bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vasoresponsiveness in patients with heart failure (VASOR): protocol for a prospective observational study
Authors: van Vessem Marieke E. , Beeres Saskia L. M. A. , de Wilde Rob B. P. , de Vries René , Berendsen Remco R. , de Jonge Evert , Danser A. H. Jan , Klautz Robert J. M. , Schalij Martin J. , Palmen Meindert 
Published: November 2019

Abstract
Background
Vasoplegia is a severe complication which may occur after cardiac surgery, particularly in patients with heart failure. It is a result of activation of vasodilator pathways, inactivation of vasoconstrictor pathways and the resistance to vasopressors. However, the precise etiology remains unclear. The aim of the Vasoresponsiveness in patients with heart failure (VASOR) study is to objectify and characterize the altered vasoresponsiveness in patients with heart failure, before, during and after heart failure surgery and to identify the etiological factors involved.

Methods
This is a prospective, observational study conducted at Leiden University Medical Center. Patients with and patients without heart failure undergoing cardiac surgery on cardiopulmonary bypass are enrolled. The study is divided in two inclusion phases. During phase 1, 18 patients with and 18 patients without heart failure are enrolled. The vascular reactivity in response to a vasoconstrictor (phenylephrine) and a vasodilator (nitroglycerin) is assessed in vivo on different timepoints. The response to phenylephrine is assessed on t1 (before induction), t2 (before induction, after start of cardiotropic drugs and/or vasopressors), t3 (after induction), t4 (15 min after cessation of cardiopulmonary bypass) and t5 (1 day post-operatively). The response to nitroglycerin is assessed on t1 and t5. Furthermore, a sample of pre-pericardial fat tissue, containing resistance arteries, is collected intraoperatively. The ex vivo vascular reactivity is assessed by constructing concentrations response curves to various vasoactive substances using isolated resistance arteries. Next, expression of signaling proteins and receptors is assessed using immunohistochemistry and mRNA analysis. Furthermore, the groups are compared with respect to levels of organic compounds that can influence the cardiovascular system (e.g. copeptin, (nor)epinephrine, ANP, BNP, NTproBNP, angiotensin II, cortisol, aldosterone, renin and VMA levels). During inclusion phase 2, only the ex vivo vascular reactivity test is performed in patients with (N = 12) and without heart failure (N = 12).

Discussion
Understanding the difference in vascular responsiveness between patients with and without heart failure in detail, might yield therapeutic options or development of preventive strategies for vasoplegia, leading to safer surgical interventions and improvement in outcome.

Trial registration
The Netherlands Trial Register (NTR), NTR5647. Registered 26 January 2016.
Experiences of patients with Poland syndrome of diagnosis and care in Italy: a pilot survey
Authors: Baldelli Ilaria , Gallo Fabio , Crimi Marco , Fregatti Piero , Mellini Lorenzo , Santi Pierluigi , Ciliberti Rosagemma 
Published: November 2019

Abstract
Background
Poland Syndrome (PS) is a rare congenital malformation involving functional and aesthetic impairments. Early diagnosis and timely therapeutic approaches play an important role in improving the quality of life of patients and kindred. This study aims to explore healthcare experiences of the diagnosis of patients affected by PS and to investigate the factors associated with diagnostic delay in Italy.

Results
Seventy-two patients affected by PS were asked to fill in a self- administered questionnaire on: a) diagnostic path; b) perceived quality of care received after diagnosis; c) knowledge of the rights and the socio-economic hardships related to their disease; d) evaluation of the integration of various professional skills involved in the diagnostic and therapeutic approach; e) perception of the social support provided by the Italian Association of Poland Syndrome (AISP). The average age at diagnosis was around 14 years; diagnosis was made at birth in only 31.58% of cases. Although typical symptomatology had appeared on average at an early age (4 months), only 23 patients (40.35%) received an early diagnosis (within the first year of life). Just over half of the patients (n = 30) were diagnosed in their region of origin, while 27 were diagnosed elsewhere. Furthermore, 12.28% were self-diagnoses. Among the patients who were diagnosed outside their region, 15 (88.24%) stated they had foregone some visits or treatments owing to costs and/or organizational issues.

