bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feasibility of Randomized Controlled Trials for Cancer Drugs Approved by the Food and Drug Administration Based on Single-Arm Studies
Authors: Rittberg Rebekah , Czaykowski Piotr , Niraula Saroj 
Published: June 2021

Abstract

Background
The US Food and Drug Administration (FDA) introduced an Accelerated Approval (AA) pathway to expedite patient access to new drugs. AA accepts less rigorous trial designs, including single-arm studies (SAS), owing to perceived lack of feasibility of timely randomized controlled trials (RCTs).

Methods
We designed hypothetical RCTs with endpoints of overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) for FDA approvals based on SAS for solid tumors during 2010-2019. Existing standards of care served as controls. RCTs were designed to detect a difference with power of 0.80, α-error of 5% (2-sided), and 1:1 randomization. Accrual duration was estimated based on participation by less than 5% of eligible patients derived from cancer-specific incidence and mortality rates in the United States.

Results
Of 172 (18.0%) approvals during the study period, 31 (18.0%) were based on SAS. Median sample size was 104 (range = 23-411), and 77.4% were AA. All studies reported ORR, 55% reported duration of response, 19.4% reported PFS, and 22.5% reported OS. Median sample sizes needed to conduct RCTs with endpoints of ORR, PFS, and OS were 206, 130, and 396, respectively. It would have been theoretically possible to conduct RCTs within duration comparable with that required by SAS for 84.6%, 94.1%, and 80.0% of approvals with endpoints of ORR, PFS, and OS, respectively.

Conclusion
An overwhelming majority of FDA approvals based on SAS should be feasible as RCTs within a reasonable time frame. Given the collateral harms to patients and to scientific rigor, drug approval based on SAS should only be permitted under exceptional circumstances.
“It’s Not Over When It’s Over”―Post-Decision Arrangements and Empirical Legitimacy
Authors: de Fine Licht Jenny , Agerberg Mattias , Esaiasson Peter 
Published: June 2021

AbstractA chronic problem for democratic governments is generating legitimacy for policy decisions that go against substantial groups of citizens’ legitimate interests. The primary means of achieving this aim involve the arrangements through which policy decisions are made. Whereas research in the field has tended to focus on the arrangements leading up to a decision, this paper draws attention to developments after a formal policy decision has been made. We theorize that the formal decision constitutes a focal event that motivates affected individuals to update their beliefs about the decision. We identify four types of potential legitimacy-enhancing post-decision arrangements: how the decision is announced; how it is publicly explained; whether the process allows for post-decision voice; and whether decision-makers take actions to mitigate its negative consequences. The results from two survey experiments with large samples of Swedish adults addressing the case of school closures suggest that post-decision procedures have legitimacy-enhancing potential and that this effect is not dependent on the pre-decision process.
#15: Risk Factors of Infection related mortality in Pediatric Acute Myeloid Leukemia- Single Institute Experience: 2016–2018
Authors: Bayoumi Ahmed 
Published: June 2021

Abstract
Children with acute myeloid leukemia (AML) are at a particularly high risk for infectious complications related to the highly intensive chemotherapy. Infections leads to mortality and prolong hospitalization. The aim of the study is to evaluate the risk factors, infectious complications and assess outcome of febrile episodes during induction and consolidation chemotherapy courses in children with AML at the Pediatric Oncology Department, National Cancer Institute, Cairo University from January 2016 to December 2018.
Infectious complications were evaluated retrospectively in 621 febrile episodes. Mortality from gram negative bacteremia was 29.9%, in febrile episodes with multidrug resistant gram negative bacteremia: Mortality was 39.2 % in febrile episodes with multidrug resistant gram negative bacteremia and septic shock. Mortality was 71.8 % (p value &lt;0.001). Mortality was high in early chemotherapy phase (intensive timing). Infection related mortality was 39%. In our institute there is epidemiological shift towards gram negative organisms.
Sepsis and septic shock are major causes of mortality during chemotherapy-induced neutropenia. Thus, awareness of the presenting characteristics and prompt management is most important. Improved management of sepsis during neutropenia may reduce the mortality of pediatric Acute myeloid leukemia. It is Important to trace the risk factors that may affect the outcome of febrile episodes.
Summary of Significant laboratory and clinical predictors of mortality Risk Factor Mortality p value Septic shock 55% &lt;0.001 Septic shock with MDRO 72% Cardiac impairment/inotropic support 65.60% Presence Of Central venous line 18.30% Episode duration &gt;18 days 20.50% Start of antimicrobial in relation to start of chemotherapy &lt; 16 days 33% Episodes: Not in remission 15.60%
Risk factor Mortality p value CRP more than or equals 90 mg/l 24.4% Not significant ANC LESS THAN 500 29.9% 0.003 Hgb less than or equals to 7 g/dl 19.9% 0.633 Platelets less than 20000/cc 29.9% 0.299 Liver impairment (grades 3 and 4) 42.2% 0.025 Electrolyte imbalance (grades 3 and 4) 24.1% 0.003 Renal impairment 56.8% 0.025 Coagulopathy 41% &lt;0.001
#14: Blastomycosis in 64 Wisconsin Children: Unanticipated Infection Risk and Severity in Urban Residents
Authors: Hall Jaimee M , Havens Peter L , Mitchell Errin A , De Vela Gabriel N , Titus Lauren L , Dasgupta Mahua , Simpson Pippa M , Kehl Sue C , Willoughby Rodney E , Henrickson Kelly J , Mitchell Michelle L , Huppler Anna R , Chusid Michael J 
Published: June 2021

