bluuebunny/crossref_metadata_2025_split huggingface dataset:
eIF4E3 forms an active eIF4F complex during stresses (eIF4FS) targeting mTOR and re-programs the translatome
Authors: Weiss Benjamin , Allen George Edward , Kloehn Joachim , Abid Karim , Jaquier-Gubler Pascale , Curran Joseph Alphonsus 
Published: March 2021

AbstractThe eIF4E are a family of initiation factors that bind the mRNA 5′ cap, regulating the proteome and the cellular phenotype. eIF4E1 mediates global translation and its activity is controlled via the PI3K/AKT/mTOR pathway. mTOR down-regulation results in eIF4E1 sequestration into an inactive complex with the 4E binding proteins (4EBPs). The second member, eIF4E2, regulates the translatome during hypoxia. However, the exact function of the third member, eIF4E3, has remained elusive. We have dissected its function using a range of techniques. Starting from the observation that it does not interact with 4EBP1, we demonstrate that eIF4E3 recruitment into an eIF4F complex occurs when Torin1 inhibits the mTOR pathway. Ribo-seq studies demonstrate that this complex (eIF4FS) is translationally active during stress and that it selects specific mRNA populations based on 5′ TL (UTR) length. The interactome reveals that it associates with cellular proteins beyond the cognate initiation factors, suggesting that it may have ‘moon-lighting’ functions. Finally, we provide evidence that cellular metabolism is altered in an eIF4E3 KO background but only upon Torin1 treatment. We propose that eIF4E3 acts as a second branch of the integrated stress response, re-programming the translatome to promote ‘stress resistance’ and adaptation.
Temozolomide-induced hypermutation is associated with distant recurrence and reduced survival after high-grade transformation of low-grade IDH-mutant gliomas
Authors: Yu Yao , Villanueva-Meyer Javier , Grimmer Matthew R , Hilz Stephanie , Solomon David A , Choi Serah , Wahl Michael , Mazor Tali , Hong Chibo , Shai Anny , Phillips Joanna J , Wainer Bruce H , McDermott Michael , Haas-Kogan Daphne , Taylor Jennie W , Butowski Nicholas , Clarke Jennifer L , Berger Mitchel S , Molinaro Annette M , Chang Susan M , Costello Joseph F , Oberheim Bush Nancy Ann 
Published: March 2021

Abstract

Background
Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas (LGGs), but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications.

Methods
We sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent reoperation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes.

Results
Hypermutation was associated with high-grade disease at the time of reoperation (OR 12.0 95% CI 2.5-115.5, P = .002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, P = .024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (P = .003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. Eight-year transformation-free survival was 53.8% (95% CI 42.8-69.2), and 61% of analyzed transformed cases were HM.

Conclusions
TMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.
The role of RB1 alteration and 4q12 amplification in IDH-WT glioblastoma
Authors: Dono Antonio , Ramesh Arvind V , Wang Emily , Shah Mauli , Tandon Nitin , Ballester Leomar Y , Esquenazi Yoshua 
Published: March 2021

Abstract

Background
Recent studies have identified that glioblastoma IDH-wildtype (GBM IDH-WT) might be comprised of molecular subgroups with distinct prognoses. Therefore, we investigated the correlation between genetic alterations and survival in 282 GBM IDH-WT patients, to identify subgroups with distinct outcomes.

Methods
We reviewed characteristics of GBM IDH-WT (2009–2019) patients analyzed by next-generation sequencing interrogating 205 genes and 26 rearrangements. Progression-free survival (PFS) and overall survival (OS) were evaluated with the log-rank test and Cox regression models. We validated our results utilizing data from cBioPortal (MSK-IMPACT dataset).

Results
Multivariable analysis of GBM IDH-WT revealed that treatment with chemoradiation and RB1-mutant status correlated with improved PFS (hazard ratio [HR] 0.25, P &lt; .001 and HR 0.47, P = .002) and OS (HR 0.24, P &lt; .001 and HR 0.49, P = .016). In addition, younger age (&lt;55 years) was associated with improved OS. Karnofsky performance status less than 80 (HR 1.44, P = .024) and KDR amplification (HR 2.51, P = .008) were predictors of worse OS. KDR-amplified patients harbored coexisting PDGFRA and KIT amplification (P &lt; .001) and TP53 mutations (P = .04). RB1-mutant patients had less frequent CDKN2A/B and EGFR alterations (P &lt; .001). Conversely, RB1-mutant patients had more frequent TP53 (P &lt; .001) and SETD2 (P = .006) mutations. Analysis of the MSK-IMPACT dataset (n = 551) validated the association between RB1 mutations and improved PFS (11.0 vs 8.7 months, P = .009) and OS (34.7 vs 21.7 months, P = .016).

