bluuebunny/crossref_metadata_2025_split huggingface dataset:
First results of a phase III multicenter randomized controlled trial of intensity modulated (IMRT) versus conventional radiotherapy (RT) in head and neck cancer (PARSPORT: ISRCTN48243537)
Authors: Nutting C. , A'Hern R. , Rogers M. S. , Sydenham M. A. , Adab F. , Harrington K. , Jefferies S. , Scrase C. , Yap B. K. , Hall E. ,   on behalf of the PARSPORT Trial Management Group
Published: August 2020

LBA6006 The full, final text of this abstract will be available in Part II of the 2009 ASCO Annual Meeting Proceedings, distributed onsite at the Meeting on May 30, 2009, and as a supplement to the June 20, 2009, issue of the Journal of Clinical Oncology. [Table: see text]
Sex Hormone Relations to Histologic Severity of Pediatric Nonalcoholic Fatty Liver Disease
Authors: Mueller Noel T , Liu Tiange , Mitchel Elana B , Yates Katherine P , Suzuki Ayako , Behling Cynthia , Lavine Joel E 
Published: August 2020

Abstract

Context
Sex hormones have been linked with presence and severity of nonalcoholic fatty liver disease (NAFLD) in adults, but it is unknown if they affect severity of pediatric NAFLD.

Objective
To examine associations of circulating SHBG, estrogens, and androgens with key histologic features of pediatric, biopsy-confirmed NAFLD.

Design
Baseline assessment of longitudinal cohorts and randomized clinical trials.

Setting
Nonalcoholic Steatohepatitis Clinical Research Network.

Patients
Children and adolescents ≤18 years with liver biopsy-confirmed NAFLD in the United States.

Main Outcome Measures
We assayed SHBG, estrone, estradiol, dehydroepiandrosterone (DHEAS), androstenedione, and testosterone in relation to grade/stage of steatosis, portal inflammation, hepatic ballooning, fibrosis, and nonalcoholic steatohepatitis (NASH) severity using linear regression.

Results
Mean age of 573 children at the time of biopsy was 13.1 years (SD 2.8). Lower SHBG was inversely associated with steatosis severity in boys and girls (P = 0.001), and with portal inflammation in girls only (P for sex interaction &lt;0.001). Higher testosterone was related to improved features of steatosis and fibrosis (P for sex interaction = 0.003 and 0.01, respectively) in boys, but detrimental in girls. In boys and girls, higher estrone, estradiol, and testosterone were associated with lower portal inflammation grade; higher estradiol was positively associated with hepatic ballooning severity; DHEAS was inversely associated with hepatic ballooning and NASH severity (all P &lt; 0.05). Androstenedione was not associated with NAFLD features.

Conclusions
Largely consistent with findings in adults, sex hormones are associated with distinct histologic features of NAFLD in children and adolescents. These hormone levels relate to differences with gender and pubertal change.
Nonalcoholic Fatty Liver Disease and Estimated Insulin Resistance in Obese Youth: A Mendelian Randomization Analysis
Authors: Morandi Anita , Di Sessa Anna , Zusi Chiara , Umano Giuseppina Rosaria , El Mazloum Dania , Fornari Elena , Miraglia del Giudice Emanuele , Targher Giovanni , Maffeis Claudio 
Published: August 2020

