bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low testosterone levels predict clinical adverse outcomes in SARS‐CoV‐2 pneumonia patients
Authors: Rastrelli Giulia , Di Stasi Vincenza , Inglese Francesco , Beccaria Massimiliano , Garuti Martina , Di Costanzo Domenica , Spreafico Fabio , Greco Graziana Francesca , Cervi Giulia , Pecoriello Antonietta , Magini Angela , Todisco Tommaso , Cipriani Sarah , Maseroli Elisa , Corona Giovanni , Salonia Andrea , Lenzi Andrea , Maggi Mario , De Donno Giuseppe , Vignozzi Linda 
Published: May 2020

AbstractBackgroundThe pandemic of new severe acute respiratory syndrome (SARS) due to coronavirus (CoV) 2 (SARS‐CoV‐2) has stressed the importance of effective diagnostic and prognostic biomarkers of clinical worsening and mortality. Epidemiological data showing a differential impact of SARS‐CoV‐2 infection on women and men have suggested a potential role for testosterone (T) in determining gender disparity in the SARS‐CoV‐2 clinical outcomes.ObjectivesTo estimate the association between T level and SARS‐CoV‐2 clinical outcomes (defined as conditions requiring transfer to higher or lower intensity of care or death) in a cohort of patients admitted in the respiratory intensive care unit (RICU).Materials and methodsA consecutive series of 31 male patients affected by SARS‐CoV‐2 pneumonia and recovered in the respiratory intensive care unit (RICU) of the “Carlo Poma” Hospital in Mantua were analyzed. Several biochemical risk factors (ie, blood count and leukocyte formula, C‐reactive protein (CRP), procalcitonin (PCT), lactate dehydrogenase (LDH), ferritin, D‐dimer, fibrinogen, interleukin 6 (IL‐6)) as well as total testosterone (TT), calculated free T (cFT), sex hormone–binding globulin (SHBG), and luteinizing hormone (LH) were determined.ResultsLower TT and cFT were found in the transferred to ICU/deceased in RICU group vs groups of patients transferred to IM or maintained in the RICU in stable condition. Both TT and cFT showed a negative significant correlation with biochemical risk factors (ie, the neutrophil count, LDH, and PCT) but a positive association with the lymphocyte count. Likewise, TT was also negatively associated with CRP and ferritin levels. A steep increase in both ICU transfer and mortality risk was observed in men with TT < 5 nmol/L or cFT < 100 pmol/L.Discussion and conclusionOur study demonstrates for the first time that lower baseline levels of TT and cFT levels predict poor prognosis and mortality in SARS‐CoV‐2‐infected men admitted to RICU.
Effect of platelet‐rich plasma on colon anastomosis in rats in which hyperthermic intra‐peritoneal chemotherapy was performed using 5‐fluorouracil
Authors: Göksu Mustafa , Alakuş Hüseyin , Ertan Siraç , Akgün Sadık 
Published: May 2020

AbstractBackgroundHyperthermic intra‐peritoneal chemotherapy (HIPEC) performed in patients with peritoneal carcinomatosis has a cytotoxic effect on tumour cells. This cytotoxic effect also adversely affects the wound healing of anastomosis, which is frequently undertaken in this patient group, and causes anastomotic leakage and intestinal fistulas. Platelet‐rich plasma (PRP) gel has been used in wound healing and has shown efficacy. We investigated the effect of PRP gel on colon anastomosis healing in rats treated with 5‐fluorouracil (5‐FU).MethodsTwenty‐four rats were divided into three groups, each containing eight rats: group 1 (control) underwent colon anastomosis alone; group 2 (5‐FU) underwent a colon anastomosis and HIPEC; and group 3 (5‐FU + PRP) underwent a colon anastomosis and HIPEC and received topical PRP gel. The rats were sacrificed on the post‐operative day 7 and the anastomotic bursting pressure (ABP) was measured. Tissue samples were obtained to measure the hydroxyproline level and investigate the histopathological changes on the anastomosis line.ResultsABP was higher in the control and 5‐FU + PRP groups than in the 5‐FU group (P = 0.009, P = 0.047). The tissue hydroxyproline levels were higher in the control and 5‐FU + PRP groups than in the 5‐FU group (P = 0.001, P = 0.030). The histopathological findings of the 5‐FU + PRP group were better than those of the 5‐FU group.ConclusionThis study showed that the application of PRP gel to colon anastomoses increased ABP in rats treated with HIPEC using 5‐FU. It also showed positive effects on anastomotic healing by increasing the tissue hydroxyproline levels on the anastomosis line and reducing the inflammatory response.
Anti‐clogging mechanisms of a motion‐activated chest tube patency maintenance system: Histology and high‐speed camera assessment
Authors: Okano Shinji , Lobosky Mark , Dessoffy Raymond , Horvath David J. , Fukamachi Kiyotaka , Karimov Jamshid H. 
Published: May 2020

