bluuebunny/crossref_metadata_2025 huggingface dataset:
Host‐related and environmental factors influence long‐term ectoparasite infestation dynamics of mouse lemurs in northwestern Madagascar
Authors: Marquès Gomila Caterina , Kiene Frederik , Klein Annette , Kessler Sharon E. , Zohdy Sarah , Rakotondravony Romule , Durden Lance A. , Radespiel Ute
Published: April 2023

Parasite infestations depend on multiple host‐related and environmental factors. In the case of ectoparasites, which are exposed to the environment beyond the host, an impact of climate, expressed by seasonal or yearly variations, can be expected. However, long‐term dynamics of ectoparasite infestations are rarely studied in nonhuman primates. We investigated the yearly variations in ectoparasite infestations of two small primates, the gray (Microcebus murinus) and the golden‐brown (Microcebus ravelobensis) mouse lemur. For a more comprehensive evaluation, we also analyzed the potential effects of yearly and monthly climatic variation (temperature, rainfall) in addition to habitat, host sex, age, species, and body mass, on ectoparasite infestation. Individuals of both host species were sampled in two study sites within the Ankarafantsika National Park in northwestern Madagascar during several months (March–November) and across 4 years (2010, 2011, 2015, 2016). Our results show significant monthly and yearly variations in the infestation rates of three native ectoparasite taxa (Haemaphysalis spp. ticks, Schoutedenichia microcebi chigger mites, Lemurpediculus spp. sucking lice) and in ectoparasite species richness in both mouse lemur species. In addition, significant impacts of several host‐related (species, sex, body mass) and environmental factors (habitat, temperature, rainfall) were found, but with differences in relevance for the different parasite taxa and partly deviating in their direction. Although some differences could be attributed to either permanent or temporary presence of the parasites on the host or to ecological differences between the host species, the lack of specific knowledge regarding the life cycle and microhabitat requirements of each parasite taxon precludes a complete understanding of the factors that determine their infestation dynamics. This study demonstrates the presence of yearly and monthly dynamics in lemur–parasite interactions in tropical, seasonal, dry deciduous forests in Madagascar, which call out for broad ecological long‐term studies focusing both on primate hosts and their parasites.
Plasma ATN(I) classification and precision pharmacology in Alzheimer's disease
Authors: Imbimbo Bruno P. , Watling Mark , Imbimbo Camillo , Nisticò Robert
Published: April 2023

Evaluating potential therapies for Alzheimer's disease (AD) depends on use of biomarkers for appropriate subject selection and monitoring disease progression. Biomarkers that predict onset of clinical symptoms are particularly important for AD because they enable intervention before irreversible neurodegeneration occurs. The amyloid‐β‐tau‐neurodegeneration (ATN) classification system is currently used as a biological staging model for AD and is based on three classes of biomarkers evaluating amyloid‐β (Aβ), tau pathology and neurodegeneration or neuronal injury. Promising blood‐based biomarkers for each of these categories have been identified (Aβ42/Aβ40 ratio, phosphorylated tau, neurofilament light chain), and this matrix is now being expanded toward an ATN(I) system, where “I” represents a neuroinflammatory biomarker. The plasma ATN(I) system, together with APOE genotyping, offers a basis for individualized evaluation and a move away from the classic “one size fits all” approach toward a biomarker‐driven individualisation of therapy for patients with AD.
Can volumetric analysis of the brain help diagnose isolated optic neuritis?
Authors: Sayin Sakul A. A. , Pence K. B. , Ormeci T. , Gunal M. Y.
Published: April 2023

Isolated optic neuritis is a single episode inflammatory optic neuropathy. This condition, which affects the optimal function of the optic nerve, is not associated with neurological or systemic diseases. Our study aimed to compare patients with isolated optic neuritis and normal healthy individuals in terms of the cerebrum, cerebellum and hippocampus volumes by using the “volBrain Online MRI Brain Volumetry System” program. Persons diagnosed with isolated optic neuritis (n = 16) and persons without any disease (n = 16) were included in the study. VolBrain was used to process the MRI data and, the findings were compared with Mann–Whitney U test. Values with a p‐value <0.05 were considered statistically significant. The cerebrum white matter volumes in the total brain and in the right–left hemispheres of the brain were statistically significantly lower in the optic neuritis group (p = 0.029; p = 0.050; p = 0.029, respectively). In the segmental cerebellum analysis, the left side lobule VIIIB, the total and right–left side lobule IX volumes were statistically significantly higher (p = 0.022; p = 0.014; p = 0.029; p = 0.018, respectively). In total, lobule I‐II volume was statistically significantly lower in the optic neuritis group (p = 0.046). In the segmental hippocampus analysis, the right side CA2‐CA3, the total and right–left side SR‐SL‐SM volumes were statistically significantly lower in the optic neuritis group (p = 0.039; p = 0.050; p = 0.016, respectively). There are neurodegenerative changes in brain volume in patients with isolated optic neuritis. Although volBrain alone is not sufficient to diagnose isolated optic neuritis, it provides quantitative data that can be used as a complementary diagnostic method.
LY6K depletion modulates TGF‐β and EGF signaling
Authors: Park Sujeong , Park Doyeon , Han Sora , Chung Ga Eun , Soh Sujung , Ka Hye In , Joo Hyun Jeong , Yang Young
Published: April 2023

Background

Lymphocyte antigen 6 complex locus K (LY6K), a glycosylphosphatidylinositol‐anchored protein, plays a dynamic role in cancer metastasis. In the current study, we deciphered the effects of LY6K on transforming growth factor‐β (TGF‐β) and epidermal growth factor (EGF) signaling through clathrin‐ and caveolin‐1 (CAV‐1)‐mediated endocytosis.

