bluuebunny/crossref_metadata_2025_split huggingface dataset:
A pharmacist-driven Food and Drug Administration incident surveillance and response program for compounded drugs
Authors: Janusziewicz Ashlee N , Glueck Shannon N , Park Sophia Y , Nguyen Dien N , Rimmel Susan C , Cascio Laurelle A , Doh Gina Y , Martin-Yeboah Garrette F 
Published: April 2021

Abstract

Purpose
To provide an overview of compounding under sections 503A and 503B of the Federal Food, Drug, and Cosmetic Act, and to describe the pharmacist’s role within the US Food and Drug Administration’s (FDA’s) Compounding Incidents Program, whose efforts are aimed at protecting the public against poor-quality compounded drugs through surveillance, review and response to adverse events and complaints.

Summary
Compounded drugs may serve an important medical need for patients who cannot be treated with medications approved by FDA; however, compounded drugs are not approved by FDA and are not subject to premarket review for safety, efficacy, or manufacturing quality; thus, they may pose safety risks to patients. Prompt reporting of adverse events or complaints related to compounding is important in identifying these risks and implementing safeguards to protect the public. FDA’s Compounding Incidents Program consists of a team of pharmacists dedicated to the surveillance and review of adverse events and complaints and follow-up actions related to safety risks associated with compounded drugs. Pharmacists are a vital component of FDA’s Compounding Incidents Program, utilizing their clinical skill set and regulatory knowledge to review and act on safety issues that affect public health.

Conclusion
As FDA continues to expand the Compounding Incidents Program and its efforts to protect the public against poor-quality compounded drugs, we encourage the continued submission of adverse event reports by healthcare professionals and consumers to FDA’s MedWatch reporting system in addition to adverse event reporting compliance by outsourcing facilities.
Wood Dust Exposure Levels and Respiratory Symptoms 6 Years Apart: An Observational Intervention Study Within the Danish Furniture Industry
Authors: Jacobsen Gitte , Schaumburg Inger , Sigsgaard Torben , Schlünssen Vivi 
Published: April 2021

Abstract

Objectives
Occupational exposure to wood dust can cause respiratory diseases, but few studies have evaluated the impact of declining exposure on health outcome. This study aimed to investigate whether a decline in wood dust exposure between two cross sectional studies performed in 1997–1998 and 2003–2004 was related to the prevalences of respiratory symptoms among woodworkers in a well-defined geographical area.

Methods
Two thousand and thirty-two woodworkers from 54 plants in study 1 and 1889 woodworkers from 52 plants in study 2 returned a questionnaire on respiratory diseases and symptoms, employment and smoking habits. Current individual wood dust exposure level was assessed from 2 study specific job exposure matrix’s based on task, factory size and personal passive dust measurements (2217 in study 1 and 1355 in study 2).

Results
The median (range) of inhalable dust was 1.0 mg/m3 (0.2–9.8), 0.6 mg/m3 (0.1–4.6) in study 1 and study 2, respectively. In study 2, the prevalence’s of self-reported asthma was higher and the prevalence’s of respiratory symptoms were lower compared to study 1. In adjusted logistic regression analyses using GEE methodology to account for clustering, dust exposure level could explain the differences in prevalence of coughing, chronic bronchitis and nasal symptoms between study 1 and study 2, while no effect was found for asthma.

Conclusions
A 40% decline in wood dust exposure in a 6 year period may serve as an explanation for the decline in most respiratory symptoms, but do not seems to impact the prevalence of self-reported asthma.
A multi-modal data harmonisation approach for discovery of COVID-19 drug targets
Authors: Chen Tyrone , Philip Melcy , Lê Cao Kim-Anh , Tyagi Sonika 
Published: April 2021