AbstractThe motion‐activated system (MAS) employs vibration to prevent intraluminal chest tube clogging. We evaluated the intraluminal clot formation inside chest tubes using high‐speed camera imaging and postexplant histology analysis of thrombus. The chest tube clogging was tested (MAS vs. control) in acute hemothorax porcine models (n = 5). The whole tubes with blood clots were fixed with formalin–acetic acid solution and cut into cross‐sections, proceeded for H&E‐stained paraffin‐embedded tissue sections (MAS sections, n = 11; control sections, n = 11), and analyzed. As a separate effort, a high‐speed camera (FASTCAM Mini AX200, 100‐mm Zeiss lens) was used to visualize the whole blood clogging pattern inside the chest tube cross‐sectional view. Histology revealed a thin string‐like fibrin deposition, which showed spiral eddy or aggregate within the blood clots in most sections of Group MAS, but not in those of the control group. Histology findings were compatible with high‐speed camera views. The high‐speed camera images showed a device‐specific intraluminal blood “swirling” pattern. Our findings suggest that a continuous spiral flow in blood within the chest tube (MAS vs. static control) contributes to the formation of a spiral string‐like fibrin network during consumption of coagulation factors. As a result, the spiral flow may prevent formation of thick band‐like fibrin deposits sticking to the inner tube surface and causing tube clogging, and thus may positively affect chest tube patency and drainage.
Children and young adults with anophthalmia and microphthalmia: Diagnosis and Management
Authors: Taha Najim Rezhna , Topa Alexandra , Jugård Ylva , Casslén Beatrice , Odersjö Marie , Andersson Grönlund Marita 
Published: May 2020

AbstractPurposeCongenital anophthalmia (A) and microphthalmia (M) are rare developmental defects, which could be isolated or syndromic. Our objective was to describe a cohort of children and young adults with A/M treated with ocular prosthesis, emphasizing clinical features, diagnosis, treatment, and follow‐up.MethodsEighteen individuals (10 female) with unilateral A (n = 3) and M (n = 15) with a mean age of 9.5 years (range 0.8–31.8) and treated with ocular prosthesis were included. Data on medical history, clinical examinations and management of ocular prosthesis were collected. Genetic screening with microarray and whole‐exome sequencing targeting 121 A/M‐related genes was performed.ResultsA/M appeared isolated (seven cases) or as part of a syndromic condition (11 cases). In 4/16 patients, mutations were detected in TFAP2A, CHD7, FOXE3 and BCOR‐genes. In one patient, a possibly causal microdeletion 10q11 was shown. Associated ocular anomalies such as cataract and cysts were found in 16 (89%) of the A/M eyes, and in nine (50%) ophthalmological findings were found in the fellow eyes. The median ages at which the conformer and ocular prosthesis first were initiated were 7.8 months and 1.5 years. 16/17 patients fulfilled satisfactory orbital growth and cosmetic results when treated with ocular prosthesis from an early age.ConclusionBased upon our findings, a multidisciplinary approach, including genetic assessment, is necessary to cover all aspects of A/M. Imaging, ultrasound and visual evoked potentials should be included. Early management is crucial for the outcome, in terms of non‐ocular findings, vision in the fellow eye, and for facial cosmetic development.
Application of electron microprobe analysis to identify the origin of ancient pottery production from the Castillo de Huarmey, Peru
Authors: Kałaska M. , Druc I. C. , Chyla J. , Pimentel R. , Syczewski M. , Siuda R. , Makowski K. , Giersz M. 
Published: May 2020

