Twofold Reduction Research Articles

Sensitivity and Costs of Intraoperative Trans-Impedance Matrix Recordings, Spread of Excitation Functions, and X-ray Imaging in Detecting Cochlear Implant Tip Foldovers.

Evaluate the sensitivity and financial costs of Trans-Impedance Matrix recordings, Spread of Excitation functions, and x-rays in detecting cochlear implant tip foldovers. Tertiary academic medical center. 113 ears of 108 patients. Following cochlear implantation and before concluding surgery, intraoperative Trans-Impedance Matrix recordings, Spread of Excitation functions, and x-rays were conducted to evaluate presence of tip foldover. Presence of tip foldover; recording time necessary for and costs of Trans-Impedance Matrix, spread of excitation, and x-rays. There were six tip foldovers. Trans-Impedance Matrix showed 100% sensitivity, 100% specificity, 100% positive predictive value, and 100% negative predicative value in detecting tip foldovers. Spread of excitation showed 29% sensitivity, 99% specificity, 67% positive predictive value, and 95% negative predicative value. Trans-Impedance Matrix recordings were completed significantly faster than spread of excitation and x-rays. Elimination of x-rays from our intraoperative workflow results in a twofold cost reduction. Trans-Impedance Matrix recordings have potential great clinical utility in evaluating proper CI placement intraoperatively and reducing costs of surgery while not compromising patient care. Given the low tip foldover rate, a multicenter study is in progress to evaluate the sensitivity, specificity, positive predictive value, and negative predicative value of Trans-Impedance Matrix in a larger dataset. This can provide better guidance to cochlear implant clinics interested in evaluating the impact of using Trans-Impedance Matrix on patient care as well as the economics of reducing use of intraoperative imaging.

Impact of Ebola Virus Disease and ECOWAS Membership on Intra-Regional Trade in West Africa

The West African sub-region bore the brunt of the world's largest Ebola outbreak, significantly impacting the economic activities and trade shares of the affected countries. This study seeks to examine the repercussions of the Ebola Virus Disease (EVD) on the trade shares of affected countries and to explore the potential influence of ECOWAS membership on intra-regional trade in West Africa. Using the Poison Pseudo Maximum Likelihood (PPML) estimation technique, an analysis of the augmented gravity model of international trade was conducted. The findings indicate a two-fold reduction in the trade shares of affected countries with their intra-regional partners due to the Ebola Virus Disease. Additionally, with Mauritania expressing its desire to join the ECOWAS sub-region, there is a need to explore the impact of the Regional Economic Community on intra-regional trade. Furthermore, the study reveals that ECOWAS membership has the potential to double trade levels in West Africa. The findings also suggest that Mauritania stands to gain significant benefits from becoming a member of the ECOWAS. In conclusion, this study highlights the necessity for ECOWAS to proactively respond to disease outbreaks and underscores the importance of increased research investment. Moreover, it emphasizes the need for the ECOWAS to further improve infrastructure to facilitate intra-regional trade, especially in transportation.

The effectiveness of combined anesthesia in comparison with general anesthesia in thyroid and parathyroid surgery: a single-center prospective randomized study

BACKGROUND. Operations on the organs of the anterior surface of the neck (thyroidectomy, carotidectomy, plastic surgery, etc.) are widespread in the Russian Federation. The development of adequate anesthesiological support for these interventions is an urgent task of modern anesthesiology. The introduction of combined regional anesthesia techniques into surgical practice makes it possible to minimize postoperative complications, manifested in the form of severe pain syndrome, postoperative nausea and vomiting. AIM. To conduct a comparative assessment of the effectiveness of combined (general + regional) and only general anesthesia during operations on the thyroid and parathyroid glands. MATERIALS AND METHODS. In a prospective randomized study, 60 patients operated on for thyroid and parathyroid gland diseases were divided into 2 groups: in group 1, general anesthesia was performed in combination with blockade of the internal fascia of the neck and bilateral blockade of the superficial branches of the cervical plexus, as well as the Berry ligament area under ultrasound navigation; patients of group 2 were operated on in conditions of combined general anesthesia. The hemodynamic profile during surgery, plasma cortisol concentration, required doses of fentanyl, intensity of postoperative pain syndrome, need for anesthesia, and recovery time were evaluated. RESULTS. Combined (general + regional) anesthesia was characterized by a decrease in fentanyl consumption compared with the group receiving only general anesthesia (p 0.0001), a decrease in cortisol content in blood plasma 12 hours after extubation (p=0.0439), a reduction in median pain after tracheal extubation 3 and 12 hours after surgery (p=0.0190, p 0.0001), as well as a twofold reduction in the time interval from the end of the operation to the moment of extubation (p=0.0001). The assessment of patients on the Aldreth awakening scale in the group of people who underwent combined anesthesia indicates a higher willingness of patients to be transferred from the operating room to the awakening ward (p=0.0114). CONCLUSION. The study demonstrated the effectiveness and safety of the combined anesthesia technique in thyroid and parathyroid surgery, which provides adequate anesthetic protection for patients.

