bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of clinical efficacy after PKP in patients of different genders
Authors: Yang Bo , Zhao Yangxue , Zhao Yu
Published: November 2022

Objective:

To investigate the clinical efficacy of Percutaneous Kyphoplasty (PKP) in male and female patients.

Method:

The clinical data of patients treated with PKP in our hospital from January 2018 to October 2020 were analyzed retrospectively. These patients were divided into female group and male group according to gender differences. The visual analogue scale (VAS) and activity function score (LAS) were recorded before operation, immediately after operation and 1 year after operation, and postoperative complications such as cement leakage and recurrent vertebral fracture were recorded. The above observation indexes between the 2 groups were statistically compared.

Results:

A total of 171 patients (118 in female group and 53 in male group) were included. There was no other difference between the 2 groups except that thoracic vertebral fracture was more common in women (P < .05). The VAS of female group and male group were (7.14 ± 0.61) and (7.11 ± 0.51) before operation, (3.05 ± 0.66) and (2.89 ± 0.64) after operation, 1 year after operation (1.10 ± 0.50) and (1.02 ± 0.37). There was no difference in each period between the 2 groups (P > .05). But there was a significant decrease after operation, which was recognized between the 2 groups (P < .05); The activity scores of female group and male group were (3.08 ± 0.48) and (3.07 ± 0.43) before operation, (1.86 ± 0.42) and (1.85 ± 0.50) after operation, 1 year after operation (1.01 ± 0.92) and (1.02 ± 0.14). There was no difference in each period between the 2 groups (P > .05). But there was a significant decrease after operation, which was recognized between the 2 groups (P < .05). Postoperative cement leakage was revealed in 21 cases (12.28%), 16 cases (13.56%) in female group and 5 cases (9.43%) in male group, which was no significant difference between the 2 groups. During the 1-year follow-up, postoperative recurrent vertebral fracture was revealed in 4 cases (2.34%), 2 cases (1.69%) in the female group and 2 case (3.77%) in the male group, which was also no significant difference between the 2 groups.

Conclusion:

Patients treated with PKP can immediately get pain relief and activity function improvement. PKP is a safe and effective minimally invasive surgery for both female and male patients.
Facilitating the transition from paediatric to adult care in endocrinology: a focus on growth disorders
Authors: Vakharia Janaki D. , Stanley Takara L.
Published: November 2022

Purpose of review

Many childhood-onset growth disorders (COGDs) require continued care into adulthood, and the time of transition between paediatric and adult providers carries a high risk for interruptions in medical care and consequent worsening of disease management.

Recent findings

Research into best practices for healthcare transition (HCT) describes three distinct stages. Stage 1, transition planning and preparation, begins in the paediatric setting during early adolescence and ensures that the patient has adequate medical knowledge, self-management skills, and readiness for transition. Stage 2, transfer to adult care, occurs with variable timing depending on transition readiness and is best facilitated by warm hand-offs and, when possible, joint visits with the paediatric and adult provider(s) and/or involvement of a care coordinator. Stage 3, intake and integration into adult care, entails retaining the patient in the adult setting, ideally through the involvement of a multidisciplinary approach.

This review covers general principles for ensuring smooth transition of adolescents and young adults (AYA) with COGD, disease-specific medical considerations for paediatric and adult endocrinologists during the transition process, and general and disease-specific resources to assess transition readiness and facilitate transition.
Pharmacokinetic Modeling of Optimized Midazolam and Pentobarbital Dosing Used in Treatment Protocols of Refractory Status Epilepticus
Authors: Luchette Matthew , LaRovere Kerri , Au Cheuk C. , Tasker Robert C. , Akhondi-Asl Alireza
Published: November 2022

OBJECTIVES:

To model bolus dosing, infusion rate, and weaning rate on theoretical serum concentration of midazolam and pentobarbital used in the treatment of refractory status epilepticus (RSE).

DESIGN:

One- and two-compartment in silico pharmacokinetic models of midazolam and pentobarbital.

SETTING:

Not applicable.

SUBJECTS:

Not applicable.

INTERVENTIONS:

We compared the model variables used in midazolam and pentobarbital protocols for standard RSE.

MEASUREMENTS AND MAIN RESULTS:

Standard RSE treatment protocols result in steady-state serum concentrations that are 6.2–9.0-fold higher for the one-compartment model and 2.3–4.7-fold higher for the two-compartment model. In the model, not including bolus doses delays the achievement of serum steady-state concentration by 0.5 and 2.7 hours for midazolam and pentobarbital, respectively. Abrupt discontinuation of these medications reduces modeled medication exposure by 1.1 and 6.4 hours, respectively.

CONCLUSIONS:

Our in silico pharmacokinetic modeling of standard midazolam and pentobarbital dosing protocols for RSE suggests potential variables to optimize in future clinical studies.
Financial Health of Private Equity-Backed Ophthalmology and Optometry Groups: an Analysis of Debt Valuations
Authors: Desai Sarishka , Memon Rohail , Chen Evan , Patil Sachi , Vail Daniel , Konda Sailesh , Parikh Ravi
Published: November 2022

Purpose

To identify debt valuations of ophthalmology and optometry private equity-backed group (OPEG) practices, which are a proxy for financial performance.

Design

Retrospective cohort study using the 2021 Business Development Company (BDC) Report and BDC quarterly/annual filings.

Participants

BDCs holding one or more ophthalmology/optometry group debt instruments.