Methods

Analysis of the TCGA and GTEx dataset were performed to explore the expression and survival of LY6K in cancer patients. Short interfering RNA (siRNA) was used to knockdown the expression of LY6K in human cervical cancer patients. The effect of lack of LY6K on cell proliferation, migration, and invasion was performed, and RT‐qPCR and immunoblotting were performed to identify LY6K‐affected TGF‐β and EGF signaling pathways. Additionally, Immunofluorescence (IF) and transmission electron microscope (TEM) were performed to identify the role of LY6K in CAV‐1‐ and Clathrin‐mediated endocytosis.

Results

Lymphocyte antigen 6 complex locus K expression level is elevated in higher grade cervical cancer patients correlating with poor overall survival, progression‐free survival, and disease‐free survival. LY6K‐depletion in HeLa and SiHa cancer cells suppressed EGF‐induced proliferation and TGF‐β‐enhanced migration and invasion. Both TGF‐β receptor‐I (TβRI) and EGF receptor (EGFR) localized at the plasma membrane regardless of LY6K expression, and LY6K bound TβRI irrespective of the presence of TGF‐β; however, LY6K did not bind EGFR. LY6K‐depleted cells showed impaired Smad2 phosphorylation upon TGF‐β treatment and lower proliferation rates following long‐term treatment with EGF. We revealed the atypical movement of TβRI and EGFR from plasma membrane upon ligand stimulation in LY6K‐depleted cells and an impaired movement of the endocytic proteins clathrin and CAV‐1.

Conclusions

Our study demonstrates the key role of LY6K in both clathrin‐ and CAV‐1‐mediated endocytic pathways regulated by TGF‐β and EGF, and it suggests a correlation between LY6K overexpression in cervical cancer cells and poor overall survival.
Added diagnostic value of routinely measured hematology variables in diagnosing immune checkpoint inhibitor mediated toxicity in the emergency department
Authors: Niemantsverdriet Michael S. A. , Vrijsen Bram E. L. , Visser ’t Hooft Therese , Suijkerbuijk Karijn P. M. , van Solinge Wouter W. , ten Berg Maarten J. , Haitjema Saskia
Published: April 2023

Background

Immune checkpoint inhibitors (ICI) show remarkable results in cancer treatment, but at the cost of immune‐related adverse events (irAE). irAE can be difficult to differentiate from infections or tumor progression, thereby challenging treatment, especially in the emergency department (ED) where time and clinical information are limited. As infections are traceable in blood, we were interested in the added diagnostic value of routinely measured hematological blood cell characteristics in addition to standard diagnostic practice in the ED to aid irAE assessment.

Methods

Hematological variables routinely measured with our hematological analyzer (Abbott CELL‐DYN Sapphire) were retrieved from Utrecht Patient Oriented Database (UPOD) for all patients treated with ICI who visited the ED between 2013 and 2020. To assess the added diagnostic value, we developed and compared two models; a base logistic regression model trained on the preliminary diagnosis at the ED, sex, and gender, and an extended model trained with lasso that also assessed the hematology variables.

Results

A total of 413 ED visits were used in this analysis. The extended model showed an improvement in performance (area under the receiver operator characteristic curve) over the base model, 0.79 (95% CI 0.75–0.84), and 0.67 (95% CI 0.60–0.73), respectively. Two standard blood count variables (eosinophil granulocyte count and red blood cell count) and two advanced variables (coefficient of variance of neutrophil depolarization and red blood cell distribution width) were associated with irAE.

Conclusion

Hematological variables are a valuable and inexpensive aid for irAE diagnosis in the ED. Further exploration of the predictive hematological variables could yield new insights into the pathophysiology underlying irAE and in distinguishing irAE from other inflammatory conditions.
Overview of Fouling – An Industrial Jeopardy
Authors: Unnikrishnan Anish , Mulky Lavanya
Published: April 2023

A brief insight into fouling and its various types, which impose a hurdle on the performance of an apparatus and ultimately a negative impact on the environment as a whole due to the excess unwanted deposits, is given. Within the various types mentioned, specific cases of fouling occurrences in each are also highlighted. The mechanism associated with the specific cases as well as the difficulties arising are mentioned as interpreted from previous literature and experiments. There are cases where more than one type of fouling is found to be simultaneously occurring, which is referred to as composite fouling. Numerous parameters control this phenomenon, along with some exceptions associated with the same. Few membranes or plates or their physical aspects prove to be quite effective in withstanding or overcoming a specific type of fouling. Mitigation of fouling demands proper monitoring and control of the chemical processes to ensure lesser damage to the equipments. Industrial fouling in general and specific scenarios of fouling are overviewed and discussed.
Bioaccessibility of ferulic acid in hulless barley varieties at stages of simulated in vitro digestion
Authors: Drawbridge Pamela C. , Apea‐Bah Franklin , Beta Trust
Published: April 2023

Background and Objectives

Ferulic acid has antioxidant, anti‐inflammatory, and antimicrobial activity. Ferulic acid in barley is present in esterified form in the bran layer, however, only the free form is bioaccessible in the upper gastrointestinal tract. The objectives of this study were to investigate the bioaccessibility of ferulic acid at four stages of simulated gastrointestinal digestion of two barley varieties to determine when ferulic acid is released and investigate factors which may affect the release of ferulic acid including digestive enzymes and pH.