Abstract
Despite the volume of experiments performed and data available, the complex biology of coronavirus SARS-COV-2 is not yet fully understood. Existing molecular profiling studies have focused on analysing functional omics data of a single type, which captures changes in a small subset of the molecular perturbations caused by the virus. As the logical next step, results from multiple such omics analysis may be aggregated to comprehensively interpret the molecular mechanisms of SARS-CoV-2. An alternative approach is to integrate data simultaneously in a parallel fashion to highlight the inter-relationships of disease-driving biomolecules, in contrast to comparing processed information from each omics level separately. We demonstrate that valuable information may be masked by using the former fragmented views in analysis, and biomarkers resulting from such an approach cannot provide a systematic understanding of the disease aetiology. Hence, we present a generic, reproducible and flexible open-access data harmonisation framework that can be scaled out to future multi-omics analysis to study a phenotype in a holistic manner. The pipeline source code, detailed documentation and automated version as a R package are accessible. To demonstrate the effectiveness of our pipeline, we applied it to a drug screening task. We integrated multi-omics data to find the lowest level of statistical associations between data features in two case studies. Strongly correlated features within each of these two datasets were used for drug–target analysis, resulting in a list of 84 drug–target candidates. Further computational docking and toxicity analyses revealed seven high-confidence targets, amsacrine, bosutinib, ceritinib, crizotinib, nintedanib and sunitinib as potential starting points for drug therapy and development.
doubletD: detecting doublets in single-cell DNA sequencing data
Authors: Weber Leah L , Sashittal Palash , El-Kebir Mohammed 
Published: April 2021

Abstract

Motivation
While single-cell DNA sequencing (scDNA-seq) has enabled the study of intratumor heterogeneity at an unprecedented resolution, current technologies are error-prone and often result in doublets where two or more cells are mistaken for a single cell. Not only do doublets confound downstream analyses, but the increase in doublet rate is also a major bottleneck preventing higher throughput with current single-cell technologies. Although doublet detection and removal are standard practice in scRNA-seq data analysis, options for scDNA-seq data are limited. Current methods attempt to detect doublets while also performing complex downstream analyses tasks, leading to decreased efficiency and/or performance.

Results
We present doubletD, the first standalone method for detecting doublets in scDNA-seq data. Underlying our method is a simple maximum likelihood approach with a closed-form solution. We demonstrate the performance of doubletD on simulated data as well as real datasets, outperforming current methods for downstream analysis of scDNA-seq data that jointly infer doublets as well as standalone approaches for doublet detection in scRNA-seq data. Incorporating doubletD in scDNA-seq analysis pipelines will reduce complexity and lead to more accurate results.

Availability and implementation
https://github.com/elkebir-group/doubletD.

Supplementary information
Supplementary data are available at Bioinformatics online.
Effects of rapid and slow maxillary expansion on root resorption: a micro-computed tomography study
Authors: Colak Canan , Aras Banu , Cheng Lam L , Elekdag-Turk Selma , Turk Tamer , Darendeliler M Ali 
Published: April 2021

Summary

Aim
To compare root resorption (RR) after rapid maxillary expansion (RME) and slow maxillary expansion (SME) through micro-computed tomography (micro-CT).

Subjects and methods
Twenty-six subjects who required maxillary expansion and bilateral upper first premolar extraction were randomly assigned to RME (n = 13, mean age: 13.25 ± 0.88 years) or SME (n = 13, mean age: 13.53±1.28 years) group. A hyrax-type acrylic bonded expansion appliance was used. The Hyrax screw was activated ¼ turn twice a day for 20 days in the RME group and ¼ turn every second day for 80 days in the SME group. One randomly selected upper first premolar was extracted in each patient after active expansion. The appliance was left in situ for a 24-week retention period then the contralateral upper first premolar was extracted. Extracted teeth were scanned with micro-CT and the volume of the resorption craters was analysed with a specialized software. Transversal skeletal and dental widths were measured on posteroanterior radiographs taken before and after expansion and retention periods.

Results
The resorption craters were concentrated mostly on the buccal surface and middle level in all samples. The total RR in the RME group was less post-expansion (P ≤ 0.05) and more post-retention (P &gt; 0.05) than the SME group. During retention, there was a significant decrease in the total RR in the SME group (P &gt; 0.05) and an increase in the RME group. Both RME and SME groups displayed a similar increase in skeletal transverse dimensions, but inter-molar width increased significantly more in the SME group during the whole experimental period.