Methods

The 2021 BDC Report was used to identify all BDCs actively filing annual reports (Form 10-Ks) and quarterly reports (Form 10-Qs) in 2021. The public filings of BDCs lending to OPEGs were searched from inception of an OPEG’s debt instrument in a BDC’s portfolio, and the amortized cost and fair value of each debt instrument were tabulated. A panel linear regression was used to evaluate temporal changes in debt valuations.

Main Outcome Measures

Trends in total debt held by OPEGs, trends in valuation (premium or discount) of OPEGs.

Results

A total of 2997 practice locations affiliated with 14 unique OPEGs and 17 BDCs were identified in 2021. Debt valuations of OPEGs decreased 0.46% per quarter over the study period (95% CI: −0.88 to −0.03, P = 0.036). In the COVID-19 pre-vaccine period (March 2020 – December 2020), there was an excess (additional) 4.93% decrease in debt valuations (95% CI: − 8.63 to −1.24, P = 0.010) when compared to prepandemic debt valuations (March 2017 – December 2019). Effects of COVID-19 on valuations stabilized during the pandemic post-vaccine period (February 2021 – March 2022), with no change in excess debt valuation compared to pre-pandemic baseline (0.60, 95% CI: −4.59 to 5.78, P = 0.822). There was an increase in practices that reported average discounted debt valuations from 20 practices (1.6%) associated with 1 OPEG to 1213 practices (40.5%) (including 100% of newly acquired practices) associated with 9 OPEGs, despite stabilization of COVID-19 related excess (additional) debt.

Conclusions

Valuations of OPEG debt have declined significantly post-PE investment from March 2017 to March 2022. An excess (additional) decline in valuations was observed during the COVID pre-vaccine period, with trends in excess debt valuations returning to baseline pre-pandemic levels by December 2021. Declining and discounted valuations of debt raise concerns about the financial viability of many PE-backed practices.
Family experiences during illness outbreaks: A systematic review
Authors: Sheen J. , Chen L. , Lee B. , Aridas A. , Reupert A.
Published: November 2022

Background

During the pandemic and associated lockdowns, many families from around the world experienced financial and confinement stress and the reorganisation of family caregiving responsibilities. Several studies have been conducted about the impact of the pandemic on family wellbeing. The aim of this systematic review was to identify, synthesize and critique relevant studies in this field.

Methods

Following Cochrane Collaboration and PRISMA guidelines, a systematic search was performed in databases including MEDLINE, PsycINFO, Embase, SocINDEX and PubMed. Peer-reviewed studies that examined the experiences of families during infectious disease outbreaks were included. Quality assessment was undertaken using the Mixed Methods Appraisal Tool. A narrative synthesis approach was employed.

Results

Eighty-four papers were found, all conducted during the Covid-19 pandemic, with the majority from the USA and presented from the perspective of parents/caregivers. Synthesized results focused on how family experiences, the dyad relationship and parenting behaviours were impacted during Covid-19.

Conclusion

Although some families reported positive growth, socially and financially vulnerable families were more negatively impacted than others during the pandemic. The review highlights the important role of families during times of stress and possible intervention targets.
A conserved sequence inDrosophilaArgonaute1 mRNA contributes to stress response via inducing miR-999 degradation
Authors: Sheng Peike , Li Lu , Li Tianqi , Wang Yuzhi , Hiers Nicholas M. , Mejia Jennifer S. , Sanchez Jossie S. , Zhou Lei , Xie Mingyi
Published: November 2022

MicroRNAs (miRNAs) load onto Argonaute (AGO) proteins and target messenger RNAs (mRNA) to directly suppress gene expression at the post-transcriptional level. However, miRNA degradation can be triggered when there is extended base-pairing between miRNAs and the target RNAs. Such base-pairing can induce confirmational change of AGO and recruitment of ZSWIM8 ubiquitin ligase to mark AGO for proteasomal degradation, while the miRNAs are subsequently degraded. This target RNA-directed miRNA degradation (TDMD) mechanism appears to be an evolutionary conserved mechanism, but recent studies have focused on identifying endogenous TDMD events in the mammalian systems. Here, we performed AGO1-CLASH (crosslinking and sequencing of miRNA-mRNA hybrids) inDrosophilaS2 cells, withDora(ortholog of vertebrate ZSWIM8) knockout (KO) mediated by CRISPR-Cas9 to identify five TDMD triggers (sequences that can induce miRNA degradation). Interestingly, one trigger residing in the 3′ UTR ofAGO1mRNA induces miR-999 degradation. CRISPR-Cas9 KO of theAGO1trigger in S2 cells and inDrosophilaelevates miR-999 abundance, with concurrent repression of the miR-999 targets.AGO1trigger-KO flies respond poorly to hydrogen peroxide-induced stress, demonstrating the physiological importance of a single TDMD event.
Graphene-based thin film microelectrode technology forin vivohigh resolution neural recording and stimulation
Authors: Viana Damià , Walston Steven T. , Illa Xavier , Valle Jaume del , Hayward Andrew , Dodd Abbie , Loret Thomas , Prats-Alfonso Elisabet , de la Oliva Natàlia , Palma Marie , Corro Elena del , Rodríguez-Meana Bruno , Pilar Bernicola María del , Rodríguez-Lucas Elisa , Gener Thomas A. , de la Cruz Jose Manuel , Torres-Miranda Miguel , Duvan Fikret Taygun , Ria Nicola , Sperling Justin , Martí-Sánchez Sara , Spadaro Maria Chiara , Hébert Clément , Masvidal-Codina Eduard , Savage Sinead , Arbiol Jordi , Guimerà-Brunet Anton , Puig M. Victoria , Navarro Xavier , Yvert Blaise , Kostarelos Kostas , Garrido Jose A.
Published: November 2022