Effectiveness of a new commercial ocular spray containing Biosecur in reducing conjunctival microbial flora as surgical prophylaxis in patients undergoing cataract surgery

IntroductionThis study is aimed to evaluate the antiseptic activity of a new ophthalmic spray containing Biosecur citrus extract as a preoperative prophylactic treatment in patients undergoing cataract intervention.MethodsA prospective, multicenter study was conducted. Patients applied Oftasecur spray on the eye scheduled for surgery, three times daily for 3 days before surgery. Conjunctival swabs were performed before and after the treatment. Qualitative and quantitative microbiological analyses were assessed.ResultsHundred and forty-seven patients (M: F = 76:71; mean age 70.74 ± 9.41 years) were enrolled. 58.5% of patients presented detectable microbial loads in the eye to be operated, before treatment. Most predominant bacterial species were: Staphylococcus epidermidis, coagulase-negative Staphylococci and Staphylococcus aureus. Patients were divided into three subgroups, according to the microbial loads measured at baseline: lower than 10 CFU/ml (41.7%), between 10 and 100 CFU/ml (31.7%), equal or greater than 100 CFU/ml (26.6%). A twofold reduction in positive patients who received Oftasecur: 44 eyes (51.2%) resulted in negative after ocular treatment. A significant reduction in bacterial loads was observed (p < 0.001). No ocular adverse reactions were recorded.ConclusionOftasecur spray effectively reduced conjunctival bacterial burden. It may represent a proper and safe antiseptic adjuvant treatment in patients undergoing cataract surgery.

DESIGN AND MANUFACTURE OF BENT AND VARIABLE SECTION TUBES MADE OF FRP COMPOSITE

Manufacturing of bent composite tubes with variable cross-section is a challenge. The traditional process in composite materials uses retractable mandrels that in case of inflated or bent tubes cannot be applied. The tubular composite elements are often used in high performance bicycles, in the manufacturing of frames, handlebars, saddle pipe supports, etc. This paper presents research on the design of a Mountain Bike (MTB) riser handlebar made of Fiber Reinforced Polymer (FRP). The handlebar is numerically analyzed to estimate the most suitable stacking sequence of Carbon Fiber Reinforced Polymer (CFRP) layers. Depending on the safety standard of bicycle handlebars, a case of longitudinal bending tests was numerically evaluated. Comparing the weight of the CFRP handlebar with the steel handlebar of the same shape, the mass reduction is 5.2 times. The obtained results indicate a two-fold reduction in the weight of the handlebar if it is compared to a handlebar made of aluminum alloys. The research also presents the manufacturing process of the composite mold, and CFRP tubular element. Prepreg CFRP materials are used to manufacture the handlebar, the employed technology being the vacuum bag forming and autoclave curing process.

