Consistent Reduction Research Articles

One-year outcomes of catheter ablation for atrial fibrillation in young patients

BackgroundAtrial fibrillation (AF) is relatively less frequent in younger patients (age < 50). Recently, studies have suggested that early restoration of sinus rhythm may lead to improved outcomes compared with rate control, however the efficacy of catheter ablation for AF in young is scarce.MethodsWe included all hospitalized patients between 18 and 50 years with a diagnosis of AF from the Nationwide Readmission Database 2016–2017 from the Healthcare Cost and Utilization Project. Demographic and comorbidity data were collected and analyzed. Outcomes assessed included one-year AF readmission rates, all-cause readmission, ischemic stroke, and all-cause mortality. Subgroup analyses were performed for all demographic and comorbidity variables.ResultsOverall, 52,598 patients (medium age 44, interquartile range 38–48, female 25.7%) were included in the study, including 2,146 (4.0%) who underwent catheter ablation for AF. Patients who underwent catheter ablation had a significantly lower rate of readmission for AF or any cause at one year (adjusted hazard ratios (HR) of 0.52 [95% confidence interval (CI): 0.43–0.63] and HR of 0.81 [95% CI: 0.72–0.89], respectively). There was no difference in 1-year readmission for stroke or all-cause mortality between the two groups. Subgroup analyses showed a consistent reduction in the risk of AF readmission among major demographic and comorbidity subgroups.ConclusionCatheter ablation in young patients with AF was associated with a reduction in 1-year AF related and all-cause readmissions. These data merit further prospective investigation for validation, through dedicated registries and multicenter collaborations to include young AF from diverse population.

Targeting the Gastrin-Releasing Peptide Receptor (GRP-R) in Cancer Therapy: Development of Bombesin-Based Peptide-Drug Conjugates.

Targeted tumour therapy has proved to be an efficient alternative to overcome the limitations of conventional chemotherapy. Among several receptors upregulated in cancer cells, the gastrin-releasing peptide receptor (GRP-R) has recently emerged as a promising target for cancer imaging, diagnosing and treatment due to its overexpression on cancerous tissues such as breast, prostate, pancreatic and small-cell lung cancer. Herein, we report on the in vitro and in vivo selective delivery of the cytotoxic drug daunorubicin to prostate and breast cancer, by targeting GRP-R. Exploiting many bombesin analogues as homing peptides, including a newly developed peptide, we produced eleven daunorubicin-containing peptide-drug conjugates (PDCs), acting as drug delivery systems to safely reach the tumour environment. Two of our bioconjugates revealed remarkable anti-proliferative activity, an efficient uptake by all three tested human breast and prostate cancer cell lines, high stability in plasma and a prompt release of the drug-containing metabolite by lysosomal enzymes. Moreover, they revealed a safe profile and a consistent reduction of the tumour volume in vivo. In conclusion, we highlight the importance of GRP-R binding PDCs in targeted cancer therapy, with the possibility of further tailoring and optimisation.

Unravelling the functional regulation of the NALCN sodium leak channel complex by G protein-coupled receptors.

The sodium leak channel NALCN (Na+ leak channel, non-selective) is expressed throughout numerous mammalian tissues, especially in neurons. It has been identified as a major contributor to background sodium conductance, and hence resting membrane potential and cellular excitability. Unsurprisingly, the extent of NALCN activity is highly regulated in most cell types. Specifically, several G protein-coupled receptors (GPCRs) have been shown to regulate NALCN, both in cell lines and native tissues. The mechanism behind this functional regulation, however, remains poorly understood. Here, we investigate the regulation of NALCN by GPCRs and the underlying signaling pathways by expressing the NALCN channel complex (including NALCN, UNC79, UNC80, and FAM155A) in Xenopus laevis oocytes together with several different GPCRs and G protein subunits, while evaluating NALCN function using two-electrode voltage-clamp (TEVC). We find that activation of the GABA-B receptor (GABA-BR) co-expressed with NALCN leads to a small, but consistent and reversible reduction in NALCN currents. We propose this effect to be mediated by the GABA-BR-coupled G αi subunit, because co-expression of it alone, but not G β1γ2, leads to a significant inhibition of NALCN currents. Using mutants that lock G αi in either its active or inactive state, we find that the active state of G αi tends to inhibit NALCN more strongly, while inactive G αi mutants show less pronounced inhibition. However, pharmacological inhibition of the adenylyl cyclase, the main downstream target of G αi, does not lead to a reduction in NALCN currents, possibly suggesting a direct interaction between the G protein and the NALCN sodium leak channel complex. Overall, our data demonstrate that GPCRs and G protein αi in particular can regulate NALCN function. However, the underlying mechanisms for these observations remain to be elucidated.