Neuroprosthetic technology aims to restore nervous system functionality in cases of severe damage or degeneration by recording and stimulating the electrical activity of the neural tissue. One of the key factors determining the quality of the neuroprostheses is the electrode material used to establish electrical communication with the neural tissue, which is subject to strict electrical, electrochemical, and mechanical specifications as well as biological and microfabrication compatibility requirements. This work presents a nanoporous graphene-based thin film technology and its engineering to form flexible neural implants. Bench measurements show that the developed microelectrodes offer low impedance and high charge injection capacity throughout millions of pulses. In vivo electrode performance was assessed in rodents both from brain surface and intracortically showing high-fidelity recording performance, while stimulation performance was assessed with an intrafascicular implant that demonstrated low current thresholds and high selectivity for activating subsets of axons within the sciatic nerve. Furthermore, the tissue biocompatibility of the devices was validated by chronic epicortical and intraneural implantation. Overall, this works describes a novel graphene-based thin film microelectrode technology and demonstrates its potential for high-precision neural interfacing in both recording and stimulation applications.
Contribution of the collective excitations to the coupled proton and energy transport along mitochondrial crista membrane in oxidative phosphorylation system
Authors: Nesterov Semen V. , Yaguzhinsky Lev S. , Vasilov Raif G. , Kadantsev Vasiliy N. , Goltsov Alexey N.
Published: November 2022

The results of many experimental and theoretical works indicate that after transport of protons across the mitochondrial inner membrane (MIM) in oxidative phosphorylation system (OXPHOS), they are retained on the membrane-water interface in non-equilibrium state with free energy excess due to low proton surface-to-bulk release. This well-established phenomenon suggests that proton trapping on the membrane interface ensures vectorial lateral transport of protons from proton pumps to ATP synthases (proton acceptors). Despite the key role of the proton transport in bioenergetics, the molecular mechanism of proton transfer in the OXPHOS system is not yet completely established. Here, we developed a dynamics model of long-range transport of energized protons along the MIM accompanied by collective excitation of localized wave proragating on the membrane surface. Our model is based on the new data on the macromolecular organization of OXPHOS showing the well-ordered structure of respirasomes and ATP synthases on the cristae membrane folds. We developed a two-component dynamics model of the proton transport considering two coupled subsystems: the ordered hydrogen bond (HB) chain of water molecules and lipid headgroups of MIM. We analytically obtained two-component soliton solution in this model, which describes the motion of the proton kink, corresponding to successive proton hops in the HB chain, and coherent motion of a compression soliton in the chain of lipid headgroups. The local deformation in a soliton range facilitates proton jumps due to water molecules approaching each other in the HB chain. We suggested that the proton-conducting structures formed along the cristae membrane surface promote direct lateral proton transfer in the OXPHOS system. Collective excitations at the water-membrane interface in a form of two-component soliton ensure the coupled non-dissipative transport of charge carriers and elastic energy of MIM deformation to ATP synthases that may be utilized in ATP synthesis providing maximal efficiency in mitochondrial bioenergetics.
A dynamic atlas of immunocyte migration from the gut
Authors: Galván-Peña Silvia , Zhu Yangyang , Hanna Bola S. , Mathis Diane , Benoist Christophe
Published: November 2022

Dysbiosis in the gut microbiota impacts several systemic diseases. One possible mechanism is the migration of perturbed intestinal immunocytes to extra-intestinal tissues. Combining the Kaede photoconvertible mouse model and single-cell genomics, we generated a detailed map of migratory trajectories from the colon, at baseline and during intestinal and extra-intestinal inflammation. All colonic lineages emigrated from the colon in an S1P-dependent manner, dominated by B lymphocytes with a large continuous circulation of follicular B cells, which carried a gut-imprinted transcriptomic signature. T cell emigration was more selective, with distinct groups of RORγ+or IEL-like CD160+cells in the spleen. Gut inflammation curtailed emigration, except for DCs disseminating to lymph nodes. Colon emigrating cells distributed differentially to tumor, skin inflammation, or arthritic synovium, the former dominated by myeloid cells in a chemokine-dependent manner. These results thus reveal specific cellular trails originating in the gut, influenced by microbiota, which can shape peripheral immunity.
Phase transition of tensin-1 during the focal adhesion disassembly and cell division
Authors: Lee Yuh-Ru Julie , Yamada Soichiro , Lo Su Hao
Published: November 2022

Biomolecular condensates are non-membranous structures that are mainly formed through liquid-liquid phase separation. Tensins are focal adhesion (FA) proteins linking the actin cytoskeleton to integrin receptors. Here we report that GFP-tagged tensin-1 (TNS1) proteins at physiological levels phase separate to form biomolecular condensates in TNS1 knockout cells. Live cell imaging showed that new TNS1 condensates are budding from the disassembling ends of FAs, and presence of these condensates is cell cycle dependent. TNS1 condensates dissolve immediately prior to mitosis and rapidly reappear while post-mitotic daughter cells establish new FAs. TNS1 condensates contain selected FA proteins and signaling molecules such as pT308Akt but not pS473Akt, suggesting previously unknown roles of TNS1 condensates in disassembling FAs, as the storage of core FA components and the signaling intermediates.
Genome-wide libraries for protozoan pathogens drug target screening using yeast surface display
Authors: Heslop Rhiannon , Gao Mengjin , Lira Andressa Brito , Sternlieb Tamara , Loock Mira , Sanghi Sahil Rao , Cestari Igor
Published: November 2022