Findings

The release of ferulic acid was strongly influenced by digestive enzymes and minimally by pH. The presence of enzymes reduced free ferulic acid but increased the amount of esterified ferulic acid. The major release of esterified ferulic acid occurred during the final hour of small intestinal digestion. The amount of bioaccessible ferulic acid remained constant throughout digestion. The bran thickness, measured by microCT imaging, significantly differed between the varieties.

Conclusion

During digestion, ferulic acid changed structurally, as observed by the changes in the amount of free and esterified ferulic acid at four digestion timepoints. The release of ferulic acid was strongly influenced by exposure to digestive enzymes and minimally by pH, although the mechanism of the presence of enzymes on ferulic acid release is unclear. The bioaccessibility of ferulic acid may be determined by the bran layer thickness and further investigation is required.

Significance and Novelty

This is the first study to investigate the bioaccessibility of ferulic acid in barley at various stages of digestion and to measure the bran thickness of barley using microCT imaging with preliminary findings indicating enhanced ferulic acid bioaccessibility in grains with a thinner bran layer.
Characterization of yellow pea (Pisum sativum L.) genotypes for performance (agronomic and quality) and stability across environments
Authors: Daba Sintayehu D. , McGee Rebecca J. , Kiszonas Alecia M.
Published: April 2023

Background and Objectives

Yellow peas (Pisum sativum L.) are preferred for protein isolation. We characterized 21 yellow pea genotypes grown at Fairfield and Pullman, Washington in 2020 and 2021. To evaluate yellow pea genotypes for agronomic and quality traits across environments, data were collected on seed, flour, protein isolate, and starch‐rich byproducts.

Findings

Seed yield and weight dropped by over 61% and 11%, respectively, in 2021 when compared to 2020. About 17%–20% of the flour was recovered as protein isolated with a protein recovery rate of 66%–69% and about 61%–64% was converted to starch‐rich byproduct. Heritability was fairly high for seed weight (TSW) and protein isolate yield but low for seed yield and the functional properties. Some genotypes combined merits for multiple traits based on the degree of relationship between those traits. It was possible to identify genotypes with favorable combinations of seed yield with either seed weight or flour protein as these two traits exhibited weak correlation with seed yield. Owing to a positive correlation between flour protein concentration and PIYLD, two genotypes combined the best of the two traits.

Significance and Novelty

Overall, the findings of this study can be used to develop a tailored pea breeding program focused on plant‐based protein. As starch‐rich byproduct is the largest portion produced due to protein extraction, it would be beneficial to conduct more research on this component to facilitate product development.
On the Stereochemistry of the NH Bond Activation of Ammonia or Amines by Disilenes: Predictability
Authors: Sharif Zahra Mohamad , Özpınar Gül Altınbaş , McOnie Sarah L. , Boyle Paul D. , Müller Thomas , Baines Kim M.
Published: April 2023

The stereochemistry of the addition of NH3to the stereoisomers of 1,2‐di‐tert‐butyl‐1,2‐bis(2,4,6‐triisopropylphenyl)disilene (Z‐5orE‐5) is 100 % stereospecific giving two isomeric disilylamines6and7, respectively, derived fromsyn‐addition to the stereoisomeric disilenes. Variable time normalization analysis studies of the reaction of tetramesityldisilene (3) with isopropylamine (iPrNH2) revealed that the order in both amine and disilene is 1. The kinetic isotope effect for the addition ofiPrNH2/iPrND2to tetramesityldisilene was determined to be 3.04±0.06 at 298 K, a primary KIE, indicating that the proton is transferred in the rate determining step. Competition studies between the addition of PrNH2andiPrNH2to tetramesityldisilene resulted in the exclusive formation of the PrNH2adduct consistent with a nucleophilic addition. Computational studies of the mechanism of the addition of ammonia toE‐5revealed the lowest energy pathway involves the formation of the donor adduct derived fromsyn‐addition, followed by intramolecularsyn‐transfer of the proton. The formation of the donor adduct is the rate determining step. The results of this study, together with previous studies on the addition of ammonia and amines to disilenes, allow for a refinement of our understanding of the mechanism of this important fundamental reaction in disilene chemistry, and allow us to understand our ability to reliably predict the stereochemical outcomes of future NH σ‐bond activation reactions.
Entospletinib with decitabine in acute myeloid leukemia with mutant TP53 or complex karyotype: A phase 2 substudy of the Beat AML Master Trial
Authors: Duong Vu H. , Ruppert Amy S. , Mims Alice S. , Borate Uma , Stein Eytan M. , Baer Maria R. , Stock Wendy , Kovacsovics Tibor , Blum William , Arellano Martha L. , Schiller Gary J. , Olin Rebecca L. , Foran James M. , Litzow Mark R. , Lin Tara L. , Patel Prapti A. , Foster Matthew C. , Redner Robert L. , Al‐Mansour Zeina , Cogle Christopher R. , Swords Ronan T. , Collins Robert H. , Vergilio Jo‐Anne , Heerema Nyla A. , Rosenberg Leonard , Yocum Ashley O. , Marcus Sonja , Chen Timothy , Druggan Franchesca , Stefanos Mona , Gana Theophilus J. , Shoben Abigail B. , Druker Brian J. , Burd Amy , Byrd John C. , Levine Ross L. , Boyiadzis Michael M.
Published: April 2023

Background

Patients with acute myeloid leukemia (AML) who have tumor protein p53 (TP53) mutations or a complex karyotype have a poor prognosis, and hypomethylating agents are often used. The authors evaluated the efficacy of entospletinib, an oral inhibitor of spleen tyrosine kinase, combined with decitabine in this patient population.