Conclusions
RB1-mutant GBM IDH-WT is a molecular subgroup with improved PFS and OS. Meanwhile, 4q12 amplification (KDR/PDGFRA/KIT) denoted patients with worse OS. Identifying subgroups of GBM IDH-WT with distinct survival is important for optimal clinical trial design, incorporation of targeted therapies, and personalized neuro-oncological care.
Poppers, by Inducing HHV-8 Virion Production, Can Act as a Promoter for HHV-8 Transmission in Men Who Have Sex With Men
Authors: Jary Aude , Gothland Adélie , Palich Romain , Leducq Valentin , Monsel Gentiane , Imbert Sébastien , Schneider Luminita , Simon Anne , Spano Jean-Philippe , Katlama Christine , Larabi Islam Amine , Alvarez Jean-Claude , Calvez Vincent , Marcelin Anne-Geneviève 
Published: March 2021

Abstract
Environmental factors were reported to increase the risk of human herpesvirus 8 (HHV-8) transmission. In a population of men who have sex with men (MSM), we found evidence that chemsex was associated with human herpesvirus 8 seropositivity in vivo and that poppers induced HHV-8 virion production in vitro. Our finding may explain the higher HHV-8 transmission in MSM.
Drought affects the rate and duration of organ growth but not inter-organ growth coordination
Authors: Verbraeken Lennart , Wuyts Nathalie , Mertens Stien , Cannoot Bernard , Maleux Katrien , Demuynck Kirin , De Block Jolien , Merchie Julie , Dhondt Stijn , Bonaventure Gustavo , Crafts-Brandner Steven , Vogel Jonathan , Bruce Wesley , Inzé Dirk , Maere Steven , Nelissen Hilde 
Published: March 2021

Abstract
Drought at flowering and grain filling greatly reduces maize (Zea mays) yield. Climate change is causing earlier and longer-lasting periods of drought, which affect the growth of multiple maize organs throughout development. To study how long periods of water deficit impact the dynamic nature of growth, and to determine how these relate to reproductive drought, we employed a high-throughput phenotyping platform featuring precise irrigation, imaging systems, and image-based biomass estimations. Prolonged drought resulted in a reduction of growth rate of individual organs—though an extension of growth duration partially compensated for this—culminating in lower biomass and delayed flowering. However, long periods of drought did not affect the highly organized succession of maximal growth rates of the distinct organs, i.e. leaves, stems, and ears. Two drought treatments negatively affected distinct seed yield components: Prolonged drought mainly reduced the number of spikelets, and drought during the reproductive period increased the anthesis-silking interval. The identification of these divergent biomass and yield components, which were affected by the shift in duration and intensity of drought, will facilitate trait-specific breeding toward future climate-resilient crops.
Reliability of Quadriceps Femoris Muscle Strength Assessment Using a Portable Dynamometer and Protocol Tolerance in Patients With Chronic Obstructive Pulmonary Disease
Authors: Sentanin Anna Claudia , de Facio Carina Araujo , da Silva Marcela Maria Carvalho , Sousa Fernanda Cristina , Arcuri Juliano Ferreira , Mendes Renata Gonçalves , Di Lorenzo Valéria Amorim Pires 
Published: March 2021

Abstract

Objective
This study aimed to evaluate the intrarater and interrater reliability of isometric quadriceps strength (IQS) using a portable dynamometer in individuals with chronic obstructive pulmonary disease (COPD) and to verify their tolerance to the protocol.

Methods
A cross-sectional reliability study was conducted with 50 individuals with stable COPD (34 men and 16 women; mean age = 70 years [SD = 8]). The main outcome measure was obtained using a portable dynamometer (Microfet 2) to assess IQS. Two masked raters performed 2 assessments in the dominant lower limb on 2 nonconsecutive days. The intraclass correlation coefficient (ICC) was used to verify the intrarater and interrater reliability and was considered excellent when &gt;0.90, with a 5% significance level.

Results
Rater 1 and 2 intrarater reliability was as follows: ICC = 0.96 (95% CI = 0.94 to 0.98) and ICC = 0.97 (95% CI = 0.95 to 0.98), respectively. The interrater reliability was as follows: ICC = 0.96 (95% CI = 0.93 to 0.98). The minimum detectable difference was 4 to 5 peak isometric strength, in mean, for intrarater and interrater reliability. Not all patients presented relevant changes in physiological responses, dyspnea, and lower limb fatigue.