Intraocular Microbiome in Diabetes and Diabetic Retinopathy: A Pilot Study.

The objective of this study was to compare the microbiome in the aqueous humour and gut of people with diabetes mellitus (DM) with and without diabetic retinopathy (DR). This was a prospective controlled study. The study included 17 people undergoing intraocular surgery in their naïve eyes. Stool samples were obtained in the perioperative period; aqueous humour samples of sufficient quantity were obtained in 12 people during intraocular surgery. Dietary information was obtained using a previously validated questionnaire. The gut and aqueous humour samples were assessed for microbiome using 16S rRNA gene sequencing coupled with QIIME and R software. Aqueous humour was analysed in 12 people: 4 each healthy controls, people with DM, and people with DR. There were minor differences at the phyla levels, but the aqueous humour microbiomes of healthy controls, DM, and DR formed three distinct clusters on heat map analysis with discriminatory genera. This genera-level clustering was more apparent for the intraocular than the gut microbiome. In people with DM and DR, we identified genera unique to the eye or the gut. There was a consistent reduction in the abundance of anti-inflammatory bacteria in people with DR than DM. There is a difference in intraocular and gut microbiome regardless of disease or health. Our preliminary findings indicate distinctive features of the intraocular microbiome in people with DR compared with those without it. While this distinctiveness appears more evident in aqueous humour than in the gut, it needs further confirmation with larger studies.

Pandemic Phase-Adjusted Analysis of COVID-19 Outcomes Reveals Reduced Intrinsic Vulnerability and Substantial Vaccine Protection From Severe Acute Respiratory Syndrome Coronavirus 2 in Patients With Breast Cancer.

Although representing the majority of newly diagnosed cancers, patients with breast cancer appear less vulnerable to COVID-19 mortality compared with other malignancies. In the absence of patients on active cancer therapy included in vaccination trials, a contemporary real-world evaluation of outcomes during the various pandemic phases, as well as of the impact of vaccination, is needed to better inform clinical practice. We compared COVID-19 morbidity and mortality among patients with breast cancer across prevaccination (February 27, 2020-November 30, 2020), Alpha-Delta (December 1, 2020-December 14, 2021), and Omicron (December 15, 2021-January 31, 2022) phases using OnCovid registry participants (ClinicalTrials.gov identifier: NCT04393974). Twenty-eight-day case fatality rate (CFR28) and COVID-19 severity were compared in unvaccinated versus double-dosed/boosted patients (vaccinated) with inverse probability of treatment weighting models adjusted for country of origin, age, number of comorbidities, tumor stage, and receipt of systemic anticancer therapy within 1 month of COVID-19 diagnosis. By the data lock of February 4, 2022, the registry counted 613 eligible patients with breast cancer: 60.1% (n = 312) hormone receptor-positive, 25.2% (n = 131) human epidermal growth factor receptor 2-positive, and 14.6% (n = 76) triple-negative. The majority (61%; n = 374) had localized/locally advanced disease. Median age was 62 years (interquartile range, 51-74 years). A total of 193 patients (31.5%) presented ≥ 2 comorbidities and 69% (n = 330) were never smokers. In total, 392 (63.9%), 164 (26.8%), and 57 (9.3%) were diagnosed during the prevaccination, Alpha-Delta, and Omicron phases, respectively. Analysis of CFR28 demonstrates comparable estimates of mortality across the three pandemic phases (13.9%, 12.2%, 5.3%, respectively; P = .182). Nevertheless, a significant improvement in outcome measures of COVID-19 severity across the three pandemic time periods was observed. Importantly, when reported separately, unvaccinated patients from the Alpha-Delta and Omicron phases achieved comparable outcomes to those from the prevaccination phase. Of 566 patients eligible for the vaccination analysis, 72 (12.7%) were fully vaccinated and 494 (87.3%) were unvaccinated. We confirmed with inverse probability of treatment weighting multivariable analysis and following a clustered robust correction for participating center that vaccinated patients achieved improved CFR28 (odds ratio [OR], 0.19; 95% CI, 0.09 to 0.40), hospitalization (OR, 0.28; 95% CI, 0.11 to 0.69), COVID-19 complications (OR, 0.16; 95% CI, 0.06 to 0.45), and reduced requirement of COVID-19-specific therapy (OR, 0.24; 95% CI, 0.09 to 0.63) and oxygen therapy (OR, 0.24; 95% CI, 0.09 to 0.67) compared with unvaccinated controls. Our findings highlight a consistent reduction of COVID-19 severity in patients with breast cancer during the Omicron outbreak in Europe. We also demonstrate that even in this population, a complete severe acute respiratory syndrome coronavirus 2 vaccination course is a strong determinant of improved morbidity and mortality from COVID-19.