The lack of genetic tools to manipulate protozoan pathogens has limited the use of genome-wide approaches to identify drug or vaccine targets and understand these organisms’ biology. We have developed an efficient method to construct genome-wide libraries for yeast surface display (YSD) and developed a YSD fitness screen (YSD-FS) to identify drug targets. We show the robustness of our method by generating genome-wide libraries forTrypanosoma brucei, Trypanosoma cruzi, andGiardia lambliaparasites. Each library has a diversity of ∼105to 106clones, representing ∼6 to 30-fold of the parasite’s genome. Nanopore sequencing confirmed the libraries’ genome coverage with multiple clones for each parasite gene. Western blot and imaging analysis confirmed surface expression of theG. lamblialibrary proteins in yeast. Using the YSD-FS assay, we identified bonafide interactors of metronidazole, a drug used to treat protozoan and bacterial infections. We also found enrichment in nucleotide-binding domain sequences associated with yeast increased fitness to metronidazole, indicating that this drug might target multiple enzymes containing nucleotide-binding domains. The libraries are valuable biological resources for discovering drug or vaccine targets, ligand receptors, protein-protein interactions, and pathogen-host interactions. The library assembly approach can be applied to other organisms or expression systems, and the YSD-FS assay might help identify new drug targets in protozoan pathogens.
Context-induced renewal of passive but not active coping behaviours in the shock-probe defensive burying task
Authors: Brown Alexa , Martins Melissa , Richard Isabelle , Chaudhri Nadia
Published: November 2022

Renewal is the return of extinguished responding after removal from the extinction context. Renewal has been extensively studied using classical aversive conditioning procedures that measure a passive freezing response to an aversive conditioned stimulus. However, coping responses to aversive stimuli are complex and can be reflected in passive and active behaviours. Using the shock-probe defensive burying task, we investigated whether different coping responses are susceptible to renewal. During conditioning, male, Long-Evans rats were placed into a specific context (context A) where an electrified shock-probe delivered a 3 mA shock upon contact. During extinction, the shock-probe was unarmed in either the same (context A) or a different context (context B). Renewal of conditioned responses was assessed in the conditioning context (ABA) or in a novel context (ABC or AAB). Renewal of passive coping responses, indicated by an increased latency and a decreased duration of shock-probe contacts, was observed in all groups. However, renewal of passive coping, measured by increased time spent on the side of the chamber opposite the shock-probe, was only found in the ABA group. Renewal of active coping responses linked to defensive burying was not observed in any group. The present findings highlight the presence of multiple psychological processes underlying even basic forms of aversive conditioning and demonstrate the importance of assessing a broader set of behaviours to tease apart these different underlying mechanisms. The current findings suggest that passive coping responses may be more reliable indicators for assessing renewal than active coping behaviours associated with defensive burying.
Board governance and audit report lag in the light of big data adoption: the case of Egypt
Authors: Ahmed Hussein Mohsen Saber , El-Halaby Sherif , Albitar Khaldoon
Published: November 2022

Purpose

This paper aims to examine the mediating role of big data adoption (BDA) on the association between board governance (BG) and audit report lag (ARL).

Design/methodology/approach

This study uses data extracted from financial reports for a sample from EGX100 over the period from 2015 to 2019. This study applies content analysis approach to measure the level of BDA. This study uses ordinary least squares, structure equation modelling and principal component analysis to investigate the relationship between BG, BDA and ARL.

Findings

The findings indicate that BDA can be used as a predictor of ARL for companies listed on the Egyptian stock exchange. The results show that board diversity has a significant effect on ARL when BDA is used as a mediator.

Research limitations/implications

This study only includes technology, telecommunications and health-care industries in the sample.

Practical implications

This paper raises investor and stakeholder awareness for the importance of BDA and corporate governance (CG) procedures in reducing audit report delays in developing countries such as Egypt. This study can assist regulators in developing audit report requirements and enforcing regulations to guarantee timely audit report publication.

Originality/value

This paper provides a shred of unique evidence on the role of BDA in mediating the relationship between BG and ARL in a developing country.
A new acoustically insulating fiber-reinforced lightweight concrete based on local materials and date palm waste
Authors: Boucedra Aissa , Bederina Madani
Published: November 2022

Purpose

This paper aims to characterize and develop a new ecological lightweight concrete reinforced by addition of palm plant fibers (from vegetal waste) to be used in the thermal and acoustical insulation of local constructions. The date palm plant fibers are characterized by their low sensitivity to chemical reactions, low cost and large availability in local regions. Therefore, the newly obtained lightweight concrete may suggest a great interest, as it seems to be able to achieve good solutions for local construction problems, technically, economically and ecologically.

Design/methodology/approach

The experimental program focused on developing the composition of palm-fiber-reinforced concrete, by studying the effect of the length of the fibers (10, 20, 30 and 40 mm) and their mass percentage (0.5%, 1%, 1.5% and 2%), on the mechanical and acoustical properties of the composite. The main measured parameters were the compressive strength and flexural strength, sound absorption coefficient, noise reduction coefficient (NRC), etc. These tests were also borne out by the measure of density and water absorption, as well as microstructure analyses. To fully appreciate the behavior of the material, visualizations under optical microscope and scanning electron microscope analyses were carried out.

