bluuebunny/crossref_metadata_2025 huggingface dataset:
INFLUENCER VE FENOMEN ARACILIĞIYLA PAZARLAMA KAVRAMLARININ DEĞERLENDİRİLMESİ VE BU ÇERÇEVEDE INFLUENCERIN TAKİPÇİLERİNE KARŞI DOĞAN SORUMLULUĞU
Authors: Bulut Hüseyin
Published: January 2024

Influencer pazarlama yeni nesil bir pazarlama aracıdır. Influencer pazarlama, takipçilerin influencera olan güvenine dayanmaktadır. İşletmeler ise bu güveni kullanarak, influencer aracılığıyla mal ve hizmetlerinin tanıtımını yapmaktadır. Influencer sosyal medyada düzenli paylaşımlarda bulunan, belli bir takipçi kitlesine ve bu kitleyi etkileme gücüne sahip olan kişidir. Influencer ile işletme arasındaki ilişki çeşitli şekillerde ortaya çıkabilmektedir. Influencer ile işletme doğrudan bir hukuki ilişki içerisine girmekte veya aracı firma olan ajanslar aracılığıyla da işletme ve influencer bir araya gelebilmektedirler.
Influencerın sosyal medyada yaptığı tanıtım faaliyetleri sonucu zarar görenlerin influencera başvurup başvuramayacağı çalışmanın konusunu oluşturmaktadır. İşletme ile takipçiler arasında mal veya hizmet alımından dolayı sözleşmesel bir ilişki bulunmaktadır. Takipçiler işletmeye akdi sorumluluk çerçevesinde başvurabilirler. Fakat influencer ile takipçiler arasında akdi bir ilişki bulunmamaktadır. Çalışmada sosyal medyada influencer pazarlamanın ortaya çıkışı, influencerın hukuki niteliği ve sorumluluğu esas olarak incelenmektedir.
Quality attributes of ghee residue prepared using Deoni and Holstein Friesian crossbred cow milk as influenced by method of preparation
Authors: Sangma Amanchi A , Sharma Monika , Ravindra, Rekha Menon , Rao K Jayaraj , Naik N Laxmana
Published: January 2024

Ghee residue (GR), a dairy by-product, was found to be nutrient dense. The ghee residue composition could be affected by clarification temperature, method of ghee preparation and breed of the cow. So, the present study was conducted to know whether the clarification temperature (110°C and 120°C),methods of ghee preparation (direct cream and creamery butter),and breed of the cow (Indigenous Deoni and Holstein Friesian crossbred) can affect the composition of ghee residue. The moisture, protein, fat, lactose and ash content of various ghee residue samples prepared from the milk of Deoni and HF crossbred cows varied from 10.50±0.22 to 14.65±0.1, 13.49±3.37 to 34.17±3.37,51.61±0.86 to 67.69±0.09, 9.44±0.06to14.15±0.22 and 1.89±0.03to5.59±0.41%, respectively. Further, the phospholipid content and antioxidant activity varied from 3.18 to 15.09 and 27.04 to 67.86%,respectively. In this study, it was found that temperature of clarification had a significant (p<0.05) effect on moisture, lactose, ash, hydroxy methyl furfural (HMF) and browning index. The clarification temperature significantly affected the protein, fat, lactose, ash, phospholipids and antioxidant activity. The protein, fat and browning index of ghee residue were also significantly different for the breeds. Thus, it can be concluded that GR’scomposition was affected by breed and method of ghee preparation.
ACE- inhibitory and antioxidant activities in probiotic Cheddar cheese incorporatedwith Inulin and Whey Protein Concentrate
Authors: Luhana Anjani B , Ghosh Bikash C
Published: January 2024

The aim of this study was to compare angiotensin-converting enzyme (ACE) - inhibitory and antioxidant activities of Cheddar and probiotic Cheddar cheese using Lactiplantibacillus plantarum DSM 20174 with inulin and whey protein concentrate (WPC). Water soluble extracts (WSE) of probiotic Cheddar cheese exhibited higher ACE-inhibitory activity than their Cheddar cheese counterparts. A similar trend was observed for antioxidant activity. The highest antioxidant activity(2183.55 μM of Trolox) was obtained when cheese supplemented with WPC and probiotic (PCW) after 6 months of ripening among all the samples followed by probiotic cheese with inulin (PCI).Similarly, PCW had highest ACE- inhibitory activity (88.51%)after 6 months of ripening. The electrophoretic and RP-HPLC profiles indicated that the rate of degradation of proteins resulted in formation of smaller peptides were highest in PCW followed by PCI among all the samples. The results suggest the potential use of WPC in presence of L. plantarum DSM 20174 for production of Cheddar cheese enhanced ACE-inhibitory and antioxidant properties.
Spray-dried Probiotic adjunct with in vitro acid and bile salt tolerance
Authors: Salaria Ameeta , Arora Shalini , Thompkinson DK , Sabikhi Latha
Published: January 2024