A vast amount of ceramics (among other grave goods) were recovered from Castillo de Huarmey, a Wari culture (650–1050 ce) archaeological site on the north coast of Peru. In order to assess ceramic production area(s) and possible trade, political or cultural interactions with other regions, and to complement earlier petrographic analysis, electron microprobe analysis (EMPA) was conducted following a rarely used methodology in archaeology. The chemical composition of individual minerals in ceramics and sediments samples from the Huarmey Valley was obtained, focusing mainly on amphiboles, feldspars and pyroxenes. The results of the analyses clearly indicate that the majority of the ceramic analysed was made of raw material of local origin.
Development of prescribing safety indicators related to mental health disorders and medications: Modified e‐Delphi study
Authors: Khawagi Wael Y. , Steinke Douglas T. , Nguyen Joanne , Pontefract Sarah , Keers Richard N. 
Published: May 2020

AimTo develop a set of prescribing safety indicators related to mental health disorders and medications, and to estimate the risk of harm associated with each indicator.MethodA modified two‐stage electronic Delphi. The first stage consisted of two rounds in which 31 experts rated their agreement with a set of 101 potential mental health related prescribing safety indicators using a five‐point scale and given the opportunity to suggest other indicators. Indicators that achieved 80% agreement were accepted. The second stage comprised a single round in which 29 members estimated the risk of harm for each accepted indicator by assessing the occurrence likelihood and outcome severity using two five‐point scales. Indicators were considered high or extreme risk when at least 80% of participants rated each indicator as high or extreme.ResultsSeventy‐five indicators were accepted in the first stage. Following the second stage, 42 (56%) were considered to be high or extreme risk for patient care. The 42 indicators comprised different types of hazardous prescribing, including drug‐disease interactions (n = 12), drug‐drug interactions (n = 9), inadequate monitoring (n = 5), inappropriate duration (n = 4), inappropriate dose (n = 4), omissions (n = 4), potentially inappropriate medications (n = 3) and polypharmacy (n = 1). These indicators also covered different mental health related medication classes, including antipsychotics (n = 14), mood stabilisers (n = 8), antidepressants (n = 6), sedative, hypnotics and anxiolytics (n = 6), anticholinergic (n = 6) and nonspecific psychotropics (n = 2).ConclusionThis study has developed the first suite of prescribing safety indicators related to mental health disorders and medications, which could inform the development of future safety improvement initiatives and interventional studies.
Triage tool for the rationing of blood for massively bleeding patients during a severe national blood shortage: guidance from the National Blood Transfusion Committee
Authors: Doughty Heidi , Green Laura , Callum Jeannie , Murphy Michael F. ,   National Blood Transfusion Committee
Published: May 2020

SummaryThe emerging COVID‐19 pandemic has overwhelmed healthcare resources worldwide, and for transfusion services this could potentially result in rapid imbalance between supply and demand due to a severe shortage of blood donors. This may result in insufficient blood components to meet every patient's needs resulting in difficult decisions about which patients with major bleeding do and do not receive active transfusion support. This document, which was prepared on behalf of the National Blood Transfusion Committee in England, provides a framework and triage tool to guide the allocation of blood for patients with massive haemorrhage during severe blood shortage. Its goal is to provide blood transfusions in an ethical, fair, and transparent way to ensure that the greatest number of life years are saved. It is based on an evidence‐ and ethics‐based Canadian framework, and would become operational where demand for blood greatly exceeds supply, and where all measures to manage supply and demand have been exhausted. The guidance complements existing national shortage plans for red cells and platelets.
Genotype–phenotype correlation in children with hereditary spherocytosis
Authors: Tole Soumitra , Dhir Priya , Pugi Jakob , Drury Luke J. , Butchart Sheila , Fantauzzi Michelle , Langer Jacob C. , Baker Jillian M. , Blanchette Victor S. , Kirby‐Allen Melanie , Carcao Manuel D. 
Published: May 2020