Liver transplantation for unresectable Klatskin tumor: experience of two centers, first distant results

Aim. Evaluation of the first distant results of the combined experience of liver transplantation for unresectable portal cholangiocarcinoma from two large specialized clinical centers.Materials and methods. In total, 23 attempts at liver transplantation for unresectable Klatskin tumor were undertaken. Out of them, 10 were conducted at the A.M. Granov Russian Research Center for Radiology and Surgical Technologies (Granov Center), and 13 were conducted at the Minsk Scientific and Practical Center for Surgery, Transplantology, and Hematology (Minsk Center). The maximum tumor size was 5 and 3 cm in patients operated at the Granov and Minsk Centers, respectively. In the Granov Center, neoadjuvant therapy included a combination of endobiliary photodynamic therapy, regional and systemic chemotherapy. Patients were included in the waiting list only in cases of decreased tumor marker levels and in the absence of disease progression and acute cholangitis. In the Minsk Center, stereotactic radiotherapy was used for neoadjuvant treatment in the absence of active cholangitis; the first 3 patients underwent liver transplantation without prior neoadjuvant treatment.Results. Due to disease progression, six patients were excluded. In three patients at the Mink Center, the diagnosis was not morphologically confirmed after liver transplantation. A total of 14 liver transplantations were performed for unresectable hilar cholangiocarcinoma. After neoadjuvant treatment at the Granov Center, normalization of the CA19-9 marker was observed in four patients, its decrease by 3–4 times was observed in two patients. Liver transplantation was performed in six patients. The average time from the onset of treatment to transplantation was 9.1 months (6–14). Out of the six patients, one was alive for 34 months, with the median overall survival being 22.2 months. Progression was the cause of death in only one patient. Out of the three patients without neoadjuvant treatment at the Minsk Center, two were alive at 16 and 134 months without progression. One patient died after transplantation from disease progression at 24 months. Stereotactic radiotherapy achieved normalization of CA19-9 in four patients; its twofold reduction was observed in one patient. The average time from the onset of treatment to transplantation was six months (3–12). The average CA19-9 tumor marker level by the time of transplantation was 11.3 IU/mL. At 20–26 months, three patients were alive without evidence of disease progression; two patients died of progression after 9 and 59 months.Conclusion. Liver transplantation for unresectable portal cholangiocarcinoma after neoadjuvant treatment regardless of the methods used is highly promising in carefully selected recipients.

Novel immunotherapeutics against LGR5 to target multiple cancer types

We have developed and validated a highly specific, versatile antibody to the extracellular domain of human LGR5 (α-LGR5). α-LGR5 detects LGR5 overexpression in >90% of colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pre-B-ALL tumour cells and was used to generate an Antibody-Drug Conjugate (α-LGR5-ADC), Bispecific T-cell Engager (α-LGR5-BiTE) and Chimeric Antigen Receptor (α-LGR5-CAR). α-LGR5-ADC was the most effective modality for targeting LGR5+ cancer cells in vitro and demonstrated potent anti-tumour efficacy in a murine model of human NALM6 pre-B-ALL driving tumour attrition to less than 1% of control treatment. α-LGR5-BiTE treatment was less effective in the pre-B-ALL cancer model yet promoted a twofold reduction in tumour burden. α-LGR5-CAR-T cells also showed specific and potent LGR5+ cancer cell killing in vitro and effective tumour targeting with a fourfold decrease in pre-B-ALL tumour burden relative to controls. Taken together, we show that α-LGR5 can not only be used as a research tool and a biomarker but also provides a versatile building block for a highly effective immune therapeutic portfolio targeting a range of LGR5-expressing cancer cells.

Influence of high-carbon wire drawing method on its production efficiency

The issue of improving the production efficiency and competitiveness of high-carbon steel wire, determined by a rational ratio of quality and costs of its production, is an urgent task. The main way to solve it is the development and implementation of an effective technical process, the main elements of which are the technological process and equipment for its realization. Since the middle of the last century, domestic steel wire production has been operating on imported equipment, which significantly hampers the use of modern technological processes. This unfavorable situation has been aggravated at present by the imposition of severe economic sanctions by “unfriendly states”. The way out of this situation in the current production is the improvement of existing and introduction of new methods of wire drawing. According to the original methodology the analysis of the existing at one of the domestic enterprises route of drawing of high-carbon wire rope wire with a diameter of 1.70 mm from wire rod of 5.50 mm with the use of standard single monolithic fibers, twin monolithic fibers, roller fibers, as well as modules including roller and monolithic fibers (combined drawing) was carried out. The obtained results have shown that when using standard fibers, the drawing route should be designed with the minimum possible multiplicity, which will provide on the existing equipment to improve the quality of wire and reduce the cost of its production. The greatest efficiency is provided by the application of combined drawing: twofold reduction of drawing multiplicity, energy saving up to 30%, improvement of wire quality by creating a favorable stress-strain state when deforming the wire first in roller and then in monolithic drawing. In addition, in comparison with the roller fibers, the equipment is simplified and the costs of its purchase and operation are reduced. Recommendations on the directions of increasing the efficiency of production in the conditions of existing production, purchase of new imported and designing of domestic drawing equipment are given