Probiotic Lactobacillus acidophilus LA1 was encapsulated using spray drying with concentrated skim milk with total solids (17%), and maltodextrin (25%), and gum acacia(15%) as carriers. The encapsulated probiotics were assessed for viability following drying at an inlet temperature of 170°C ±3°C and an outlet temperature of 80°C ± 3°C. The viable countenumerated after drying was 108 log cfu/g. The prepared probiotic adjunct was further assessed for viability through in vitro acidand bile salt exposure assay. The results indicated that the cellcount decreased at lower pH (1, 2) and high incubation periods(1 hr and 2 hr). A similar trend was observed with bile. However, they showed better survivability for different incubation periods at low pH and in high bile salt concentrations. The spray-dried probiotic adjunct was kept for storage at three different temperatures i.e., 8 °C, 25 °C, and 37 °C for eight weeks, and assessed weekly for cell viability. An inverse relationship between cell survival and storage temperature was observed during storage.
Nutritional elucidation of rice- and maize gluten meal-based diets: in vitro gas production, digestibility, methane and rumen fermentation
Authors: Mahesh MS , Thakur SS , Nampoothiri Vinu M
Published: January 2024

This experiment intends to elucidate the nutritional potential of alternative ingredient – rice gluten meal (RGM) with groundnut cake (GNC) and maize gluten meal (MGM) at incremental levels in the complete diets under in vitro system. Nine complete diets were formulated using concentrate mixture, green maize and wheat straw in the ratio of 40:40:20 on a dry basis. The dietary treatments differed in the source of major protein sources used in three concentrate mixtures, i.e., GNC in control, while incremental levels of RGM and MGM – both at 25,50, 75 and 100% substituted GNC on an isonitrogenous basis. These diets were characterised for chemical composition, protein fractions, in vitro gas production profile as well as rumen fermentation attributes. The chemical composition of diets showed a mean crude protein (CP) and total digestible nutrient values of 12.9 and 63.6%, respectively. The range of values obtained for various CNCPS protein fractions (% CP) was 11.3-12.4, 9.42-14.0, 40.9-44.4, 19.1-20.1 and 13.6-15.9 for PA, PB1, PB2,PB3 and PC, respectively across the diets. Furthermore, rumen undegradable protein was maximum at 100% MGM inclusion and least for the control. However, intestinal protein digestibility did not differ due to treatments. While the GV24 was maximum (P<0.01)in the control, it was lowest at 100% MGM. Additionally, in vitro dry matter and organic matter digestibilities were higher (P<0.01)for 100% MGM diet and lowest (P<0.01) at 100% RGM level. Moreover, the control diet generated maximum (P<0.01) CH4 but was minimum (P<0.01) for 100% MGM diet. The values of PF,MBP and MBP:GV24 were highest(P<0.01) for 100% MGM and lowest (P<0.01) for control diet. The pH of rumen fluid did not differ; however, concentrations of ammonia nitrogen and total volatile fatty acids were recorded to be maximum (P<0.01) in controland minimum (P<0.01) at 100% MGM. Further, the molar concentration of acetic acid was higher (P<0.01) with MGM-based diets than that of control and RGM diets. Lastly, the proportions of both propionic and butyric acids were minimumwith MGM-based diets than with either control or RGM-baseddiets. Therefore, it could be recommended that RGM could substitute 50-75% of GNC, corresponding to 5-8% inclusion in the complete diet of ruminants. In addition, MGM-based diets excelled in terms of greater digestibility, reduced CH4 emission as well as beneficially influenced rumen fermentation
Impact and determinants of membership in dairy cooperative society: The case of smallholder dairy farmers in Barpeta District of Assam
Authors: Bhattacharjee Shraddhanjali , Nath Dharmendra
Published: January 2024

Dairy cooperatives are associated with creating opportunities for attaining higher level of market integration having implications for significant improvement in income of the dairy farmers. Given the positive impact of DCS membership from the analysis of multivariate regression the study further looks for factors that determine the decision to become membership of DCS. The analysis of the determinants based on logistic regression shows that milch animal holding, credit accessibility, availability of other services from DCS have positive relation with the membership decision, while dairy farming experience, distance to the cooperative collection centre and price of milk are negatively and significantly associated with cooperative membership. The study suggests that facilitating access to credit through dairy cooperatives to meet the financial viability, offering services to dairy farmers like fodder seed, subsidized concentrate feed, veterinary services, and establishment of more collection centre and improving market infrastructure can be instrumental in stimulating farmers’ membership decision to join cooperatives. Overall, to increase farmer’s membership the study recommends policies to take up more awareness programmes and trainings from time to time among the younger farmers on the beneficial effects of participating in cooperative system of dairying. The study concludes that cooperatives can be efficient in fostering wellbeing of the farmers with relatively higher income, employment and nutritional status.
Risk association of metabolites and immune response mediator indicators withthe occurrence of retained placenta in Murrah buffaloes (Bubalus bubalis)
Authors: Mili Bhabesh , Pandita Sujata
Published: January 2024

This study was designed to investigate the risk association of metabolites and immune response mediator indicators with the occurrence of retained placenta (RP) in Murrah buffaloes (Bubalus bubalis). A total of six (n=6) healthy pregnant Murrah buffaloes and four (n=4) buffaloes suffering from RP were selected from the ICAR-NDRI cattle herd. Blood samples were collected from each healthy buffalo on days -56,-48,-42,-35,-28, -21, -14, -7, 0, +7, +14, +21, +28, +35, +35, +42, +48, +56 relative to calving. Blood samples were also collected from the buffaloes on the day of diagnosis of the RP as well as on an alternate day. The result revealed that plasma β-Hydroxybutyric acid (β-HBA)and nitric oxide (NO) levels were significantly (P< 0.05) higher in buffaloes suffering from RP compared to normal parturient buffaloes. The level of IgG was significantly (P<0.05) lowered in buffaloes suffering from RP (8.84±0.85 mg/mL) compared to normal parturient buffaloes (17.41±1.68 mg/mL). However, plasma Non-esterified fatty acids (NEFA), glucose, Blood Urea Nitrogen (BUN),calcium, Interleukin 6 (IL-6), and Total Antioxidant Activities(TAA) levels were non-significant differences between buffaloes suffering from RP and normal parturient buffaloes. A binary logistic regression assay revealed the positive association of postpartum β-HBA with RP (Odds ratio= 1.85). Overall results suggest that plasma β-HBA, IgG, and NO can be used as screening biomarkers during the transition period for the risk assessment of RP in buffaloes.
Application of Taguchi orthogonal array design to optimize microencapsulationof zinc by spray-drying
Authors: P Abhinash , Emerald F Magdaline Eljeeva , Pushpadass Heartwin A , Dhotre Anant V , Rao SB Nageswara
Published: January 2024

