bluuebunny/crossref_metadata_2025_split huggingface dataset:
Correlation between testicular volume and histological findings in children with unilateral cryptorchidism: Potential impact on future fertility
Authors: Spinelli Claudio , Morelli Girolamo , Cito Gianmartin , Bertocchini Alessia , Ghionzoli Marco , Pucci Angela , Cocci Andrea , Morganti Riccardo , Strambi Silvia 
Published: March 2021

Objectives: Our aim is to assess the correlation between testicular volume and histological findings in children with unilateral cryptorchidism. Methods: From September 2016 to August 2018, from 60 patients surgically treated for cryptorchidism, 45 children were enrolled in this single-center prospective study. Depending on the degree of testicular volume reduction, patients were divided into Group 1 with <20% reduction and Group 2 with reduction ⩾20%. Patients underwent unilateral orchidopexy and simultaneous biopsy of the undescended testis. Tanner stage was assigned. Tubular Fertility Index was measured. Results: Group 1 included 20 patients (44.4%) and Group 2 included 25 patients (55.5%). Mean age was 2.10 years (range 12 months–3.8 years) in Group 1 and 2.8 years (range 18 months–4.41 years) in Group 2. Although there is a positive correlation between testicular volume and Tubular Fertility Index, no significant association was found between groups ( p-value = 0.29). Furthermore, histological patterns did not differ significantly among groups. Conclusions: The degree of volume reduction in undescended testis does not seem to correlate significantly with the severity of histological changes that accompany cryptorchidism. Tubular Fertility Index could serve as objective tool for the assessment of future fertility.
Bevacizumab simultaneous combined with dexamethasone implant for treatment of neovascular serous retinal pigment epithelial detachment secondary to neovascular age-related macular degeneration
Authors: Limon Utku , Sezgin Akcay Betül Ilkay 
Published: March 2021

Purpose: To evaluate the add-on effect of simultaneous intravitreal dexamethasone implant to bevacizumab for treatment of neovascular serous retinal pigment epithelial detachment (PED) secondary to neovascular age-related macular degeneration (nAMD). Methods: A 72-year-old male patient was previously treated with intravitreal bevacizumab and aflibercept for neovascular serous PED secondary to nAMD. Because of the recurrences in neovascular PED patient was treated with simultaneous intravitreal injection of bevacizumab and dexamethasone implant. Results: At the initial visit, the patient’s the best corrected visual acuity (BCVA) in the left eye was 20/800. His left eye had neovascular serous PED with a height of 1100 µm and a largest linear diameter of 3953 µm accompanied by subretinal fluid. He received four intravitreal bevacizumab and five intravitreal aflibercept injections. Although there was a decrease in PED sizes from time to time during the 16-month treatment period, PED height was 926 µm and PED greatest linear diameter was 5820 µm at the end of 16th month. Later, the patient could not have an injection for 3 months (he could not come to his controls during the pandemic period), and when he arrived 3 months later, the PED height was 910 µm and the greatest linear diameter was 5830 µm. With a single simultaneous intravitreal injection of bevacizumab and dexamethasone implant, the PED regressed to 168 µm in height after 3 months. The BCVA increased to 20/200. Any clinical toxic effects did not occur and intraocular pressure did not rise for 3 months after injection. Conclusion: Simultaneous intravitreal bevacizumab and dexamethasone implant injection effectively and safely treated treatment-resistant neovascular serous PED. This therapy may be a novel alternative therapy for treatment resistant neovascular serous PED secondary to nAMD. However, further studies are required to understand its effectiveness and safety.
Biomimetic oligopeptide formed enamel-like tissue and dentin tubule occlusion via mineralization for dentin hypersensitivity treatment
Authors: Wang Qing-qing , Wang Siqing , Zhao Tian , Li Yan , Yang Jie , Liu Yumei , Zhang He , Miao Leiying , Sun Weibin 
Published: March 2021