Conclusions
An analysis of the patients’ experiences highlights several gaps and a lack of homogeneity in the diagnostic and therapeutic follow-up of PS patients in Italy. A specific national diagnostic and therapeutic path is essential to guarantee patients complete and appropriate health services, compliant with the ethical principles of non-discrimination, justice and empathy. Implementation of an effective information and research network and empowerment of patients’ associations are necessary conditions to encourage clinical collaboration and improve the quality of life of people living with rare diseases.
Targeted capture enrichment followed by NGS: development and validation of a single comprehensive NIPT for chromosomal aneuploidies, microdeletion syndromes and monogenic diseases
Authors: Koumbaris George , Achilleos Achilleas , Nicolaou Michalis , Loizides Charalambos , Tsangaras Kyriakos , Kypri Elena , Mina Petros , Sismani Carolina , Velissariou Voula , Christopoulou Georgia , Constantoulakis Pantelis , Manolakos Emmanouil , Papoulidis Ioannis , Stambouli Danai , Ioannides Marios , Patsalis Philippos 
Published: November 2019

Abstract
Background
Non-invasive prenatal testing (NIPT) has been widely adopted for the detection of fetal aneuploidies and microdeletion syndromes, nevertheless, limited clinical utilization has been reported for the non-invasive prenatal screening of monogenic diseases. In this study, we present the development and validation of a single comprehensive NIPT for prenatal screening of chromosomal aneuploidies, microdeletions and 50 autosomal recessive disorders associated with severe or moderate clinical phenotype.

Results
We employed a targeted capture enrichment technology powered by custom TArget Capture Sequences (TACS) and multi-engine bioinformatics analysis pipeline to develop and validate a novel NIPT test. This test was validated using 2033 cell-fee DNA (cfDNA) samples from maternal plasma of pregnant women referred for NIPT and paternal genomic DNA. Additionally, 200 amniotic fluid and CVS samples were used for validation purposes. All NIPT samples were correctly classified exhibiting 100% sensitivity (CI 89.7–100%) and 100% specificity (CI 99.8–100%) for chromosomal aneuploidies and microdeletions. Furthermore, 613 targeted causative mutations, of which 87 were unique, corresponding to 21 monogenic diseases, were identified. For the validation of the assay for prenatal diagnosis purposes, all aneuploidies, microdeletions and point mutations were correctly detected in all 200 amniotic fluid and CVS samples.

Conclusions
We present a NIPT for aneuploidies, microdeletions, and monogenic disorders. To our knowledge this is the first time that such a comprehensive NIPT is available for clinical implementation.
Postsynaptic density protein 95 (PSD-95) is transported by KIF5 to dendritic regions
Authors: Yoo Ki-Seo , Lee Kina , Oh Jun-Young , Lee Hyoeun , Park Hyungju , Park Young Seok , Kim Hyong Kyu 
Published: November 2019

AbstractPostsynaptic density protein 95 (PSD-95) is a pivotal postsynaptic scaffolding protein in excitatory neurons. Although the transport and regulation of PSD-95 in synaptic regions is well understood, dendritic transport of PSD-95 before synaptic localization still remains to be clarified. To evaluate the role of KIF5, conventional kinesin, in the dendritic transport of PSD-95 protein, we expressed a transport defective form of KIF5A (ΔMD) that does not contain the N-terminal motor domain. Expression of ΔMD significantly decreased PSD-95 level in the dendrites. Consistently, KIF5 was associated with PSD-95 in in vitro and in vivo assays. This interaction was mediated by the C-terminal tail regions of KIF5A and the third PDZ domain of PSD-95. Additionally, the ADPDZ3 (the association domain of NMDA receptor and PDZ3 domain) expression significantly reduced the levels of PSD-95, glutamate receptor 1 (GluA1) in dendrites. The association between PSD-95 and KIF5A was dose-dependent on Staufen protein, suggesting that the Staufen plays a role as a regulatory role in the association. Taken together, our data suggest a new mechanism for dendritic transport of the AMPA receptor-PSD-95.
Pre-sternal thyroid swellings: a case of rare aberrant site recurrence and review of literature
Authors: Bains Lovenish , Bhatia Sushant , Kaushik Rohit , Jain Sudhir Kumar , Singh Chandra Bhushan , Mandal Shramana , Kaur Daljit 
Published: November 2019

Abstract
Background
Thyroid swellings enlarge caudally into the mediastinum behind the sternum. Pre-sternal swelling of thyroid origin is very rare. We present our case of pre-sternal thyroid swelling which was albeit a surprisingly rare site of papillary thyroid carcinoma recurrence and review of pre-sternal thyroid swellings reported till date.