Cytotoxicity Evaluation of Erythrina lithosperma Miq. Leaf Extract against Vero Cell Lines: In Vitro Study

In several societies, the development of traditional medicine employing plants to enhance medicinal formulations has been promoted as a valuable offering in therapeutic applications. Bali Province in Indonesia, which has a healthy culture until now, has a rich history of traditional medicine regarding the utilization of local plants. The purpose of this study was to determine the cytotoxicity of Erythrina lithosperma Miq leaf extract (ELLE) on Vero cells to gain knowledge of its potential as a standardized traditional medicine. A cytotoxicity test was performed on Vero cell lines grown on M119 medium with 10% FBS and incubated at 37°C in a CO2 incubator until confluent. Cells were collected and grown in 96 well microplates at a cell density of 2x104 cells/100mL/well at the start. After a 24-hour incubation period, extracts were subjected to concentrations ranging from 31.25 to 10,000µg/ml. Cell viability was determined using the MTT technique (3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyltetrazolium bromide). A one-way ANOVA test with a significance level of 5% was performed. Cell viability increased with decreasing concentration extracts used. There was no significant difference between concentrations of 500, 250, 125, 63, and 31µg/ml. A consistent and significant reduction occurred in cell proliferation added with very high extract concentrations. Empirically ELLE can be used as a traditional medicine for certain diseases, this experiment reduces the viability of Vero cells lines at very high concentrations. Overall, the findings of this study suggest that the investigated ELLE might be developed as a novel dietary component and traditional medicinal preparation for promoting human health.

A 21st‐Century perspective on snow drought in the Upper Colorado River Basin

AbstractIn the Upper Colorado River Basin (UCRB), there is a deep reliance on seasonal snowpack for maintenance of water resources. The term “snow drought” has recently emerged to describe periods of anomalously low snowpack. Unique seasonal patterns in precipitation and temperature that drive snow drought can have distinct hydrologic signatures, and these relationships have not been carefully studied in the UCRB. Here we examine snow drought with a new classification scheme using peak snow water equivalent (SWE) and the ratio of basin‐wide modeled peak SWE to accumulated (onset to peak) precipitation (SWE/P) that clusters snow drought years into three distinct groups—“warm,” “dry,” and “warm &amp; dry”—that minimize within‐group variance. Over the period 1916–2018, we identify 14 warm years ( = 160 mm; = 0.24), 24 dry years ( = 117 mm; = 0.35), and 21 warm &amp; dry years ( = 94 mm; = 0.23). An elevation‐based analysis reveals two distinct patterns: warm snow droughts see severe SWE reductions primarily at lower (&lt;2600 m) elevations (65% at lower elevations, 37% overall), whereas “dry” scenarios exhibit a consistent reduction across all elevations (39% overall). Using naturalized streamflow data, we also differentiate snow droughts by their earlier streamflow timing and decreased peakedness (warm: 7 days, 2%; dry: 7 days, 2%; warm &amp; dry: 13 days, 5%). This research provides new insights into snow drought patterns relevant for regional water management.

Management of Persistent Erectile Dysfunction after COVID-19 Infection: An 18-Month Follow-Up Case Report