Conclusion
RME does not have an advantage over SME in terms of skeletal expansion and the amount of RR when a retention period of six months is followed.
Cartelization and firm performance in Upper Silesia 1880–1913
Authors: Beyer Christian 
Published: April 2021

AbstractIn this article the effects of cartelization on firms’ efficiency are investigated using the example of an early twentieth century coal-mining cartel in Upper Silesia: the Upper Silesian Coal Convention. Established in 1898, the cartel comprised various types of private, as well as state-owned, mining enterprises. Using a microeconomic dataset based on firm-level data of the Upper Silesian mines, I focus on the cartel’s effect on efficiency. The cartel did not significantly reduce technical efficiency among mines. This finding confirms previous research on cartels’ effects on efficiency.
Transcriptomic response ofCryptococcus neoformansto ecologically relevant nitrogen concentrations
Authors: Bosch Caylin , Bhana Zoë , Toplis Barbra , Volschenk Heinrich , Botha Alfred 
Published: April 2021

ABSTRACTNitrogen availability is vital for the growth and survival of Cryptococcus neoformans in the natural environment. Two major ecological reservoirs were previously described for C. neoformans, namely, pigeon guano and the woody debris of various tree species. In contrast to the abundance of available nitrogen in guano, C. neoformans must adapt to severely limited nitrogen conditions within arboreal ecological niches. Previously, we demonstrated the role of nitrogen limitation in the production of cryptococcal virulence factors and drug tolerance. The genetic response underlying this adaptation to nitrogen deficiency, however, remains to be determined. Therefore, in the present study we investigated the transcriptomic response of C. neoformans to ecologically relevant nitrogen concentrations using RNA-sequencing. Our data revealed that low nitrogen conditions modulate the expression of numerous virulence genes in C. neoformans. Among these were, CTR4 and CGP1, which showed highly significant modulation under low nitrogen conditions. Furthermore, data analysis revealed the upregulation of antifungal tolerance-related genes in low nitrogen conditions, including genes involved in ergosterol biosynthetic processes and cell wall integrity. Overall, our findings provide insight into the survival of C. neoformans in nitrogen-poor ecological niches and suggest that pre-adaptation to these conditions may influence the pathobiology of this yeast.
Is the transperineal ultrasonography approach effective for the diagnosis of rectocele?
Authors: Yao Yi-Bo , Yin Hao-Qiang , Wang Hai-Jun , Liang Hong-Tao , Wang Bo , Wang Chen 
Published: April 2021

AbstractBackgroundTransperineal ultrasonography has been used as a diagnostic imaging modality for rectocele for many years. However, the consistency of ultrasonography and defecography in evaluating the severity of rectocele was not satisfactory. This study aimed to evaluate the agreement in the measurement of rectocele parameters between the two methods in different positions and provide clinical implications for the diagnosis of rectocele.MethodsIn this pilot study, participants were recruited in an outpatient clinic of a tertiary hospital between December 2017 and December 2019. All participants separately underwent defecation proctography at sitting and squatting positions, and undertook transperineal ultrasonography at left lateral, sitting, and squatting positions. The consistency of ultrasonography and defecography was evaluated.ResultsThirty female volunteers with rectocele were included in this study. The degree of anorectal angle was significantly larger at rest and during contraction, maximal Valsalva, and evacuation; the depth of the rectocele was significantly deeper during maximal Valsalva and evacuation; and the length of the perineum descending was significantly longer during contraction and maximal Valsalva in using squatting position compared to the sitting position when performing the defecation proctography. The degree of anorectal angle, the depth of rectocele, the area of levator hiatus, and the volume of the rectocele were significantly different in using squatting, sitting, and left lateral positions when performing the transperineal ultrasonography. Bland-Altman semi-quantitative plots showed good consistency in the measurement of the anorectal angle and the depth of the rectocele between proctography and ultrasonography in both sitting and squatting positions.ConclusionsThe findings of our study may be considered as the preliminary evidence to support the use of transperineal ultrasonography with sitting and squatting positions as the imaging test of choice for evaluating patients with rectocele.
A multicenter study assessing the prevalence of germline genetic alterations in Chinese gastric-cancer patients
Authors: Zhang Yin-Jie , Yang Yang , Wei Qing , Xu Ting , Zhang Xiao-Tian , Gao Jing , Tan Si-Yi , Liu Bao-Rui , Zhang Jing-Dong , Chen Xiao-Bing , Wang Zhao-Jie , Qiu Meng , Wang Xin , Shen Lin , Wang Xi-Cheng 
Published: April 2021

Abstract

Background
Approximately 10% of patients with gastric cancer (GC) have a genetic predisposition toward the disease. However, there is scant knowledge regarding germline mutations in predisposing genes in the Chinese GC population. This study aimed to determine the spectrum and distribution of predisposing gene mutations among Chinese GC patients known to have hereditary high-risk factors for cancer.