Zinc is an essential trace element for the body to maintain normal health and perform important functions. As zinc is not stored in the body, it needs to be replenished through our daily diet. Microencapsulation technique can be used to encapsulate the functional ingredient such as zinc by masking its metallic taste and enhancing its bioavailability. Among the micro encapsulation techniques, spray-drying is the most economical and scalable method. Zinc was micro encapsulatedby spray-drying using maltodextrin, HI-CAP® 100 and WPI along with gum Arabic as wall materials. The spray-drying conditionswere optimized using Taguchi L18 orthogonal array design usingencapsulation efficiency and bulk density as response factors. The influence of wall materials, wall material to zinc ratio and inlet air temperature was evaluated. Microcapsules prepared with HI-CAP® 100 in the ratio of 20:1 at 185°C showed maximum encapsulation efficiency, whereas microcapsules with HI-CAP®100 in the ratio of 10:1 at 185°C had maximum bulk density. The microencapsulated zinc powder had bulk density of 437.40-541.20kg/m3 and encapsulation efficiency of 76.86-92.65%. Validation experiments confirmed that Taguchi orthogonal array design was successful in optimizing microencapsulation of zinc. Microencapsulated zinc can be fortified in various delivery systems such as milk and milk products.
Evaluating Knowledge, Preventive Measures, and Treatment Awareness Regarding Gonorrhea Among Adolescents and Adults in Sagbama, Bayelsa State
Authors: Owonaro Peter A. , Gilbert Timothy , Owonaro Awala Daughter
Published: January 2024

Background of study: Gonorrhea is a sexually transmitted infection caused by the bacterium Neisseria gonorrhoeae. This study aimed to assess the level of knowledge, prevention, and treatment of gonorrhea among those aged 15 – 25 in Sagbama, Bayelsa State.Method: A descriptive study design was used. The population of the study comprises all the aged 15 – 25 years in Sagbama town. The questionnaire was used to select one hundred (100) respondents for the study. Data was analyzed using Statistical Package for Social Sciences (SPSS), version 25, and expressed using frequency distribution tables and percentages.Results: The result revealed that 55% of the respondents have a fair knowledge of gonorrhea while 45% of the respondents had a low knowledge about gonorrhea. 62% of the respondents have good knowledge of the prevention of gonorrhea while 38% of the respondents have low knowledge of the prevention of gonorrhea. Also, the results revealed that 56(56%) of the respondents affirmed that ceftriaxone 500mg IM in a single dose be administered for persons weighing <150kg as a means of gonorrhea treatment, 28(28%) said no while 15(15%) of the respondents have no idea. 49(49%) agree that for persons weighing >150kg, should 1g ceftriaxone.Conclusion: This study clearly identifies adequate knowledge, prevention, and treatment of gonorrhea. This reported knowledge of adequate knowledge, prevention, and treatment of gonorrhea might be due to the participant's information sheet containing detailed information about the study provided for them to read before undertaking this study. However, we suggest further study in the local council areas.
Multi-Objective Optimization for Economic and Environmental Sustainability in Apparel E-commerce Reverse Logistics
Authors: Sharma Nikhil , Saraswat Chirag , Sharma Jeetesh , Mittal Murari Lal , Keprate Arvind
Published: January 2024

In the realm of supply chains, the necessity of a robust reverse logistics network is paramount. While substantial efforts have been directed towards enhancing forward logistics, the domain of reverse logistics remains underdeveloped. This article presents an approach that centers on the formulation of a reverse logistics network for an Indian e-commerce company specializing in apparel sales. Through the construction of single and multi-objective integer programs, the aim is to simultaneously mitigate economic costs and environmental repercussions. To tactfully address environmental concerns while maintaining cost efficiency, different network designs are proposed via the utilization of multi-objective Integer programs, solved using IBM ILOG CPLEX Optimization Studio an optimization software based upon simplex algorithm. The Environmental-Cost-Efficiency (ECE) framework is used to evaluate the multiple network designs. Scrutinizing the intricate equilibrium between costs and ecological implications, the study ultimately identifies an optimized reverse logistics network that yields maximal returns on investment in terms of environmental impact reduction. This comprehensive exploration of the cost-environment trade-off offers valuable guidance to similar organizations aiming to prudently minimize ecological footprints without compromising financial viability. Just as the reverse logistics network is vital within supply chains, this article underscores the potential of its strategic enhancement in driving eco-friendly and economically efficient practices.
Case Report: The management of hemorrhagic shock of different origins by target-controlled coagulation and extracorporeal organ support (continuous renal replacement therapy)
Authors: Pertich Ákos , Lovas András
Published: January 2024

Introduction

Trauma-related severe bleeding and peripartum hemorrhage complicated by shock state is challenging for acute care physicians. Management steps relating to each other include damage control surgery, maintenance of optimal clotting preconditions, point-of-care and targeted supplementation of coagulation factors, control of hyperfibrinolysis, and supplementation of thrombocytes. Extensive tissue damage and surgical management of bleeding activate the proinflammatory process, leading to a dysregulated immune response. The originating systemic inflammation produces further damage, harmfully altering clot formation through the activation of immunothrombosis.