Abstract

Background
Blastomycosis is an endemic mycosis of immunocompetent individuals, typically seen after exposure to wooded areas near rivers, lakes, and streams in rural locations, and often not considered a disease of urban environments. Disease can be isolated to lung, or disseminate to skin, bone, or central nervous system. Factors influencing disease acquisition and severity in children are unknown.

Methods
We analyzed acquisition risk factors and disease characteristics of blastomycosis in children treated at a tertiary care center from 1998–2018 to identify exposure source and measure disease severity, to identify cases without “typical exposure”, and to measure the effect of race on disease severity.

Results
Of 64 children, median age was 13.3 years, 72% were male, 38% resided in urban counties, and 50% had typical environmental exposure. Isolated pulmonary infection occurred in 33 (52%). The remaining children had evidence of dissemination including skin (N=13), bone (N=16; 7 clinically silent), and central nervous system (N=7; 3 clinically silent). Infection was moderate/severe in 19 (30%). Two children (3%) died. 79% of children with moderate/severe disease (p=0.008) and 71% of urban children (p=0.007) had no typical environmental exposure. Comparing children from urban counties to other residences, 63% versus 5% were black (p&lt;0.001) and 71% versus 35% developed extrapulmonary dissemination (p=0.006). Moderate/severe disease occurred in 7/17 (42%) black and 12/47 (26%) children of other race (p=0.23).

Conclusions
Blastomycosis, endemic in urban children in the absence of typical exposure history, has frequent, sometimes clinically silent, extrapulmonary dissemination, with a trend toward more severe disease in black children.
#23: Investigation of Phosphomannomutase as an Antimalarial Drug Target
Authors: Frasse Philip , Goldberg Daniel , John Audrey Odom 
Published: June 2021

Abstract

Background
Malaria continues to pose an enormous economic and global health threat, killing over 200,000 people annually, primarily children under the age of 5. With the constant barrier of antimalarial resistance and the rise of delayed clearance by artemisinin, it is especially important to identify drug/target pairs that rapidly kill parasites. We study targetable metabolic pathways in the malaria parasite, Plasmodium falciparum, to guide such future drug development against this disease. In recent years, we have discovered that a large family of hydrolases, the Haloacid Dehalogenase (HAD) Superfamily of proteins, are implicated in regulating a variety of P. falciparum metabolic pathways, which can lead to dramatic changes in central carbon metabolism and drug resistance. We now turn our attention to a related HAD protein, the putative phosphomannomutase in these parasites, HAD5, responsible for the interconversion of mannose-6-phosphate and mannose-1-phosphate. This is an essential process for all stages of the parasite, and thus has potential as a broad antimalarial target. We examined the role of HAD5 in these parasites, and its potential to be chemically inhibited.

Methods
Recombinant protein was generated and purified for enzymatic assays to determine HAD5 activity and test inhibitor potency against HAD5 compared to recombinant human orthologs, PMM1 and PMM2. In parallel, CRISPR/Cas9 was used to generate inducible knockdown parasite strains to demonstrate this gene’s essentiality and its role in parasite biology. Parasite growth was measured by flow cytometry and light microscopy. Immunofluorescence analysis (IFA) was used to track the parasite development on a molecular scale.

Results
Inhibition of HAD5 was achieved in biochemical assays, with an IC50 of 68µM in our most potent compound, representing roughly 10-fold increased potency against the parasite protein compared to human orthologs. In culture, knockdown of HAD5 leads to interrupted egress from and reinvasion into red blood cells, culminating in parasite death. In IFA-visualized parasites, reinvasion-facilitating proteins were no longer anchored to parasite surfaces, accounting for the inhibition of the parasite life cycle.