Conclusion
There was an excellent intrarater and interrater reliability for IQS, and the participants tolerated the protocol.

Impact
This tool can be used to assess quadriceps strength in clinical practice in patients with COPD.
Pulmonary involvement in primary systemic vasculitides
Authors: Makhzoum Jean-Paul , Grayson Peter C , Ponte Cristina , Robson Joanna , Suppiah Ravi , Watts Richard A , Luqmani Raashid , Merkel Peter A , Pagnoux Christian ,   for the DCVAS Collaborators
Published: March 2021

Abstract

Objectives
This study describes the spectrum and initial impact of pulmonary manifestations in the primary systemic vasculitides.

Methods
Description and comparison of pulmonary manifestations in adults with Takayasu’s arteritis (TAK), GCA, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic GPA (EGPA), polyarteritis nodosa (PAN) and IgA vasculitis (IgAV), using data collected within the Diagnostic and Classification Criteria in Vasculitis study.

Results
Data from 1952 patients with primary vasculitides were included: 170 TAK, 657 GCA, 555 GPA, 223 MPA, 146 EGPA, 153 IgAV and 48 PAN. Pulmonary manifestations were observed in patients with TAK (21.8%), GCA (15.8%), GPA (64.5%), MPA (65.9%), EGPA (89.0%), PAN (27.1%) and IgAV (5.9%). Dyspnoea occurred in patients with TAK (14.7%), GCA (7.8%), GPA (41.8%), MPA (43.5%), EGPA (65.8%), PAN (18.8%) and IgAV (2.6%). Cough was reported in TAK (7.6%), GCA (9.3%), GPA (34.8%), MPA (37.7%), EGPA (55.5%), PAN (16.7%) and IgAV (3.3%). Haemoptysis occurred mainly in patients with ANCA-associated vasculitis (AAV). Fibrosis on imaging at diagnosis was documented in GPA (1.9%), MPA (24.9%) and EGPA (6.3%). Only patients with AAV (GPA 2.7%, MPA 2.7% and EGPA 3.4%) required mechanical ventilation. At 6 months, the presence of at least one pulmonary item in the Vasculitis Damage Index was observed in TAK (4.1%), GCA (3.3%), GPA (15.4%), MPA (28.7%), EGPA (52.7%), PAN (6.2%) and IgAV (1.3%).

Conclusion
Pulmonary manifestations can occur in all primary systemic vasculitides, but are more frequent and more often associated with permanent damage in AAV.
Therapeutic Potential of Digital Nerve Block in Rheumatoid Arthritis Patients
Authors: Elsaman Ahmed M. , Hamed Ahmed , Radwan Ahmed R. 
Published: March 2021

Background:
This study attempted to test the effectiveness of digital nerve block (DNB) in active rheumatoid arthritis (RA) joints with respect to local disease control.

Methods:
The study included 83 RA patients aged 18 years or above and diagnosed, after American College of Rheumatology/European League Against Rheumatism criteria 2010, with bilateral proximal interphalangeal (PIP) arthritis. PIPs were examined by European League Against Rheumatism-outcome measures in rheumatoid arthritis clinical trials scoring system at 0, 2, and 8 weeks. Visual analog scales for each hand were also done at the same intervals. DNBs of the second and third PIPs were performed to the dominant hand in 50% of participants. The other hand was used as a control, and saline was injected in the same level at the control side.

Results:
At 2 weeks and 8 weeks intervals, the active side showed significantly less clinical and ultrasound scores when compared to the control side and the baseline values. The mean OMERACT score for the active hand dropped from 3.37±1.43 at 0 time to 2.31±1.66 after 2 weeks and 2.55±1.43 at 8 weeks (P<0.001). Also, visual analog scale decreased from 59 at 0 time to 41 at 2 weeks and 43 at 8 weeks (P<0.001). The amelioration was greater when the active side was the dominant one. The injected PIPs showed maximum improvement at 2 weeks. Improvement was more significant in the second PIP. Early patients achieved better outcomes.

Conclusion:
DNB is a new promising therapy for RA. It can control pain and inflammation of the PIPs. It has relatively short-term effect, yet it could limit escalation of systemic treatment plans.
Communicable and noncommunicable liver disease in HIV
Authors: Mauss Stefan , Boesecke Christoph 
Published: March 2021

Purpose of review
The aim of this study was to highlight the profound changes in the cause in chronic liver disease in HIV-infected individuals.