Clinical findings

The case report presents one obstetric, massive bleeding patient and one politraumatized patient with severe hemorrhage. Both underwent extended surgery regarding bleeding control intervention.

Interventions and outcome

Elimination of coagulation disorder was driven by point-of-care viscoelastometry and targeted clotting factor supplementation. Continuous renal replacement therapy and the hemadsorption technique augmented the well-established, up-to-date recommendations-guided care throughout the treatment line. The patients could leave the intensive care unit 4 and 8 days following the initial injury.

Conclusion

Prompt administration of extracorporeal organ support enhanced the recovery from hemorrhagic shock.
Improving regulatory efficiency for biotechnology products
Authors: Koch Muffy , Pence Matthew G. , DeMond Jaylee , Rudgers Gary
Published: January 2024

Small procedural changes in how regulatory agencies implement biotech policies can make significant differences in improving regulatory efficiency. This paper discusses how science based, crop specific guidance documents can improve dossier content and the review and approval of biotech varieties. In addition, we describe how the adoption of established risk assessment methodology and applying policy-linked decision making at the agency level can boost both efficiency and developer, public and government confidence in agency decision making and in biotech crops.
hiPSC-derived cardiomyocytes as a model to study the role of small-conductance Ca2+-activated K+ (SK) ion channel variants associated with atrial fibrillation
Authors: Babini Hosna , Jiménez-Sábado Verónica , Stogova Ekaterina , Arslanova Alia , Butt Mariam , Dababneh Saif , Asghari Parisa , Moore Edwin D. W. , Claydon Thomas W. , Chiamvimonvat Nipavan , Hove-Madsen Leif , Tibbits Glen F.
Published: January 2024

Atrial fibrillation (AF), the most common arrhythmia, has been associated with different electrophysiological, molecular, and structural alterations in atrial cardiomyocytes. Therefore, more studies are required to elucidate the genetic and molecular basis of AF. Various genome-wide association studies (GWAS) have strongly associated different single nucleotide polymorphisms (SNPs) with AF. One of these GWAS identified the rs13376333 risk SNP as the most significant one from the 1q21 chromosomal region. The rs13376333 risk SNP is intronic to the KCNN3 gene that encodes for small conductance calcium-activated potassium channels type 3 (SK3). However, the functional electrophysiological effects of this variant are not known. SK channels represent a unique family of K+ channels, primarily regulated by cytosolic Ca2+ concentration, and different studies support their critical role in the regulation of atrial excitability and consequently in the development of arrhythmias like AF. Since different studies have shown that both upregulation and downregulation of SK3 channels can lead to arrhythmias by different mechanisms, an important goal is to elucidate whether the rs13376333 risk SNP is a gain-of-function (GoF) or a loss-of-function (LoF) variant. A better understanding of the functional consequences associated with these SNPs could influence clinical practice guidelines by improving genotype-based risk stratification and personalized treatment. Although research using native human atrial cardiomyocytes and animal models has provided useful insights, each model has its limitations. Therefore, there is a critical need to develop a human-derived model that represents human physiology more accurately than existing animal models. In this context, research with human induced pluripotent stem cells (hiPSC) and subsequent generation of cardiomyocytes derived from hiPSC (hiPSC-CMs) has revealed the underlying causes of various cardiovascular diseases and identified treatment opportunities that were not possible using in vitro or in vivo studies with animal models. Thus, the ability to generate atrial cardiomyocytes and atrial tissue derived from hiPSCs from human/patients with specific genetic diseases, incorporating novel genetic editing tools to generate isogenic controls and organelle-specific reporters, and 3D bioprinting of atrial tissue could be essential to study AF pathophysiological mechanisms. In this review, we will first give an overview of SK-channel function, its role in atrial fibrillation and outline pathophysiological mechanisms of KCNN3 risk SNPs. We will then highlight the advantages of using the hiPSC-CM model to investigate SNPs associated with AF, while addressing limitations and best practices for rigorous hiPSC studies.
Accounting of value of ecosystem services in the desert: an example of the Kubuqi Desert ecosystem
Authors: Liu Yanbing , Kong Lingqiao , Jiang Chaoqiang , Zhang Xiaoling , Ouyang Zhiyun
Published: January 2024