Case summary
A 60 year old female presented with a painless, progressive swelling on the anterior part of the chest for the past 2 years. A 15 cm × 8 cm vertically aligned, non tender, well defined swelling was present on the pre-sternal region, with consistency ranging from soft to firm. The swelling was fixed to the underlying tissues and a fixed level IV lymph node was palpable on the right side. Ultrasonography revealed a large mass of 15 × 7 cm with multiple cystic areas. Fine needle aspiration cytology was inconclusive twice. Patient had undergone a total thyroidectomy for papillary carcinoma 10 years back. Computed tomography findings revealed a large 15 × 6.6 × 7 cm lobulated, pre-sternal, soft tissue lesion with solid & cystic components. The mass was infiltrating the right sided strap muscles and sternocleidomastoid. FNAC was inconclusive and thyroid scan could not pick up any activity in the mass. Henceforth a PET scan was done that showed increased FDG uptake by the lesion and the level IV lymph node. The patient underwent wide excision of the mass with right functional neck dissection, along with removal with both sternal head of sternocleido-mastoid, the strap muscles and the surrounding fascia. Histopathology confirmed papillary thyroid carcinoma. Patient received post-operative radioactive iodine ablation and is healthy with no recurrence up to 30 months of follow up.

Discussion
The mechanisms for pre-sternal thyroid swelling are not understood due to paucity of cases. The mechanisms proposed are invasion of strap muscles and cervical linea alba and tumor cells spread anterior to sternum, truly ectopic thyroid tissue, de novo carcinogenesis in the embryonal remnants like the thyro-thymic residues, sequestered thyroid tissue which grows later or migration of thyroid cells, incomplete clearance at the time of primary surgery or intraoperative seeding.

Conclusion
Pre-sternal region masses of thyroid origin are very rare. A proper work up, suspicion for thyroid mass and array of tests will be required to come to a provisional diagnosis. Since the masses reported in literature were primarily malignant, any such mass may be treated on lines of malignancy with radical surgery.
Chimeric antigen receptor T cell therapies for multiple myeloma
Authors: Wu Chao , Zhang Lina , Brockman Qierra R. , Zhan Fenghuang , Chen Lijuan 
Published: November 2019

AbstractMultiple myeloma (MM) is the second most common hematologic malignancy and remains incurable despite the advent of numerous new drugs such as proteasome inhibitors (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies. There is an unmet need to develop novel therapies for refractory/relapsed MM. In the past few years, chimeric antigen receptor (CAR)-modified T cell therapy for MM has shown promising efficacy in preclinical and clinical studies. Furthermore, the toxicities of CAR-T cell therapy are manageable. This article summarizes recent developments of CAR-T therapy in MM, focusing on promising targets, new technologies, and new research areas. Additionally, a comprehensive overview of antigen selection is presented along with preliminary results and future directions of CAR-T therapy development.
Downregulation of class II phosphoinositide 3-kinase PI3K-C2β delays cell division and potentiates the effect of docetaxel on cancer cell growth
Authors: Cisse Ouma , Quraishi Muzthahid , Gulluni Federico , Guffanti Federica , Mavrommati Ioanna , Suthanthirakumaran Methushaa , Oh Lara C. R. , Schlatter Jessica N. , Sarvananthan Ambisha , Broggini Massimo , Hirsch Emilio , Falasca Marco , Maffucci Tania 
Published: November 2019

Abstract
Background
Alteration of signalling pathways regulating cell cycle progression is a common feature of cancer cells. Several drugs targeting distinct phases of the cell cycle have been developed but the inability of many of them to discriminate between normal and cancer cells has strongly limited their clinical potential because of their reduced efficacy at the concentrations used to limit adverse side effects. Mechanisms of resistance have also been described, further affecting their efficacy. Identification of novel targets that can potentiate the effect of these drugs or overcome drug resistance can provide a useful strategy to exploit the anti-cancer properties of these agents to their fullest.