Findings

The addition of plant fibers to concrete made it possible to formulate a new lightweight concrete having interesting properties. The addition of date palm fibers significantly decreased the density of the concrete and consequently reduced its mechanical strength, particularly in compression. Acceptable compressive strength values were possible, according to the fibers content, while better values have been obtained in flexion. On the other hand, good acoustical performances were obtained: a considerable increase in the sound absorption coefficient and the NRC was recorded, according to the content and length of fibers. Even the rheological behavior has been improved with the addition of fibers, but with short fibers only.

Originality/value

Over the recent decades, many studies have attempted to search for more sustainable and environmentally friendly building materials. Therefore, this work aims to study the possibility of using waste from date palm trees as fibers in concrete instead of the conventionally used fibers. Although many researches have already been conducted on the effect of palm plant fibers on the mechanical/physical properties of concrete, no information is available neither on the formulation of this type of concrete nor on its acoustical properties. Indeed, due to the scarcity of raw materials and the excessive consumption of energy, the trend of plant fibers as resources, which are natural and renewable, is very attractive. It is therefore a major recycling project of waste and recovery of local materials.
It depends on personal networks: Feelings of stigmatisation among populist radical right party members
Authors: AMMASSARI SOFIA
Published: November 2022

Stigmatisation has been recognised as a major factor influencing the fortunes of populist radical right (PRR) parties. While scholars have examined it by taking parties as units of analysis, this study focuses on the individual level by asking Which PRR party members are more likely to feel stigmatised? After offering a novel theoretical explanation for feelings of stigmatisation based on the personal networks in which PRR grassroots members are embedded, it then investigates stigma using an original membership survey of about 7,000 members of the Sweden Democrats (SD) and interviews with 30 of them. The survey results show that the higher the educational qualification PRR grassroots members have achieved, the more likely they will feel stigmatised. In addition, those who have never had any relatives and/or friends in the SD, and those who are employed in the public sector, are more likely to consider membership discrediting. The interview data shed light on the survey results, by illustrating how public employees and university students find it hard to be open about their membership as they are surrounded by people with left‐wing views. By contrast, having relatives and/or friends who are members of the party reduces the stigma of joining PRR parties, becoming active in them, and talking about politics in public. Along with countering some of the prevailing wisdom about stigmatisation in PRR parties, the findings contribute to our understanding of PRR grassroots membership, which has long been an overlooked topic in the literature.
Comparison mitochondrial DNA DAMPs changes in platelet prepared by apheresis and PRP
Authors: Chegini Azita , Vakili Leila , Samiee Shahram , Shaiegan Mojgan
Published: November 2022

Introduction

Mt DNA (DAMPs) plays a key modulatory role in immune cells and may also mediate a variety of adverse transfusion reactions.

Material and Method

The cross‐sectional study was performed on 22 (PRP) and 14 (SDP) between February 2019 and 2020. mtDNA DAMPs by quantitative real‐time PCR was assessed on days 1, 3, and 5 of platelets storage. The data was entered in REST 2009 software, and the amount of fold change was calculated. Multiple t tests were also used.

Results

The mtDNA DAMPs fold change in SDP on days 1–3, 1.3 times, on days 3–5, 1.5 times, and on days 1–5, 2.1 times increased. The fold change on days 1–3, 0.8 times, on days 3–5, 0.6 times, and on days 1–5, 0.49 times decreased in PRP products.

Conclusion

The method of preparation and processing can affect mtDNA DAMPs fold changes.
Impact of folic acid on regulatory B lymphocytes from patients with systemic lupus erythematosus in vitro
Authors: Nikolova‐Ganeva Kalina , Vasilev Vasil , Kerezieva Simona , Tchorbanov Andrey
Published: November 2022

Background

Epigenetic modifications of genomes are of particular interest as numerous studies indicate the correlation between DNA methylation and the development of systemic lupus. As a major methyl group donor, folic acid is an important participant in this process. The aim of this study is to determine the effect of low or high dose folate co‐culturing with peripheral blood mononuclear cells (PBMCs) on the secretion of interleukin (IL)10 from regulatory cells from lupus patients or from healthy volunteers.

Methods

PBMCs from lupus patients and healthy volunteers were isolated and separated CD19+ B cell populations were cultured in the presence of 4 μg/mL or of 16 μg/mL of folic acid and the DNA methylation level as well as the percentages of B lymphocytes were measured. In another experiment, PBMCs were stimulated in vitro for IL10 production with 1 μg/mL recombinant human CD40L and with 2.5 μg/mL unmethylated CpG dinucleotides and cultured in the presence of 4 μg/mL or of 16 μg/mL of folic acid.

Results

Although co‐culturing with low or high folic acid concentrations had no effect on the methylation level of B lymphocytes, particular patients showed an increase in the population of CD19+ IL10+ as well as of CD19– IL10+ cells.

