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Background:The relative vaccine effectiveness (rVE) of high-dose quadrivalent influenza vaccines (QIV-HD) versus standard-dose quadrivalent influenza vaccines (QIV-SD) against hospitalizations and mortality in the general older population has not been evaluated in an individually randomized trial. Because of the large sample size required, such a trial will need to incorporate innovative, pragmatic elements. Methods:We conducted a pragmatic, open-label, active-controlled, randomized feasibility trial in Danish citizens aged 65 to 79 years during the 2021–2022 influenza season. Participants were randomly assigned 1:1 to receive QIV-HD or QIV-SD. Randomization was integrated into routine vaccination practice, and the trial relied solely on nationwide administrative health registries for data collection. Outcomes consisted of a feasibility assessment and descriptive rVE estimates. Results:We invited 34,000 persons to participate. A total of 12,477 randomly assigned participants were included in the final analyses. Mean (±SD) age was 71.7±3.9 years, and 5877 (47.1%) were women. Registry-based data collection was feasible, with complete follow-up data for 99.9% of participants. Baseline characteristics were comparable to those of the overall Danish population aged 65 to 79 years. The incidence of hospitalization for influenza or pneumonia was 10 (0.2%) of 6245 in the QIV-HD group and 28 (0.4%) of 6232 in the QIV-SD group (rVE, 64.4%; 95% confidence interval, 24.4 to 84.6). All-cause death occurred in 21 (0.3%) and 41 (0.7%) participants in the QIV-HD and QIV-SD groups, respectively (rVE, 48.9%; 95% confidence interval, 11.5 to 71.3). Conclusions:Conducting a pragmatic randomized trial of QIV-HD versus QIV-SD using existing infrastructure and registry-based data collection was feasible. The findings of lower incidence of hospitalization for influenza or pneumonia and all-cause mortality in the QIV-HD group compared with the QIV-SD group require replication in a future, fully powered trial. (Funded by Sanofi; ClinicalTrials.gov number, NCT05048589.)

Mathematics teacher educators in primary teacher education need expert knowledge and skills in teaching in primary school, in subject matter and research. Most starting mathematics teacher educators possess only part of this knowledge and skills. A professional development trajectory for this group is developed and tested, where a design based research is used to evaluate the design. This paper describes the professional development trajectory and design. We conclude that the professional development design should focus on mathematical knowledge for teaching, should refer to both teacher education and primary education, should offer opportunities for cooperative learning, and need to use practice based research as a developmental tool.

Investment banking is a financial entity. Investment banking is an important financial intermediary that is indispensable in the capital market. The increasing interest of investors in investing in the stock market has increased because the stock market offers flexible and transparent money options opportunities for risk sharing with the potential for positive returns. Every investor wants a high rate of return with a low risk value. Risk cannot be eliminated, but can be minimized. Clustering means finding and defining a number of clusters (or groups) in a data set. Grouping is done based on numerical equations or distances (dissimilarities). The k-means algorithm is a grouping algorithm based on distance. In the k-means algorithm, the smaller the distance between the samples, the higher the similarity. The k-medoids algorithm is used to find medoids in a cluster which is the center point of the cluster. The return value or commonly known as the return on the funds invested in the investment. Portfolio is a collection of several investment instruments formed with the aim of meeting investment goals. obtained 5 clusters using k-means algorithm with total of wss 23,606. The optimal portfolio weight percentage for each stock formed is BMAS (9.11%%), BANK (32.78%), ARTO (28.84%), BBYB (16.72%), and BBHI (12.54%). Furthermore, from the results of the optimization calculations that have been obtained,the expected return portfolio value is and the portfolio variance is . Investing Rp.1.000.000.000,-, then the expected return value that will be obtained when choosing this portfolio is Rp.11.094.300,-.