Methods
A total of 40 GC patients from 40 families were recruited from seven medical institutions in China. Next-generation sequencing was performed on 171 genes associated with cancer predisposition. For probands carrying pathogenic/likely pathogenic germline variants, Sanger sequencing was applied to validate the variants in the probands as well as their relatives.

Results
According to sequencing results, 25.0% (10/40) of the patients carried a combined total of 10 pathogenic or likely pathogenic germline variants involving nine different genes: CDH1 (n = 1), MLH1 (n = 1), MSH2 (n = 1), CHEK2 (n = 1), BLM (n = 1), EXT2 (n = 1), PALB2 (n = 1), ERCC2 (n = 1), and SPINK1 (n = 2). In addition, 129 variants of uncertain significance were identified in 27 patients.

Conclusions
This study indicates that approximately one in every four Chinese GC patients with hereditary high risk factors may harbor pathogenic/likely pathogenic germline alterations in cancer-susceptibility genes. The results further indicate a unique genetic background for GC among Chinese patients.
Distinguishing Between Selection and Population Expansion in an Experimental Lineage of Bacteriophage T7
Authors: Hahn Matthew W , Rausher Mark D , Cunningham Clifford W 
Published: April 2021

Abstract
Experimental evolution of short-lived organisms offers the opportunity to study the dynamics of polymorphism over time in a controlled environment. Here, we characterize DNA polymorphism data over time for four genes in bacteriophage T7. Our experiment ran for 2500 generations and populations were sampled after 500, 2000, and 2500 generations. We detect positive selection, purifying (“negative”) selection, and population expansion in our experiment. We also present a statistical test that is able to distinguish demographic from selective events, processes that are hard to identify individually because both often produce an excess of rare mutations. Our “heterogeneity test” modifies common statistics measuring the frequency spectrum of polymorphism (e.g., Fu and Li’s D) by looking for processes producing different patterns on nonsynonymous and synonymous mutations. Test results agree with the known conditions of the experiment, and we are therefore confident that this test offers a tool to evaluate natural populations. Our results suggest that instances of segregating deleterious mutations may be common, but as yet undetected, in nature.
Increased or Decreased Levels ofCaenorhabditis elegans lon-3, a Gene Encoding a Collagen, Cause Reciprocal Changes in Body Length
Authors: Nyström Josefin , Shen Zai-Zhong , Aili Margareta , Flemming Anthony J , Leroi Armand , Tuck Simon 
Published: April 2021

AbstractBody length in C. elegans is regulated by a member of the TGFβ family, DBL-1. Loss-of-function mutations in dbl-1, or in genes encoding components of the signaling pathway it activates, cause worms to be shorter than wild type and slightly thinner (Sma). Overexpression of dbl-1 confers the Lon phenotype characterized by an increase in body length. We show here that loss-of-function mutations in dbl-1 and lon-1, respectively, cause a decrease or increase in the ploidy of nuclei in the hypodermal syncytial cell, hyp7. To learn more about the regulation of body length in C. elegans we carried out a genetic screen for new mutations causing a Lon phenotype. We report here the cloning and characterization of lon-3. lon-3 is shown to encode a putative cuticle collagen that is expressed in hypodermal cells. We show that, whereas putative null mutations in lon-3 (or reduction of lon-3 activity by RNAi) causes a Lon phenotype, increasing lon-3 gene copy number causes a marked reduction in body length. Morphometric analyses indicate that the lon-3 loss-of-function phenotype resembles that caused by overexpression of dbl-1. Furthermore, phenotypes caused by defects in dbl-1 or lon-3 expression are in both cases suppressed by a null mutation in sqt-1, a second cuticle collagen gene. However, whereas loss of dbl-1 activity causes a reduction in hypodermal endoreduplication, the reduction in body length associated with overexpression of lon-3 occurs in the absence of defects in hypodermal ploidy.
Mutational Bisection of the Mitochondrial DNA Stability and Amino Acid Biosynthetic Functions of Ilv5p of Budding Yeast
Authors: Bateman Joseph M , Perlman Philip S , Butow Ronald A 
Published: April 2021

