundNeonatal hypoxia-ischemia often leads to lifelong disabilities with limited treatments currently available. The brain vasculature is an important factor in many neonatal brain pathologies but there is a lack of diagnostic tools to evaluate the brain vascular health of neonates in a clinical setting. Measurement of blood-brain barrier tight-junction proteins have shown promise as biomarkers for brain injury in the adult. Here we tested the biomarker potential of tight-junctions in the context of neonatal brain injury.MethodsThe levels of TJ-proteins (occluding, claudin-5, and zonula occludens-1) in both blood plasma and cerebrospinal fluid (CSF) as well as blood-brain barrier function were measured in a clinically relevant hypoxia/ischemia model in neonatal rats.ResultsTemporally acute elevated levels of occludin and claudin-5 could be measured in blood and CSF after hypoxia/ischemia with males generally having higher levels than females. The levels of claudin-5 in CSF correlated with the severity of the brain injury at 24h post- hypoxia/ischemia. Simultaneously, we detected early increase in blood-brain barrier-permeability at 6 and 24h after hypoxia/ischemia.ConclusionsLevels of circulating claudin-5 and occludin are increased after hypoxic/ischemic brain injuries and blood-brain barrier-impairment and have promise as early biomarkers for cerebral vascular health and as a tool for risk assessment of neonatal brain injuries.
The Epidemiology and Detectability of Asymptomatic Plasmodium Vivax and Plasmodium Falciparum Infections in Low, Moderate and High Transmission Settings in Ethiopia 
Authors: Hailemeskel Elifaged , Tebeje Surafel K , Behaksra Sinknesh , Shumie Girma , Shitaye Getasew , Keffale Migbaru , Chali Wakweya , Gashaw Abrham , Ashine Temesgen , Drakeley Chris , Bousema Teun , Gadisa Endalamaw , Tadesse Fitsum G
Published: October 2020

Background: As countries move to malaria elimination, detecting and targeting asymptomatic malaria infections might be needed. Here, we investigated the epidemiology and detectability of asymptomatic Plasmodium falciparum and P. vivax infections in different transmission settings in Ethiopia.Method: A total of 1093 dried blood spot (DBS) samples were collected from afebrile and apparently healthy individuals across ten study sites in Ethiopia from 2016 to 2020. Of these, 862 were from community and 231 from school based cross-sectional surveys. Malaria infection status was determined by microscopy or rapid diagnostics tests (RDT) and 18S rRNA based nested PCR (nPCR). The annual parasite index (API) was used to classify endemicity as low (API>0 and<5), moderate (API ≥5 and <100) and high transmission (API≥100) and detectability of infections was assessed in these settings. Results: In community surveys, the overall prevalence of asymptomatic Plasmodium infections by microscopy/RDT, nPCR and all methods combined was 12.2% (105/860), 21.6% (183/846) and 24.1% (208/862), respectively. The proportion of nPCR positive infections that was detectable by microscopy/RDT was 48.7% (73/150) for P. falciparum and 4.6% (2/44) for P. vivax. Compared to low transmission settings, the likelihood of detecting infections by microscopy/RDT was increased in moderate (Adjusted odds ratio [AOR]: 3.4; 95% confidence interval [95%CI]:1.6-7.2, P=0.002) and high endemic settings (AOR=5.1; 95%CI=2.6-9.9, P<0.001). After adjustment for site and correlation between observations from the same survey, the likelihood of detecting asymptomatic infections by microscopy/RDT (AOR per year increase = 0.95, 95%CI=0.9-1.0, P=0.013) declined with age.Conclusion: Conventional diagnostics missed nearly half of the asymptomatic Plasmodium reservoir detected by nPCR. The detectability of infections was particularly low in older age groups and low transmission settings. These findings highlight the need for sensitive diagnostic tools to detect the entire parasite reservoir and potential infection transmitters.
Patient Participation and Associated Factors in the Discussions on Do-Not-Attempt-Resuscitation and End-of-Life Disclosure: A Retrospective Chart Review Study
Authors: Abe Akiko , Kobayashi Masato , Kohno Takashi , Takeuchi Mari , Hashiguchi Saori , Mimura Masaru , Fujisawa Daisuke
Published: October 2020