Methods

This was a multicenter, open‐label, phase 2 substudy of the Beat AML Master Trial (ClinicalTrials.gov identifier NCT03013998) using a Simon two‐stage design. Eligible patients aged 60 years or older who had newly diagnosed AML with mutations in TP53 with or without a complex karyotype (cohort A; n = 45) or had a complex karyotype without TP53 mutation (cohort B; n = 13) received entospletinib 400 mg twice daily with decitabine 20 mg/m2 on days 1–10 every 28 days for up to three induction cycles, followed by up to 11 consolidation cycles, in which decitabine was reduced to days 1–5. Entospletinib maintenance was given for up to 2 years. The primary end point was complete remission (CR) and CR with hematologic improvement by up to six cycles of therapy.

Results

The composite CR rates for cohorts A and B were 13.3% (95% confidence interval, 5.1%–26.8%) and 30.8% (95% confidence interval, 9.1%–61.4%), respectively. The median duration of response was 7.6 and 8.2 months, respectively, and the median overall survival was 6.5 and 11.5 months, respectively. The study was stopped because the futility boundary was crossed in both cohorts.

Conclusions

The combination of entospletinib and decitabine demonstrated activity and was acceptably tolerated in this patient population; however, the CR rates were low, and overall survival was short. Novel treatment strategies for older patients with TP53 mutations and complex karyotype remain an urgent need.
A classification approach to improve out of sample predictability of structure‐based constitutive models for ascending thoracic aortic tissue
Authors: Tong Tuan‐Thinh , Nightingale Miriam , Scott Michael B. , Sigaeva Taisiya , Fedak Paul W. M. , Barker Alex J. , Di Martino Elena S.
Published: April 2023

In this research, a pipeline was developed to assess the out‐of‐sample predictive capability of structure‐based constitutive models of ascending aortic aneurysmal tissue. The hypothesis being tested is that a biomarker can help establish similarities among tissues sharing the same level of a quantifiable property, thus enabling the development of biomarker‐specific constitutive models. Biomarker‐specific averaged material models were constructed from biaxial mechanical tests of specimens that shared similar biomarker properties such as level of blood‐wall shear stress or microfiber (elastin or collagen) degradation in the extracellular matrix. Using a cross‐validation strategy commonly used in classification algorithms, biomarker‐specific averaged material models were assessed in contrast to individual tissue mechanics of out of sample specimens that fell under the same category but did not contribute to the averaged model's generation. The normalized root means square errors (NRMSE) calculated on out‐of‐sample data were compared with average models when no categorization was performed versus biomarker‐specific models and among different level of a biomarker. Different biomarker levels exhibited statistically different NRMSE when compared among each other, indicating more common features shared by the specimens belonging to the lower error groups. However, no specific biomarkers reached a significant difference when compared to the average model created when No Categorization was performed, possibly on account of unbalanced number of specimens. The method developed could allow for the screening of different biomarkers or combinations/interactions in a systematic manner leading the way to larger datasets and to more individualized constitutive approaches.
Practice Insight: Court‐connected mediation in Jordan—Considerations for choosing a mediator
Authors: Al Serhan Bakr Abdel Fattah , Al Shawawreh Wesam Faisal , Collins Pauline
Published: April 2023

A model of court‐connected mediation following Western practice was adopted in Jordan in 2003. Its success has been limited. This practice insight addresses the current mediation legislation in Jordan in relation to civil and commercial disputes. The law allows the parties three options in choosing a mediator, one being a judge mediator. This raises important considerations for parties when they are choosing a mediator. The practice insight addresses these considerations with a view to improving party awareness when exercising their choice of mediator. It also takes the opportunity to suggest legislative changes to improve the uptake of mediation.
Gallbladder perforation following peroral cholangioscopy‐guided lithotripsy: A case report
Authors: Kaneko Junichi , Watahiki Moeka , Jindo Osamu , Matsumoto Keigo , Kosugi Toshikatsu , Kusama Daisuke , Tamakoshi Hiroki , Niwa Tomoyuki , Takeshita Yu , Takinami Masaki , Kiuchi Ryota , Tsuji Atsushi , Nishino Masafumi , Takahashi Yurimi , Sasada Yuzo , Kawata Kazuhito , Yamada Takanori , Sakaguchi Takanori
Published: April 2023

Peroral cholangioscopy‐guided lithotripsy is highly effective in clearing difficult bile duct stones. It can cause adverse events, such as cholangitis and pancreatitis; however, gallbladder perforation is extremely rare. Herein, we describe the case of a 77‐year‐old woman who developed gallbladder perforation following peroral cholangioscopy ‐guided lithotripsy. She was referred to our hospital to treat multiple large bile duct stones. She underwent peroral cholangioscopy‐guided lithotripsy because of conventional lithotripsy failure. After a cholangioscope was advanced into the bile duct, saline irrigation was used for visualization. Electronic hydraulic lithotripsy was performed, but it took time for fragmentation because the calculus was hard. The 2‐h endoscopic procedure did not completely remove the stone, and treatment was discontinued after placing a biliary plastic stent and nasobiliary tube. After the endoscopic procedure, she started experiencing right hypochondrial pain, which worsened the next day. Computed tomography showed a gallbladder wall defect in the gallbladder fundus with pericholecystic fluid. She was diagnosed with gallbladder perforation and underwent emergency surgery. A perforation site was found at the gallbladder fundus. Open cholecystectomy, choledochotomy, and extraction of residual bile duct stones were performed. The patient was discharged 9 days post‐surgery without any complications. The saline irrigation used for visualization may have caused a surge in intra‐gallbladder pressure, resulting in gallbladder perforation. Therefore, endoscopists may need to conserve irrigation water during peroral cholangioscopy‐guided lithotripsy.
Distance and density dependence in two native Bornean dipterocarp species
Authors: Malik Nazrin , Edwards David , Freckleton Robert P.
Published: April 2023