AbstractContextNonalcoholic fatty liver disease (NAFLD) is associated with insulin resistance (IR) and predicts type 2 diabetes. Currently, it is uncertain whether NAFLD may directly cause IR or vice versa.ObjectiveTo test the hypothesis that NAFLD is causally related to IR.Design and MethodsWe performed a Mendelian randomization (MR) in 904 obese children/adolescents using an NAFLD-related genetic risk score (GRS) as an instrumental variable. We assessed NAFLD by ultrasonography and IR by homeostasis model assessment (HOMA-IR). We also interrogated the MAGIC Consortium dataset of 46 186 adults to assess the association between PNPLA3 rs738409 (ie, the most robust NAFLD-related polymorphism) and HOMA-IR, and we performed a 2-sample MR with 2 large datasets to test reverse causation (HOMA-IR increasing the risk of NAFLD).ResultsNonalcoholic fatty liver disease prevalence increased by 20% for every increase in the GRS (β-coefficient = 0.20, P &lt; 0.001), and NAFLD was associated with ln-HOMA-IR (β-coefficient = 0.28, P &lt; 0.001). Thus, the expected increase in ln-HOMA-IR for every increase in the GRS (expected β-coefficient) was 0.056 (0.28*0.20) in the case of complete NAFLD-HOMA-IR causal association, and 0.042 in the case of 75% causality. In our cohort, the GRS did not predict ln-HOMA-IR (β-coefficient = 0.007, P = 0.75). In the MAGIC cohort, the PNPLA3 rs738409 did not associate with ln-HOMA-IR. The 2-sample MR failed to show a causal association between ln-HOMA-IR and NAFLD.ConclusionsOur study shows that genetically-influenced NAFLD does not increase HOMA-IR, and genetically-influenced HOMA-IR does not increase the risk of NAFLD. Shared pathogenic pathways or NAFLD subtypes not “captured” by our MR design might underpin the association between NAFLD and HOMA-IR.
Congenital Hypothyroidism Due to Truncating PAX8 Mutations: A Case Series and Molecular Function Studies
Authors: Iwahashi-Odano Megumi , Nagasaki Keisuke , Fukami Maki , Nishioka Junko , Yatsuga Shuichi , Asakura Yumi , Adachi Masanori , Muroya Koji , Hasegawa Tomonobu , Narumi Satoshi 
Published: August 2020

Abstract

Context
PAX8 is a transcription factor required for thyroid development, and its mutation causes congenital hypothyroidism (CH). More than 20 experimentally verified loss-of-function PAX8 mutations have been described, and all but one were located in the DNA-binding paired domain.

Objective
We report the identification and functional characterization of 3 novel truncating PAX8 mutations located outside the paired domain.

Methods
Three CH probands, diagnosed in the frame of newborn screening, had thyroid hypoplasia and were treated with levothyroxine. Next-generation sequencing-based mutation screening was performed. Functionality of the identified mutations were verified with Western blotting, intracellular localization assays, and transactivation assays with use of HeLa cells. Luciferase complementation assays were used to evaluate the effect of mutations on the interaction between PAX8 and its partner, NKX2-1.

Results
Each proband had novel truncating PAX8 mutations that were I160Sfs*52, Q213Efs*27, and F342Rfs*85. Western blotting showed destabilization of the I160fs-PAX8 protein. Q213fs-PAX8 and F342fs-PAX8 showed normal protein expression levels and normal nuclear localization, but showed loss of transactivation of the luciferase reporter. By luciferase complementation assays, we showed that PAX8-NKX2-1 interaction was defective in Q213fs-PAX8. We also characterized the recombinant PAX8 proteins, and found that the protein sequence corresponding to exon 10 (363-400 aa residues) was essential for the PAX8-NKX2-1 interaction.

Conclusions
Clinical and molecular findings of 3 novel truncating PAX8 mutations located outside the paired domain were reported. Experiments using cultured cells and recombinant proteins showed that the C-terminal portion (ie, 363-400 aa) of PAX8 is required for the PAX8-NKX2-1 interaction.
Clinical Adverse Events of High-Dose vs Low-Dose Sodium–Glucose Cotransporter 2 Inhibitors in Type 2 Diabetes: A Meta-Analysis of 51 Randomized Clinical Trials
Authors: Shi Fang-Hong , Li Hao , Yue Jiang , Jiang Yi-Hong , Gu Zhi-Chun , Ma Jing , Lin Hou-Wen 
Published: August 2020

Abstract

Aims
The aims of this work are to assess the clinical adverse events (AEs) of high-dose vs low-dose sodium–glucose cotransporter 2 inhibitors (SGLT2 inhibitors) in patients with type 2 diabetes mellitus (T2DM).