Objective: Dentin hypersensitivity (DH) is a common oral disease with approximately 41.9% prevalence. Reconstruction of dental hard tissues is the preferred treatment for relieving DH. Here, we applied biomineralization method using oligopeptide simulating cementum protein 1 (CEMP1) to regenerate hard tissues on demineralized dentin. Methods: The self-assembly and biomineralization property of the oligopeptide were detected by scanning electron microscopy (SEM), circular dichroism spectroscopy, and transmission electron microscopy. Oligopeptide’s binding capacity to demineralized dentin was evaluated by SEM and attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR). Remineralization was characterized using SEM, ATR-FTIR, X-ray diffraction, and nanoindentation. Oligopeptide’s biocompatibility was evaluated using periodontal ligament cells. Results: Oligopeptides self-assembled into nano-matrix and templated mineral precursor formation within 24 h. Moreover, oligopeptide nano-matrix bound firmly on demineralized dentin and resisted water rinsing. Then, bound nano-matrix served as a template to initiate nucleation and transformation of hydroxyapatite on demineralized dentin. After 96 h, oligopeptide nano-matrix regenerated an enamel-like tissue layer with a thickness of 15.35 μm, and regenerated crystals occluded dentin tubules with a depth of 31.27 μm. Furthermore, the oligopeptide nano-matrix had good biocompatibility when co-cultured with periodontal ligament cells. Conclusions: This biomimetic oligopeptide simulating CEMP1 effectively induced remineralization and reconstructed hard tissues on demineralized dentin, providing a potential biomaterial for DH treatment.
Safety and tolerability of eptinezumab in patients with migraine: a pooled analysis of 5 clinical trials
Authors: Smith Timothy R. , Spierings Egilius L. H. , Cady Roger , Hirman Joe , Schaeffler Barbara , Shen Vivienne , Sperling Bjørn , Brevig Thomas , Josiassen Mette Krog , Brunner Elizabeth , Honeywell Loan , Mehta Lahar 
Published: March 2021

AbstractBackgroundThe humanized anti-CGRP monoclonal antibody eptinezumab has been evaluated in five large-scale clinical trials conducted in patients with migraine. This integrated analysis was conducted to evaluate the comprehensive safety and tolerability of eptinezumab in patients with migraine across these studies.MethodsData were pooled from four randomized, double-blind, placebo-controlled studies and the first year of one open-label study.ResultsThe pooled population comprised 2867 adults with migraine: eptinezumab,n = 2076 (4797 infusions); placebo,n = 791 (1675 infusions). A total of 1137/2076 (54.8%) patients who received eptinezumab and 414/791 (52.3%) patients who received placebo experienced ≥1 treatment-emergent adverse event (TEAE); rates were similar across eptinezumab dose groups (10–1000 mg). For most patients with TEAEs, the events were mild or moderate in severity and considered unrelated to study drug by the investigators. Thirty infusion-site AEs occurred in 27/2076 (1.3%) patients who received eptinezumab and 7 in 7/791 (0.9%) patients who received placebo. Infusion-site AEs led to infusion interruption in 19/2076 (0.9%) and 5/791 (0.6%) patients in the eptinezumab and placebo groups, respectively. Nasopharyngitis occurred in ≥2% of patients in the eptinezumab 300-mg group and with an incidence of at least 2 percentage points greater than in the placebo group; however, in most patients (eptinezumab, 139/140; placebo 40/41), its occurrence was considered not related to study treatment. Adverse events coded to hypersensitivity occurred for 23/2076 (1.1%) patients treated with eptinezumab and no patients in the placebo group. If additional TEAE terms that could indicate hypersensitivity are considered (e.g., urticaria, flushing/hot flush, rash, and pruritus), hypersensitivity reactions in the two pivotal placebo-controlled phase 3 studies occurred in ≥2% of patients in the eptinezumab 100-mg and 300-mg groups, and the incidence was at least 2 percentage points greater in either of these groups than in the placebo group. Most hypersensitivity reactions were not serious and resolved with standard medical treatment or observation without treatment, usually within 1 day.ConclusionsIn adults with migraine, the intravenous administration of eptinezumab every 12 weeks demonstrated a favorable safety and tolerability profile.Trial registrationClinicalTrials.gov (Identifiers:NCT01772524,NCT02275117,NCT02559895,NCT02974153,NCT02985398).
Large-scale labeling and assessment of sex bias in publicly available expression data
Authors: Flynn Emily , Chang Annie , Altman Russ B. 
Published: March 2021