The Janzen–Connell hypothesis proposes that density and distance‐dependent mortality generated by specialist natural enemies prevent competitive dominance. Much literature on Janzen–Connell mechanisms comes from the neotropics, and evidence of the role of distance and density‐dependence is still relatively sparse. We tested the predictions of the Janzen–Connell hypothesis in a South‐East Asian system dominated by mast fruiting species. We hypothesized that seedling survival would decrease with distance and density, seedling growth would increase, and herbivory would decrease, according to the predictions of the Janzen–Connell hypothesis. Experiments were conducted to determine the strength of the Janzen–Connell mechanism by manipulating the density and identity of tree species as a function of the distance from parent trees. Survival of conspecific seedlings was reduced near adult trees of one species, but not another. High densities of seedlings decreased the growth of conspecific seedlings of both species. In both species, herbivory rates decreased with distance in low‐density areas. This study indicates that dipterocarp species experienced weak Janzen–Connell effects of distance and density dependence at the growth stage studied. Future studies in this system might focus on earlier life‐history stages such as seeds and small seedlings, as well as studying mortality during mast‐seeding events.
Synthesis and Crystal Structure of the Zinc Borate Zn3B4O9
Authors: Ziegler Raimund , Seibald Markus , Stoll Christiane , Huppertz Hubert
Published: April 2023

The new zinc borate Zn3B4O9was synthesized at high‐pressure/high‐temperature conditions of 10 GPa and 1173 K in a Walker‐type multianvil pressure device. It crystallizes in the space groupP(no. 2) witha=5.5028(2) Å,b=6.7150(3) Å,c=7.8887(3) Å,α=83.99(1)°,β=73.38(1)°,γ=74.75(1)°,V=269.35(2) Å3, and two formula units (Z=2) per unit cell. The structure was confirmed via single‐crystal X‐ray diffraction. Zn3B4O9can be synthesized phase pure, which is shown with a Rietveld refinement. IR‐spectroscopic data of a powder sample were collected.
FKBP5 blockade may provide a new horizon for the treatment of stress‐associated disorders: An in‐silico study
Authors: Asadi‐Pooya Ali A. , Malekpour Mahdi , Zamiri Bardia , Kashkooli Mohammad , Firouzabadi Negar
Published: April 2023

Objective

We searched for, from the FDA (Food and Drug Administration‐USA)‐approved drugs, inhibitors of FKBP5 with tolerable adverse effect profiles (eg, mild headache, sedation, etc.) and with the ability to cross the blood brain barrier (BBB), using bio‐informatics tools (in‐silico). This may pave the road for designing clinical trials of such drugs in patients with functional seizures (FS) and other stress‐associated disorders.

Methods

Several databases were used to find all the approved drugs that potentially have interactions with FKBP51 protein [ie, CTD gene‐chemical interaction section of FKBP51 protein of Harmonizome of Mayaanlab, DrugCenteral database, PDID (Protein Drug Interaction Database), DGIdb (the Drug Gene Interaction database)]. Other databases were also searched [eg, clinicaltrials.gov; DRUGBANK (the FASTA format of the FKBP51 protein was imported to the target sequencing section of the database to find the associated drugs), and the STITCH database (to find the related chemical interaction molecules)].

Results

After a comprehensive search of the designated databases, 28 unique and approved drugs were identified. Fluticasone propionate and Mifepristone and Ponatinib, Mirtazapine, Clozapine, Enzalutamide, Sertraline, Prednisolone, Fluoxetine, Dexamethasone, Clomipramine, Duloxetine, Citalopram, Chlorpromazine, Nefazodone, and Escitalopram are inhibitors of FKBP5 and have BBB permeability.

Significance

While the current in‐silico repurposing study could identify potential drugs (that are already approved and are widely available) for designing clinical trials in patients with stress‐associated disorders (eg, FS), any future clinical trial should consider the pharmacological profile of the desired drug and also the characteristics and comorbidities of the patients in order to foster a success.
The sequence kernel association test for multicategorical outcomes
Authors: Jiang Zhiwen , Zhang Haoyu , Ahearn Thomas U. , Garcia‐Closas Montserrat , Chatterjee Nilanjan , Zhu Hongtu , Zhan Xiang , Zhao Ni
Published: April 2023