Efficacy and safety of conservative treatment in patients with neurologically intact thoracolumbar burst fractures: a meta-analysis

Objective. To conduct a meta-analysis of studies focused on the conservative treatment of thoracolumbar burst fractures, and to determine the efficacy and safety of this method in the observed group of patients.Material and Methods. The study was performed following PRISMA guidelines. Inclusion criteria for meta-analysis were as follows: availability of full-text version of the article in English or Russian; A3 or A4 type fractures according to the AOSpine classification, or burst fractures of types IIA, IIB or IIC according to the Denis classification, or a direct indication of the presence of a burst fracture without its classification; absence of neurological deficit; age over 18 years; detailed description of treatment outcomes or complications; and a follow-up for at least one year.Results. The meta-analysis included 29 articles describing the results of treatment of 1107 patients. At the time of admission, the following radiographic parameters were calculated for patients: mean kyphotic angle, 13.6 (95 % CI, 10.8–16.5), degree of vertebral body compression, 39.9 % (95 % CI, 27.7–52.0), and the degree of compression of the spinal canal lumen, 41.7 % (95 % CI, 29.2–54.2). A follow-up examination revealed a significant increase in segmental kyphosis by 3%, in vertebral body compression by 3.7 %, and lysis of bone fragments with a decrease in the degree of spinal canal stenosis by 2 times. The incidence of neurological deficit and progression of thoracic and lumbar spine instability was 5.8 % (95 % CI, 4.1–8.1) and 6.5 % (95 % CI, 4.5–9.3), respectively. Recovery of work ability according to Denis scale was as follows: W1 and W2 – 74.7 % (95 % CI, 63.9–83.1); W3 – 14.1 % (95 % CI, 10.2–19.3); and W4 and W5 – 14.8 % (95 % CI, 8.8–23.9).Conclusion. Conservative treatment of neurologically intact thoracolumbar burst fractures can be an effective and safe option if the angular deformity does not exceed 16 degrees and the anterior vertebral body compression rate is up to 52 %. With conservative therapy, a twofold reduction in spinal canal stenosis was observed due to the lysis of bone fragments. The pooled prevalence of radiculopathy or myelopathy with conservative therapy was 5.8 %. Orthopedic intervention due to the progression of instability of the damaged segment may be required in 6.5 % of patients. More than 90 % of patients returned to full-time work following conservative therapy. Comparative studieson the effectiveness of conservative therapy versus surgical treatment should be continued to form clear recommendations for the choice of treatment tactics for patients with uncomplicated fractures of the thoracic and lumbar spine.

Efficient high-throughput method utilizing neural network potentials to calculate interaction energies, validated by clean transfer experiment of CVD graphene with polymer mixtures

In this study, we designed a computational model involving energy decomposition using ground state energy minimized geometries resulting from a general-purpose neural network potential (ANI-1ccx). The numerical simulations show a distribution of energies, which indicate a two-fold reduction in interaction energy and polarity shift in electrostatic interaction, highlighting the computational novelty in exploring over a million metastable configurations. Experimentally, we validate our model by observing that using a mixture of two distinct polymers in the wet transfer process reduces transfer-induced doping and strain on transferred CVD graphene compared to the conventional single polymer wet transfer method, primarily due to decreased polymer contamination from the transfer process. This reduction is linked to the decreased interaction energy in the mixture of polymethyl methacrylate and angelica lactone polymer on graphene.

Rerouting cardiovascular management following gastric bypass surgery: Dose optimization of carvedilol using population-based analysis.