International audience; Hydraulic systems are used in several industrial applications, including manufacturing, automobiles and energy for example. Monitoring the condition of hydraulic equipment is essential to maintain high productivity and reduce the costs of system process. Best practices have been evolving from reactive maintenance to predictive maintenance, with intelligent fault diagnosis, using recent advances in industrial Internet of Things, artificial intelligence, edge computing, etc. Beyond design, the digital twins offer advantages in predictive maintenance and provides a new paradigm for fault diagnosis. The CETIM's "Fluid & Sealing Technologies" department proposes to present its R&D work to illustrate the concept of a digital twin of a fluidic loop. For this purpose, a closed hydraulic loop has been instrumented. It is equipped with a pump, a heat exchanger, a tank, a regulation valve and three piping sections. The objective of the study is to identify process faults (pipe clogging, exchanger performance degradation, etc.). These defects are manifested by a difference between the process variables (pressure, flow, and temperature) evaluated by the model and measured on the physical loop.

Inzulinska rezistenca oziroma stanje zmanjšanega biološkega odziva na fiziološke ravni inzulina je ključni dejavnik tveganja za srčnožilne bolezni, zato je pogosto prisotna pri bolnikih v srčnožilni kirurgiji. Vnetni procesi, poškodba tkiva in hormonski odziv v perioperativnem obdobju dodatno prispevajo k inzulinski rezistenci, ki vodi v različne biokemične spremembe. Le-te negativno vplivajo na delovanje organov, na zaplete po operaciji in na okrevanje po njej. Inzulinska rezistenca se kaže kot širok nabor kliničnih stanj, ki se postopno razvijajo od hiperinzulinemije do motene tolerance za glukozo in končno hiperglikemije, ko se normoglikemija ne more več vzdrževati kljub povečanemu izločanju inzulina. Priporočila različnih strokovnih združenj glede ciljnih vrednosti krvnega sladkorja v perioperativnem obdobju niso enoznačna. Prelomne raziskave so sprva dokazale, da strog glikemični nadzor vodi do boljših izidov, vendar je pojavnost hipoglikemij pomemben varnostni zadržek. Zato se v danes uveljavljenih protokolih za perioperativno odmerjanje inzulina cilja na vrednosti glikemije med 7,8 in 10 mmol/l. Hkrati pa je nejasno, ali na obolevnost in smrtnost vpliva stopnja hiperglikemije ali že zgolj prisotnost sladkorne bolezni oziroma sama inzulinska rezistenca. Procesom inzulinske rezistence v perioperativnem obdobju se lahko izognemo z minimalno invazivnim kiruškim pristopom, ustrezno anestezijo ter analgezijo in skrajšanjem obdobij stradanja. Prispevek obravnava patofiziologijo in klinične posledice odpornosti na inzulin oziroma hiperglikemije ter opiše perioperativne strategije za zmanjševanje inzulinske rezistence, izbiro najbolj primernega načina zdravljenja in pristope za hitrejše okrevanje po posegu na srcu in po kompleksnih operacijah aorte.