Conclusion

The observed increase may be a consequence of additional indirect or direct methylation of DNA in specific loci of the targeted cells. However, further analysis would clarify the exact mechanism of action of folate and would reveal its immunomodulating potential in this autoimmune disease.
Moderate prenatal alcohol exposure produces sex‐specific social impairments and attenuates prelimbic excitability and amygdala‐cortex modulation of adult social behaviour
Authors: Przybysz Kathryn R. , Spodnick Mary B. , Johnson Julia M. , Varlinskaya Elena I. , Diaz Marvin R.
Published: November 2022

Lifelong social impairments are common in individuals with prenatal alcohol exposure (PAE), and preclinical studies have identified gestational day (G)12 as a vulnerable timepoint for producing social deficits following binge‐level PAE. While moderate (m)PAE also produces social impairments, the long‐term neuroadaptations underlying them are poorly understood. Activity of the projection from the basolateral amygdala to the prelimbic cortex (BLA → PL) leads to social avoidance, and the PL is implicated in negative social behaviours, making each of these potential candidates for the neuroadaptations underlying mPAE‐induced social impairments. To examine this, we first established that G12 mPAE produced sex‐specific social impairments lasting into adulthood in Sprague–Dawley rats. We then chemogenetically inhibited the BLA → PL using clozapine N‐oxide (CNO) during adult social testing. This revealed that CNO reduced social investigation in control males but had no effect on mPAE males or females of either exposure, indicating that mPAE attenuated the role of this projection in regulating male social behaviour and highlighting one potential mechanism by which mPAE affects male social behaviour more severely. Using whole‐cell electrophysiology, we also examined mPAE‐induced changes to PL pyramidal cell physiology and determined that mPAE reduced cell excitability, likely due to increased suppression by inhibitory interneurons. Overall, this work identified two mPAE‐induced neuroadaptations that last into adulthood and that may underlie the sex‐specific vulnerability to mPAE‐induced social impairments. Future research is necessary to expand upon how these circuits modulate both normal and pathological social behaviours and to identify sex‐specific mechanisms, leading to differential vulnerability in males and females.
Anti‐KIT antibody, barzolvolimab, reduces skin mast cells and disease activity in chronic inducible urticaria
Authors: Terhorst‐Molawi Dorothea , Hawro Tomasz , Grekowitz Eva , Kiefer Lea , Merchant Kunal , Alvarado Diego , Thomas Lawrence J. , Hawthorne Thomas , Crowley Elizabeth , Heath‐Chiozzi Margo , Metz Martin , Maurer Marcus
Published: November 2022

Background

Chronic inducible urticaria (CIndU) is characterized by mast cell (MC)‐mediated wheals in response to triggers: cold in cold urticaria (ColdU) and friction in symptomatic dermographism (SD). KIT receptor activation by stem cell factor (SCF) is essential for MC function. Barzolvolimab (CDX‐0159) is a humanized antibody that inhibits KIT activation by SCF and was well tolerated in healthy volunteers with dose‐dependent plasma tryptase suppression indicative of systemic mast cell ablation.

Methods

This is an open‐label, trial in patients with antihistamine refractory ColdU or SD, receiving one IV dose of barzolvolimab (3 mg/kg), with a 12‐week follow‐up. Primary endpoint was safety/tolerability; pharmacodynamic (PD)/clinical endpoints included serum tryptase, plasma SCF, skin MC histology, provocation tests, urticaria control test (UCT), and dermatology life quality index (DLQI).

Results

Analysis populations were safety (n = 21) and pharmacodynamics/clinical activity (n = 20). Barzolvolimab was well tolerated; most adverse events were mild and resolved. Treatment resulted in significant depletion of skin MCs, decreased tryptase (<limit of detection), and increased soluble SCF through Week 12. Complete responses (negative provocation test) occurred in 95% (n = 19/20) of patients (n = 10/10 ColdU; n = 9/10 SD), and all (n = 20/20) showed improvement in urticaria control (UCT ≥ 12). The kinetics of clinical activity mirrored that of MC and tryptase reduction. DLQI‐measured impairment significantly decreased to minimal/none in 93% of patients on study.

Conclusion

In CIndU patients, barzolvolimab was well tolerated, demonstrated marked, rapid, durable depletion of skin MCs, circulating tryptase, and reductions in clinical activity with significant improvements in disease control and quality of life (QoL) demonstrating potential therapeutic effects for MC‐mediated disorders.
Dose optimalization of subcutaneous ravulizumab is predicted to yield significant savings and to improve patient friendliness
Authors: ter Avest Mendy , Langemeijer Saskia M. C. , Blijlevens Nicole M. A. , van de Kar Nicole C. A. J. , ter Heine Rob
Published: November 2022

Ravulizumab is an expensive complement C5‐inhibitor for the treatment of paroxysmal nocturnal haemoglobinuria. Recently, a subcutaneous formulation has entered the market, for which the approved dosing regimen results in supratherapeutic ravulizumab concentrations in the majority of patients in the registration studies. Therefore, we explored alternative dosing regimens in silico based on the registration data of the manufacturer. Extending the interval from 1 to 2 weeks or individualized dosing based on therapeutic drug monitoring resulted in therapeutic ravulizumab concentrations and comparable predicted efficacy in terms of lactate dehydrogenase normalization, with dose reductions up to 64%. We here show that with an individualized dose, a substantial dose reduction for subcutaneous ravulizumab might be possible with improved patient‐friendliness.
Human leukocyte antigen evolutionary divergence influences outcomes of paediatric patients and young adults affected by malignant disorders given allogeneic haematopoietic stem cell transplantation from unrelated donors
Authors: Merli Pietro , Crivello Pietro , Strocchio Luisa , Pinto Rita Maria , Algeri Mattia , Del Bufalo Francesca , Pagliara Daria , Becilli Marco , Carta Roberto , Gaspari Stefania , Galaverna Federica , Quagliarella Francesco , Boz Giulia , Catanoso Maria Luigia , Boccieri Emilia , Troiano Maria , Fleischhauer Katharina , Andreani Marco , Locatelli Franco
Published: November 2022