Methods
We searched MEDLINE, EMBASE, and Cochrane Library from January 1, 2006 to March 10, 2020, for identifying eligible randomized clinical trials (RCTs) that reported AEs by high-dose and low-dose SGLT2 inhibitors in T2DM patients. Random-effects models was used to obtain summary relative risks (RRs) with associated 95% CIs. Prespecified subgroup analyses according to individual SGLT2 inhibitors and follow-up duration, and leave-one-out sensitivity analysis were conducted.

Results
A total of 51 RCTs involving 24 371 patients (12 208 received high-dose and 12 163 received low-dose SGLT2 inhibitors) were included. Overall, the heterogeneity among included studies was relatively low (I2 &lt; 50% for each outcome). No significant differences between high-dose and low-dose SGLT2 inhibitors were observed for overall safety (including any AEs, serious AEs, AEs leading to discontinuation, and death) and specified safety (including infections and infestations, musculoskeletal disorders, gastrointestinal disorders, osmotic diuresis-related AEs, volume-related AEs, renal-related AEs, and metabolism and nutrition), except for a mild increase in risk for AEs related to study drugs (RR: 1.08; 95% CI, 1.01-1.16) that mainly derived from canagliflozin (RR: 1.17; 95% CI, 1.05-1.30). Subgroup analyses were consistent with the primary outcomes.

Conclusions
This study provided substantial evidence that AEs of SGLT2 inhibitors were not dose related.
Testicular Involvement is a Hallmark of Apo A-I Leu75Pro Mutation Amyloidosis
Authors: Delbarba Andrea , Facondo Paolo , Fisogni Simona , Izzi Claudia , Maffezzoni Filippo , Pezzaioli Letizia Chiara , Di Lodovico Elena , Facchetti Fabio , Cappelli Carlo , Scolari Francesco , Ferlin Alberto 
Published: August 2020

Abstract

Context
Apo A-I Leu75Pro is a rare hereditary form of amyloidosis that mainly involves the kidney, the liver, and the testis.

Objective
To define the characteristics of organ damage and testis impairment in the largest cohort collected to date of men with Apo A-I Leu75Pro amyloidosis.

Design, Setting, and Patients
Retrospective study from a prospectively collected database of 129 male subjects &gt;18 years with Apo A-I Leu75Pro amyloidosis from a reference center at the University Hospital of Brescia, Italy.

Main outcome measures
We evaluated liver and renal function, scrotal ultrasound, reproductive hormone levels, testis biopsy, hypogonadal symptoms, and fertility.

Results
Progressive involvement of testis, kidney, and liver was observed in 96/129 (74.4%) cases. Testis impairment was found in 88/129 patients (68.2%), liver in 59 (45.7%) and renal in 50 (38.8%). Testis damage was often the first manifestation of the disease and the only dysfunction in 30% of younger patients (&lt;38 years). Testicular involvement was characterized mainly by primary (73/88 patients, 83.0%) and subclinical (8/88, 9.1%) hypogonadism. Almost all (85/88, 96.6%) also had high follicle-stimulating hormone, suggesting a primary global damage of endocrine and spermatogenic functions, and 30% of them did not conceive. Macroorchidism was found in 53/88 (60.2%) patients, especially in men &lt;54 years (30/33, 90.9%). Apo A-I amyloid deposits were found in Sertoli cells, germinal epithelium, and vessel walls.