Tehnologije sekvenciranja nove generacije omogočajo analizo večjega dela človeškega genoma, vključno z nekodirajočimi področji in predstavljajo pomemben napredek v diagnostiki monogenskih bolezni. Izziv predstavlja karakterizacija najdenih različic kot patoloških ali nepatoloških, opredelitev njihovega učinka ter mehanizma patogenosti. V raziskavi smo analizirali vzorce dveh skupin preiskovancev z nediagnosticiranimi redkimi boleznimi, tiste z ugotovljeno kandidatno različico z nejasnim kliničnim pomenom ter tiste brez ugotovljene različice. Z uporabo metod analize RNA-prepisov smo določili in razjasnili pojav, mehanizem in učinek najdenih patoloških različic, pri preiskovancih brez ugotovljenih različic pa smo v večini identificirali verjetno vzročne različice. Ugotovljenim različicam smo po smernicah American College of Medical Genetics in Association for Clinical Genomic Science opredelili patogenost in določili klinični pomen opredelitve. V vseh primerih je preiskava izboljšala klasifikacijo patogenosti in vzročnosti. V primerih patogenih in verjetno patogenih različic so te nastale kot posledica okvarjenega procesa spajanja eksonov. V štirih primerih smo zaznali pojav preskoka eksonov, v treh primerih smo zaznali premik bralnega okvirja, v po enem primeru pa smo zaznali pojav zadržanja introna ter pojav nastanka novih mest izrezovanj. Z opravljeno analizo RNA-prepisov smo izboljšali funkcijsko karakterizacijo, izboljšali njihovo klasifikacijo v smislu povezave z monogenskimi boleznimi ter razjasnili mehanizme njihovega nastanka. Z analizo izbranih genov smo izboljšali identifikacijo patoloških genetskih različic v nekodirajočih področjih pri bolnikih z nepojasnjenimi monogenskimi boleznimi. Next-generation sequencing represents an important step in diagnostics of monogenic conditions, as it allows the analysis of the majority of the human genome, including non-coding regions. However, characterization of the pathogenic effect of variants identified by these approaches and their functional assessment remain a challenge. The aim of this research is analysis of cases with undiagnosed genetic conditions that harbor genetic variants of uncertain clinical significance, and cases in which conventional genetic approaches identified no causal variants. Using next-generation sequencing based RNA analysis, we explained the pathogenic and functional effects and mechanisms in cases with known suspect variants. Additionally, we were able to identify disease-causing variants in samples with unknown variants. Based on the functional data, we reassessed the pathogenicity of variants according to American College of Medical Genetics and Association for Clinical Genomic Science standards and we found that the clinical classification of pathogenicity has improved in every case. In four cases we confirmed exon skipping, in three cases a frameshift mutation, and one case of each intron retention and novel splice site introduction. In conclusion, using the RNA transcript analysis we improved the functional characterization and classification of pathogenicity as well as identified the mechanism of their development. We demonstrate that next-generation sequencing-based RNA analysis can improve the assessment of the pathogenic effect of variants in coding and non-coding regions of the genome.

Background Recently adopted mini-thoracotomy approach for surgical aortic valve replacement has shown benefits such as reduced pain and shorter recovery, compared to more conventional mini-sternotomy access. However, whether limited exposure of the heart and ascending aorta resulting from an incision in the second intercostal space may lead to increased intraoperative cerebral embolization and more prominent postoperative neurologic decline, remains inconclusive. The aim of our study was to assess potential neurological complications after two different minimal invasive surgical techniques for aortic valve replacement by measuring cerebral microembolic signal during surgery and by follow-up cognitive evaluation. Methods Trans-cranial Doppler was used for microembolic signal detection during aortic valve replacement performed via mini-sternotomy and mini-thoracotomy. Patients were evaluated using Addenbrooke’s Cognitive Examination Revised Test before and 30 days after surgical procedure. Results A total of 60 patients were recruited in the study. In 52 patients, transcranial Doppler was feasible. Of those, 25 underwent mini-sternotomy and 27 had mini-thoracotomy. There were no differences between groups with respect to sex, NYHA class distribution, Euroscore II or aortic valve area. Patients in mini-sternotomy group were younger (60.8 ± 14.4 vs.72 ± 5.84, p = 0.003), heavier (85.2 ± 12.4 vs.72.5 ± 12.9, p = 0.002) and had higher body surface area (1.98 ± 0.167 vs. 1.83 ± 0.178, p = 0.006). Surgery duration was longer in mini-sternotomy group compared to mini-thoracotomy (158 ± 24 vs. 134 ± 30 min, p p = 0.027). Addenbrooke’s Cognitive Examination Revised Test score decreased equivalently in both groups (p = 0.630) (MS: 85.2 ± 9.6 vs. 82.9 ± 11.4, p = 0.012; MT: 85.2 ± 9.6 vs. 81.3 ± 8.8, p = 0.001). Conclusion There is no difference in microembolic load between the groups. Total intraoperative microembolic signals count was associated with cardiopulmonary bypass duration. Age, but not micorembolic signals load, was associated with postoperative neurologic decline. Trial registry number clinicaltrials.gov, NCT02697786 14.