Disease heterogeneity is ubiquitous in biomedical and clinical studies. In genetic studies, researchers are increasingly interested in understanding the distinct genetic underpinning of subtypes of diseases. However, existing set‐based analysis methods for genome‐wide association studies are either inadequate or inefficient to handle such multicategorical outcomes. In this paper, we proposed a novel set‐based association analysis method, sequence kernel association test (SKAT)‐MC, the sequence kernel association test for multicategorical outcomes (nominal or ordinal), which jointly evaluates the relationship between a set of variants (common and rare) and disease subtypes. Through comprehensive simulation studies, we showed that SKAT‐MC effectively preserves the nominal type I error rate while substantially increases the statistical power compared to existing methods under various scenarios. We applied SKAT‐MC to the Polish breast cancer study (PBCS), and identified gene FGFR2 was significantly associated with estrogen receptor (ER)+ and ER− breast cancer subtypes. We also investigated educational attainment using UK Biobank data () with SKAT‐MC, and identified 21 significant genes in the genome. Consequently, SKAT‐MC is a powerful and efficient analysis tool for genetic association studies with multicategorical outcomes. A freely distributed R package SKAT‐MC can be accessed at https://github.com/Zhiwen-Owen-Jiang/SKATMC.
Risk selection reduces efficiency of value‐based healthcare
Authors: Leao Diogo L. L. , Pavlova Milena , Groot Wim
Published: April 2023

Value‐based healthcare aims to improve efficiency and value for patients. Value‐based payment models are a form of provider reimbursement to achieve this. Studies on these models have found positive results, but may be biased by unintended consequences, such as risk selection. Risk selection is a multi‐dimensional phenomenon that occurs at the patient, hospital, and system level, and is a source of inefficiency and inequality in healthcare. Risk selection may occur because of selection bias in the outcomes that are evaluated and rewarded, or due to the selection of lower cost patients. Risk selection may also stem from professional reputation. The motivation to engage in risk selection may also arise from differences in the meaning of value. To mitigate these unintended consequences, several strategies can be adopted. These include making value‐based payment models attractive, but not mandatory, as well as incentivising transparent reporting of best practices, using adequate risk adjustment, expanding performance metrics, and including patient‐reported experience measures. Other mitigation strategies could include adopting a mixture of performance measures, using mixed methods of paying physicians, and implementing monitoring and evaluation mechanisms. However, such approaches are not flawless, and the problem may never be fully solved. This perspective serves as a warning for the constant presence of risk selection, as well as informing policy makers, politicians, and organisations implementing VBP models on ways to minimise the possibility of risk selection.
Socioeconomic and residence‐based related inequality in childhood vaccination in Sub‐Saharan Africa: Evidence from Benin
Authors: Budu Eugene , Ahinkorah Bright O. , Guets Wilfried , Ameyaw Edward K. , Essuman Mainprice A. , Yaya Sanni
Published: April 2023

Background and Aims

Childhood vaccination remains a cost‐effective strategy that has expedited the control and elimination of numerous diseases. Although coverage of new vaccines in low‐ and middle‐income countries increased exponentially in the last two decades, progress on expanding routine vaccination services to reach all children remains low, and coverage levels in many countries remains inadequate. This study aimed to examine the pattern of wealth and residence‐based related inequality in vaccination coverage through an equity lens.

Methods

We used data from the 2017−2018 Benin Demographic and Health Survey. Statistical and econometrics modeling were used to investigate factors associated with childhood vaccination. The Wagstaff decomposition analysis was used to disentangle the concentration index.

Results

A total of 1993 children were included, with 17% in the wealthiest quintile and 63% were living in rural areas. Findings showed that wealth is positively and significantly associated with vaccination coverage, particularly, for middle‐wealth households. A secondary or higher education level of women and partners increased the odds of vaccination compared to no education (p < 0.05). Women with more antenatal care visits, with multiple births, attending postnatal care and delivery in a health facility had increased vaccination coverage (p < 0.01). Inequalities in vaccination coverage are more prominent in rural areas; and are explained by wealth, education, and antenatal care visits.

Conclusion

Inequality in child vaccination varies according to socioeconomic and sociodemographic characteristics and is of interest to health policy. To mitigate inequalities in child vaccination coverage, policymakers should strengthen the availability and accessibility of vaccination and implement educational programs dedicated to vulnerable groups in rural areas.
Gender‐based reasoning about novel toys: The role of child and parental factors
Authors: Lam Virginia L.
Published: April 2023

Much has been established about children's preference for gender‐typed toys, but far less is known about their reasoning about novel toys. Using such toys, this study explored children's emerging use of gender to make predictions about peers as a form of stereotype construction with its correlates. Two to 4‐year‐olds were shown novel, nonstereotyped toys and asked if they and others would like each item. Gender‐typing was measured by liking for familiar gender‐typed toys, and categorization skills by sorting. Parents completed measures on gender language and behavioural expectations. It was found that gender‐centric reasoning (what children like, they expect same‐gender peers but not other‐gender peers to like) was apparent from age 3 years, with boys showing a higher tendency. Apart from age in months, categorization skills and parental behavioural expectations uniquely contributed to children's degree of gender‐centrism. The findings are discussed in relation to cognitive development, parental gender socialization, stereotype formation and practical implications.

Highlights

From age 3, children tend to predict peers' liking for novel, nonstereotyped toys based on their own and peers' gender as a form of stereotype construction.

Older boys are more likely to differentiate between their own novel toy‐liking and that of outgroup peers (girls) compared to girls.

Children's categorization skills and their parents' behavioural expectations contribute to gender‐based reasoning, giving scope for interventions based on modifiable factors.
Risk factors for retained placenta in a first pregnancy—A clinical trial
Authors: Cohen Gal , Kovo Michal , Biron‐Shental Tal , Markovitch Ofer , Daykan Yair , Schreiber Hanoch
Published: April 2023

Objective

To evaluate potential risk factors for retained placenta in a first pregnancy.