Ecological products and ecosystem services are essential for human survival and development. Gross Ecosystem Product (GEP) is a method to combine the value of ecosystem services and can reflect the status of ecosystem and ecological conservation and restoration performance. The conservation and restoration of desert ecosystems play an important role in expanding global cultivated land, ensuring food security, and improving human wellbeing. However, ecosystem services and the value of GEP in deserts have been neglected. Taking the Kubuqi Desert ecosystem as an example, this study evaluated the pattens, GEP value, and its change in the Kubuqi Desert ecosystem from 2000 to 2020. Our study found that 1) over the past 20 years, the areas of wetlands, forests, grasslands, and shrubs in the Kubuqi desert ecosystem had increased by 100.65%, 6.05%, 2.24%, and 2.03%, respectively, while that of desert had decreased by 10.62%; 2) the GEP of Kubuqi in 2020 was 55.48 billion CNY, among which its sandstorm prevention value was the highest (39.39%); 3) The value of ecosystem services in the Kubuqi desert ecosystem were all increased over the 20-year period and the largest increase came from sandstorm prevention (increased by 195.09%). This study emphasizes how GEP accounting can promote desert conservation and restoration, quantifies the contribution of desert ecosystems to human wellbeing, and provides future GEP accounting suggestions for desert ecosystems. This study can provide scientific information on the conservation and restoration of global desert ecosystems.
Lithospheric deformation revealed by teleseismic phases SKS PKS and SKKS splitting in the NE margin of the Tibetan plateau
Authors: Xia Xinyu , Gao Yuan , Wu Yue
Published: January 2024

The NE margin of the Tibetan plateau influenced by multiple blocks, the regional dynamic model and lithospheric deformation characteristics are still controversial. In this study, 15 years data from permanent broadband seismic stations of the seismic network in the study area were adopted for splitting analyses of teleseismic phases XKS (SKS PKS and SKKS, shortly named XKS) using a grid search method, longer observations provided each station with a large number of clear seismic phases. The results show that the fast wave directions of XKS splitting are oriented toward WNW or NW, with reference to the direction of absolute plate motion, the lithospheric deformation is dominantly driven by the asthenosphere, although there are local variations. On both sides of the Haiyuan fault zone, there is a noticeable variation in lithospheric azimuthal anisotropy, further enhances the possibility that it is an extended boundary of the Tibetan plateau. Rheological anisotropic features on the western side of the Ordos block emphasize the obstruction of the rigid Ordos lithosphere. The crust and mantle seem to be coupled below the Qinling orogen, possibly related to the lateral movement of lithospheric material. However, in the Hexi corridor, there may be layered anisotropy within the lithosphere, which is inferred to relate to the subductions of the Alxa block and the Qilian orogen. The thicker lithosphere on the southern margin of the Alxa block may influence the asthenospheric flow. In addition, anisotropy results at the southeastern edge of the Alxa block and the Yinchuan graben reflect the possibility that the lithosphere may be characterized by a combination of horizontal and vertical movements. These results have greatly improved our understanding of the dynamic models and lithospheric deformation characteristics of the northeastern margin of the Tibetan plateau and adjacent areas.
A MIC-LSTM based parameter extraction method for single-diode PV model
Authors: Hao Xiaobo , Liu Pengcheng , Deng Yanhui , Meng Xiangjian
Published: January 2024

In recent years, the installed capacity of renewable energy systems has seen rapid growth, particularly in photovoltaic (PV) power. Photovoltaic modules, being the fundamental elements of the PV system, play a crucial role in determining system performance. However, the challenge arises from the inconsistent decay rates of PV modules, which significantly impact the accuracy of PV system modeling. To address this issue, this paper introduces a novel MIC-LSTM based parameter extraction method for the single-diode PV model. This method focuses on accurately deriving PV module model parameters under various decay rates. By establishing a mapping relationship between the current-voltage (I-V) curve characteristics and the five unknown parameters in the photovoltaic module model, the proposed method demonstrates high precision in parameter extraction. Simulation and experimental verifications are carried out to validate the proposed method, where the extraction accuracy is 99.3%, 98.39%, 98.85%, 97.91%, and 98.36% for the five unknown model parameters.
The expansion of liquid biopsies to vascular care: an overview of existing principles, techniques and potential applications to vascular malformation diagnostics
Authors: Mansur Ann , Radovanovic Ivan
Published: January 2024

Vascular malformations are congenital lesions that occur due to mutations in major cellular signalling pathways which govern angiogenesis, cell proliferation, motility, and cell death. These pathways have been widely studied in oncology and are substrates for various small molecule inhibitors. Given their common molecular biology, there is now a potential to repurpose these cancer drugs for vascular malformation care; however, a molecular diagnosis is required in order to tailour specific drugs to the individual patient’s mutational profile. Liquid biopsies (LBs), emerging as a transformative tool in the field of oncology, hold significant promise in this feat. This paper explores the principles and technologies underlying LBs and evaluates their potential to revolutionize the management of vascular malformations. The review begins by delineating the fundamental principles of LBs, focusing on the detection and analysis of circulating biomarkers such as cell-free DNA, circulating tumor cells, and extracellular vesicles. Subsequently, an in-depth analysis of the technological advancements driving LB platforms is presented. Lastly, the paper highlights the current state of research in applying LBs to various vascular malformations, and uses the aforementioned principles and techniques to conceptualize a liquid biopsy framework that is unique to vascular malformation research and clinical care.
Association of serum Nrf2 protein levels with disease activity and renal impairment in lupus nephritis
Authors: Li Jicui , Guo Qiaoyan , Wei Xianping , Zhu Yuexin , Luo Manyu , Luo Ping
Published: January 2024

Introduction

We aimed to investigate the relationship between nuclear factor erythroid 2-related factor 2 (Nrf2) protein expression levels, lupus nephritis (LN) disease activity, and the degree of renal injury (based on the estimated glomerular filtration rate [eGFR]) in patients with LN.

Methods

We selected 40 healthy control participants and 102 patients with LN who were treated in the Second Hospital of Jilin University, China, for inclusion in this study. Patients with LN were classified into LN with high-eGFR and LN with low-eGFR groups. Nrf2 protein levels were measured in the serum and renal tissues of the participants in both groups to assess the correlation between Nrf2 protein levels and different LN disease states.