The coronavirus disease 2019 (COVID-19) is an emerging pandemic caused by a novel coronavirus (SARS-CoV-2). Since December 2019 the new virus has spread all over the world and has become a major health problem also because of the public measures that could affect people’s sexual activity. We report a case of a 35-year-old married male admitted to the andrology outpatient clinic in July 2021 because of sudden onset erectile dysfunction (ED). The diagnostic workup showed no risk factor for ED, normal levels of testosterone, increased levels of endothelial dysfunction markers, such as CRP (C-Reactive Protein) and Endothelin-1, and reduced Vitamin D (VD) levels. Dynamic penile duplex ultrasound (D-PDU) revealed dysfunctional penile arterial flow. The five-item International Index of Erectile Function (IIEF-5) and the Short-Form Health Survey (SF-36) showed a reduction in all domain scores. The patient, initially unresponsive to the high dose oral phosphodiesterase 5 inhibitors (PDE-5is), was treated with vitamin-D and then submitted to LI-SWT (low intensity shockwave treatment), with a progressive clinical benefit at the 12-month follow-up. After 18 months, hormone levels persisted in normal ranges, with a consistent reduction in CRP and Endothelin-1. Additionally, IIEF-5, SF-36 and arterial flow significantly improved over the follow-up period. Thus far, the erectile function was restored and the patient is no more treated with PDE-5i.

A hierarchical two-level MILP optimization model for the management of grid-connected BESS considering accurate physical model

This work proposes a new Energy Management System (EMS) for Battery Energy Storage Systems (BESS). The goal is to make a BESS profitable in the new environment considering massive use of batteries that can be foreseen in the next future, due to the predictive increase of clean energy resources. The developed EMS considers two levels of optimization. The first level models the participation of the BESS in an Ancillary Service Market and schedules the BESS. The second level, the most innovative, is responsible for optimally distributing the power set-points obtained previously among the various battery banks considering, in addition to the battery aging, also the different efficiencies of battery banks, converters, and transformers. Moreover, this second-level manages both active and reactive power flows, and losses. Both optimization algorithms have been modeled as Mixed Integer Linear Programming (MILP) and implemented in GAMS using CPLEX as a solver. The results are encouraging: compared with the common industrial practice in which the load profile is equally shared among the individual batteries within a BESS, the two new proposed EMS strategies guarantee for a long period of operation (10-years) a consistent reduction in the number of batteries replacement (around 47%), thus ensuring significant cost savings. Moreover, the proposed BESS model accurately approximates the real physical behavior of the system, leading to an average error in State-of Energy (SoE) evaluation below 0.6%, which is almost one order of magnitude lower than the ones obtained by simpler models from literature with degradation only SoE-dependent.

Resveratrol Derivative Exhibits Marked Antiproliferative Actions, Affecting Stemness in Pancreatic Cancer Cells.

Pancreatic cancer (PC) is one of the deadliest malignancies, with an increasing incidence and limited response to current therapeutic options. Therefore, more effective and low-toxic agents are needed to improve PC patients' outcomes. Resveratrol (RSV) is a natural polyphenol with multiple biological properties, including anticancer effects. In this study, we explored the antiproliferative activities of newly synthetized RSV analogues in a panel of PC cell lines and evaluated the physicochemical properties of the most active compound. This derivative exhibited marked antiproliferative effects in PC cells through mechanisms involving DNA damage, apoptosis induction, and interference in cell cycle progression, as assessed using flow cytometry and immunoblot analysis of cell cycle proteins, PARP cleavage, and H2AX phosphorylation. Notably, the compound induced a consistent reduction in the PC cell subpopulation with a CD133+EpCAM+ stem-like phenotype, paralleled by dramatic effects on cell clonogenicity. Moreover, the RSV derivative had negligible toxicity against normal HFF-1 cells and, thus, good selectivity index values toward PC cell lines. Remarkably, its higher lipophilicity and stability in human plasma, as compared to RSV, might ensure a better permeation along the gastrointestinal tract. Our results provide insights into the mechanisms of action contributing to the antiproliferative activity of a synthetic RSV analogue, supporting its potential value in the search for effective and safe agents in PC treatment.

Serine/Threonine Kinase 11 Plays a Canonical Role in Malignant Progression of KRAS -Mutant and GNAS -Wild-Type Intraductal Papillary Mucinous Neoplasms of the Pancreas.