Methods
The class II PI3K isoform PI3K-C2β was downregulated in prostate cancer PC3 cells and cervical cancer HeLa cells using selective siRNAs and the effect on cell growth was determined in the absence or presence of the microtubule-stabilizing agent/anti-cancer drug docetaxel. Mitosis progression was monitored by time-lapse microscopy. Clonogenic assays were performed to determine the ability of PC3 and HeLa cells to form colonies upon PI3K-C2β downregulation in the absence or presence of docetaxel. Cell multi-nucleation was assessed by immunofluorescence. Tumour growth in vivo was assessed using a xenograft model of PC3 cells upon PI3K-C2β downregulation and in combination with docetaxel.

Results
Downregulation of PI3K-C2β delays mitosis progression in PC3 and HeLa cells, resulting in reduced ability to form colonies in clonogenic assays in vitro. Compared to control cells, PC3 cells lacking PI3K-C2β form smaller and more compact colonies in vitro and they form tumours more slowly in vivo in the first weeks after cells implant. Stable and transient PI3K-C2β downregulation potentiates the effect of low concentrations of docetaxel on cancer cell growth. Combination of PI3K-C2β downregulation and docetaxel almost completely prevents colonies formation in clonogenic assays in vitro and strongly inhibits tumour growth in vivo.

Conclusions
These data reveal a novel role for the class II PI3K PI3K-C2β during mitosis progression. Furthermore, data indicate that blockade of PI3K-C2β might represent a novel strategy to potentiate the effect of docetaxel on cancer cell growth.
Derivation and validation of an easy-to-compute trauma score that improves prognostication of mortality or the Trauma Rating Index in Age, Glasgow Coma Scale, Respiratory rate and Systolic blood pressure (TRIAGES) score
Authors: Shiraishi Atsushi , Otomo Yasuhiro , Yoshikawa Shunsuke , Morishita Koji , Roberts Ian , Matsui Hiroki 
Published: November 2019

Abstract
Background
Multiple trauma scores have been developed and validated, including the Revised Trauma Score (RTS) and the Mechanism, Glasgow Coma Scale, Age, and Arterial Pressure (MGAP) score. However, these scores are complex to calculate or have low prognostic abilities for trauma mortality. Therefore, we aimed to develop and validate a trauma score that is easier to calculate and more accurate than the RTS and the MGAP score.

Methods
The study was a retrospective prognostic study. Data from patients registered in the Japan Trauma Databank (JTDB) were dichotomized into derivation and validation cohorts. Patients’ data from the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage-2 (CRASH-2) trial were assigned to another validation cohort. We obtained age and physiological variables at baseline, created ordinal variables from continuous variables, and defined integer weighting coefficients. Score performance to predict all-cause in-hospital death was assessed using the area under the curve in receiver operating characteristics (AUROC) analyses.

Results
Based on the JTDB derivation cohort (n = 99,867 with 12.5% mortality), the novel score ranged from 0 to 14 points, including 0–2 points for age, 0–6 points for the Glasgow Coma Scale, 0–4 points for systolic blood pressure, and 0–2 points for respiratory rate. The AUROC of the novel score was 0.932 for the JTDB validation cohort (n = 76,762 with 10.1% mortality) and 0.814 for the CRASH-2 cohort (n = 19,740 with 14.6% mortality), which was superior to RTS (0.907 and 0.808, respectively) and MGAP score (0.918 and 0.774, respectively) results.