Conclusion
In men with Apo A-I Leu75Pro amyloidosis, testicular involvement is the hallmark of the disease, characterized by global primary testicular dysfunction and macroorchidism due to amyloid deposits.
Rabgap1 promotes recycling of active β1 integrins to support effective cell migration
Authors: Samarelli Anna V. , Ziegler Tilman , Meves Alexander , Fässler Reinhard , Böttcher Ralph T. 
Published: August 2020

ABSTRACT
Integrin function depends on the continuous internalization of integrins and their subsequent endosomal recycling to the plasma membrane to drive adhesion dynamics, cell migration and invasion. Here we assign a pivotal role for Rabgap1 (GAPCenA) in the recycling of endocytosed active β1 integrins to the plasma membrane. The phosphotyrosine-binding (PTB) domain of Rabgap1 binds to the membrane-proximal NPxY motif in the cytoplasmic domain of β1 integrin subunits on endosomes. Silencing Rabgap1 in mouse fibroblasts leads to the intracellular accumulation of active β1 integrins, alters focal adhesion formation, and decreases cell migration and cancer cell invasion. Functionally, Rabgap1 facilitates active β1 integrin recycling to the plasma membrane through attenuation of Rab11 activity. Taken together, our results identify Rabgap1 as an important factor for conformation-specific integrin trafficking and define the role of Rabgap1 in β1-integrin-mediated cell migration in mouse fibroblasts and breast cancer cells.
An indispensable role for dynamin-related protein 1 in beige and brown adipogenesis
Authors: Mooli Raja Gopal Reddy , Mukhi Dhanunjay , Chen Zhonghe , Buckner Nia , Ramakrishnan Sadeesh K. 
Published: August 2020

ABSTRACT
Emerging evidence indicates that proper mitochondrial dynamics are critical for adipocyte differentiation and functional thermogenic capacity. We found that the mitochondrial fission protein dynamin-related protein 1 (DRP1, also known as DNML1) is highly expressed in brown adipose tissue compared to expression in white adipose tissue, and these expression levels increase during brown adipocyte differentiation. Our results reveal that the inhibition of DRP1 using mdivi-1 mitigates beige adipocyte differentiation and differentiation-associated mitochondrial biogenesis. We found that DRP1 is essential for the induction of the early-phase beige adipogenic transcriptional program. Intriguingly, inhibition of DRP1 is dispensable following the induction of beige adipogenesis and adipogenesis-associated mitochondrial biogenesis. Altogether, we demonstrate that DRP1 in preadipocytes plays an essential role in beige and brown adipogenesis.
This article has an associated First Person interview with the first author of the paper.
High dose oral rifampicin to improve survival from adult tuberculous meningitis: A randomised placebo-controlled double-blinded phase III trial (the HARVEST study)
Authors: Marais Suzaan , Cresswell Fiona V , Hamers Raph L. , te Brake Lindsey H.M. , Ganiem Ahmad R. , Imran Darma , Bangdiwala Ananta , Martyn Emily , Kasibante John , Kagimu Enock , Musubire Abdu , Maharani Kartika , Estiasari Riwanti , Kusumaningrum Ardiana , Kusumadjayanti Nadytia , Yunivita Vycke , Naidoo Kogieleum , Lessells Richard , Moosa Yunus , Svensson Elin M. , Huppler Hullsiek Katherine , Aarnoutse Rob E. , Boulware David R. , van Crevel Reinout , Ruslami Rovina , Meya David B. 
Published: August 2020