We aimed to elucidate the clinicopathobiological significance of Serine/Threonine Kinase 11 (STK11) in pancreatic intraductal papillary mucinous neoplasms (IPMNs). STK11 is a tumor suppressor involved in certain IPMNs; however, its significance is not well known. In 184 IPMNs without Peutz-Jeghers syndrome, we analyzed expression of STK11 and phosphorylated-AMPKa in all cases, and p16, p53, SMAD4, and β-catenin in 140 cases by immunohistochemistry; and we analyzed mutations in 37 genes, including whole coding exons of STK11, CDKN2A, TP53, and SMAD4, and hotspots of KRAS, BRAF, and GNAS in 64 cases by targeted sequencing. KRAS and GNAS were additionally analyzed in 86 STK11-normal IPMNs using digital-PCR. Consistent loss or reduction of STK11 expression was observed in 26 of 184 (14%) IPMNs. These STK11-aberrant IPMNs were 17 of 45 (38%) pancreatobiliary, 8 of 27 (30%) oncocytic, 1 of 54 (2%) gastric, and 0 of 58 (0%) intestinal subtypes ( P = 8.5E-11), and 20 of 66 (30%) invasive, 6 of 74 (8%) high-grade, and 0 of 44 (0%) low-grade ( P = 3.9E-06). Sixteen somatic STK11 mutations (5 frameshift, 6 nonsense, 1 splicing, and 4 missense) were detected in 15/26 STK11-aberrant IPMNs ( P = 4.1E-06). All STK11-aberrantIPMNs were GNAS -wild-type and 96% of them were KRAS or BRAF -mutant.Morphologically, STK11-aberrant IPMNs presented "fern-like" arborizing papillae with thin fibrovascular core. Phosphorylated-AMPKa was down-regulated in STK11-aberrant IPMNs (92%, P = 6.8E-11). Patients with STK11-aberrant IPMNs showed poorer survival than patients with STK11-normal IPMNs ( P = 3.6E-04 overall; P = 6.1E-04 disease-free). STK11 may play a canonical role in malignant progression and poor survival of patients with IPMNs. Aberrant STK11-driven phosphorylated AMPK downregulation may provide therapeutic opportunities with mTOR inhibitors/AMPK activators.

The Double-Edged Sword of Oleuropein in Ovarian Cancer Cells: From Antioxidant Functions to Cytotoxic Effects

Oleuropein plays a key role as a pro-oxidant as well as an antioxidant in cancer. In this study, the activity of oleuropein, in an in vitro model of ovarian (OCCs) and breast cancer cells (BCCs) was investigated. Cell viability and cell death were analyzed. Oxidative stress was measured by CM-H2DCFDA flow cytometry assay. Mitochondrial dysfunction was evaluated based on mitochondrial reactive oxygen species (ROS) and GPX4 protein levels. Further, the effects on iron metabolism were analyzed by measuring the intracellular labile iron pool (LIP). We confirmed that high doses of oleuropein show anti-proliferative and pro-apoptotic activity on HEY and MCF-7 cells. Moreover, our results indicate that low doses of oleuropein impair cell viability without affecting the mortality of cells, and also decrease the LIP and ROS levels, keeping them unchanged in MCF-7 cells. For the first time, our data show that low doses of oleuropein reduce erastin-mediated cell death. Interestingly, oleuropein decreases the levels of intracellular ROS and LIP in OCCs treated with erastin. Noteworthily, we observed an increased amount of ROS scavenging enzyme GPX4 together with a consistent reduction in mitochondrial ROS, confirming a reduction in oxidative stress in this model.

Trends of Tuberculosis Prevalence, Treatment and Prevention Efforts in Yenagoa, Bayelsa State

Background: Tuberculosis is still rampant in Nigeria, and contributes significantly to TB burden globally. This study was conducted with the main objective of determining the trends of TB prevalence, treatment and preventive efforts by the government of Bayelsa State, and providing insight into the level of progress in the fight against TB in the State. Methods: It is a retrospective study of TB programme data consisting of 10,512 patients who accessed healthcare services at the health facilities from 2017 to 2021. Enrolment registers, TB Treatment registers, Test Result Request Forms and Laboratory registers were consulted to obtain accurate data. Additionally, observation of the processes at the various health facilities and the review of TB programme documents, including periodic reports, training manuals, presentation slides and the Information, Education and Communication (IEC) materials were conducted to garner information about TB prevention and control efforts in the state. Results: This study finds that there is a consistent reduction in TB prevalence rates from 2017 (23.2%) to 2021 (17.6%). The average cumulative five-year prevalence for all TB cases is 22.4% and 2.8% for Drug-Resistant TB (DR-TB). The results further indicated that less females (9.3%) than males (13.8%) were infected with TB (p&lt;0.05), while the age group 25-34 years recorded the highest TB prevalence. The study participants had a mean age of 31.67 ± 18.59 years. There is a strong evidence that difference in prevalence is statistically significant across sex/gender (X2 = 22.011, df = 4, p-value = 0.0002), age groups (F(7, 24) = 13.871, p = 0.0001), and years ((F(4, 24) = 80.925, p = 0.0001). TB Treatment initiation rate is optimal but declined by 1.7% in 2021. Conclusion: TB Prevalence in Yenagoa is high and intensified TB Case finding, contact tracing efforts are necessary to quickly curb transmission rate. Systematic screening and presumptive TB identification appears inadequate compared to the number of TB cases detected each year.