Method

This retrospective case–control study included all primigravida with a singleton, live, vaginal birth at 24 weeks or later, at a tertiary hospital, 2014–2020. The cohort was divided into those with retained placenta versus controls. Retained placenta was defined as the need for manual extraction of the placenta or portions of it, immediately postpartum. Maternal and delivery characteristics, and obstetric and neonatal adverse outcomes, were compared between groups. Multivariable regression was performed to reveal potential risk factors for retained placenta.

Results

Among 10 796 women, 435 (4.0%) had retained placenta and 10 361 (96.0%) controls did not. Multivariable logistic regression revealed nine potential risk factors for retained placenta: abruption (adjusted odds ratio [aOR] 3.58, 95% confidence interval [CI] 2.36–5.43), hypertensive disorders (aOR 1.74, 95% CI 1.17–2.57), prematurity (<37 weeks, aOR 1.63, 95% CI 1.13–2.35), maternal age older than 30 years (aOR 1.55, 95% CI 1.27–1.90), intrapartum fever (aOR 1.48, 95% CI 1.03–2.11), lateral placentation (aOR 1.39, 95% CI 1.01–1.91), oxytocin administration (aOR 1.39, 95% CI 1.11–1.74), diabetes mellitus (aOR 1.35, 95% CI 1.01–1.79), and female fetus (aOR 1.26, 95% CI 1.03–1.53).

Conclusion

Retained placentas in first deliveries are associated with obstetric risk factors, some of which could be related to abnormal placentation.
The association between normal 50‐g glucose challenge test results and risk for future metabolic morbidities: A retrospective cohort study
Authors: Vinograd Adi , Wainstock Tamar , Sergienko Ruslan , Simon‐Tuval Tzahit , Yoles Israel
Published: April 2023

Objective

To study the association between normal glucose challenge test (GCT) results during pregnancy and the incidence of future maternal metabolic morbidities.

Method

This was a population‐based retrospective cohort study conducted between the years 2005 and 2020. The study included all women aged 17–55 years who underwent GCT as part of the routine prenatal care at the Central District of Clalit Health Services, Israel. The highest GCT result per woman was categorized into five study groups: <120 (reference), 120–129, 130–139, 140–149, and ≥150 mg/dL. Adjusted hazard ratios of the study groups for metabolic morbidities were calculated with Cox proportional survival analysis models.

Results

Among a total of 77 568 women participants, 53%, 12.3%, and 10.3% had normal GCT results of <120, 120–129, and 130–139 mg/dL, respectively. During the study period of 6.07 ± 4.35 years, 13 151 (17.0%) cases of metabolic morbidities were documented. High‐normal GCT results of 120–129 and 130–139 mg/dL were significantly associated with increased risk for future metabolic morbidity compared with <120 mg/dL (adjusted hazard ratio [aHR] 1.15, 95% confidence interval [CI] 1.08–1.22 and aHR 1.32, 95% CI 1.24–1.41, respectively).

Conclusion

Although GCT is only recommended as a screening tool for gestational diabetes mellitus, high results, even within the normal range, may point to maternal increased risk for future metabolic morbidity.
A comparison of synchronous and noncontingent stimulus delivery on task engagement
Authors: Hardesty Elizabeth M. , Lerman Dorothea C. , Hardee Jordan L.
Published: April 2023

Synchronous schedules of reinforcement are those in which the onset and offset of a reinforcer are synchronized with the onset and offset of a target behavior. The current study replicated and extended Diaz de Villegas et al. (2020) by comparing synchronous reinforcement to noncontingent stimulus delivery while evaluating on‐task behavior of school‐age children. A concurrent‐chains preference assessment was then used to determine the preferred schedule. Results indicated that the synchronous schedule was more effective than the continuous, noncontingent delivery of the stimulus at increasing on‐task behavior but that the children preferred noncontingent delivery. Additionally, the use of synchronous and noncontingent delivery did not alter the children's preference for the task.
Evaluation of interfacial adaptation and penetration of bioceramic‐based sealers in oval root canals: A confocal laser scanning microscope study
Authors: Chew Soo Teng , Eshak Zolkapli , Al‐Haddad Afaf
Published: April 2023

To assess the interfacial adaptation and penetration depth of three different bioceramic‐based sealers (CeraSeal, EndoSeal MTA, Nishika Canal Sealer BG) compared to an epoxy resin‐based sealer (AH Plus) in oval root canals. Fourty extracted single‐rooted mandibular premolar with oval canal were prepared and randomly allocated according to the obturation into; CeraSeal, EndoSeal MTA, Nishika Canal Sealer BG and AH Plus. The roots were sectioned at 3, 6 and 9 mm from the apex. The sealer adaptation and the penetration depth were evaluated under confocal laser scanning microscope. One‐way ANOVA and Repeated measure ANOVA were used to statistically analyze the data. Nishika Canal Sealer BG showed significantly higher sealer adaptation than EndoSeal MTA (P < .001) at apical and middle thirds. Meanwhile, AH Plus showed significantly higher sealer adaptation than EndoSeal MTA (P = 0.011) at middle third. For sealer penetration, Nishika Canal Sealer BG showed the longest sealer penetration that was significant compared to AH Plus (P < .001) and EndoSeal MTA (P < .001) whereas CeraSeal was significantly higher than EndoSeal MTA (P = 0.029) at coronal third. For AH Plus, there was a significant less sealer penetration at coronal third compared to apical and middle thirds (P < .05). Whereas for EndoSeal MTA, the coronal third has significant less penetration compared to the middle third (P = 0.032). Endoseal has the lowest adaptation and penetration depth. Nishika Canal Sealer BG has better adaptation and penetration depth using single cone obturation technique in oval canal.