A population-based pharmacokinetic (PK) modeling approach (PopPK) was used to investigate the impact of Roux-en-Y gastric bypass (RYGB) on the PK of (R)- and (S)-carvedilol. We aimed to optimize carvedilol dosing for these patients utilizing a pharmacokinetic/pharmacodynamic (PK/PD) link model. PopPK models were developed utilizing data from 52 subjects, including nonobese, obese, and post- RYGB patients who received rac- carvedilol orally. Covariate analysis included anthropometric and laboratory data, history of RYGB surgery, CYP2D6 and CYP3A4 in vivo activity, and relative intestinal abundance of major drug- metabolizing enzymes and transporters. A direct effect inhibitory Emax pharmacodynamic model was linked to the PK model of (S)- carvedilol to simulate the changes in exercise- induced heart rate. A 2-compartmental model with linear elimination and parallel first-order absorptions best described (S)-carvedilol PK. RYGB led to a twofold reduction in relative oral bioavailability compared to nonoperated subjects, along with delayed absorption of both enantiomers. The intestinal ABCC2 mRNA expression increases the time to reach the maximum plasma concentration. The reduced exposure (AUC) of (S)-carvedilol post-RYGB corresponded to a 33% decrease in the predicted area under the effect curve (AUEC) for the 24-hour β-blocker response. Simulation results suggested that a 50-mg daily dose in post-RYGB patients achieved comparable AUC and AUEC to 25-mg dose in nonoperated subjects. Integrated PK/PD modeling indicated that standard dosage regimens for nonoperated subjects do not provide equivalent β-blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.

Shared-Memory Parallel Edmonds Blossom Algorithm for Maximum Cardinality Matching in General Graphs.

The Edmonds Blossom algorithm is implemented here using depth-first search, which is intrinsically serial. By streamlining the code, our serial implementation is consistently three to five times faster than the previously fastest general graph matching code. By extracting parallelism across iterations of the algorithm, with coarse-grain locking, we are able to further reduce the run time on random regular graphs four-fold and obtain a two-fold reduction of run time on real-world graphs with similar topology. Solving very sparse graphs (average degree less than four) exhibiting community structure with eight threads led to a slow down of three-fold, but this slow down is replaced by marginal speed up once the average degree is greater than four. We conclude that our parallel coarse-grain locking implementation performs well when extracting parallelism from this augmenting-path-based algorithm and may work well for similar algorithms.

Association of Genetic Polymorphism rs 77630697(Gly64Asp) of Multidrug and Toxin Extrusion -1 with glycemic response to metformin in patients with Type 2 Diabetes Mellitus.

To determine the relationship between Gly64Asp (rs77630697) polymorphism of multidrug and toxin extrusion-1 (MATE-1) and therapeutic response of metformin in Type-2 diabetic patients. A longitudinal study was conducted at Riphah International Hospital, Islamabad from June 2020 to December 2021. Type-2 diabetic patients (n=200) on metformin monotherapy fulfilling the inclusion criteria were enrolled and followed up till three months. Based on change in HbA1c, they were divided into responders and non-responders. DNA was extracted and genotyping was done by TETRA ARMS PCR. Data was entered and association was analyzed by SPSS 22. Out of 200 participants, 104 were categorized as responders and 96 as non-responders. The genotype and allelic distribution of rs77630697 was significantly different between responders and non-responders. The variant genotype (GG) was most prevalent among the study population and among responders. After follow up of three months, difference in glycemic response was found to be statistically significant (p < 0.05) among three genotypes (GG, GA and AA). The decline in HbA1c was highest in GG genotype with almost two-fold reduction in comparison with GA and AA. Carriers of allele A were significantly associated with impaired response to metformin. The variable therapeutic response to metformin in the responders and non-responders may be contributed to rs77630697 isoform variation of MATE-1.