Synthesis and Characterization of Sweet Potato Starch Biocomposite Incorporated with ZnO Nanoparticles

The rapid rise in the production of hazardous waste in the environment, particularly single-use plastics, has prompted the development of sustainable yet cost-effective alternatives. This research aims to create bioplastic films using renewable energy sources. To prevent toxic side products, the composite bioplastics synthesized from sweet potato starch are incorporated with biogenically synthesized ZnO NPs. Biocomposite films were characterized by their morphology, water vapor permeability (WVP), biodegradability, thermal and mechanical properties. It was noted that the ZnO NPs had substantial effects on the tensile properties of the nanocomposite films. The addition of ZnO NPs to the starch bioplastic films considerably enhanced tensile strength from 1.41 to 2.26 MPa, elongation from 78.20 to 114.91%, and Young’s modulus from 1.62 to 2.40 MPa. The incorporation of ZnO NPs lowered the degree of WVP and film solubility value compared to those of the starch films. The bioplastic film incorporated with ZnO NPs had effective UV absorption and transparency. The shift in the peaks in the FT-IR spectra confirmed the relationship between the polymer matrix and the ZnO NPs. Thermal degradation of bio nanocomposite at 339.60 and#176;C is shown by a consistent reduction in TGA between 240 and#176;C and 410 and#176;C. The high melting temperature (Tm) of 144 oC for starch film and 201.86 oC for bio nanocomposite was found using DSC analysis. SEM analysis revealed that biocomposite films had better compatible morphologies with small cracks and the roughness of films increased with the addition of ZnO NPs content. The biodegradability of the biocomposite films was analyzed through the soil burial method. The bioplastic produced in this study has the potential to be a viable alternative to existing conventional plastics in the packaging industry.

Պետական պարտքի կառավարման արդյունավետության մեծացման մեթոդական հենքի բարելավման հիմնախնդիրները Հայաստանի Հանրապետությունում / The problems of improving the methodological basis for increasing the public debt management efficiency in the Republic of Armenia

The amount of public debt and its ratio to the GDP are one of the most important economic indicators of the state. It is a matter of concern indeed that both indicators are steadily increasing in Armenia. In particular, in recent years the total public debt has almost doubled. By way of various methods (statistical data study, comparative analysis, generalization, etc.), the article not only examines the public debt of the Republic of Armenia and its ratio to the with GDP, but also the prospects for increasing the efficiency of debt management. Meanwhile, aspects of debt security are analyzed in the general system of economic threats to the security of the Republic of Armenia. Throughout the research, special attention is paid not only to the amount of debt and its ratio to the GDP, but also to various theoretical and practical ways of effective management of debt, targeted at its consistent reduction. The author comes up with a few innovative models and mechanisms for solving this problem. More particularly, the method of “Conversion of external public debt into environmental projects”, which has been successfully tested by a number of developing Eastern European, Asian, African and Latin American countries, is proposed as one of the most optimal and effective mechanisms for debt reduction. Its essence lies in the fact that with the creditors’ consent, the debt is partially or completely written off if the debtor state invests these funds in environmental programs carried out on its territory. A good method of debt reduction is the restructuring of the external debt, namely, the one Russia has turned to in order to reduce its debt to the London Club. To sum up, the author has come up with a number of recommendations to optimize the debt management, in particular, reformation of the RA legislation in the financial and budgetary sphere

Current Update on Rotavirus in-Silico Multiepitope Vaccine Design.