Research Highlights

All the tested root canal sealers have some percentage of gaps and vary in their penetration capability into dentinal tubules.

Nishika Canal Sealer BG has significantly better sealer adaptation to root dentinal walls than that of EndoSeal MTA at the apical and middle third but not significantly different from other type of sealers used.

Nishika Canal Sealer BG has significantly better penetration depth than AH Plus and EndoSeal MTA at the coronal third of radicular dentin.
Advances in therapies for neurological lysosomal storage disorders
Authors: Ellison S. , Parker H. , Bigger B.
Published: April 2023

Lysosomal Storage Disorders (LSDs) are a diverse group of inherited, monogenic diseases caused by functional defects in specific lysosomal proteins. The lysosome is a cellular organelle that plays a critical role in catabolism of waste products and recycling of macromolecules in the body. Disruption to the normal function of the lysosome can result in the toxic accumulation of storage products, often leading to irreparable cellular damage and organ dysfunction followed by premature death. The majority of LSDs have no curative treatment, with many clinical subtypes presenting in early infancy and childhood. Over two‐thirds of LSDs present with progressive neurodegeneration, often in combination with other debilitating peripheral symptoms. Consequently, there is a pressing unmet clinical need to develop new therapeutic interventions to treat these conditions. The blood–brain barrier is a crucial hurdle that needs to be overcome in order to effectively treat the central nervous system (CNS), adding considerable complexity to therapeutic design and delivery. Enzyme replacement therapy (ERT) treatments aimed at either direct injection into the brain, or using blood–brain barrier constructs are discussed, alongside more conventional substrate reduction and other drug‐related therapies. Other promising strategies developed in recent years, include gene therapy technologies specifically tailored for more effectively targeting treatment to the CNS. Here, we discuss the most recent advances in CNS‐targeted treatments for neurological LSDs with a particular emphasis on gene therapy‐based modalities, such as Adeno‐Associated Virus and haematopoietic stem cell gene therapy approaches that encouragingly, at the time of writing are being evaluated in LSD clinical trials in increasing numbers. If safety, efficacy and improved quality of life can be demonstrated, these therapies have the potential to be the new standard of care treatments for LSD patients.
Maternal and fetal outcomes in acute hepatic porphyria: A Swedish National Cohort Study
Authors: Mantel Ängla , Vassiliou Daphne , Lissing Mattias , Stephansson Olof , Wahlin Staffan , Sardh Eliane
Published: April 2023

Current knowledge of pregnancy and perinatal outcomes in women with acute hepatic porphyria (AHP) is largely based on biochemical disease models, case reports, and case series. We performed a nationwide, registered‐based cohort study to investigate the association between maternal AHP and the risk of adverse pregnancy and perinatal outcomes. All women in the Swedish Porphyria Register with confirmed AHP aged 18 years or older between 1987 and 2015 and matched general population comparators, with at least one registered delivery in the Swedish Medical Birth Register were included. Risk ratios (RRs) of pregnancy complications, delivery mode and perinatal outcomes were estimated and adjusted for maternal age at delivery, area of residency, birth year and parity. Women with acute intermittent porphyria (AIP), the most common form of AHP, were further categorized according to maximal lifetime urinary porphobilinogen (U‐PBG) levels. The study included 214 women with AHP and 2174 matched comparators. Women with AHP presented with a higher risk for pregnancy‐induced hypertensive disorder (aRR 1.73, 95% CI 1.12–2.68), gestational diabetes (aRR 3.41, 95% CI 1.69–6.89), and small‐for‐gestational‐age birth (aRR 2.08, 95% CI 1.26–3.45). In general, RRs were higher among women with AIP who had high lifetime U‐PBG levels. Our study shows an increased risk for pregnancy induced hypertensive disease, gestational diabetes, and small for gestational age births for AHP women, with higher relative risks for women with biochemically active AIP. No increased risk for perinatal death or malformations was observed.
Phenotypic prediction in glutaric aciduria type 1 combining in silico and in vitro modeling with real‐world data
Authors: Yuan Yuheng , Dimitrov Bianca , Boy Nikolas , Gleich Florian , Zielonka Matthias , Kölker Stefan
Published: April 2023

Glutaric aciduria type 1 (GA1) is caused by inherited deficiency of glutaryl‐CoA dehydrogenase (GCDH). To further understand the unclear genotype–phenotype correlation, we transfected mutated GCDH into COS‐7 cells resembling known biallelic GCDH variants of 47 individuals with GA1. In total, we modeled 36 genotypes with 32 missense variants. Spectrophotometry demonstrated an inverse correlation between residual enzyme activity and the urinary concentration of glutaric acid and 3‐hydroxyglutaric acid, confirming previous studies (Pearson correlation, r = −0.34 and r = −0.49, p = 0.045 and p = 0.002, respectively). In silico modeling predicted high pathogenicity for all genotypes, which caused a low enzyme activity. Western blotting revealed a 2.6‐times higher GCDH protein amount in patients with an acute encephalopathic crisis (t‐test, p = 0.015), and high protein expression correlated with high in silico protein stability (Pearson correlation, r = −0.42, p = 0.011). The protein amount was not correlated with the enzyme activity (Pearson correlation, r = 0.09, p = 0.59). To further assess protein stability, proteolysis was performed, showing that the p.Arg88Cys variant stabilized a heterozygous less stable variant. We conclude that an integration of different data sources helps to predict the complex clinical phenotype in individuals with GA1.