AbstractBackgroundWomen are at more than 1.5-fold higher risk for clinically relevant adverse drug events. While this higher prevalence is partially due to gender-related effects, biological sex differences likely also impact drug response. Publicly available gene expression databases provide a unique opportunity for examining drug response at a cellular level. However, missingness and heterogeneity of metadata prevent large-scale identification of drug exposure studies and limit assessments of sex bias. To address this, we trained organism-specific models to infer sample sex from gene expression data, and used entity normalization to map metadata cell line and drug mentions to existing ontologies. Using this method, we inferred sex labels for 450,371 human and 245,107 mouse microarray and RNA-seq samples from refine.bio.ResultsOverall, we find slight female bias (52.1%) in human samples and (62.5%) male bias in mouse samples; this corresponds to a majority of mixed sex studies in humans and single sex studies in mice, split between female-only and male-only (25.8% vs. 18.9% in human and 21.6% vs. 31.1% in mouse, respectively). In drug studies, we find limited evidence for sex-sampling bias overall; however, specific categories of drugs, including human cancer and mouse nervous system drugs, are enriched in female-only and male-only studies, respectively. We leverage our expression-based sex labels to further examine the complexity of cell line sex and assess the frequency of metadata sex label misannotations (2–5%).ConclusionsOur results demonstrate limited overall sex bias, while highlighting high bias in specific subfields and underscoring the importance of including sex labels to better understand the underlying biology. We make our inferred and normalized labels, along with flags for misannotated samples, publicly available to catalyze the routine use of sex as a study variable in future analyses.
Autosomal recessive loci contribute significantly to quantitative variation of male fertility in a dairy cattle population
Authors: Hiltpold Maya , Kadri Naveen Kumar , Janett Fredi , Witschi Ulrich , Schmitz-Hsu Fritz , Pausch Hubert 
Published: March 2021

AbstractBackgroundCattle are ideally suited to investigate the genetics of male fertility. Semen from individual bulls is used for thousands of artificial inseminations for which the fertilization success is monitored. Results from the breeding soundness examination and repeated observations of semen quality complement the fertility evaluation for each bull.ResultsIn a cohort of 3881 Brown Swiss bulls that had genotypes at 683,609 SNPs, we reveal four novel recessive QTL for male fertility on BTA1, 18, 25, and 26 using haplotype-based association testing. A QTL for bull fertility on BTA1 is also associated with sperm head shape anomalies. All other QTL are not associated with any of the semen quality traits investigated. We perform complementary fine-mapping approaches using publicly available transcriptomes as well as whole-genome sequencing data of 125 Brown Swiss bulls to reveal candidate causal variants. We show that missense or nonsense variants inSPATA16,VWA3A, ENSBTAG00000006717andENSBTAG00000019919are in linkage disequilibrium with the QTL. Using whole-genome sequence data, we detect strong association (P = 4.83 × 10− 12) of a missense variant (p.Ile193Met) inSPATA16with male fertility. However, non-coding variants exhibit stronger association at all QTL suggesting that variants in regulatory regions contribute to variation in bull fertility.ConclusionOur findings in a dairy cattle population provide evidence that recessive variants may contribute substantially to quantitative variation in male fertility in mammals. Detecting causal variants that underpin variation in male fertility remains difficult because the most strongly associated variants reside in poorly annotated non-coding regions.
Transcriptional profiling reveals potential involvement of microvillous TRPM5-expressing cells in viral infection of the olfactory epithelium
Authors: Baxter B. Dnate’ , Larson Eric D. , Merle Laetitia , Feinstein Paul , Polese Arianna Gentile , Bubak Andrew N. , Niemeyer Christy S. , Hassell James , Shepherd Doug , Ramakrishnan Vijay R. , Nagel Maria A. , Restrepo Diego 
Published: March 2021

Abstract
Background
Understanding viral infection of the olfactory epithelium is essential because the olfactory nerve is an important route of entry for viruses to the central nervous system. Specialized chemosensory epithelial cells that express the transient receptor potential cation channel subfamily M member 5 (TRPM5) are found throughout the airways and intestinal epithelium and are involved in responses to viral infection.

Results
Herein we performed deep transcriptional profiling of olfactory epithelial cells sorted by flow cytometry based on the expression of mCherry as a marker for olfactory sensory neurons and for eGFP in OMP-H2B::mCherry/TRPM5-eGFP transgenic mice (Mus musculus). We find profuse expression of transcripts involved in inflammation, immunity and viral infection in TRPM5-expressing microvillous cells compared to olfactory sensory neurons.