SummaryHereditary spherocytosis (HS) is a common inherited haemolytic anaemia attributed to disturbances in five different red cell membrane proteins. We performed a retrospective study of 166 children with HS and describe the clinical phenotype according to the genotype. In 160/166 (97%) children with HS a disease‐causing mutation was identified. Pathogenic variants in ANK1, SPTB, SLC4A1 and SPTA1 were found in 49%, 33%, 13% and 5% of patients. Children with SLC4A1‐HS had the mildest phenotype, showing the highest haemoglobin (P < 0·001), lowest reticulocyte counts (P < 0·001) and lowest unconjugated bilirubin levels (P = 0·006), and none required splenectomy in childhood (P < 0·001). Conversely, children with autosomal recessive SPTA1‐HS had the most severe clinical phenotype, with almost all patients undergoing splenectomy in early childhood. Patients with ANK1 and SPTB variants showed a similar clinical phenotype. Within each gene, variant type or location did not predict disease severity or likelihood of splenectomy. Among patients with a genetic diagnosis, 47 (29%) underwent splenectomy (23 partial; 24 total) while 57 (36%) underwent cholecystectomy. Total splenectomy led to greater improvements in haemoglobin (P = 0·02). Select use of genetic testing (especially in patients without a family history) may help predict clinical phenotype in childhood and guide family counselling.
Multiparametric MRI‐ultrasonography software fusion prostate biopsy: initial results using a stereotactic robotic‐assisted transperineal prostate biopsy platform comparing systematic vs targeted biopsy
Authors: Lee Alvin Y.M. , Yang Xin Yan , Lee Han Jie , Law Yan Mee , Huang Hong Hong , Lau Weber K.O. , Lee Lui Shiong , Ho Henry S.S. , Tay Kae Jack , Cheng Christopher W.S. , Yuen John S.P. , Chen Kenneth 
Published: May 2020