BackgroundPatient participation is a key foundation for advance care planning (ACP). However, a patient himself/herself may be left out from sensitive conversations such as end-of-life (EOL) care discussions. The objectives of this study were to investigate patients’ participation rate in the discussion of Cardiopulmonary Resuscitation (CPR) / Do-Not-Attempt-Resuscitation (DNAR) order, and in the discussion that the patient is at his/her EOL stage (EOL disclosure), and explore their associated factors.MethodsThis is a retrospective chart review study. The participants were all the patients who were hospitalized and died in a university-affiliated teaching hospital (tertiary medical facility) in central Tokyo, Japan during the period from April 2018 to March 2019. The following patients were excluded: (1) cardiopulmonary arrest on arrival (CPAOA); (2) stillbirth; (3) under 18 years old at the time of death; and (4) refusal by their bereaved family. Presence or absence of CPR/DNAR discussion and EOL disclosure, patients’ involvement in those discussions, and their related factors were investigated.ResultsCPR/DNAR discussion was observed in 336 out of the 359 patients (93.6%). The patient participation rate was 33.3% (n= 112). Male gender (odds ratio (OR) = 2.37 [95% confident interval (CI) 1.32-4.25]), living alone (OR = 2.51 [1.34 - 4.71]) and one year or more from diagnosis (OR = 1.78 [1.03 - 3.10]) were associated with patient’s participation in CPR/DNAR discussion. EOL disclosure was observed in 341 out of the 359 patients (95.0%). Half of the patients (n=171; 50.1%) participated in the discussion. Patients who died of cancer (OR = 2.41[1.45-4.03]) and patients without mental illness (OR=2.41 [1.11-5.25]) were more likely to participate in EOL disclosure.ConclusionsIn this clinical sample, only up to half of the patients participated in CPR/DNAR discussion and EoL disclosure. Further attempts to facilitate patients' participation, based on their preference, are warranted. A few sociodemographic, psychosocial, and medical factors that relate to patients’ participation in the discussion on CPR/DNAR and EOL disclosure were demonstrated.
Growth Patterns and Clinical Outcomes in Association with Breastfeeding in HIV Exposed and Unexposed Infants in KwaZulu Natal, South Africa
Authors: Pillay Larisha , Moodley Dhayendre , Emel Lynda Marie , Nkwanyana Ntombifikile Maureen , Naidoo Kimesh Loganathan
Published: October 2020

BackgroundExclusive breastfeeding for six months and breastfeeding with complementary feeds until 12 months for infants exposed to HIV (IEH) or 24 months for infants unexposed to HIV (IUH) is the current World Health Organisation (WHO) recommendation for LMICs to improve clinical outcomes and growth trajectories in infants. In a post hoc evaluation of IEH and IUH cohorts, we examine growth patterns and clinical outcomes in the first six months of infancy in association with breastfeeding duration. MethodsTwo non–contemporaneous cohorts of infants born to women living with HIV and women without HIV, from a low-socioeconomic township in South Africa, were evaluated from birth until nine months of age. Clinical, anthropometric and infant feeding data were analysed. Standard descriptive statistics and regression analysis were performed to determine the effect of HIV exposure and breastfeeding duration on growth and clinical outcomes. ResultsIncluded in this secondary analysis were 123 IEH and 157 IUH infants breastfed for a median of 26 weeks and 14 weeks respectively. Median WLZ score was consistently and significantly lower in IEH than IUH at 3, 6 and 9 months (-0.19 vs 2.09; -0.81 vs 0.28; 0.05 vs 0.97 respectively). In contrast, the median LAZ score was significantly lower among IUH at 3 and 6 (-1.63 vs 0.91; -0.37 vs 0.51). A significantly higher proportion of IUH was classified as stunted (LAZ<-2SD) at 3 and 6 months (3.9% vs 44.9%, 4.8% vs 20.9% respectively) and a higher proportion of IEH experienced one or more episodes of skin rash (44.5% vs 12.8%) and upper respiratory tract infection (30.1% vs 10.9%) (p<0.0001). In a multivariable analysis, the odds of occurrence of wasting, skin rash, URTI or any clinical adverse event in IEH were 2.86, 7.06, 3.01 and 8.89 times higher than IUH after adjusting for breastfeeding duration. ConclusionOur study has generated additional evidence that IEH is at substantial risk of infectious morbidity and decreased growth trajectories independent of breastfeeding duration. We further report shorter breastfeeding duration in infants not exposed to HIV and the higher prevalence of stunting in this cohort is also independent of breastfeeding duration.
Pretreatment neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio to guide the treatment decision (radical surgery versus definitive chemoradiotherapy) for locally advanced squamous cell carcinoma located in the middle and upper esophagus
Authors: Chen Wang , Tong Jia Qi , Tang Meng Qiu , Lu Yun Yun , Liang Gao Feng , Zhang Zhan Chun , Chen Tian
Published: October 2020