Conclusion
In the search for new antimalarial targets, identifying proteins that are essential across multiple parasite life-stages while being distinct from human orthologs is necessary to block parasite transmission, cure symptomatic infection, and minimize off-target effects. HAD5 is an essential protein in malaria parasites that is expressed throughout the parasite’s life cycle, and can be specifically targeted by inhibitors, giving it promise as a future drug target.
Autophagy complements metalloprotease FtsH6 in degrading plastid heat shock protein HSP21 during heat stress recovery
Authors: Sedaghatmehr Mastoureh , Thirumalaikumar Venkatesh P , Kamranfar Iman , Schulz Karina , Mueller-Roeber Bernd , Sampathkumar Arun , Balazadeh Salma 
Published: June 2021

AbstractModerate and temporary heat stresses prime plants to tolerate, and survive, a subsequent severe heat stress. Such acquired thermotolerance can be maintained for several days under normal growth conditions, and can create a heat stress memory. We recently demonstrated that plastid-localized small heat shock protein 21 (HSP21) is a key component of heat stress memory in Arabidopsis thaliana. A sustained high abundance of HSP21 during the heat stress recovery phase extends heat stress memory. The level of HSP21 is negatively controlled by plastid-localized metalloprotease FtsH6 during heat stress recovery. Here, we demonstrate that autophagy, a cellular recycling mechanism, exerts additional control over HSP21 degradation. Genetic and chemical disruption of both metalloprotease activity and autophagy trigger superior HSP21 accumulation, thereby improving memory. Furthermore, we provide evidence that autophagy cargo receptor ATG8-INTERACTING PROTEIN1 (ATI1) is associated with heat stress memory. ATI1 bodies co-localize with both autophagosomes and HSP21, and their abundance and transport to the vacuole increase during heat stress recovery. Together, our results provide new insights into the module for control of the regulation of heat stress memory, in which two distinct protein degradation pathways act in concert to degrade HSP21, thereby enabling cells to recover from the heat stress effect at the cost of reducing the heat stress memory.
On the Turing complexity of learning finite families of algebraic structures
Authors: Bazhenov Nikolay , San Mauro Luca 
Published: June 2021

Abstract
In previous work, we have combined computable structure theory and algorithmic learning theory to study which families of algebraic structures are learnable in the limit (up to isomorphism). In this paper, we measure the computational power that is needed to learn finite families of structures. In particular, we prove that, if a family of structures is both finite and learnable, then any oracle which computes the Halting set is able to achieve such a learning. On the other hand, we construct a pair of structures which is learnable but no computable learner can learn it.
The characteristics of daughter waves emerging from colliding solitary waves in astrophysical plasma media
Authors: Abdikian A , Vasheghani Farahani S , Hussain S 
Published: June 2021

ABSTRACT
The aim is to state the properties of ion acoustic solitary waves in course of collision and extract characteristics of the daughter wave in a magnetized electron–ion plasma. The magnetized plasma medium that is a constituent of white dwarfs and astrophysical plasmas that possesses relativistically degenerate electrons and thermal ions in the presence of a constant background magnetic field. The model is based on the extended Poincaré–Lighthill–Kuo (ePLK) method where a set of Korteweg–de Vries equations is obtained to show the phase shifts of colliding waves together with the amplitude and width of the born daughter solitary waves. The numerical results and presented figures regarding the amplitude and width of solitons provide a description of the influence of plasma parameters on soliton interactions, namely ion to electron temperature ratio (σi), ion cyclotron frequency (ωci), and angle between magnetic field and collision line (θ) together with their interplay in shaping the character of solitary waves. It is concluded that only rarefactive electrostatic non-linear waves are able to propagate in such plasma media. The daughter wave amplitude possesses a scaling behaviour regarding the impact angle. Interplay of the parameters on the phase shifts is presented. Ratio of amplitude and width of the daughter wave is directly proportional to the background field, the impact angle controls its maximum. It is observed that the magnetic field elevates ratio of the solitary wave amplitude to width leading it to a shorter life and hence interaction range with neighbouring sites.
C2H2···CO complex and its radiation-induced transformations: a building block for cold synthetic astrochemistry
Authors: Zasimov Pavel V , Ryazantsev Sergey V , Tyurin Daniil A , Feldman Vladimir I 
Published: June 2021