Conclusions
We report an easy-to-use trauma score with better prognostication ability for in-hospital mortality compared to the RTS and MGAP score. Further studies to test clinical applicability of the novel score are warranted.
Why physiology will continue to guide the choice between balanced crystalloids and normal saline: a systematic review and meta-analysis
Authors: Zwager Charlotte L. , Tuinman Pieter Roel , de Grooth Harm-Jan , Kooter Jos , Ket Hans , Fleuren Lucas M. , Elbers Paul W. G. 
Published: November 2019

AbstractBackgroundCrystalloids are the most frequently prescribed drugs in intensive care medicine and emergency medicine. Thus, even small differences in outcome may have major implications, and therefore, the choice between balanced crystalloids versus normal saline continues to be debated. We examined to what extent the currently accrued information size from completed and ongoing trials on the subject allow intensivists and emergency physicians to choose the right fluid for their patients.MethodsSystematic review and meta-analysis with random effects inverse variance model. Published randomized controlled trials enrolling adult patients to compare balanced crystalloids versus normal saline in the setting of intensive care medicine or emergency medicine were included. The main outcome was mortality at the longest follow-up, and secondary outcomes were moderate to severe acute kidney injury (AKI) and initiation of renal replacement therapy (RRT). Trial sequential analyses (TSA) were performed, and risk of bias and overall quality of evidence were assessed. Additionally, previously published meta-analyses, trial sequential analyses and ongoing large trials were analysed for included studies, required information size calculations and the assumptions underlying those calculations.ResultsNine studies (n = 32,777) were included. Of those, eight had data available on mortality, seven on AKI and six on RRT. Meta-analysis showed no significant differences between balanced crystalloids versus normal saline for mortality (P = 0.33), the incidence of moderate to severe AKI (P = 0.37) or initiation of RRT (P = 0.29). Quality of evidence was low to very low. Analysis of previous meta-analyses and ongoing trials showed large differences in calculated required versus accrued information sizes and assumptions underlying those. TSA revealed the need for extremely large trials based on our realistic and clinically relevant assumptions on relative risk reduction and baseline mortality.ConclusionsOur meta-analysis could not find significant differences between balanced crystalloids and normal saline on mortality at the longest follow-up, moderate to severe AKI or new RRT. Currently accrued information size is smaller, and the required information size is larger than previously anticipated. Therefore, completed and ongoing trials on the topic may fail to provide adequate guidance for choosing the right crystalloid. Thus, physiology will continue to play an important role for individualizing this choice.
Evaluation of honey-baited FTA cards in combination with different mosquito traps in an area of low arbovirus prevalence
Authors: Wipf Nadja C. , Guidi Valeria , Tonolla Mauro , Ruinelli Michela , Müller Pie , Engler Olivier 
Published: November 2019

AbstractBackgroundThe threat of mosquito-borne diseases is increasing in continental Europe as demonstrated by several autochthonous chikungunya, dengue and West Nile virus outbreaks. In Switzerland, despite the presence of competent vectors, routine surveillance of arboviruses in mosquitoes is not being carried out, mainly due to the high costs associated with the need of a constant cold chain and laborious processing of thousands of mosquitoes. An alternative approach is using honey-baited nucleic acid preserving cards (FTA cards) to collect mosquito saliva that may be analysed for arboviruses. Here, we evaluate whether FTA cards could be used to detect potentially emerging viruses in an area of low virus prevalence in combination with an effective mosquito trap.MethodsIn a field trial in southern Switzerland we measured side-by-side the efficacy of the BG-Sentinel 2, the BG-GAT and the Box gravid trap to catchAedesandCulexmosquitoes in combination with honey-baited FTA cards during 80 trapping sessions of 48 hours. We then screened both the mosquitoes and the FTA cards for the presence of arboviruses using reverse-transcription PCR. The efficacy of the compared trap types was evaluated using generalized linear mixed models.ResultsThe Box gravid trap collected over 11 times more mosquitoes than the BG-GAT and BG-Sentinel 2 trap. On average 75.9% of the specimens fed on the honey-bait with no significant difference in feeding rates between the three trap types. From the total of 1401 collected mosquitoes, we screened 507Aedesand 500Culexfemales for the presence of arboviruses. A pool of sixCx. pipiens/Cx. torrentiummosquitoes and also the FTA card from the same Box gravid trap were positive for Usutu virus. Remarkably, only two of the sixCulexmosquitoes fed on the honey-bait, emphasising the high sensitivity of the method. In addition, twoAe. albopictuscollections but no FTA cards were positive for mosquito-only flaviviruses.ConclusionsBased on our results we conclude that honey-baited FTA cards, in combination with the Box gravid trap, are an effective method for arbovirus surveillance in areas of low prevalence, particularly where resources are limited for preservation and screening of individual mosquitoes.