ObjectiveTo compare the detection rates of prostate cancer between systematic biopsy and targeted biopsy using a stereotactic robot‐assisted transperineal prostate platform.Materials and MethodsWe identified consecutive patients with suspicious lesion(s) on multiparametric magnetic resonance imaging (mpMRI), who underwent both systematic and MRI‐transrectal ultrasonography (US) fusion targeted biopsy using our proprietary transperineal robot‐assisted prostate biopsy platform between January 2015 and January 2019 at our institution, for retrospective analysis. Comparative analysis was performed between systematic and targeted biopsy using McNemar’s test, and the cohort was further stratified by prior biopsy status and Prostate Imaging Reporting and Data System (PI‐RADS) v2.0 score. International Society of Urological Pathology (ISUP) grade group (GG) ≥2 cancers (previously known as Gleason grade ≥7) were considered to be clinically significant.ResultsA total of 500 patients were included in our final analysis, of whom 67 (13%) were patients with low‐risk cancer on active surveillance. Of the 433 patients without prior diagnosis of cancer, 288 (67%) were biopsy‐naïve. A total of 248 (57%) were diagnosed with prostate cancer, with 199 (46%) having clinically significant prostate cancer (ISUP GG ≥2). There were no statistically significant differences in the overall prostate cancer and clinically significant prostate cancer detection rate between systematic and targeted biopsy (51% vs 49% and 40% vs 38% respectively; P = 0.306 and P = 0.609). Of the 248 prostate cancers detected, 75% (187/248) were detected on both systematic and targeted biopsy, 14% (35/248) were detected on systematic biopsy alone and 11% (26/248) were detected on targeted biopsy alone. Of the 199 clinically significant cancers detected, 69% (138/199) were detected on both systematic and targeted biopsy, 17% (33/199) on systematic biopsy alone and 14% (28/199) on targeted biopsy alone. There were no statistically significant differences in the detection rate between systematic and targeted biopsy for both overall and clinically significant prostate cancer, even when the cohort was stratified by prior biopsy status and PI‐RADS score. Targeted biopsy has greater sampling efficiency compared to systematic biopsy for both overall and clinically significant prostate cancer (23.2% vs 9.8%, P < 0.001 and 14.8% vs 5.6%, P < 0.001).ConclusionsUsing our robot‐assisted transperineal prostate platform, combined MRI‐US targeted biopsy with concurrent systematic prostate systematic biopsy probably represents the optimal method for the detection of clinically significant prostate cancer.
Transgenic LQT2, LQT5, and LQT2‐5 rabbit models with decreased repolarisation reserve for prediction of drug‐induced ventricular arrhythmias
Authors: Hornyik Tibor , Castiglione Alessandro , Franke Gerlind , Perez‐Feliz Stefanie , Major Péter , Hiripi László , Koren Gideon , Bősze Zsuzsanna , Varró András , Zehender Manfred , Brunner Michael , Bode Christoph , Baczkó István , Odening Katja E. 
Published: May 2020

Background and PurposeReliable prediction of pro‐arrhythmic side effects of novel drug candidates is still a major challenge. Although drug‐induced pro‐arrhythmia occurs primarily in patients with pre‐existing repolarisation disturbances, healthy animals are employed for pro‐arrhythmia testing. To improve current safety screening, transgenic long QT (LQTS) rabbit models with impaired repolarisation reserve were generated by overexpressing loss‐of‐function mutations of human HERG (HERG‐G628S, loss of IKr; LQT2), KCNE1 (KCNE1‐G52R, decreased IKs; LQT5), or both transgenes (LQT2‐5) in the heart.Experimental ApproachEffects of K+ channel blockers on cardiac repolarisation and arrhythmia susceptibility were assessed in healthy wild‐type (WT) and LQTS rabbits using in vivo ECG and ex vivo monophasic action potential and ECG recordings in Langendorff‐perfused hearts.Key ResultsLQTS models reflect patients with clinically “silent” (LQT5) or “manifest” (LQT2 and LQT2‐5) impairment in cardiac repolarisation reserve: they were more sensitive in detecting IKr‐blocking (LQT5) or IK1/IKs‐blocking (LQT2 and LQT2‐5) properties of drugs compared to healthy WT animals. Impaired QT‐shortening capacity at fast heart rates was observed due to disturbed IKs function in LQT5 and LQT2‐5. Importantly, LQTS models exhibited higher incidence, longer duration, and more malignant types of ex vivo arrhythmias than WT.Conclusion and ImplicationsLQTS models represent patients with reduced repolarisation reserve due to different pathomechanisms. As they demonstrate increased sensitivity to different specific ion channel blockers (IKr blockade in LQT5 and IK1 and IKs blockade in LQT2 and LQT2‐5), their combined use could provide more reliable and more thorough prediction of (multichannel‐based) pro‐arrhythmic potential of novel drug candidates.
High glucose‐mediated PICALM and mTORC1 modulate processing of amyloid precursor protein via endosomal abnormalities
Authors: Chae Chang Woo , Lee Hyun Jik , Choi Gee Euhn , Jung Young Hyun , Kim Jun Sung , Lim Jae Ryong , Kim Seo Yihl , Hwang In Koo , Seong Je Kyung , Han Ho Jae 
Published: May 2020