Background: Tuberculous meningitis (TBM), the most severe form of tuberculosis (TB), results in death or neurological disability in >50%, despite World Health Organisation recommended therapy. Current TBM regimen dosages are based on data from pulmonary TB alone. Evidence from recent phase II pharmacokinetic studies suggests that high dose rifampicin (R) administered intravenously or orally enhances central nervous system penetration and may reduce TBM associated mortality. We hypothesize that, among persons with TBM, high dose oral rifampicin (35 mg/kg) for 8 weeks will improve survival compared to standard of care (10 mg/kg), without excess adverse events. Protocol: We will perform a parallel group, randomised, placebo-controlled, double blind, phase III multicentre clinical trial comparing high dose oral rifampicin to standard of care. The trial will be conducted across five clinical sites in Uganda, South Africa and Indonesia. Participants are HIV-positive or negative adults with clinically suspected TBM, who will be randomised (1:1) to one of two arms: 35 mg/kg oral rifampicin daily for 8 weeks (in combination with standard dose isoniazid [H], pyrazinamide [Z] and ethambutol [E]) or standard of care (oral HRZE, containing 10 mg/kg/day rifampicin). The primary end-point is 6-month survival. Secondary end points are: i) 12-month survival ii) functional and neurocognitive outcomes and iii) safety and tolerability. Tertiary outcomes are: i) pharmacokinetic outcomes and ii) cost-effectiveness of the intervention. We will enrol 500 participants over 2.5 years, with follow-up continuing until 12 months post-enrolment. Discussion: Our best TBM treatment still results in unacceptably high mortality and morbidity. Strong evidence supports the increased cerebrospinal fluid penetration of high dose rifampicin, however conclusive evidence regarding survival benefit is lacking. This study will answer the important question of whether high dose oral rifampicin conveys a survival benefit in TBM in HIV-positive and -negative individuals from Africa and Asia. Trial registration: ISRCTN15668391 (17/06/2019)
Partial catalytic Cys oxidation of human GAPDH to Cys-sulfonic acid.
Authors: Lia Andrea , Dowle Adam , Taylor Chris , Santino Angelo , Roversi Pietro 
Published: August 2020

Background: n-Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) catalyses the NAD+-dependent oxidative phosphorylation of n-glyceraldehyde-3-phosphate to 1,3-diphospho-n-glycerate and its reverse reaction in glycolysis and gluconeogenesis.Methods: Four distinct crystal structures of human n-Glyceraldehyde-3-phosphate dehydrogenase (HsGAPDH) have been determined from protein purified from the supernatant of HEK293F human epithelial kidney cells.Results: X-ray crystallography and mass-spectrometry indicate that the catalytic cysteine of the protein (HsGAPDH Cys152) is partially oxidised to cysteine S-sulfonic acid. The average occupancy for the Cys152-S-sulfonic acid modification over the 20 crystallographically independent copies ofHsGAPDH across three of the crystal forms obtained is 0.31±0.17.Conclusions: The modification induces no significant structural changes on the tetrameric enzyme, and only makes aspecific contacts to surface residues in the active site, in keeping with the hypothesis that the oxidising conditions of the secreted mammalian cell expression system result inHsGAPDH catalytic cysteine S-sulfonic acid modification and irreversible inactivation of the enzyme.
Survey of satisfaction regarding palliative care provided to patients who died at home or in a hospital
Authors: Katsuki Masaaki , Nakamata Momoka , Ezaki Arisa , Yamanaka Sayaka , Imamura Sakiko , Honda Chika , Kubota Toshio , Moriuchi Hiroshi , Irikura Mitsuru 
Published: August 2020

Background: Improvement in quality of life (QoL) of patients is one of the most important goals of palliative care, but evaluation of QoL of patients is difficult. Aim: To evaluate QoL of patients who died at home or in a hospital. Methods: We administered the Good Death Inventory (10 core and 8 optional domains) to the bereaved families of patients who died at home or in a hospital. A total of 107 bereaved families undertook a survey. Findings: If a bereaved family chose ‘somewhat agree’, ‘agree’ or ‘absolutely agree’, the answer was regarded as a ‘satisfactory answer’. Regarding the 10 core domains, of patients who died in a hospital, <50% respondents gave a ‘satisfactory answer’ to three questions, whereas of patients who died at home, >60% of respondents gave a ‘satisfactory answer’ to seven questions. Regarding the eight optional domains, of patients who died in a hospital, <50% respondents gave a ‘satisfactory answer’ to five questions, whereas of patients who died at home, >60% of respondents gave a ‘satisfactory answer’ to four questions. Conclusions: QoL of patients who died at home appeared higher than that of those who died in a hospital. Patients prefer to remain at home rather than in a hospital, probably because at home they are surrounded by familiar things and can live according to their usual habits.
Trauma Reporting: A Journalist’s Guide to Covering Sensitive Stories, Jo Healey (2019)
Authors: Gearing Amanda 
Published: August 2020