Abstract
Ilv5p is a bifunctional yeast mitochondrial enzyme required for branched chain amino acid biosynthesis and for the stability of mitochondrial DNA (mtDNA) and its parsing into nucleoids. The latter occurs when the general amino acid control (GAC) pathway is activated. We have isolated ilv5 mutants that lack either the enzymatic (a−D+) or the mtDNA stability function (a+D−) of the protein. The affected residues in these two mutant classes cluster differently when mapped to the 3-D structure of the spinach ortholog of Ilv5p. a−D+ mutations map to conserved internal domains known to be important for substrate and cofactor binding, whereas the a+D− mutations map to a C-terminal region on the surface of the protein. The a+D− mutants also have a temperature-sensitive phenotype when grown on a glycerol medium, which correlates with their degree of mtDNA instability. Analysis of an a+D− mutant with a strong mtDNA instability phenotype shows that it is also unable to parse mtDNA into nucleoids when activated by the GAC pathway. Finally, the wild-type Escherichia coli ortholog of Ilv5p behaves like a+D− mutants when expressed and targeted to mitochondria in ilv5Δ yeast cells, suggesting that yeast Ilv5p acquired its mtDNA function after the endosymbiotic event.
Role of the Tsc1-Tsc2 Complex in Signaling and Transport Across the Cell Membrane in the Fission YeastSchizosaccharomyces pombe
Authors: Matsumoto Sanae , Bandyopadhyay Amitabha , Kwiatkowski David J , Maitra Umadas , Matsumoto Tomohiro 
Published: April 2021

AbstractHeterozygous inactivation of either human TSC1 or TSC2 causes tuberous sclerosis (TSC), in which development of benign tumors, hamartomas, occurs via a two-hit mechanism. In this study, fission yeast genes homologous to TSC1 and TSC2 were identified, and their protein products were shown to physically interact like the human gene products. Strains lacking tsc1+ or tsc2+ were defective in uptake of nutrients from the environment. An amino acid permease, which is normally positioned on the plasma membrane, aggregated in the cytoplasm or was confined in vacuole-like structures in Δtsc1 and Δtsc2 strains. Deletion of tsc1+ or tsc2+ also caused a defect in conjugation. When a limited number of the cells were mixed, they conjugated poorly. The conjugation efficiency was improved by increased cell density. Δtsc1 cells were not responsive to a mating pheromone, P-factor, suggesting that Tsc1 has an important role in the signal cascade for conjugation. These results indicate that the fission yeast Tsc1-Tsc2 complex plays a role in the regulation of protein trafficking and suggest a similar function for the human proteins. We also show that fission yeast Int6 is involved in a similar process, but functions in an independent genetic pathway.
Chromosomal Elements Evolve at Different Rates in the Drosophila Genome
Authors: González Josefa , Ranz José María , Ruiz Alfredo 
Published: April 2021

AbstractRecent results indicate that the rate of chromosomal rearrangement in the genus Drosophila is the highest found so far in any eukaryote. This conclusion is based chiefly on the comparative mapping analysis of a single chromosomal element (Muller's element E) in two species, D. melanogaster and D. repleta, representing the two farthest lineages within the genus (the Sophophora and Drosophila subgenera, respectively). We have extended the analysis to two other chromosomal elements (Muller's elements A and D) and tested for differences in rate of evolution among chromosomes. With this purpose, detailed physical maps of chromosomes X and 4 of D. repleta were constructed by in situ hybridization of 145 DNA probes (gene clones, cosmids, and P1 phages) and their gene arrangements compared with those of the homologous chromosomes X and 3L of D. melanogaster. Both chromosomal elements have been extensively reshuffled over their entire length. The number of paracentric inversions fixed has been estimated as 118 ± 17 for element A and 56 ± 8 for element D. Comparison with previous data for elements E and B shows that there are fourfold differences in evolution rate among chromosomal elements, with chromosome X exhibiting the highest rate of rearrangement. Combining all results, we estimated that 393 paracentric inversions have been fixed in the whole genome since the divergence between D. repleta and D. melanogaster. This amounts to an average rate of 0.053 disruptions/Mb/myr, corroborating the high rate of rearrangement in the genus Drosophila.