Assessment of prospects for achieving the national goal of halving the poverty rate compared to the 2017

The paper presents research on the problem of reducing poverty in Russian Federation. The purpose of the research is to assess the prospects for achieving the national goal of twofold poverty level reducing in Russia by 2030 compared to the 2017. However, in terms of dynamics to the approaches to the poverty, it will be possible to achieve the twofold poverty reduction by 2030 compared to the 2017. It can be implemented in accordance with Presidential Decree No. 474 on 21 July 2020. Moreover, it is not the problem solving; the measurement scale transformation is not the proper tool that can eliminate (or at least reduce) poverty in society. The practical significance of the research is the introduction of a differentiated progressive taxation scale and development of favourable conditions for the intensive development of high-tech and competitive production as the most effective tools for poverty reduction. It will cause an increase in the population’s income, strengthening of the national distributive and redistributive functions. Additionally, it allows ones’ to reduce the income gap between the richest and poorest segments of the population (reduction of the Gini index).

Druggability properties of a L309K mutation in the antibody CH2 domain.

In the early stages of antibody drug development, it is imperative to conduct a comprehensive assessment and enhancement of the druggability attributes of potential molecules by considering their fundamental physicochemical properties. This study specifically concentrates on the surface-exposed hydrophobic region of the candidate antibody aPDL1-WT and explores the effectiveness of the L309K mutation strategy. The resulting aPDL1-LK variant demonstrates a notable enhancement over the original antibody in addressing the issue of aggregation and formation of large molecular impurities under accelerated high-temperature conditions. The mutated molecule, aPDL1-LK, exhibits excellent physicochemical properties such as hydrophilicity, conformational stability, charge variant stability, post-translational modifications, and serum stability. In terms of biological function, aPDL1-LK maintains the same glycosylation pattern as the original antibody and shows no significant difference in affinity for antigen hPDL1 protein, CD16a-F158, CD64, CD32a-H131, and complement C1q, compared to aPDL1-WT. The L309K mutation results in an approximately twofold reduction in its affinity for CD16a-V158 and CD32a-R131. In vitro biological assays, including antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), reveal that the L309K mutation may decrease CD16a-V158-mediated ADCC activity due to the mutation-induced decrease in ligand affinity, while not affect CD32a-R131-mediated ADCP activity. In conclusion, the L309K mutation offers a promising strategy to enhance the druggability properties of candidate antibodies.

Comprehensive analysis of two hotspot codons in the TUBB4B gene and associated phenotypes

Our purpose was to elucidate the genotype and ophthalmological and audiological phenotype in TUBB4B-associated inherited retinal dystrophy (IRD) and sensorineural hearing loss (SNHL), and to model the effects of all possible amino acid substitutions at the hotspot codons Arg390 and Arg391. Six patients from five families with heterozygous missense variants in TUBB4B were included in this observational study. Ophthalmological testing included best-corrected visual acuity, fundus examination, optical coherence tomography, fundus autofluorescence imaging, and full-field electroretinography (ERG). Audiological examination included pure-tone and speech audiometry in adult patients and auditory brainstem response testing in a child. Genetic testing was performed by disease gene panel analysis based on genome sequencing. The molecular consequences of the substitutions of residues 390 and 391 on TUBB4B and its interaction with α-tubulin were predicted in silico on its three-dimensional structure obtained by homology modelling. Two independent patients had amino acid exchanges at position 391 (p.(Arg391His) or p.(Arg391Cys)) of the TUBB4B protein. Both had a distinct IRD phenotype with peripheral round yellowish lesions with pigmented spots and mild or moderate SNHL, respectively. Yet the phenotype was milder with a sectorial pattern of bone spicules in one patient, likely due to a genetically confirmed mosaicism for p.(Arg391His). Three patients were heterozygous for an amino acid exchange at position 390 (p.(Arg390Gln) or p.(Arg390Trp)) and presented with another distinct retinal phenotype with well demarcated pericentral retinitis pigmentosa. All showed SNHL ranging from mild to severe. One additional patient showed a variant distinct from codon 390 or 391 (p.(Tyr310His)), and presented with congenital profound hearing loss and reduced responses in ERG. Variants at codon positions 390 and 391 were predicted to decrease the structural stability of TUBB4B and its complex with α-tubulin, as well as the complex affinity. In conclusion, the twofold larger reduction in heterodimer affinity exhibited by Arg391 substitutions suggested an association with the more severe retinal phenotype, compared to the substitution at Arg390.