Review of: Trauma Reporting: A Journalist’s Guide to Covering Sensitive Stories, Jo Healey (2019)
London: Routledge, 206 pp.,
ISBN 978-1-13848-210-4, p/bk, $52.99,
ISBN 978-1-13848-209-8, h/bk, $231.00,
ISBN 978-1-35105-911-4, ebk, $43.16
Hypersensitivity to IV Ustekinumab but Tolerance to Subcutaneous Ustekinumab in a Patient With Crohn's Disease
Authors: Krugliak Cleveland Noa , Masching Alexandra , Rubin David T. 
Published: August 2020

ABSTRACT
Ustekinumab is a monoclonal antibody against the p40 subunit of interleukin (IL)-12 and IL-23 and is US Food and Drug Administration (FDA)-approved for plaque psoriasis, moderately to severely active Crohn's disease, and ulcerative colitis. We describe a case of an immediate hypersensitivity reaction to ustekinumab infusion with no reaction to subsequent ustekinumab subcutaneous maintenance therapy. We identify ethylenediaminetetraacetic acid as a unique excipient found in the intravenous formulation compared with the prefilled syringe used for subcutaneous injections, which is likely to account for this observation. No similar cases have been reported in the literature.
Anthropometric Measurements Of The Ventrogluteal İnjectıon Area: A Cross-sectional Study
Authors: Tuğrul Emel , Khorshıd Leyla , Tunçyürek Özüm 
Published: August 2020

Research Problem / Aim: The ventrogluteal injection area is one of the areas most frequently used by nurses in intramuscular injection applications. The thicknesses of the subcutaneous tissue and the muscle tissue in this area are important for a safe injection. The aim of this study is the determination of the subcutaneous and muscle tissue thicknesses on the ventrogluteal injection area and the anthropometric data about it.
Method: The study has designed a cross-sectional study. 150 individuals who applied to the ultrasound unit of the hospital and accepted to participate in the study were included in the study. The ventrogluteal injection area was determined with the ‘’V’’ method by the researcher. The subcutaneous and muscle tissue thicknesses from the areas on the injection area and the areas 2 and 4 cm around the injection area were determined using the ultrasound device. Moreover, the relation between the anthropometric measurements of the individuals (height, weight, waist, hip and crista iliaca circumferences, distance between the large trochanter and crista iliaca and crista iliaca anterior) and the tissue thicknesses on the injection area were evaluated. The data of the research were evaluated with definitive statistics, ANOVA test and posthoc Tukey test, t test and correlation analysis. The p<0.05 value was accepted as statistically significant for all results.
Findings: The average subcutaneous tissue thickness in the injection area was determined as 15.44±8.01 mm and the average tissue thickness there was determined as 31.75±11.86 mm. The subcutaneous tissue thickness in women was found more than the subcutaneous tissue thickness in men. When the tissue thicknesses 2 and 4 cm around the injection area were analyzed, it was found that the area where the total tissue thickness was the least was over 2 cm (41.67±14.83) and over 4 cm (35.79±15.55) of the injection area. It was determined that the average total thickness 4 cm around the injection area was less than 38 mm in underwight individuals.
Conclusions: According to the results obtained from the study, the weight and body mass index of the individual should be considered in the choice of the injection area and the length of the needle to be used when the ventrogluteal injection area was used in intramuscular injections. Especially in obese individuals, longer needles can be preferred. Besides, it must be thought that there may be the risk of bone injury 4 cm around the injection area in asthenic individuals and individuals with normal weight. Moreover, since the individuals’ having a large waist and hip circumference is related to their subcutaneous tissue thickness, it is recommended that long needles should be chosen in these individuals.