Background: Various inflammatory biomarkers, such as the neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR), have been well authenticated to predict clinical outcomes in numerous types of cancer. The optimal treatment for patients with locally advanced esophageal squamous cell carcinoma (ESCC) located in middle or upper region is still inconclusive. The aim of the study was to examine pretreatment NLR and PLR to select from radical surgery or definitive chemoradiotherapy (dCRT) for these patients. The linkage between pretreatment NLR / PLR and prognosis was also analyzed.Methods: NLR and PLR were calculated in 113 locally advanced ESCC located in middle or upper esophagus of patients who underwent radical surgery or dCRT between January 2014 and December 2019. A receiver operating characteristic curve was plotted to select the best cut-off value of NLR and PLR for predicting survival. A survival curve was plotted using the Kaplan–Meier method. Univariate and multivariate Cox regression analyses were applied to assess predictors for survival. Results: NLR and PLR was both associated with the extent of lymph node metastasis (NLR: P = 0.045; PLR: P = 0.002). Additionally, high PLR and recurrence with distant organs metastasis were closely related (P = 0.014), and NLR was related to the tumor stage (P = 0.043). The results of multivariate analysis revealed that NLR (> 2.07) and PLR (> 183.06) were independently associated with poor prognosis. It is noteworthy that surgery was associated with a superior OS compared with dCRT in the low NLR population (P = 0.045). Conclusions: Low pretreatment NLR patients made a decision to undergo radical surgery with a substantial therapeutic benefit. Pretreatment NLR and PLR are independent predictors for patients with locally advanced ESCC located in the middle and upper esophagus who underwent radical surgery or dCRT.
Comparison of epidermal growth factor receptor tyrosine kinase inhibitors for patients with lung adenocarcinoma harboring different epidermal growth factor receptor mutation types
Authors: Park Sojung , Lee Sung Yong , Kim Dojin , Sim Yun Su , Ryu Jeong-Seon , Choi Juwhan , Lee Su Hwan , Ryu Yon Ju , Lee Jin Hwa , Chang Jung Hyun
Published: October 2020

Background: Epidermal growth factor receptor (EGFR) mutations in non–small-cell lung cancer predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs). EGFR mutation types are associated with efficacy of EGFR TKIs. We investigated the clinical outcomes of afatinib, erlotinib, and gefitinib according to EGFR mutation type in patients with lung adenocarcinoma.Methods: Between May 2010 and December 2018, we investigated 363 patients with advanced lung adenocarcinoma harboring EGFR mutations who received EGFR TKIs. Efficacies of EGFR TKIs such as response rate, progression-free survival (PFS), and overall survival (OS) were retrospectively evaluated according to exon 19 deletion (E19del), L858R point mutation (L858R) and uncommon mutations. Results: The frequency of E19del was 48.2%, that of L858R was 42.4%, and that of uncommon mutations was 9.4%. E19del and L858R were associated with superior PFS and OS compared with uncommon mutations. Erlotinib showed significantly inferior OS than other TKIs (30.8 ± 3.3 in erlotinib vs. 39.1 ± 4.3 in afatinib vs. 48.4 ± 6.3 in gefitinib; p = 0.031) in patients with L858R. Gefitinib showed significantly inferior PFS (4.6 ± 1.1 in gefitinib vs. 11.6 ± 2.7 in afatinib vs. 10.6 ± 2.7 in erlotinib; p = 0.049) in patients with uncommon mutations. Conclusion: Afatinib was significantly associated with a longer PFS, presenting constant effectiveness in all EGFR mutation types. Caution may be needed on the use of erlotinib for L858R and the use of gefitinib for uncommon EGFR mutations.