Conclusion
Our study provides new insights into a potential role for TRPM5-expressing microvillous cells in viral infection of the olfactory epithelium. We find that, as found for solitary chemosensory cells (SCCs) and brush cells in the airway epithelium, and for tuft cells in the intestine, the transcriptome of TRPM5-expressing microvillous cells indicates that they are likely involved in the inflammatory response elicited by viral infection of the olfactory epithelium.
Diversity and characterization of temperate bacteriophages induced in Pasteurella multocida from different host species
Authors: Abdulrahman Rezheen F. , Davies Robert L. 
Published: March 2021

Abstract
Background
Bacteriophages play important roles in the evolution of bacteria and in the emergence of new pathogenic strains by mediating the horizontal transfer of virulence genes. Pasteurella multocida is responsible for different disease syndromes in a wide range of domesticated animal species. However, very little is known about the influence of bacteriophages on disease pathogenesis in this species.

Results
Temperate bacteriophage diversity was assessed in 47 P. multocida isolates of avian (9), bovine (8), ovine (10) and porcine (20) origin. Induction of phage particles with mitomycin C identified a diverse range of morphological types representing both Siphoviridae and Myoviridae family-types in 29 isolates. Phage of both morphological types were identified in three isolates indicating that a single bacterial host may harbour multiple prophages. DNA was isolated from bacteriophages recovered from 18 P. multocida isolates and its characterization by restriction endonuclease (RE) analysis identified 10 different RE types. Phage of identical RE types were identified in certain closely-related strains but phage having different RE types were present in other closely-related isolates suggesting possible recent acquisition. The host range of the induced phage particles was explored using plaque assay but only 11 (38%) phage lysates produced signs of infection in a panel of indicator strains comprising all 47 isolates. Notably, the majority (9/11) of phage lysates which caused infection originated from two groups of phylogenetically unrelated ovine and porcine strains that uniquely possessed the toxA gene.

Conclusions
Pasteurella multocida possesses a wide range of Siphoviridae- and Myoviridae-type bacteriophages which likely play key roles in the evolution and virulence of this pathogen.
Source–sink manipulations differentially affect carbon and nitrogen dynamics, fruit metabolites and yield of Sacha Inchi plants
Authors: Cai Zhiquan , Xie Tao , Xu Jin 
Published: March 2021

Abstract
Background
Being a promising tropical woody oilseed crop, the evergreen and recurrent plants of Sacha Inchi (Plukenetia volubilis L.) has complex phenology and source–sink interactions. Carbon source–sink manipulations with control and two treatments (reduce source, ca. 10% mature leaf pruning; reduce sink, 10% fruitlet thinning) were conducted on 2.5-year-old field-grown P. volubilis plantation during the early-wet season in a seasonal tropical area.

Results
Leaf photosynthetic rate and specific leaf area largely remained unchanged in response to defoliation or defloration. Compared with control, higher N contents on average were observed in both remaining leaves and branches of the defoliated plants, suggesting that N-mobilization was mainly due to the enhanced N uptake from soil. Carbon, but not N, is a source-driven growth process of P. volubilis plants, as defoliation reduced the contents of non-structural carbohydrates (especially sugar) in branches, although temporally, whereas defloration increased available C reserve. The seasonal dynamic pattern of fruit ripening was altered by source–sink regulations. Total seed yield throughout the growing season, which depends on fruit set and retention (i.e., number of matured fruit) rather than individual fruit development (size), was slightly increased by defloration but was significantly decreased by defoliation. Compared with control, defloration did not enrich the KEGG pathway, but defoliation downregulated the TCA cycle and carbohydrate and lipid metabolisms in fruitlets after 24 days of the applications of source–sink manipulation.

Conclusion
Carbohydrate reserves serve to buffer sink–source imbalances that may result from temporary adjustment in demand for assimilates (e.g., defloration) or shortfalls in carbon assimilation (e.g., defoliation). Defoliation is disadvantageous for the yield and also for carbohydrate and lipid accumulation in fruits of P. volubilis plants. Although more studies are needed, these results provide new insights to the further improvement in seed yield of the strong source-limited P. volubilis plants by source/sink manipulations.
Feasibility and efficacy of modified fixed citrate concentration protocol using only commercial preparations in critically ill patients: a prospective cohort study with a historical control group
Authors: Shi Yan , Qin Han-Yu , Peng Jin-Min , Hu Xiao-Yun , Du Bin 
Published: March 2021