High genetic heterogeneity in the human leukocyte antigen (HLA) increases the likelihood of efficient immune response to pathogens and tumours. As measure of HLA diversity, HLA evolutionary divergence (HED) has been shown to predict the response of tumours to immunotherapy and haematopoietic stem cell transplantation (HSCT) in adults. We retrospectively investigated the association of HED with outcomes of 153 paediatric/young adults patients, treated for malignant disorders with HSCT from 9–10/10 HLA‐matched unrelated donors. HED was calculated as pairwise genetic distance between alleles in patient HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1 and ‐DPB1, using the locus median to stratify patients with ‘high’ or ‘low’ HED. Patients with high HED‐B and ‐DRB1 showed significantly improved disease‐free survival (DFS), especially when combined (70.8% vs 53.7% p = 0.008). High HED‐B + ‐DRB1 was also associated with improved overall survival (OS) (82.1 vs 66.4% p = 0.014), and concomitant reduction of non‐relapse‐mortality (5.1% vs 21.1% p = 0.006). The impact on OS and DFS of combined HED‐B + ‐DRB1 was confirmed in multivariate analysis [hazard ratio (HR) 0.39, p = 0.009; and HR 0.45, p = 0.007 respectively]. Only high HED scores for HLA‐DPB1 were associated, in univariate analysis, with reduced incidence of relapse (15.9% vs 31.1%, p = 0.03). These results support HED as prognostic marker in allogeneic HSCT and, if confirmed in larger cohorts, would allow its use to inform clinical risk and potentially influence clinical practice.
Repurposing of drugs targeting the cytokine storm induced by SARS‐CoV‐2
Authors: Ng Wern Hann , Tang Patrick Chun Hean , Mahalingam Suresh , Liu Xiang
Published: November 2022

A cytokine storm is one of the leading causes of acute respiratory distress syndrome (ARDS) and sepsis‐associated multiple organ failure in many respiratory viral infections, including severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). The coronavirus disease 2019 (COVID‐19) pandemic has caused millions of deaths worldwide, resulting in an urgent need for effective therapeutic interventions. Repurposing immunosuppressive drugs that target cytokines with immunomodulatory properties is a promising approach to counteract SARS‐CoV‐2‐induced ARDS at the infective and post‐infective stages. In this minireview, we examine drugs targeting IL‐1β, IL‐4/IL‐13, IL‐6 and TNF‐α tested in COVID‐19 patients.
Discovery of novel DNA‐damaging agents through phenotypic screening for DNA double‐strand break
Authors: Zhang Doudou , Shimokawa Takashi , Guo Qianqian , Dan Shingo , Miki Yoshio , Sunada Shigeaki
Published: November 2022

DNA double‐strand breaks (DSBs) seriously damage DNA and promote genomic instability that can lead to cell death. They are the source of conditions such as carcinogenesis and aging, but also have important applications in cancer therapy. Therefore, rapid detection and quantification of DSBs in cells are necessary for identifying carcinogenic and anticancer factors. In this study, we detected DSBs using a flow cytometry‐based high‐throughput method to analyze γH2AX intensity. We screened a chemical library containing 9600 compounds and detected multiple DNA‐damaging compounds, although we could not identify mechanisms of action through this procedure. Thus, we also profiled a representative compound with the highest DSB potential, DNA‐damaging agent‐1 (DDA‐1), using a bioinformatics‐based method we termed “molecular profiling.” Prediction and verification analysis revealed DDA‐1 as a potential inhibitor of topoisomerase IIα, different from known inhibitors such as etoposide and doxorubicin. Additional investigation of DDA‐1 analogs and xenograft models suggested that DDA‐1 is a potential anticancer drug. In conclusion, our findings established that combining high‐throughput DSB detection and molecular profiling to undertake phenotypic analysis is a viable method for efficient identification of novel DNA‐damaging compounds for clinical applications.
Pyrrole‐based EGFR inhibitors for the treatment of NCSLC: Binding modes and SARs investigations
Authors: He Jie , Luo Leixuan , Xu Shidi , Yang Feiyi , Zhu Wufu
Published: November 2022

The treatment of advanced non‐small cell lung cancer (NSCLC) has made substantial progress due to the rapid development of small molecule targeted therapy, with dramatically prolonged survival. As an effective drug for the treatment of NSCLC, epidermal growth factor receptor (EGFR) inhibitors are currently experiencing issues like severe adverse events and drug resistance. It is urgent to develop novel types of EGFR inhibitors to overcome the abovementioned limitations. Pyrrole always works well as a probe for the creation of novel medication candidates for hard‐to‐treat conditions like lung cancer. Although the design, synthesis, and biological assays of pyrrole derivatives have been reported, their inhibitory actions against the receptor tyrosine kinase (RTK) EGFR have not been in‐depthly studied. This review highlights the small molecule EGFR inhibitors containing pyrrole heterocyclic pharmacophores in recent years, and the research on their mechanism, biological activity, and structure–activity relationship (SAR).
Preliminary observations on the use of ertugliflozin in the management of hyperinsulinaemia and laminitis in 51 horses: A case series
Authors: Sundra Tania , Kelty Erin , Rendle David
Published: November 2022

Background

Hyperinsulinaemia‐associated laminitis (HAL) is encountered commonly in equine practice. There are currently no registered medications which specifically target hyperinsulinaemia in horses and ponies. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have been demonstrated to limit post‐prandial insulin responses and prevent the development of diet‐induced laminitis.