Background and PurposeAlthough diabetes mellitus (DM) is an important risk factor for Alzheimer's disease (AD), the detailed mechanism(s) by which DM regulates amyloid β (Aβ) processing is still unclear. The longer residence time of amyloid precursor protein (APP) in endosomes is critical for Aβ production and DM is known to cause endosomal dysregulation. Here we have examined the effects of high glucose on APP‐producing endosomes and related signaling pathways.Experimental ApproachTo identify the underlying mechanisms, we investigated the effects of high glucose on abnormalities in early endosomes and related signalling pathways in human neuroblastoma cells. In vivo, diabetic mice treated with pharmacological inhibitors were used to examine endosomal dysfunction.Key ResultsThe hippocampus of diabetic animals presented endosomal abnormalities and Aβ up‐regulation. High glucose increased Aβ production through early endosomal enlargement achieved by increased lipid raft‐mediated APP endocytosis. High glucose induced ROS‐stimulated Sp1 activation, up‐regulating phosphatidylinositol binding clathrin assembly protein (PICALM), clathrin heavy chain, and adaptor‐related protein complex 2 alpha 1. PICALM facilitated clathrin‐mediated APP endocytosis resulting in early endosomal enlargement. Meanwhile, AMPK/mTORC1‐mediated autophagy defect and ROS‐ and mTORC1‐mediated lysosomal dysfunction aggravated early endosomal enlargement under high glucose. Moreover, the increased Aβ production and cognitive deficits in diabetic mice were reversed by inhibition of early endosomal enlargement.Conclusion and ImplicationsHigh glucose induces early endosomal abnormalities through PICALM‐induced APP endocytosis and mTORC1‐inhibited endosomal clearance, up‐regulating Aβ production. Thus, targeting PICALM and mTORC1 to prevent endosomal disorders is a promising strategy for managing diabetes‐induced AD.
Signalling, trafficking and glucoregulatory properties of glucagon‐like peptide‐1 receptor agonists exendin‐4 and lixisenatide
Authors: Pickford Philip , Lucey Maria , Fang Zijian , Bitsi Stavroula , de la Serna Jorge Bernardino , Broichhagen Johannes , Hodson David J. , Minnion James , Rutter Guy A. , Bloom Stephen R. , Tomas Alejandra , Jones Ben 
Published: May 2020

Background and PurposeAmino acid substitutions at the N‐termini of glucagon‐like peptide‐1 (GLP‐1) receptor agonist peptides result in distinct patterns of intracellular signalling, sub‐cellular trafficking and efficacy in vivo. Here, we to determine whether sequence differences at the ligand C‐termini of clinically approved GLP‐1 receptor agonists exendin‐4 and lixisenatide lead to similar phenomena.Experimental ApproachExendin‐4, lixisenatide and N‐terminally substituted analogues with biased signalling characteristics were compared across a range of in vitro trafficking and signalling assays in different cell types. Fluorescent ligands and new time‐resolved FRET approaches were developed to study agonist behaviours at the cellular and sub‐cellular level. Anti‐hyperglycaemic and anorectic effects of each parent ligand and their biased derivatives were assessed in mice.Key ResultsLixisenatide and exendin‐4 showed equal binding affinity, but lixisenatide was fivefold less potent for cAMP signalling. Both peptides induced extensive GLP‐1 receptor clustering in the plasma membrane and were rapidly endocytosed, but the GLP‐1 receptor recycled more slowly to the cell surface after lixisenatide treatment. These combined deficits resulted in reduced maximal sustained insulin secretion and reduced anti‐hyperglycaemic and anorectic effects in mice with lixisenatide. N‐terminal substitution of His1 by Phe1 to both ligands had favourable effects on their pharmacology, resulting in improved insulin release and lowering of blood glucose.Conclusion and ImplicationsChanges to the C‐terminus of exendin‐4 affect signalling potency and GLP‐1 receptor trafficking via mechanisms unrelated to GLP‐1 receptor occupancy. These differences were associated with changes in their ability to control blood glucose and therefore may be therapeutically relevant.