Rotavirus gastroenteritis is one of the leading causes of pediatric morbidity and mortality worldwide in infants and under-five populations. The World Health Organization (WHO) recommended global incorporation of the rotavirus vaccine in national immunization programs to alleviate the burden of the disease. Implementation of the rotavirus vaccination in certain regions of the world brought about a significant and consistent reduction of rotavirus-associated hospitalizations. However, the efficacy of licensed vaccines remains suboptimal in low-income countries where the incidences of rotavirus gastroenteritis continue to happen unabated. The problem of low efficacy of currently licensed oral rotavirus vaccines in low-income countries necessitates continuous exploration, design, and development of new rotavirus vaccines. Traditional vaccine development is a complex, expensive, labor-intensive, and time-consuming process. Reverse vaccinology essentially utilizes the genome and proteome information on pathogens and has opened new avenues for in-silico multiepitope vaccine design for a plethora of pathogens, promising time reduction in the complete vaccine development pipeline by complementing the traditional vaccinology approach. A substantial number of reviews on licensed rotavirus vaccines and those under evaluation are already available in the literature. However, a collective account of rotavirus in-silico vaccines is lacking in the literature, and such an account may further fuel the interest of researchers to use reverse vaccinology to expedite the vaccine development process. Therefore, the main focus of this review is to summarize the research endeavors undertaken for the design and development of rotavirus vaccines by the reverse vaccinology approach utilizing the tools of immunoinformatics.

Protein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies (PCSK9mab) in Clinical Practice at Secondary Care - Real World Multicentre Experience.

Background and Aims Protein convertase subtilisin/Kexin type 9 monoclonal antibodies (PCSK9mab) are a novel addition to the therapeutic options for managing hyperlipidemia. Various guidelines have advocated the addition of these agents if the target low-density lipoprotein-cholesterol ( LDL-C) is not achieved by maximum lipid-lowering therapy. They have shown a robust and consistent reduction in LDL-C in clinical trials. However, the translation of these results in a real-world setting is limited and confined mainly to tertiary lipid centers. This service evaluation aimed to assess their efficacy in a real-world outpatient setting of secondary care centers. Methods Data was collected retrospectively from four hospitals in the North-West of England. Patients were required to attend a lipid clinic for follow-up investigations to continue with the prescription of PCSK9mab. Results A total of 175 patients were identified. Efficacy outcomes were measured in 169 patients. 6 discontinued the agent within 3 months of initiation and were excluded from the efficacy outcomes. 19.5% (n=33) had confirmed familial hypercholesterolemia. 61% (n=103) of the patients were intolerant to statins. 53.2% (n=90) of the patients have been prescribed Alirocumab. Mean LDL-C reduction was 50.6% at 6-month which was sustained at 48.9% at 12 months. There was no difference in % reduction of LDL-C between Alirocumab and Evolocumab. LDL-C reduction was more significant in patients who were on concomitant statins. 9.1% of patients experienced side effects, and 5.1% discontinued the PCSK9mab during treatment. Conclusion The efficacy of lipid reduction and the side effect profile of PCSK9mab from these secondary care services are similar to randomized clinical trials and real-world observational studies from tertiary lipid centers.

Сокращение расхода электроэнергии грузовыми магистральными электровозами 2(3)ЭС5С при работе в энергоэффективном режиме по итогам эксплуатационных испытаний

Purpose: To evaluate the reduction in power specific consumption by freight mainline loco-motives 2(3)ES5S when operating in power-efficient mode (automatic speed control in com-bination with discrete-adaptive switch on/off of Traction Electric Drive depending on an in-stantaneous load), obtained from the results of operational tests. Methods: Array records analysis of on-board recorder made it possible to establish the nature of the dependence of locomotive efficiency degree from its power consumption. Way for controlling multi-engine traction electric drive efficiency in traction mode has been developed and patented. Computer modeling has allowed to obtain preliminary estimate to increase power efficiency. Speed au-tomatic controller block is built using finite automation theory method. The proposed changes, aimed at locomotive power efficiency improvement, have been introduced into top-level con-trol system. Final ratings of power consumption have been obtained during operational trials. Results: The analysis of results obtained during two trips on about 7-thousand-ton mass trains along section with hilly profile of 108 km length is presented. Ceteris paribus, during second trip, when electric locomotive was operating in power-efficient mode (discrete-adaptive con-trol of operating traction drive number in combination with speed automatic control), specific consumption reduction of electric power for traction was achieved on 25% in comparison with the first trip when all 12 traction motors were constantly working. Practical importance: Long-term development program of JSC Russian Railways provides for cost consistent reduc-tion for electric power that’s a purchased (consumed) product. In particular, optimization is planned in such direction as reducing specific consumption of power and fuel for train trac-tion.