AbstractBackgroundThe cumbersome program and the shortage of commercial solution hindered the regular application of regional citrate anticoagulation (RCA). It is urgent to simplify the protocol using only commercial preparations. The aim of this study was to explore the feasibility and efficacy of the modified protocol for continuous veno-venous hemofiltration (CVVH) in unselected critically ill patients.MethodsA prospective cohort study was conducted in 66 patients who received a new protocol combining fixed citrate concentration with modified algorithm for supplements (i.e., fixed protocol), and compared the efficacy, safety and convenience for this group to a historical control group with a traditional protocol (n = 64), where citrate was titrated according to the circuit ionized calcium concentration (i.e., titrated protocol). The convenience was defined as the demand for monitoring test and dose adjustment of any supplement.ResultsThe filter lifespan was 63.2 ± 16.1 h in the fixed group and 51.9 ± 17.7 h in the titrated group, respectively. Kaplan-Meier survival analysis demonstrated longer circuit lifetime for fixed group (log-rank,p = 0.026). The incidence of circuit clotting was lower in the fixed protocol (15.2% vs. 29.7% in the titrated protocol,p = 0.047). Moreover, compared with the titrated group, patients with fixed protocol had less demand for monitoring test and dose adjustment of any supplement (the number of times per person per day) (3.3 [IQR 2.3–4.5] vs. 5.7 [IQR 3.3–6.9],p = 0.001 and 1.9 [IQR 0.5–2.7] vs. 6.3 [IQR 4.2–7.9],p < 0.001; respectively). No new onset bleeding complications occurred in all patients. The overall incidence of suspected citrate accumulation was 4.6% and there was no difference between the two groups (p = 0.969), yet a lower rate of metabolic alkalosis was found in the fixed group (3.0% vs. 14.1%,p = 0.024).ConclusionsOur modified fixed citrate concentration protocol is feasible, safe and effective to enhance the circuit lifespan and the convenience of implementation while maintaining a similar safety when compared to the traditional protocol. Using only commercial preparations may be helpful for widespread application of RCA.Trial registrationClinicaltrials.gov.NCT02663960. Registered 26 January 2016.
Comparing the use of aggregate data and various methods of integrating individual patient data to network meta-analysis and its application to first-line ART
Authors: Kanters Steve , Karim Mohammad Ehsanul , Thorlund Kristian , Anis Aslam H. , Zoratti Michael , Bansback Nick 
Published: March 2021

AbstractBackgroundThe 2018 World Health Organization HIV guidelines were based on the results of a network meta-analysis (NMA) of published trials. This study employed individual patient-level data (IPD) and aggregate data (AgD) and meta-regression methods to assess the evidence supporting the WHO recommendations and whether they needed any refinements.MethodsAccess to IPD from three trials was granted throughClinicalStudyDataRequest.com(CSDR). Seven modelling approaches were applied and compared: 1) Unadjusted AgD network meta-analysis (NMA) – the original analysis; 2) AgD-NMA with meta-regression; 3) Two-stage IPD-AgD NMA; 4) Unadjusted one-stage IPD-AgD NMA; 5) One-stage IPD-AgD NMA with meta-regression (one-stage approach); 6) Two-stage IPD-AgD NMA with empirical-priors (empirical-priors approach); 7) Hierarchical meta-regression IPD-AgD NMA (HMR approach). The first two were the models used previously. Models were compared with respect to effect estimates, changes in the effect estimates, coefficient estimates, DIC and model fit, rankings and between-study heterogeneity.ResultsIPD were available for 2160 patients, representing 6.5% of the evidence base and 3 of 24 edges. The aspect of the model affected by the choice of modeling appeared to differ across outcomes. HMR consistently generated larger intervals, often with credible intervals (CrI) containing the null value. Discontinuations due to adverse events and viral suppression at 96 weeks were the only two outcomes for which the unadjusted AgD NMA would not be selected. For the first, the selected model shifted the principal comparison of interest from an odds ratio of 0.28 (95% CrI: 10.17, 0.44) to 0.37 (95% CrI: 0.23, 0.58). Throughout all outcomes, the regression estimates differed substantially between AgD and IPD methods, with the latter being more often larger in magnitude and statistically significant.ConclusionsOverall, the use of IPD often impacted the coefficient estimates, but not sufficiently as to necessitate altering the final recommendations of the 2018 WHO Guidelines. Future work should examine the features of a network where adjustments will have an impact, such as how much IPD is required in a given size of network.