Results

There was a significantly positive correlation between serum Nrf2 protein levels, the degree of renal injury, and systemic lupus erythematosus disease activity index (SLEDAI) scores in patients with LN. Nrf2 protein levels were higher in the LN with high-eGFR group than in the healthy control and LN with low-eGFR groups. In follow-up patients in the LN high eGFR group, Nrf2 protein levels decreased significantly after remission of disease activity.

Conclusion

Nrf2 protein expression has a dual role in patients with LN. Nrf2 protein levels not only correlate with disease activity in patients with LN, but also with the degree of kidney injury. Before implementing targeted therapy for Nrf2, evaluating both Nrf2 protein expression and the disease state in patients with LN is necessary to better identify and place each patient in an appropriate patient group.
Antagonism of regulatory ISGs enhances the anti-melanoma efficacy of STING agonists
Authors: Filderman Jessica N. , Taylor Jennifer L. , Wang Jianmin , Zhang Yali , Singh Prashant , Ross Mark A. , Watkins Simon C. , Nedal Al Bzour Ayah , Karapetyan Lilit , Kalinski Pawel , Storkus Walter J.
Published: January 2024

Background

Stimulator of Interferon Genes (STING) is a dsDNA sensor that triggers type I inflammatory responses. Recent data from our group and others support the therapeutic efficacy of STING agonists applied intratumorally or systemically in a range of murine tumor models, with treatment benefits associated with tumor vascular normalization and improved immune cell recruitment and function within the tumor microenvironment (TME). However, such interventions are rarely curative and STING agonism coordinately upregulates expression of immunoregulatory interferon-stimulated genes (ISGs) including Arg2, Cox2, Isg15, Nos2, and Pdl1 that may limit treatment benefits. We hypothesized that combined treatment of melanoma-bearing mice with STING agonist ADU-S100 together with antagonists of regulatory ISGs would result in improved control of tumor growth vs. treatment with ADU-S100 alone.

Methods

Mice bearing either B16 (BRAFWTPTENWT) or BPR20 (BRAFV600EPTEN-/-) melanomas were treated with STING agonist ADU-S100 plus various inhibitors of ARG2, COX2, NOS2, PD-L1, or ISG15. Tumor growth control and changes in the TME were evaluated for combination treatment vs ADU-S100 monotherapy by tumor area measurements and flow cytometry/transcriptional profiling, respectively.

Results

In the B16 melanoma model, we noted improved antitumor efficacy only when ADU-S100 was combined with neutralizing/blocking antibodies against PD-L1 or ISG15, but not inhibitors of ARG2, COX2, or NOS2. Conversely, in the BPR20 melanoma model, improved tumor growth control vs. ADU-S100 monotherapy was only observed when combining ADU-S100 with ARG2i, COX2i, and NOS2i, but not anti-PD-L1 or anti-ISG15. Immune changes in the TME associated with improved treatment outcomes were subtle but included increases in proinflammatory innate immune cells and activated CD8+CD69+ T cells and varied between the two tumor models.

Conclusions

These data suggest contextual differences in the relative contributions of individual regulatory ISGs that serve to operationally limit the anti-tumor efficacy of STING agonists which should be considered in future design of novel combination protocols for optimal treatment benefit.
Metabolomic and immune alterations in long COVID patients with chronic fatigue syndrome
Authors: Saito Suguru , Shahbaz Shima , Luo Xian , Osman Mohammed , Redmond Desiree , Cohen Tervaert Jan Willem , Li Liang , Elahi Shokrollah
Published: January 2024

Introduction

A group of SARS-CoV-2 infected individuals present lingering symptoms, defined as long COVID (LC), that may last months or years post the onset of acute disease. A portion of LC patients have symptoms similar to myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), which results in a substantial reduction in their quality of life. A better understanding of the pathophysiology of LC, in particular, ME/CFS is urgently needed.

Methods

We identified and studied metabolites and soluble biomarkers in plasma from LC individuals mainly exhibiting ME/CFS compared to age-sex-matched recovered individuals (R) without LC, acute COVID-19 patients (A), and to SARS-CoV-2 unexposed healthy individuals (HC).

Results

Through these analyses, we identified alterations in several metabolomic pathways in LC vs other groups. Plasma metabolomics analysis showed that LC differed from the R and HC groups. Of note, the R group also exhibited a different metabolomic profile than HC. Moreover, we observed a significant elevation in the plasma pro-inflammatory biomarkers (e.g. IL-1α, IL-6, TNF-α, Flt-1, and sCD14) but the reduction in ATP in LC patients. Our results demonstrate that LC patients exhibit persistent metabolomic abnormalities 12 months after the acute COVID-19 disease. Of note, such metabolomic alterations can be observed in the R group 12 months after the acute disease. Hence, the metabolomic recovery period for infected individuals with SARS-CoV-2 might be long-lasting. In particular, we found a significant reduction in sarcosine and serine concentrations in LC patients, which was inversely correlated with depression, anxiety, and cognitive dysfunction scores.