Recent findings
Hepatitis C virus (HCV) has been transformed into a curable viral infection by highly effective treatments. This has resulted in elimination of chronic hepatitis C in HIV-coinfected individuals at least in resource-rich settings. Hepatitis B virus (HBV) has become a chronic infection, which is easily controlled by long-term therapy with HBV polymerase inhibitors. As a result, nonalcoholic steatohepatitis (NASH) has gained clinical importance. The obesity epidemic in the general population has also included people with HIV and weight gain has been associated with some newer antiretroviral drugs, such as HIV integrase inhibitors and tenofovir alafenamide fumarate. Medical treatment for obesity is a focus of intense research efforts, but currently, the only convincing therapeutic option in morbidly obese patients is bariatric surgery, which can also improve liver outcomes. The wider use of this approach has included HIV-infected individuals allowing to assess at least the safety aspects of bariatric surgery in this special population.

Summary
The shift from communicable to noncommunicable liver disease is changing the clinical practice in HIV-infected individuals. Research activities are focusing more on treatment of NASH and obesity, although a curative therapy for HBV infection would have a great clinical impact.
Major Prehospital Trauma and In-Hospital Emergencies
Authors: Estebaranz-Santamaría Cristina , Palmar-Santos Ana María , Pedraz-Marcos Azucena 
Published: March 2021

Background
Massive transfusion (MT) in trauma is initiated on the basis of factors of different natures and depending on protocols and scales used both in prehospital and in-hospital care areas.

Objective
The main goal was to analyze and relate factors and predictive variables for MT requirements considering both health care areas.

Method
This was a retrospective cohort study that included patients who were treated either at the emergency department of a large hospital or through prehospital care before arrival at the hospital. The patients included were adults who received MT, defined as a blood bank request of 10 or more units of red cells in the first 24 hours or 5 or more within 4 hours of trauma, from January 1, 2009, to January 1, 2017. The variables included were individual characteristics and those associated with the trauma, clinical-analytical assessment, resuscitation, timing, and survival.

Results
A total of 52 patients who received MT were included. The average age of the patients was 41.23 ± 16.06 years, a mean of 19.56 ± 12.77 units was administered, and the mortality rate was 21.2%.

Discussion
Injury mechanism, clinical-analytical variables, and resuscitation strategies have a significant influence on the need for MT; therefore, early identification is fundamental for performing quality management and addressing avoidable factors during MT processes.
An analysis of prehospital critical care events and management patterns from 97 539 emergency helicopter medical service missions
Authors: Saviluoto Anssi , Laukkanen-Nevala Päivi , Raatiniemi Lasse , Jäntti Helena , Nurmi Jouni O. 
Published: March 2021

BACKGROUND
It is largely unknown how often physicians in emergency helicopter medical services (HEMS) encounter various critical care events and if HEMS exposure is associated with particular practice patterns or outcomes.

OBJECTIVES
This study aimed: to describe the frequency and distribution of critical care events; to investigate whether HEMS exposure is associated with differences in practice patterns and determine if HEMS exposure factors are associated with mortality.

DESIGN
A retrospective registry-based study.

SETTING
Physician-staffed HEMS in Finland between January 2012 and August 2019.

PARTICIPANTS
Ninety-four physicians who worked at least 6 months in the HEMS during the study period. Physicians with undeterminable HEMS exposure were excluded from practice pattern comparisons and mortality analysis, leaving 80 physicians.

MAIN OUTCOME MEASURES
The primary outcome measure was a physician's average annual frequencies for operational events and clinical interventions. Our secondary outcomes were the proportion of missions cancelled or denied, time onsite (OST) and proportion of unconscious patients intubated. Our tertiary outcome was adjusted 30-day mortality of patients.

RESULTS
The physicians encountered 62 [33 to 98], escorted 31 [17 to 41] and transported by helicopter 2.1 [1.3 to 3.5] patients annually, given as median [interquartile range; IQR]. Rapid sequence intubation was performed 11 [6.2 to 16] times per year. Physicians were involved in out-of-hospital cardiac arrest (OHCA) 10 [5.9 to 14] and postresuscitation care 5.5 [3.1 to 8.1] times per year. Physicians with longer patient intervals had shorter times onsite. Proportionally, they cancelled more missions and intubated fewer unconscious patients. A short patient interval [odds ratio (OR); 95% confidence interval (CI)] was associated with decreased mortality (0.87; 95% CI, 0.76 to1.00), whereas no association was observed between mortality and HEMS career length.