A retrospective analysis of mid-infrared observations of the Comet D/Shoemaker-Levy 9 and Wesley impacts on Jupiter

We present a retrospective analysis of Earth-based mid-infrared observations of Jupiter capturing the aftermath of the impacts by Comet D/Shoemaker-Levy 9 (henceforth SL9) in July 1994 and the unknown object previously termed the “Wesley impactor” in July 2009. While the effects of both impacts on Jupiter’s atmosphere have been reported previously, we were motivated to re-examine both events using consistent data reduction and analysis methods to enable robust, quantitative comparisons. To study the aftermath of the SL9 impacts, we examined infrared (7.8–20.5μm) spectrophotometry of Jupiter measured by the MIRAC (Mid-Infrared Camera) on NASA’s Infrared Telescope Facility on July 20, 21 1994 and low-resolution (R = 100) N-band (7–13μm) spectroscopy measured by SpectroCam-10 on the Palomar Telescope on July 22 1994. To study the aftermath of the Wesley impact, we examined low-resolution (R = 100) N- and Q-band (R = 80, 17–25μm) spectroscopy recorded by Gemini South Telescope’s T-ReCS (Thermal-Region Camera Spectrograph). We analyzed the observations with two independent analyses: (1) a least-squares search over a grid of candidate mineral species to determine the composition of impact residue and (2) a radiative transfer analysis to derive atmospheric information. We observe that the SL9 impact sites are enhanced in stratospheric CH4 emissions at 7.9μm, due to shock heating and adiabatic compression from plume re-entry, and from 8.5–11.5μm due to stratospheric NH3 emission and non-gaseous cometary material, in agreement with previous work. In the G impact site, we derive NH3 concentrations of 5.7−2.8+4.5 ppmv at 30 mbar. In new findings, we find that the SL9 impact sites also exhibit a non-gaseous emission feature at 18–19μm. The non-gaseous emission at 8.5–11.5μm and 18–19μm emission result is best reproduced by predominantly amorphous olivine and (obsidian) silica at similar abundances. The Wesley impact site exhibits enhanced emissions from 8.8–11.5μm and 18–19μm. We found this could be reproduced by predominantly amorphous olivine and stratospheric gaseous NH3 at concentrations of 150−121+338 ppbv retrieved at 30 mbar. Stratospheric abundances of NH3 are a factor of ∼40 higher in the SL9 impacts compared to the Wesley impact, which confirms the former reached deeper, NH3-richer altitudes of Jupiter’s atmosphere compared to the latter. The absence of silicas in the Wesley impact would place an upper limit of 10 km/s on the incident angle and ∼9∘ on the entry angle of the impactor such that shock heating associated with the impact did not reach temperatures required for silicates to be converted.

Pregnancy-related factors may signal additional protection or risk of future cardiovascular diseases

BackgroundCardiovascular disease (CVD) guidelines recommend using the Pooled Cohort Equation (PCE) to assess 10-year CVD risk based on traditional risk factors. Pregnancy-related factors have been associated with future CVD. We examined the contribution of two pregnancy-related factors, (1) history of a low birthweight (LBW) infant and (2) breastfeeding to CVD risk accounting for traditional risk factors as assessed by the PCE.MethodsA nationally representative sample of women, ages 40–79, with a history of pregnancy, but no prior CVD, was identified using NHANES 1999–2006. Outcomes included (1) CVD death and (2) CVD death plus CVD surrogates. We used Cox proportional hazards models to adjust for PCE risk score.ResultsAmong 3,758 women, 479 had a LBW infant and 1,926 reported breastfeeding. Mean follow-up time was 12.1 years. Survival models showed a consistent reduction in CVD outcomes among women with a history of breastfeeding. In cause-specific survival models, breastfeeding was associated with a 24% reduction in risk of CVD deaths (HR 0.76; 95% CI 0.45─1.27, p = 0.30) and a 33% reduction in risk of CVD deaths + surrogate CVD, though not statistically significant. (HR 0.77; 95% CI 0.52─1.14, p = 0.19). Survival models yielded inconclusive results for LBW with wide confidence intervals (CVD death: HR 0.98; 95% CI 0.47─2.05; p = 0.96 and CVD death + surrogate CVD: HR 1.29; 95% CI 0.74─2.25; p = 0.38).ConclusionPregnancy-related factors may provide important, relevant information about CVD risk beyond traditional risk factors. While further research with more robust datasets is needed, it may be helpful for clinicians to counsel women about the potential impact of pregnancy-related factors, particularly the positive impact of breastfeeding, on cardiovascular health.