Conclusion

Our study findings provide a comprehensive metabolomic knowledge base and other soluble biomarkers for a better understanding of the pathophysiology of LC and suggests sarcosine and serine supplementations might have potential therapeutic implications in LC patients. Finally, our study reveals that LC disproportionally affects females more than males, as evidenced by nearly 70% of our LC patients being female.
Anthrax outbreak: exploring its biological agents and public health implications
Authors: Ogunleye Seto C. , Olorunshola Mercy M. , Fasina Kolapo A. , Aborode Abdullahi T. , Akinsulie Olalekan C. , Amoo Abimbola , Olatoye Boluwatife J. , Bakare Akeem , Lawal Mariam A. , Adekanye Oluwabori , Chinyere Ezemba C.
Published: January 2024

The (re)emergence of several infectious zoonoses underlines the need for the re-evaluation of the transmission patterns and key players responsible for effective inter-species transfer of diseases. Anthrax is caused by Bacillus anthracis, a zoonotic rod-shaped, Gram-positive, spore-forming bacterium that is highly fatal to both human and animal populations. B. anthracis is widespread across several regions of the world, including Africa, Asia, southern Europe, North and South America, and Australia, and it has a remarkably high attendant impact on the sustainability and profitability of livestock. The current trend in the global distribution of anthrax necessitates an urgent contextual understanding of the key drivers of the spread of B. anthracis in different parts of the world toward the end goal of an anthrax-free world. The understanding of the drivers is integral for the development of control and preventive measures, and also the development of agents such as therapeutics and vaccines against B. anthracis. This review presents a holistic description of the transmission pattern and epidemiology of B. anthracis, and updates on the diagnostic techniques and approaches available for the detection of B. anthracis. In addition, this review highlights plausible prevention and control strategies for the bacterium. This review further underscores the need for participatory epidemiology, hygiene, and safety protocols, the establishment of comprehensive surveillance systems, and global collaborative efforts toward vaccine development as critical steps in controlling anthrax.
Isolation and Cs+ resistance mechanism of Escherichia coli strain ZX-1
Authors: Kojima Daiki , Tanaka Shunsuke , Kurosaki Ayane , Zhiyu Xiong , Ito Masahiro
Published: January 2024

This research aims to elucidate the physiological mechanisms behind the accidental acquisition of high-concentration cesium ions (Cs+) tolerance of Escherichia coli and apply this understanding to develop bioremediation technologies. Bacterial Cs+ resistance has attracted attention, but its physiological mechanism remains largely unknown and poorly understood. In a prior study, we identified the Cs+/H+ antiporter TS_CshA in Microbacterium sp. TS-1, resistant to high Cs+ concentrations, exhibits a low Cs+ affinity with a Km value of 370 mM at pH 8.5. To enhance bioremediation efficacy, we conducted random mutagenesis of TS_cshA using Error-Prone PCR, aiming for higher-affinity mutants. The mutations were inserted downstream of the PBAD promoter in the pBAD24 vector, creating a mutant library. This was then transformed into E. coli-competent cells. As a result, we obtained a Cs+-resistant strain, ZX-1, capable of thriving in 400 mM CsCl—a concentration too high for ordinary E. coli. Unlike the parent strain Mach1™, which struggled in 300 mM CsCl, ZX-1 showed robust growth even in 700 mM CsCl. After 700 mM CsCl treatment, the 70S ribosome of Mach1™ collapsed, whereas ZX-1 and its derivative ΔZX-1/pBR322ΔAp remained stable. This means that the ribosomes of ZX-1 are more stable to high Cs+. The inverted membrane vesicles from strain ZX-1 showed an apparent Km value of 28.7 mM (pH 8.5) for Cs+/H+ antiport activity, indicating an approximately 12.9-fold increase in Cs+ affinity. Remarkably, the entire plasmid isolated from ZX-1, including the TS_cshA region, was mutation-free. Subsequent whole-genome analysis of ZX-1 identified multiple SNPs on the chromosome that differed from those in the parent strain. No mutations in transporter-related genes were identified in ZX-1. However, three mutations emerged as significant: genes encoding the ribosomal bS6 modification enzyme RimK, the phage lysis regulatory protein LysB, and the flagellar base component protein FlgG. These mutations are hypothesized to affect post-translational modifications, influencing the Km value of TS_CshA and accessory protein expression. This study unveils a novel Cs+ resistance mechanism in ZX-1, enhancing our understanding of Cs+ resistance and paving the way for developing technology to recover radioactive Cs+ from water using TS_CshA-expressing inverted membrane vesicles.
Cost-effectiveness analysis of toripalimab for metastatic or recurrent triple-negative breast cancer
Authors: Shao Jiangbo , Zhan Cuiping , Jin Chunxiang , Jin Ying
Published: January 2024

Background

Toliparibizumab in combination with nab-paclitaxel (T+N) has excellent efficacy inmetastatic or recurrent triple-negative breast cancer (TNBC), but the optimal choice of sequence of therapy is unclear given the trade-offs between quality of life and cost. Cost-effectiveness analyses can quantify these tradeoffs, leading to more informed decisions. Our objective was to assess the societal cost-effectiveness of the T+N regimen for metastatic or recurrent TNBC.

Methods

Clinical data were extracted from a multicenter, randomized, double-blind trial, TORCHLIGHT (NCT04085276). Patients were randomized into the T+N group or placebo plus nab-paclitaxel (P+N) group. 531 patients from 53 study locations were randomly assigned (T+N, n=353; P+N, n=178) into intend to treat (ITT) population; 200 and 100 patients, respectively had programmed death protein 1 (PD-L1) positive TNBC. A Markov model was established with a 21-day cycle length. Costs were acquired from local hospitals, effect parameters included quality-adjusted life year (QALY) and incremental cost-effectiveness ratio (ICER).