ABSTRACTIn this work, we have examined the radiation-induced synthetic chemistry occurring in an astrochemically important C2H2–CO system at the molecular level using a matrix isolation approach. The 1:1 C2H2···CO intermolecular complex of linear structure was obtained in the solid low-temperature (5 K) noble gas matrices by deposition of the C2H2/CO/Ng (Ng = Ar, Kr, Xe) gaseous mixtures and characterized by Fourier-transform infrared spectroscopy. It was found that the X-ray radiolysis of the C2H2···CO complex resulted in formation of C3O (tricarbon monoxide), HCCCHO (propynal), c-H2C3O (cyclopropenone), H2CCCO (propadienone), and HC3O (oxoprorynyl radical). This means that the studied complex may be considered as the simplest building block (or minimal size of intermolecular reactor) for cold astrochemistry occurring in mixed interstellar ices. Remarkably, the discovered transformations of the complex actually represent synthetic routes leading to various C3 species, whereas the acetylenic C–H bond cleavage yielding ethynyl radical appears to be a minor process. Prolonged irradiation results in dehydrogenation, while the C3 skeleton is retained. The interpretation of the C2H2···CO radiolysis mechanism (possible reactions pathways) is provided based on the analysis of kinetic curves and matrix effect. Astrochemical implications of the results are discussed.
Detection of quasi-periodic oscillations in the long-term radio light curves of the blazar OT 081
Authors: Li Xiao-Pan , Cai Yan , Yang Hai-Tao , Luo Yu-Hui , Yan Yue , He Jia-Ying , Wang Li-Sha 
Published: June 2021

ABSTRACT
We report the detection of quasi-periodic oscillations (QPOs) in the radio light curves at 4.8, 8, and 14.5 GHz of the blazar OT 081, by means of the Weighted Wavelet Z-transform (WWZ) and Lomb–Scargle periodogram (LSP) methods. The LSP diagrams and time-averaged WWZ powers demonstrate several significant claims of QPOs above the 4σ confidence level: QPOs of ∼850 and ∼1500 d in the 4.8-GHz light curve, ∼850, ∼1120, and ∼1540 d in the 8-GHz light curve, ∼850 and ∼1130 d in the 14.5-GHz light curve. The Keplerian orbit parameters in a binary black hole system have been estimated, assuming the QPO of ∼850 d appearing in all three wavebands is a real periodicity. Moreover, a pure geometrical scenario with blobs moving helically inside the jet provides another plausible explanation for the detected QPOs.
Development of a Quantitative Antigen Assay to Detect Coccidioidal Chitinase-1 (CTS1)
Authors: Grill Francisca J , Grys Thomas E , Grill Marie F , Roeder Alexa , Blair Janis E , Lake Douglas F 
Published: June 2021

Abstract

Background
Coccidioidomycosis is often diagnosed with a collection of tests that measure a patient’s ability to mount an immune response to the fungus (antibody-based diagnostics) utilizing fungal protein preparations. Here we present an antigen-based assay that detects and quantifies coccidioidal chitinase-1 (CTS1) in diagnostic antigen preparations with potential for use in human serum.

Methods
An inhibition-based enzyme-linked immunoassay (ELISA) was developed that utilizes a monoclonal antibody specific for coccidioidal CTS1. CTS1 was quantified in commercial antigen preparations using recombinant CTS1 as a standard. Sera from 192 individuals from an endemic area were tested which included 78 patients (40.6%) with proven or probable coccidioidomycosis.

Results
The quantity of CTS1 in diagnostic commercial antigen preparations from different suppliers varied. Temporal constraints of availability of different lots of commercial antigens does not allow for immediate comparison of lot-to-lot variability. Assay results from patient serum samples correlated with low- and high-titer serology from patients with a coccidioidomycosis diagnosis. Further analysis suggested that patient derived anti-CTS1 antibodies may overlap with the mouse monoclonal antibody used in the assay. This unexpected overlap in CTS1 binding suggests the assay can detect antigen, antibody, or both, which contributes to its high level of clinical sensitivity of 89.74% and specificity of 94.90%.