Objectives

The objective of the study was to evaluate the efficacy of an SGLT2i, ertugliflozin, in the management of hyperinsulinaemia and laminitis.

Study design

Retrospective case series.

Methods

Medical records of 51 horses and ponies that had presented with laminitis and hyperinsulinaemia and had been treated with oral ertugliflozin at 0.05 mg/kg once daily for a minimum of 30 days were reviewed.

Results

After 30 days of treatment with ertugliflozin, there was a reduction in insulin concentrations from a median of >300 μu/ml (IQR: 149, >300) to 43 μu/ml (IQR: 20, 66) (p < 0.001). Modified Obel laminitis scores improved, reducing from a median of 10/12 to 1/12 (p < 0.001). Median serum triglyceride concentrations increased from 0.6 (IQR: 0.4, 0.9) before treatment to 1.4 (IQR: 0.8, 3.7) mmol/L after 30 days of treatment (p < 0.001) before declining, however, none of the horses developed any clinical signs of hyperlipaemia. Ten horses (19%) were reported to have polyuria and polydipsia during treatment, otherwise no adverse clinical effects were identified.

Main limitations

The study was limited by the absence of a control group, the retrospective data collection and the short period of follow‐up.

Conclusions

Ertugliflozin may be effective in reducing insulin concentrations in horses and ponies with equine metabolic syndrome and its use may hasten recovery from laminitis associated with hyperinsulinaemia.
Theses and dissertations completed in family and consumer sciences: 2021
Authors: Wilmarth Melissa J. , Milstead Morgan
Published: November 2022

Graduate student degree completion and research has been collected annually since 1992. This year's data collection began with an e‐mail invitation to 593 institutional contacts at 165 U.S. universities and colleges in June 2022. This e‐mail requested information on family and consumer sciences graduate degrees and research completed in 2021. A total of 150 master's theses, 122 doctoral dissertations, and 664 non‐thesis master's degrees were conferred in 2021 from family and consumer sciences programs. This report presents the submitted information on theses and dissertations categorized into 16 subject‐matter categories by degree level.
Opposing seasonal temperature dependencies of CO2 and CH4 emissions from wetlands
Authors: Li Jinquan , Pei Junmin , Fang Changming , Li Bo , Nie Ming
Published: November 2022

Wetlands are critically important to global climate change because of their role in modulating the release of atmospheric greenhouse gases (GHGs) carbon dioxide (CO2) and methane (CH4). Temperature plays a crucial role in wetland GHG emissions, while the general pattern for seasonal temperature dependencies of wetland CO2 and CH4 emissions is poorly understood. Here we show opposite seasonal temperature dependencies of CO2 and CH4 emissions by using 36,663 daily observations of simultaneous measurements of ecosystem‐scale CO2 and CH4 emissions in 42 widely distributed wetlands from the FLUXNET‐CH4 database. Specifically, the temperature dependence of CO2 emissions decreased with increasing monthly mean temperature, but the opposite was true for that of CH4 emissions. Neglecting seasonal temperature dependencies may overestimate wetland CO2 and CH4 emissions compared to the use of a year‐based static and consistent temperature dependence parameter when only considering temperature effects. Our findings highlight the importance of incorporating the remarkable seasonality in temperature dependence into process‐based biogeochemical models to predict feedbacks of wetland GHG emissions to climate warming.
‘It feels like my metabolism has shut down’. Negotiating interactional roles and epistemic positions in a primary care consultation
Authors: Lian Olaug S. , Nettleton Sarah , Grange Huw , Dowrick Christopher
Published: November 2022

Introduction

Our aim is to explore the ways in which a patient and a general practitioner (GP) negotiate knowledge claims stemming from different epistemic domains while dealing with a mismatch between experiential and biomedical knowledge during the clinical consultation. We interpret their interaction in relation to the sociocultural context in which their negotiation is embedded and identify factors facilitating their successful negotiation (a medical error is avoided).

Methods

Based on a narrative analysis of a verbatim transcript of a complete naturally occurring primary care consultation, we explore the moment‐to‐moment unfolding of talk between the patient and the GP (two women).

Findings

The patient experiences symptoms of what she interprets as a thyroid condition, and indirectly asks for medication. She presents her case by drawing on experiential knowledge (‘it feels like my metabolism has shut down’) and biomedical knowledge (while suggesting a diagnosis and a diagnostic test). The GP informs her that her thyroid blood tests are normal and uses biomedical knowledge to explain why she turns down the patient's request. This stages a potential conflict between the patient's embodied experiential knowledge and the doctor's biomedical knowledge. However, during their encounter, the patient and the GP manage to co‐construct the patient's illness story and make shared decisions about further actions.

Conclusion

The transition from potential conflict to consensus is a result of the mutual efforts of two parties: a patient who persistently claims experiential as well as biomedical knowledge while at the same time deferring to the GP's professional knowledge, and a GP who maintains her epistemic authority while also acknowledging the patient's experiential and biomedical knowledge.

Patient and Public Contribution

Our empirical data are sourced from a data archive and patients were not involved in the design or conduct of the study, but our study is based on a naturally occurring clinical consultation with a patient.