Results

The cost differences were 47,538.3 CNY in ITT population (T+N, 143,725.67 CNY; P+N group, 96,187.37 CNY) and 29,258.84 CNY in PD-L1+ subgroup (T+N, 100,128.28 CNY; P+N group, 70,869.45 CNY). Meanwhile, the IEs were 0.03409 in the ITT population (T+N, 0.55323 QALY; P+N, 0.51914 QALY) and 0.03409 in the PD-L1+ subgroup (T+N, 0.42327 QALY; P+N, 0.37628 QALY). The ICERs between T+N and P+N groups were 1,394,548.41 CNY/QALY in the ITT population and 622,663.98 CNY/QALY in the PD-L1+ subgroup. We also analyzed the cost-effectiveness of toripalimab could be received in the Chinese medical insurance catalog. If toripalimab could be reimbursed at an 80% rate, the cost differences were changed to 16,598.99 CNY in ITT population (T+N, 112,786.36 CNY; P+N group, 96,187.37 CNY) and 7,704.58 CNY in PD-L1+ subgroup (T+N, 78,574.03 CNY; P+N group, 70,869.45 CNY). Meanwhile, the IEs remained unchanged. The ICERs between T+N and P+N groups were changed to 486,935.82 CNY/QALY in the ITT population and 163,962.96 CNY/QALY in the PD-L1+ subgroup. Sensitivity analyses indicated the stability of the model and the impact of utility.

Conclusion

At current drug prices, the T+N group is not more cost-effective than the P+N group, but after incorporating toripalimab into medical insurance, the T+N group will be more cost-effective for patients with PD-L1+ metastatic or recurrent triple-negative breast cancer.
Perceived potentially inappropriate treatment in the PICU: frequency, contributing factors and the distress it triggers
Authors: Sarpal Amrita , Miller Michael R. , Martin Claudio M. , Sibbald Robert W. , Speechley Kathy N.
Published: January 2024

Background

Potentially inappropriate treatment in critically ill adults is associated with healthcare provider distress and burnout. Knowledge regarding perceived potentially inappropriate treatment amongst pediatric healthcare providers is limited.

Objectives

Determine the frequency and factors associated with potentially inappropriate treatment in critically ill children as perceived by providers, and describe the factors that providers report contribute to the distress they experience when providing treatment perceived as potentially inappropriate.

Methods

Prospective observational mixed-methods study in a single tertiary level PICU conducted between March 2 and September 14, 2018. Patients 0–17 years inclusive with: (1) ≥1 organ system dysfunction (2) moderate to severe mental and physical disabilities, or (3) baseline dependence on medical technology were enrolled if they remained admitted to the PICU for ≥48 h, and were not medically fit for transfer/discharge. The frequency of perceived potentially inappropriate treatment was stratified into three groups based on degree of consensus (1, 2 or 3 providers) regarding the appropriateness of ongoing active treatment per enrolled patient. Distress was self-reported using a 100-point scale.

Results

Of 374 patients admitted during the study, 133 satisfied the inclusion-exclusion criteria. Eighteen patients (unanimous - 3 patients, 2 providers - 7 patients; single provider - 8 patients) were perceived as receiving potentially inappropriate treatment; unanimous consensus was associated with 100% mortality on 3-month follow up post PICU discharge. Fifty-three percent of providers experienced distress secondary to providing treatment perceived as potentially inappropriate. Qualitative thematic analysis revealed five themes regarding factors associated with provider distress: (1) suffering including a sense of causing harm, (2) conflict, (3) quality of life, (4) resource utilization, and (5) uncertainty.

Conclusions

While treatment perceived as potentially inappropriate was infrequent, provider distress was commonly observed. By identifying specific factor(s) contributing to perceived potentially inappropriate treatment and any associated provider distress, organizations can design, implement and assess targeted interventions.
Mild phenotype of CHAT-associated congenital myasthenic syndrome: case series
Authors: Murtazina Aysylu , Borovikov Artem , Marakhonov Andrey , Sharkov Artem , Sharkova Inna , Mirzoyan Alena , Kulikova Sviatlana , Ganieva Ralina , Zabnenkova Viktoriia , Ryzhkova Oksana , Nikitin Sergey , Dadali Elena , Kutsev Sergey
Published: January 2024

Congenital myasthenic syndrome with episodic apnea is associated with pathogenic variants in the CHAT gene. While respiratory disorders and oculomotor findings are commonly reported in affected individuals, a subset of patients only present with muscle weakness and/or ptosis but not apneic crises. In this case series, we describe five individuals with exercise intolerance caused by single nucleotide variants in the CHAT gene. The age of onset ranged from 1 to 2.5 years, and all patients exhibited a fluctuating course of congenital myasthenic syndrome without disease progression over several years. Notably, these patients maintained a normal neurological status, except for the presence of abnormal fatigability in their leg muscles following prolonged physical activity. We conducted a modified protocol of repetitive nerve stimulation on the peroneal nerve, revealing an increased decrement in amplitude and area of compound muscle action potentials of the tibialis anterior muscle after 15–20 min of exercise. Treatment with 3,4-diaminopyridine showed clear improvement in two children, while one patient experienced severe adverse effects and is currently receiving a combination of Salbutamol Syrup and pyridostigmine with slight positive effects. Based on our findings and previous cases of early childhood onset with muscle fatigability as the sole manifestation, we propose the existence of a mild phenotype characterized by the absence of apneic episodes.