Conventional type 1 dendritic cells are essential for the development of primary biliary cholangitis.

Primary biliary cholangitis (PBC) is a progressive-cholestatic autoimmune liver disease. Dendritic cells (DC) are professional antigen-presenting cells and their prominent presence around damaged bile ducts of PBC patients are documented. cDC1 is a rare subset of DC known for its cross-presentation abilities and interleukin 12 production. Our aim was to assess the role of cDC1 in the pathogenesis of PBC. We utilized an inducible murine model of PBC and took advantage of the DC reporter mice Zbtb46gfp and the Batf3-/- mice that specifically lack the cDC1 subset. cDC1 cells were sorted from blood of PBC patients and healthy individuals and subjected to Bulk-MARS-seq transcriptome analysis. Histopathology assessment demonstrated peri-portal inflammation in wild type (WT) mice, whereas only minor abnormalities were observed in Batf3-/- mice. Flow cytometry analysis revealed a two-fold reduction in hepatic CD8/CD4 T cells ratio in Batf3-/- mice, suggesting reduced intrahepatic CD8 T cells expansion. Histological evidence of portal fibrosis was detected only in the WT but not in Batf3-/- mice. This finding was supported by decreased expression levels of pro-fibrotic genes in the livers of Batf3-/- mice. Transcriptome analysis of human cDC1, revealed 78 differentially expressed genes between PBC patients and controls. Genes related to antigen presentation, TNF and IFN signalling and mitochondrial dysfunction were significantly increased in cDC1 isolated from PBC patients. Our data illustrated the contribution the cDC1 subset in the pathogenesis of PBC and provides a novel direction for immune based cell-specific targeted therapeutic approach in PBC.

Cardiorespiratory Disturbances in Alzheimer's Disease: A Focus on the Contribution of Sympathetic Premotor Neurons

While therapeutic approaches targeting neurodegenerative mechanisms associated with cognitive impairment in Alzheimer's disease (AD) have been intensively explored, other comorbidities closely linked to AD progression, such as sleep-disordered breathing and autonomic dysfunction, have not been thoroughly investigated. In preliminary studies, we showed an increase in neural activity of catecholaminergic premotor neurons located in the rostral ventrolateral medulla region (RVLM-C1), a main region involved in cardiorespiratory regulation, in experimental AD. Therefore, in the present study, we aimed first to characterize cardiorespiratory function in AD patients and then to determine the role of RVLM-C1 neurons in autonomic and sleep-disordered breathing in APP/PS1 double transgenic mice, an experimental model showing AD-like pathology. Sixteen subjects (8 AD and 8 age-matched controls) were enrolled to assess sleep breathing disorders and to record cardiac autonomic function. Whole-body plethysmography and blood pressure monitoring in freely moving mice were used to study sleep-associated cardiorespiratory disorders. Bilateral stereotaxic injections of anti-dopamine β-hydroxylase-saporin (DβH-SAP) into the RVLM were used to selectively destroy C1 neurons. Compared to age-matched healthy subjects, patients with AD showed larger increases in neural sympathetic discharges during autonomic testing. In addition, heart rate variability analysis in AD patients showed a shift in spectral components towards a more sympathetic influence. Remarkably, we found that autonomic function impairment in the APP/PS1 mice resembles what we found in AD patients. Compared to wild type (WT), APP/PS1 mice displayed sympatho-excitation (ΔHR: -80±5 vs -125±10, WT vs APP/PS1, respectively), a higher incidence of cardiac arrhythmias (events/h 6.0±1.0 vs 12±1.5, WT vs APP/PS1, respectively), and sleep-disordered breathing (AHI: 8.5±2.0 vs 18.0±3.0, WT vs APP/PS1, respectively). Partial ablation of RVLM-C1 neurons (~70%) in APP/PS1 mice resulted in a two-fold and three-fold reduction in cardiac sympathetic drive and arrhythmogenesis, respectively. Furthermore, APP/PS1 mice treated with DβH-SAP showed marked improvements in breathing regularity (IS: 7.9±1.1 vs 16.9±2.2, APP/PS1DβH-SAP vs APP/PS1, respectively) and a restoration of normal sleep effciency (SE: 75.5±4.3 vs 58.1±6.4, APP/PS1DβH-SAP vs APP/PS1, respectively) compared to untreated APP/PS1 mice. Our results show that RVLM-C1 neurons play a main role in the development/maintenance of cardiorespiratory disorders in experimental AD. FONDECYT 11220962, 1220950. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Can strength training or tai ji quan training reduce frailty in postmenopausal women treated with chemotherapy? A secondary data analysis of the GET FIT trial.