Conclusions
The CTS1 inhibition ELISA described in this report is a promising tool to aid in quality control of antigens used in the diagnosis of coccidioidomycosis. Further optimization is needed to harness its utility as a diagnostic tool to aid in diagnosis and disease monitoring of coccidioidomycosis.
Massive star formation in the Carina nebula complex and Gum 31. II. A cloud–cloud collision in Gum 31
Authors: Fujita Shinji , Sano Hidetoshi , Enokiya Rei , Hayashi Katsuhiro , Kohno Mikito , Tsuge Kisetsu , Tachihara Kengo , Nishimura Atsushi , Ohama Akio , Yamane Yumiko , Ohno Takahiro , Yamada Rin I , Fukui Yasuo 
Published: June 2021

Abstract
We present the results of analyses of the 12CO (J = 1–0), 13CO (J = 1–0), and 12CO (J = 2–1) emission data toward Gum 31. Three molecular clouds separated in velocity were detected at −25, −20, and −10 km s−1. The velocity structure of the molecular clouds in Gum 31 cannot be interpreted as an expanding motion. Two of them, the −25 km s−1 cloud and the −20 km s−1 cloud, are likely to be associated with Gum 31, because their 12CO (J = 2–1)$/$12CO (J = 1–0) intensity ratios are high. We found that these two clouds show the observational signatures of cloud–cloud collisions (CCCs): a complementary spatial distribution and a V-shaped structure (bridge features) in the position–velocity diagram. In addition, their morphology and velocity structures are very similar to the numerical simulations conducted by the previous studies. We propose a scenario that the −25 km s−1 cloud and the −20 km s−1 cloud collided and triggered the formation of the massive star system HD 92206 in Gum 31. This scenario can explain the offset of the stars from the center and the morphology of Gum 31 simultaneously. The timescale of the collision was estimated to be ∼1 Myr by using the ratio between the path length of the collision and the assumed velocity separation. This is consistent with that of the CCCs in the Carina Nebula Complex in our previous study.
Roles of IDM3 and SDJ1/2/3 in Establishment and/or Maintenance of DNA Methylation in Arabidopsis
Authors: Miao Wei , Dai Jie , Wang Yutong , Wang Qianqian , Lu Chong , La Yumei , Niu Jiayu , Tan Feng , Zhou Shaoxia , Wu Yufeng , Chen Huhui , La Honggui 
Published: June 2021

Abstract
Previous studies had demonstrated that in Arabidopsis, IDM3 is involved in ROS1-mediated DNA demethylation pathway, and SUVH-SDJ complex functions as a DNA methylation reader complex for enhancing gene transcription, which presumably recruits ROS1 to the promoters of target genes for DNA demethylation. Here, our analyses, however, showed that the IDM3 and SDJ1/2/3, the components of the SUVH-SDJ complex, are implicated in establishing and/or maintaining DNA methylation as well through DDR (DRD1-DMS3-RDM1) complex. idm3-3 or sdj1/2/3 mutations led to genome-wide DNA hypomethylation, and both mutants shared a large number of common hypo-DMRs (Differentially Methylated Regions) with rdm1-4 and dms3-4, suggesting that IDM3 and SDJ1/2/3 help establish and/or maintain DNA methylation, mediated by RdDM pathway, at a subset of genomic regions largely through DDR complex. IDM3 is able to strongly interact with RDM1 and DMS3, but weakly with SDJ1 and SDJ3; SDJ1 and SDJ3 is capable of interacting separately with RDM1 and DMS3. Furthermore, comparisons of DNA methylation features in idm3-3 and sdj1/2/3 indicated that idm3-3 and sdj1/2/3 mutations make differential impacts on DNA methylation levels and patterns on a genome-wide scale, indicating that they are targeted to quite distinct genomic regions for aiding in DNA methylation. Further analyses on ChIP-seq data demonstrated that RDM1, DMS3 and NRPE1 are enriched in IDM3- and SDJ1/2/3-targted regions. Altogether, our results provide clear demonstration that IDM3 and SDJ1/2/3 play a part in establishing and/or maintaining DNA methylation of a group of genomic regions, through the DDR complex.
Dessins D’enfants and Some Holomorphic Structures on the Loch Ness Monster
Authors: Atarihuana Yasmina , García Juan , Hidalgo Rubén A , Quispe Saúl , Ramírez Maluendas Camilo 
Published: June 2021

Abstract
The theory of dessins d’enfants on compact Riemann surfaces, which are bipartite maps on compact orientable surfaces, are combinatorial objects used to study branched covers between compact Riemann surfaces and the absolute Galois group of the field of rational numbers. In this paper, we show how this theory is naturally extended to non-compact orientable surfaces and, in particular, we observe that the Loch Ness monster (LNM; the surface of infinite genus with exactly one end) admits infinitely many regular dessins d’enfants (either chiral or reflexive). In addition, we study different holomorphic structures on the LNM, which come from homology covers of compact Riemann surfaces, and infinite hyperelliptic and infinite superelliptic curves.