CONCLUSION
Prehospital exposure is distributed unevenly, and some physicians receive limited exposure to prehospital critical care. This seems to be associated with differences in practice patterns. Rare HEMS patient contacts may be associated with increased mortality.
Associations of plasma PAPP-A2 and genetic variations with salt sensitivity, blood pressure changes and hypertension incidence in Chinese adults
Authors: Wang Yang , Jia Hao , Gao Wei-Hua , Zou Ting , Yao Shi , Du Ming-Fei , Zhang Xiao-Yu , Chu Chao , Liao Yue-Yuan , Chen Chen , Wang Dan , Ma Qiong , Hu Jia-Wen , Wang Ke-Ke , Yan Yu , Sun Yue , Hu Gui-Lin , Niu Ze-Jiaxin , Zhou Hao-Wei , Zhang Xi , Wang Xin , Li Chun-Hua , Chen Fang-Yao , Gao Ke , Zhang Jie , Guan Yong-Juan , Chang John , Yang Tie-Lin , Mu Jian-Jun 
Published: March 2021

Objective:
Pregnancy-associated plasma protein-A2 (PAPP-A2) is the homolog of PAPP-A in the vertebrate genome and its role in protecting against salt-induced hypertension in salt-sensitive rats has been confirmed. We sought to examine the associations of plasma PAPP-A2 levels and its genetic variants with salt sensitivity, blood pressure (BP) changes and hypertension incidence in humans.

Methods:
Eighty participants (18–65 years old) sequentially consuming a usual diet, a 7-day low-salt diet (3.0 g/day) and a 7-day high-salt diet (18 g/day). In addition, we studied participants of the original Baoji Salt-Sensitive Study, recruited from 124 families in Northern China in 2004 who received the same salt intake intervention, and evaluated them for the development of hypertension over 14 years.

Results:
The plasma PAPPA2 levels significantly decreased with the change from baseline to a low-salt diet and decreased further when converting from the low-salt to high-salt diet. SNP rs12042763 in the PAPP-A2 gene was significantly associated with systolic BP responses to both low-salt and high-salt diet while SNP rs2861813 showed a significant association with the changes in SBP and pulse pressure at 14-year follow-up. Additionally, SNPs rs2294654 and rs718067 demonstrated a significant association with the incidence of hypertension over the 14-year follow-up. Finally, the gene-based analysis found that Pappa2 was significantly associated with longitudinal SBP changes and the incidence of hypertension over the 14-year follow-up.

Conclusions:
This study shows that dietary salt intake affects plasma PAPP-A2 levels and that PAPP-A2 may play a role in salt sensitivity, BP progression and development of hypertension in the Chinese populations.
Personality Traits and Social Supports in Adolescents With Persistent Postconcussion Symptoms
Authors: Atif Hamna , Morgan Brianne , Tuohy Kyle , Zukowski Monica , Foster Zachary , Loeffert Andrea , Yeates Keith O. , Hicks Steven D. 
Published: March 2021

Objectives:
To determine whether adolescents with persistent postconcussion symptoms (PPCS) differ from healthy peers in their personality traits and social supports.

Setting:
Specialty Concussion Clinic and Primary Care Clinic affiliated with an academic medical center.

Participants:
Ninety-seven adolescents (42 with PPCS, 55 healthy peers; age: 15 ± 2 years).

Design:
Participants completed a web-based survey that included medical and demographic characteristics, mechanisms of concussion, 10-item Big Five Inventory, and Child and Adolescent Social Support Scale. A Student's 2-tailed t test with multiple testing corrections was used to compare the youths with PPCS to healthy peers.

Main Measures:
The primary outcome was PPCS, defined by the presence of 2 or more concussion-related symptoms on the Post-Concussion Symptom Scale (PCSS), lasting for more than 4 weeks after initial injury. The secondary outcome was perceived personality traits and social support, based on the 10-item Big Five Inventory and the Child and Adolescent Social Support Scale, respectively.

Results:
The PPCS group had higher neuroticism scores on their Big Five Inventory than healthy peers. They also reported less social support from teachers and classmates than healthy peers.

Conclusion:
Youths with PPCS report specific personality and social support characteristics that differ from their peers. These findings suggest that individual personality and school-based social supports may influence concussion recovery.