To determine whether strength training or tai ji quan can reduce frailty in older, postmenopausal women treated with chemotherapy for cancer. We conducted a secondary data analysis from a 3-arm, single-blind, randomized controlled trial where older (50-75years), postmenopausal women cancer survivors were randomized to supervised group exercise programs: tai ji quan, strength training, or stretching control for 6months. We assessed frailty using a 4-criteria model consisting of weakness, fatigue, inactivity, and slowness. Using logistic regression, we determined whether the frailty phenotype (pre-frailty or frailty) decreased post-intervention, how many and which frailty criteria decreased, and what characteristics identified women most likely to reduce frailty. Data from 386 women who completed baseline and 6-month testing were used (mean age of 62.0 ± 6.4years). The odds of reducing overall frailty over 6months were significantly higher in the strength training group compared to controls (OR [95%CI] 1.86 [1.09, 3.17]) but not for tai ji quan (1.44 [0.84, 2.50]). Both strength training (OR 1.99 [1.10, 3.65]) and tai ji quan (OR 2.10 [1.16, 3.84]) led to significantly higher odds of reducing ≥ 1 frailty criterion compared to controls. Strength training led to a three-fold reduction in inactivity (p < 0.01) and tai ji quan to a two-fold reduction in fatigue (p = 0.08) versus control. Higher baseline BMI, comorbidity score, and frailty status characterized women were more likely to reduce frailty than other women. Strength training appears superior to tai ji quan and stretching with respect to reducing overall frailty phenotype among postmenopausal women treated with chemotherapy for cancer, but tai ji quan favorably reduced the number of frailty criteria. ClinicalTrials.gov identifier: GET FIT was registered as a clinical trial in clinicaltrials.gov: NCT01635413. Supervised, group exercise training that emphasizes strength training and/or tai ji quan may help combat accelerated aging and reduce frailty after cancer treatment.

Experimental study on an eco-friendly gemini foaming agent for enhancing foam drilling applications

Underbalanced foam drilling (UBFD) represents a pivotal technique aimed at enhancing safety and operational efficiency within drilling operations. Despite its recognized benefits, the challenge of maintaining foam stability persists, particularly in conditions characterized by elevated water salinity and alkalinity. This study endeavors to bridge this gap by introducing the eco-friendly Gemini surfactant (GS12) for drilling foams and evaluating its performance under mildly alkaline conditions. Employing a dynamic foam analyzer, diverse foam properties of GS12 foams were systematically assessed, including stability, foamability, and bubble structure. Results elucidate that the optimal surfactant concentration for maximal foam stability stands at 1.5 wt%; however, a threefold concentration increase (from 0.5 to 1.5 wt%) merely yields a 30% improvement, emphasizing the economic viability of a 0.5 wt% concentration for practical UB applications. Additionally, the study demonstrates a correlation between foam stability and water salinity, with seawater exhibiting a twofold reduction in foam half-life compared to deionized water (decreasing from 27 to 13 min), mitigated by the addition of PAC polymer, which increases foam half-life from 13 to 56 min. Moreover, GS12 + PAC foaming systems exhibit surpassing stability compared to a typical commercial blend, boasting a 78% increase in foam half-life (245 min) and a 21% increase in initial foam volume (245 mL), thereby positioning it as a promising candidate for UB drilling applications. The introduction of GS12 for UB drilling and its comprehensive evaluation under mildly alkaline conditions underscore its potential for sustainable foam drilling, advocating for the utilization of environmentally friendly surfactants and green polymers to enhance drilling sustainability and address pressing industry challenges.